gout overview and review of the confirms trial
DESCRIPTION
GoutTRANSCRIPT
GOUT
Aneet Kaur MD
PGY-2
Internal Medicine
History
The word gout is believed to be derived from the Latin lsquoguttarsquo which means lsquodroprsquo-referring to the ldquonotion of the lsquodroppingrsquo of a morbid material from the blood in and around the jointsrdquo
Gout was commonly known as lsquothe disease of Kingsrsquo or lsquorich manrsquos diseasersquo as a result of the assumption that an affluent lifestyle was the cause of this painful inflammatory condition
Definition
Gout is an inflammatory arthritis associated
with hyperuricemia resulting from
deposition of monosodium urate crystals in
joint tendons and surrounding tissue
Risk factors for gout
Hyperuricemia is the most important risk factor for the
development of gout with the likelihood of developing
gout rising exponentially in line with serum urate levels
Despite this strong association the majority of patients
with hyperuricemia do not develop gout the annual
incidence of gout is estimated to be only 5 in patients
with levels of serum urate above 9 mgdl
Mechanisms of hyperuricemia and gout
Other risk factors
Hypertension hypertriglyceridemia
hypercholesterolemia diabetes and obesity are also
each associated with higher risk of incident gout andor
gout flare
Gout is extremely uncommon in premenopausal women
but postmenopausal women are at risk
Studies have indicated that menopause especially at an
earlier age increased the risk of gout in women
whereas post menopausal hormone therapy modestly
reduced risk of gout
Clinical gout is about five times more common in men
than in women
MANAGEMENT OF
GOUT
DRUGS USED IN GOUT AND THEIR MECHANISM OF ACTION
2012 ACR Management Guidelines
Lifestyle Modification for all patients with gout
Xanthine Oxidase Inhibitor (XOI) first-line urate-lowering
pharmacologic therapy
Target sUA lt6 at minimum sUA lt5 better
Continue prophylaxis for 3 (no tophi) ndash 6 months (tophi)
after achieving target sUA
2012 ACR Management Guidelines
Consider HLA screening for HLA-B5801 in certain populations considered high risk for allopurinol hypersensitivity syndrome
Koreans with stage 3 CKD or worse
Han Chinese
Thai descent
Combination oral ULT with 1 XOI agent and 1 uricosuric agent is appropriate when sUA not at target by XOI alone
Pegloticase appropriate for severe refractory disease or intolerance of standard regimens (Pegloticase is a porcine uricase which was approved by the FDA in September 2010 for the treatment of gout in patients who had failed conventional therapy)
2012 ACR Management Guidelines for
Acute Gouty Arthritis
The choice of pharmacologic agent depends on severity of the attack
Monotherapy for mildmoderate attack
Combination therapy for severe attack or those refractory to monotherapy
Acceptable combination therapy approaches include
Colchicine and NSAIDS
Oral steroids and colchicine
Intra-articular steroids with all other modalities
Continue current therapy during flare
Patient education on signs of flare for self treatment
Indications for pharmacological
treatment of gout
Any patient with established diagnosis of gouty arthritis
Tophus or tophi by clinical exam or imaging study
Frequent attacks of gouty arthritis (gt= 2 attacksyr)
CKD stage 2 or worse
Past urolithiasis
23
Gout Management Approach
bullTreat acute flare rapidly with anti-
inflammatory agent
bullInitiate urate-lowering therapy to
achieve sUA lt6
bullUse concomitant anti-inflammatory
prophylaxis for up to 6 mo to prevent
mobilization flares
INITIATE(acute flare)
RESOLVE(urate-lowering therapy)
bullContinue urate lowering therapy
to control flares and avoid crystal
deposition
bullProphylaxis use for at least 3-6
months until sUA normalizes
MAINTAIN(treatment to control sUA)
24
Allopurinol vs Febuxostat
Allopurinol Febuxostat (Uloric)
FDA-approved 1966 FDA-approved 2009
Purine-selective XO Inhibitor Non-Purine Selective XO
Inhibitor
Prevents uric acid production Prevents uric acid production
Renal Metabolism Liver Metabolism
FEBUXOSTAT
For treatment of hyperuricemia in patients with gout
febuxostat is recommended at 40 mg or 80 mg once daily and
can be increased to 120 mg once daily if clinically indicated
The adverse effects associated with febuxostat therapy
include nausea diarrhea arthralgia headache increased
hepatic serum enzyme levels and rash
The manufacturer recommends liver function monitoring on
initiation of therapy at two and four months after initiation
and periodically thereafter
FEBUXOSTAT
Febuxostat is US Food and Drug Administration pregnancy
category C2
Febuxostat is contraindicated with concomitant use of
theophylline and chemotherapeutic agents namely
azathioprine and 6- mercaptopurine because it could
increase blood plasma concentrations of these drugs and
therefore their toxicity
Dosage adjustments are unnecessary for mild to moderate
renal or hepatic impairment
A one-month supply of 40 or 80-mg febuxostat costs
$28243 This price far exceeds the cost of allopurinol
which is $2424 for 100 100 mg tablets
CrCl (mLmin)
Maintenance Dose of
Allopurinol
0 100mg every 3d
10 100mg every 2d
20 100mg
40 150mg
60 200mg
80 250mg
100 300mg
120 350mg
140 400mg
Maintenance Doses of Allopurinol for
Adults based on CrCl
28
Hande KR et al Am J Med 1984
Stage 1 renal damage with
normal GFR
(GFR gt 90 mlmin)
Stage 2 Mild CKD (GFR = 60-
89 mlmin)
Stage 3 Moderate CKD (GFR
= 30-59 mlmin)
Stage 4 Severe CKD (GFR =
15-29 mlmin)
Stage 5 End Stage CKD (GFR
lt15 mlmin)
Allopurinol Hypersensitivity
Syndrome
2 of all allopurinol users develop cutaneous rash
Frequency of hypersensitivity 1 in 260
DRESS syndrome
Drug Reaction Eosinophilia Systemic Symptoms
20 mortality rate
Life threatening toxicity vasculitis rash eosinophilia hepatitis progressive renal failure
Treatment early recognition withdrawal of drug supportive care Steroids N-acetyl-cysteine dialysis prn
29
Markel A IMAJ 2005
Terkeltaub RA in Primer on the Rheumatic Disease 13th ed 2008
The urate lowering efficacy and safety
of febuxostat in the treatment of the
hyperuricemia of gout
The CONFIRMS trial
Becker MA Schumacher HR Espinoza LR et al The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemia of gout the CONFIRMS trial Arthritis Res
Ther 201012(2)R63
Many long and short-term clinical trials have
proved the efficacy of Febuxostat in the treatment
of gout and lowering uric acid levels In these
studies Febuxostat was found to be superior to
allopurinol in reducing the serum uric acid levels
Some notable landmark clinical trials are FACT
APEX EXCEL FOCUS and CONFIRMS
Febuxostat versus Allopurinol Controlled Trial
(FACT) 2005
52 week randomized double-blind multicenter clinical trial that compared the safety and efficacy of febuxostat with allopurinol
760 patients with gout and a sUA gt80 mgdl were randomly assigned to receive either febuxostat 80 or 120mg or allopurinol 300mg once daily for 52 weeks
The primary endpoint was the proportion of patients to achieve a sUA concentration below 60 mgdl at the last three monthly measurements
The primary endpoint was achieved in 53 of patients receiving 80 mg febuxostat 62 of patients receiving 120mg and 21 of those receiving allopurinol (p lt0001 for each febuxostat group compared with allopurinol)
There was no statistical significance in the change in tophi size and number or the incidence of gout flare between the groups
Allopurinol Placebo controlled Efficacy study
of febuxostat (APEX) 2008
28 week randomized double-blind study of 1072 patients comparing the safety and efficacy of febuxostat allopurinol and placebo
Patients were randomized to a once daily fixed dose of placebo febuxostat 80mg120mg or 240 mg or allopurinol 300mg or 100mg depending on their baseline serum creatinine (le15 mgdl or ge16 to lt20 mgdl respectively)
After 1 year of treatment 82 of the patients in all febuxostat groups achieved sUA levels below 60 mgdl compared with 39 of the patients in both allopurinol groups In groups with moderate renal impairment the primary endpoint was achieved by 44 receiving febuxostat 80mg 45 receiving 120mg and 60 receiving 240mg compared with 0 in the allopurinol and placebo groups
However clinical endpoints were not statistically significant
The number of patients with moderate renal impairment was small
Febuxostat Comparative Extension Long-Term
study (EXCEL) 2009
160 week extension study for patients completing FACT and APEX
The studyrsquos aim was to determine long-term efficacy in sUA
lowering clinical benefits and safety of febuxostat or allopurinol
1086 patients were enrolled to receive fixed daily doses of
febuxostat 80mg or 120 mg or allopurinol 300 mg
After the first month of treatment nearly 80 of patients receiving
either febuxostat dose achieved sUA less than 6 mgdl compared
with only 46 of subjects on allopurinol There was no difference in
gout flare incidence and tophi reduction between the groups
Overall adverse events did not show significant differences among
groups
Febuxostat Open Label of Urate-Lowering
Efficacy and Safety (FOCUS) 2009
The FOCUS trial was a 5-year extension study that
assessed reduction and maintenance of sUA levels below
60 mgdl as the primary efficacy endpoint A total of
116 patients were initially enrolled to receive a dose of
80mg febuxostat with dose adjustment to either 40 or
120mg between weeks 4 and 24 93 maintained a sUA
level below 60 mgdl at 5 years
Objectives of CONFIRMS trial
The three-fold objectives of this Phase 3 double-blind RCT study were
1) To compare the UL efficacy of febuxostat at a dose of 40 mg with that of allopurinol at doses most commonly utilized in clinical practice
2) To evaluate UL efficacies of 80 mg and 40 mg daily doses of febuxostat compared with that of allopurinol in subjects with mild or moderate renal impairment
3) To gain prospective uniformly reviewed information regarding the safety of these agents particularly their comparative CV safety
Materials and methods
Subjects aged 18 to 85 years with a diagnosis of gout fulfilling American Rheumatology Association preliminary criteria and sUA ge 80 mgdL were eligible for enrollment
Subjects were enrolled at 324 sites in the United States
IRB approval was obtained and all the subjects provided written informed consent
At least 35 of subjects enrolled were to have mild or moderate renal impairment defined as baseline estimated creatinine clearance (eCLcr) of 60 to 89 mlminutes or 30 to 59 mlminutes
Subjects successfully completing either of the previously
reported long-term open-label febuxostat or
febuxostatallopurinol extension studies were also eligible for
enrollment
Exclusion criteria secondary hyperuricemia (for example
due to myeloproliferative disorder) xanthinuria severe renal
impairment (eCLcr lt30 mlminutes) alanine
aminotransferase and aspartate aminotransferase values gt15
times the upper limit of normal consumption of more than 14
alcoholic drinks per week or a history of alcoholism or drug
abuse within five years or a medical condition that in the
investigators opinion would interfere with treatment safety
or adherence to the protocol
Baseline characteristics of randomized subjects
Baseline characteristics of randomized subjects (cont)
Baseline characteristics of randomized subjects (cont)
2269 Subjects were randomized 111 on Day 1 to
receive daily febuxostat 40 mg febuxostat 80 mg or
allopurinol Among subjects randomized to allopurinol
those with normal renal function or mild renal
impairment received 300 mg daily and those with
moderate renal impairment received 200 mg
Throughout the subsequent six-month treatment period for all subjects prophylaxis for gout flares was given either as colchicine 06 mg daily or naproxen 250 mg twice daily All subjects receiving naproxen prophylaxis also received lansoprazole 15 mg daily
Choice of prophylaxis regimen was made by the investigator and subject taking into account prior drug tolerance and prophylaxis experience
In addition subjects with eCLcr lt50 mlminute were not to receive naproxen
Gout flares were regarded as expected gout manifestations rather than as AEs
The primary efficacy endpoint was the proportion of
subjects in each treatment group with sUA lt60 mgdL
at the final visit
Secondary efficacy variables included
1) The proportion of subjects with mild or moderate
renal impairment and final sUA lt60 mgdL
2) The proportion of subjects with sUA lt60 mgdL lt50
mgdL and lt40 mgdL at each visit
Efficacy analysisResults
Primary efficacy endpoint
1) The proportions of subjects achieving a final visit sUA lt60
mgdL were 452 671 and 421 in the febuxostat 40 mg
febuxostat 80 mg and allopurinol groups respectively
2) UL by febuxostat 40 mg was non-inferior to that by
allopurinol but the difference in the response rates between
the two groups (31 95 CI -19 to 81) was not significant
3) However the greater UL response rate with febuxostat 80 mg
compared with either febuxostat 40 mg (219) or allopurinol
(249) was significant (P lt 0001)
Secondary efficacy endpoints
Among subjects with any (mild or moderate) renal
impairment the UL response rate in the febuxostat 80
mg group (716 360503) significantly exceeded those
observed in the febuxostat 40 mg (497 238479) and
allopurinol (423 212501) groups (P le 0001 for each
comparison)
In addition among the total group of subjects with
renal impairment the UL response rate in the
febuxostat 40 mg group was significantly higher than
that in the allopurinol 300200 mg group (P = 0021)
At any sUA endpoint (lt60 mgdL lt50 mgdL or lt40 mgdL) and at any scheduled visit a significantly higher proportion of subjects receiving febuxostat 80 mg achieved the target endpoint than subjects receiving febuxostat 40 mg or allopurinol (P lt 0001)
Greater proportion of subjects in the febuxostat 40 mg group than the allopurinol group achieved sUAlt60 mgdL (at Month 2 visit P = 0031) and lt50 mgdL (at two- and six month visits P le 005) but significant differences were not seen at other visits including the final visit
Effect of baseline characteristic on treatment response
Adverse events
Adverse events
CONCLUSIONS
Results of the CONFIRMS trial establish equivalent UL efficacy for febuxostat 40 mg daily and allopurinol 300200 mg daily
At all levels of renal function studied UL efficacy of febuxostat 80 mg daily was superior to that of febuxostat 40 mg or allopurinol 300200 mg and was comparably safe
In subjects with mildly or moderately impaired renal function however febuxostat 40 mg daily was significantly more effective in lowering sUA than allopurinol
At the doses studied safety of febuxostat and allopurinol including CV safety was comparable
Febuxostat at 40 mg or 80 mg daily offers a well-tolerated UL alternative to allopurinol particularly for patients with mild or moderate renal impairment
Study limitations
The study does not address the efficacy of febuxostat compared with allopurinol in reducing clinically meaningful acute flares of gout
No mention is made of long-term cost-effectiveness of therapy
Additionally this study does not address the efficacy of febuxostat compared with allopurinol dosing that is more aggressive (ie gt 300 mg daily)
Allopurinol dosing was not titrated
The study population was not similar to the general population (majority of patients were white males)
Possible funding bias
Uloric Related Current Clinical
Trials
References
Dalbeth N Gracey E Pool B et al Identification of dairy fractions with anti-inflammatory properties in models of acute gout Ann
Rheum Dis 2010 69766ndash769
Choi HK Willett W Curhan G Coffee consumption and risk of incident gout in men a prospective study Arthritis Rheum 2007 562049ndash
2055
Hak AE Curhan GC Grodstein F Choi HK Menopause postmenopausal hormone use and risk of incident gout Ann Rheum Dis 2010
691305ndash1309
Becker MA Schumacher HR Wortmann RL et al (December 2005) Febuxostat compared with allopurinol in patients with hyperuricemia
and gout N Engl J Med 353 (23) 2450ndash61
Sarawate CA Patel PA Schumacher HR Yang W Brewer KK Bakst AW Serum urate levels and gout flares analysis from managed care
data J Clin Rheumatol 2006 1261-65
Schumacher HR Jr Becker MA Lloyd E MacDonald PA Lademacher C Febuxostat in the treatment of gout 5-yr findings of the FOCUS
efficacy and safety study Rheumatology (Oxford) 2009 48188-194
14 Becker MA Schumacher HR MacDonald PA Lloyd E Lademacher C Clinical efficacy and safety of successful long-term urate
lowering with febuxostat or allopurinol in subjects with gout J Rheumatol 2009 361273-1278
2012 ACR guidelines for management of gout
Uptodate
Medcape
Statistical Power
Power
The probability that the study will support the research hypothesis if it is true
1 Sample size (n)
2 Effect Size (d)
3 Significance Level (α)
4 Power (β)
As effect size increases power increases
As sample size increases power increases
As significance level increases power increases
Resources
httpwwwncbinlmnihgovpmcarticlesPMC3409926
httpswwwsealedenvelopecompowerbinary-superiority
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
History
The word gout is believed to be derived from the Latin lsquoguttarsquo which means lsquodroprsquo-referring to the ldquonotion of the lsquodroppingrsquo of a morbid material from the blood in and around the jointsrdquo
Gout was commonly known as lsquothe disease of Kingsrsquo or lsquorich manrsquos diseasersquo as a result of the assumption that an affluent lifestyle was the cause of this painful inflammatory condition
Definition
Gout is an inflammatory arthritis associated
with hyperuricemia resulting from
deposition of monosodium urate crystals in
joint tendons and surrounding tissue
Risk factors for gout
Hyperuricemia is the most important risk factor for the
development of gout with the likelihood of developing
gout rising exponentially in line with serum urate levels
Despite this strong association the majority of patients
with hyperuricemia do not develop gout the annual
incidence of gout is estimated to be only 5 in patients
with levels of serum urate above 9 mgdl
Mechanisms of hyperuricemia and gout
Other risk factors
Hypertension hypertriglyceridemia
hypercholesterolemia diabetes and obesity are also
each associated with higher risk of incident gout andor
gout flare
Gout is extremely uncommon in premenopausal women
but postmenopausal women are at risk
Studies have indicated that menopause especially at an
earlier age increased the risk of gout in women
whereas post menopausal hormone therapy modestly
reduced risk of gout
Clinical gout is about five times more common in men
than in women
MANAGEMENT OF
GOUT
DRUGS USED IN GOUT AND THEIR MECHANISM OF ACTION
2012 ACR Management Guidelines
Lifestyle Modification for all patients with gout
Xanthine Oxidase Inhibitor (XOI) first-line urate-lowering
pharmacologic therapy
Target sUA lt6 at minimum sUA lt5 better
Continue prophylaxis for 3 (no tophi) ndash 6 months (tophi)
after achieving target sUA
2012 ACR Management Guidelines
Consider HLA screening for HLA-B5801 in certain populations considered high risk for allopurinol hypersensitivity syndrome
Koreans with stage 3 CKD or worse
Han Chinese
Thai descent
Combination oral ULT with 1 XOI agent and 1 uricosuric agent is appropriate when sUA not at target by XOI alone
Pegloticase appropriate for severe refractory disease or intolerance of standard regimens (Pegloticase is a porcine uricase which was approved by the FDA in September 2010 for the treatment of gout in patients who had failed conventional therapy)
2012 ACR Management Guidelines for
Acute Gouty Arthritis
The choice of pharmacologic agent depends on severity of the attack
Monotherapy for mildmoderate attack
Combination therapy for severe attack or those refractory to monotherapy
Acceptable combination therapy approaches include
Colchicine and NSAIDS
Oral steroids and colchicine
Intra-articular steroids with all other modalities
Continue current therapy during flare
Patient education on signs of flare for self treatment
Indications for pharmacological
treatment of gout
Any patient with established diagnosis of gouty arthritis
Tophus or tophi by clinical exam or imaging study
Frequent attacks of gouty arthritis (gt= 2 attacksyr)
CKD stage 2 or worse
Past urolithiasis
23
Gout Management Approach
bullTreat acute flare rapidly with anti-
inflammatory agent
bullInitiate urate-lowering therapy to
achieve sUA lt6
bullUse concomitant anti-inflammatory
prophylaxis for up to 6 mo to prevent
mobilization flares
INITIATE(acute flare)
RESOLVE(urate-lowering therapy)
bullContinue urate lowering therapy
to control flares and avoid crystal
deposition
bullProphylaxis use for at least 3-6
months until sUA normalizes
MAINTAIN(treatment to control sUA)
24
Allopurinol vs Febuxostat
Allopurinol Febuxostat (Uloric)
FDA-approved 1966 FDA-approved 2009
Purine-selective XO Inhibitor Non-Purine Selective XO
Inhibitor
Prevents uric acid production Prevents uric acid production
Renal Metabolism Liver Metabolism
FEBUXOSTAT
For treatment of hyperuricemia in patients with gout
febuxostat is recommended at 40 mg or 80 mg once daily and
can be increased to 120 mg once daily if clinically indicated
The adverse effects associated with febuxostat therapy
include nausea diarrhea arthralgia headache increased
hepatic serum enzyme levels and rash
The manufacturer recommends liver function monitoring on
initiation of therapy at two and four months after initiation
and periodically thereafter
FEBUXOSTAT
Febuxostat is US Food and Drug Administration pregnancy
category C2
Febuxostat is contraindicated with concomitant use of
theophylline and chemotherapeutic agents namely
azathioprine and 6- mercaptopurine because it could
increase blood plasma concentrations of these drugs and
therefore their toxicity
Dosage adjustments are unnecessary for mild to moderate
renal or hepatic impairment
A one-month supply of 40 or 80-mg febuxostat costs
$28243 This price far exceeds the cost of allopurinol
which is $2424 for 100 100 mg tablets
CrCl (mLmin)
Maintenance Dose of
Allopurinol
0 100mg every 3d
10 100mg every 2d
20 100mg
40 150mg
60 200mg
80 250mg
100 300mg
120 350mg
140 400mg
Maintenance Doses of Allopurinol for
Adults based on CrCl
28
Hande KR et al Am J Med 1984
Stage 1 renal damage with
normal GFR
(GFR gt 90 mlmin)
Stage 2 Mild CKD (GFR = 60-
89 mlmin)
Stage 3 Moderate CKD (GFR
= 30-59 mlmin)
Stage 4 Severe CKD (GFR =
15-29 mlmin)
Stage 5 End Stage CKD (GFR
lt15 mlmin)
Allopurinol Hypersensitivity
Syndrome
2 of all allopurinol users develop cutaneous rash
Frequency of hypersensitivity 1 in 260
DRESS syndrome
Drug Reaction Eosinophilia Systemic Symptoms
20 mortality rate
Life threatening toxicity vasculitis rash eosinophilia hepatitis progressive renal failure
Treatment early recognition withdrawal of drug supportive care Steroids N-acetyl-cysteine dialysis prn
29
Markel A IMAJ 2005
Terkeltaub RA in Primer on the Rheumatic Disease 13th ed 2008
The urate lowering efficacy and safety
of febuxostat in the treatment of the
hyperuricemia of gout
The CONFIRMS trial
Becker MA Schumacher HR Espinoza LR et al The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemia of gout the CONFIRMS trial Arthritis Res
Ther 201012(2)R63
Many long and short-term clinical trials have
proved the efficacy of Febuxostat in the treatment
of gout and lowering uric acid levels In these
studies Febuxostat was found to be superior to
allopurinol in reducing the serum uric acid levels
Some notable landmark clinical trials are FACT
APEX EXCEL FOCUS and CONFIRMS
Febuxostat versus Allopurinol Controlled Trial
(FACT) 2005
52 week randomized double-blind multicenter clinical trial that compared the safety and efficacy of febuxostat with allopurinol
760 patients with gout and a sUA gt80 mgdl were randomly assigned to receive either febuxostat 80 or 120mg or allopurinol 300mg once daily for 52 weeks
The primary endpoint was the proportion of patients to achieve a sUA concentration below 60 mgdl at the last three monthly measurements
The primary endpoint was achieved in 53 of patients receiving 80 mg febuxostat 62 of patients receiving 120mg and 21 of those receiving allopurinol (p lt0001 for each febuxostat group compared with allopurinol)
There was no statistical significance in the change in tophi size and number or the incidence of gout flare between the groups
Allopurinol Placebo controlled Efficacy study
of febuxostat (APEX) 2008
28 week randomized double-blind study of 1072 patients comparing the safety and efficacy of febuxostat allopurinol and placebo
Patients were randomized to a once daily fixed dose of placebo febuxostat 80mg120mg or 240 mg or allopurinol 300mg or 100mg depending on their baseline serum creatinine (le15 mgdl or ge16 to lt20 mgdl respectively)
After 1 year of treatment 82 of the patients in all febuxostat groups achieved sUA levels below 60 mgdl compared with 39 of the patients in both allopurinol groups In groups with moderate renal impairment the primary endpoint was achieved by 44 receiving febuxostat 80mg 45 receiving 120mg and 60 receiving 240mg compared with 0 in the allopurinol and placebo groups
However clinical endpoints were not statistically significant
The number of patients with moderate renal impairment was small
Febuxostat Comparative Extension Long-Term
study (EXCEL) 2009
160 week extension study for patients completing FACT and APEX
The studyrsquos aim was to determine long-term efficacy in sUA
lowering clinical benefits and safety of febuxostat or allopurinol
1086 patients were enrolled to receive fixed daily doses of
febuxostat 80mg or 120 mg or allopurinol 300 mg
After the first month of treatment nearly 80 of patients receiving
either febuxostat dose achieved sUA less than 6 mgdl compared
with only 46 of subjects on allopurinol There was no difference in
gout flare incidence and tophi reduction between the groups
Overall adverse events did not show significant differences among
groups
Febuxostat Open Label of Urate-Lowering
Efficacy and Safety (FOCUS) 2009
The FOCUS trial was a 5-year extension study that
assessed reduction and maintenance of sUA levels below
60 mgdl as the primary efficacy endpoint A total of
116 patients were initially enrolled to receive a dose of
80mg febuxostat with dose adjustment to either 40 or
120mg between weeks 4 and 24 93 maintained a sUA
level below 60 mgdl at 5 years
Objectives of CONFIRMS trial
The three-fold objectives of this Phase 3 double-blind RCT study were
1) To compare the UL efficacy of febuxostat at a dose of 40 mg with that of allopurinol at doses most commonly utilized in clinical practice
2) To evaluate UL efficacies of 80 mg and 40 mg daily doses of febuxostat compared with that of allopurinol in subjects with mild or moderate renal impairment
3) To gain prospective uniformly reviewed information regarding the safety of these agents particularly their comparative CV safety
Materials and methods
Subjects aged 18 to 85 years with a diagnosis of gout fulfilling American Rheumatology Association preliminary criteria and sUA ge 80 mgdL were eligible for enrollment
Subjects were enrolled at 324 sites in the United States
IRB approval was obtained and all the subjects provided written informed consent
At least 35 of subjects enrolled were to have mild or moderate renal impairment defined as baseline estimated creatinine clearance (eCLcr) of 60 to 89 mlminutes or 30 to 59 mlminutes
Subjects successfully completing either of the previously
reported long-term open-label febuxostat or
febuxostatallopurinol extension studies were also eligible for
enrollment
Exclusion criteria secondary hyperuricemia (for example
due to myeloproliferative disorder) xanthinuria severe renal
impairment (eCLcr lt30 mlminutes) alanine
aminotransferase and aspartate aminotransferase values gt15
times the upper limit of normal consumption of more than 14
alcoholic drinks per week or a history of alcoholism or drug
abuse within five years or a medical condition that in the
investigators opinion would interfere with treatment safety
or adherence to the protocol
Baseline characteristics of randomized subjects
Baseline characteristics of randomized subjects (cont)
Baseline characteristics of randomized subjects (cont)
2269 Subjects were randomized 111 on Day 1 to
receive daily febuxostat 40 mg febuxostat 80 mg or
allopurinol Among subjects randomized to allopurinol
those with normal renal function or mild renal
impairment received 300 mg daily and those with
moderate renal impairment received 200 mg
Throughout the subsequent six-month treatment period for all subjects prophylaxis for gout flares was given either as colchicine 06 mg daily or naproxen 250 mg twice daily All subjects receiving naproxen prophylaxis also received lansoprazole 15 mg daily
Choice of prophylaxis regimen was made by the investigator and subject taking into account prior drug tolerance and prophylaxis experience
In addition subjects with eCLcr lt50 mlminute were not to receive naproxen
Gout flares were regarded as expected gout manifestations rather than as AEs
The primary efficacy endpoint was the proportion of
subjects in each treatment group with sUA lt60 mgdL
at the final visit
Secondary efficacy variables included
1) The proportion of subjects with mild or moderate
renal impairment and final sUA lt60 mgdL
2) The proportion of subjects with sUA lt60 mgdL lt50
mgdL and lt40 mgdL at each visit
Efficacy analysisResults
Primary efficacy endpoint
1) The proportions of subjects achieving a final visit sUA lt60
mgdL were 452 671 and 421 in the febuxostat 40 mg
febuxostat 80 mg and allopurinol groups respectively
2) UL by febuxostat 40 mg was non-inferior to that by
allopurinol but the difference in the response rates between
the two groups (31 95 CI -19 to 81) was not significant
3) However the greater UL response rate with febuxostat 80 mg
compared with either febuxostat 40 mg (219) or allopurinol
(249) was significant (P lt 0001)
Secondary efficacy endpoints
Among subjects with any (mild or moderate) renal
impairment the UL response rate in the febuxostat 80
mg group (716 360503) significantly exceeded those
observed in the febuxostat 40 mg (497 238479) and
allopurinol (423 212501) groups (P le 0001 for each
comparison)
In addition among the total group of subjects with
renal impairment the UL response rate in the
febuxostat 40 mg group was significantly higher than
that in the allopurinol 300200 mg group (P = 0021)
At any sUA endpoint (lt60 mgdL lt50 mgdL or lt40 mgdL) and at any scheduled visit a significantly higher proportion of subjects receiving febuxostat 80 mg achieved the target endpoint than subjects receiving febuxostat 40 mg or allopurinol (P lt 0001)
Greater proportion of subjects in the febuxostat 40 mg group than the allopurinol group achieved sUAlt60 mgdL (at Month 2 visit P = 0031) and lt50 mgdL (at two- and six month visits P le 005) but significant differences were not seen at other visits including the final visit
Effect of baseline characteristic on treatment response
Adverse events
Adverse events
CONCLUSIONS
Results of the CONFIRMS trial establish equivalent UL efficacy for febuxostat 40 mg daily and allopurinol 300200 mg daily
At all levels of renal function studied UL efficacy of febuxostat 80 mg daily was superior to that of febuxostat 40 mg or allopurinol 300200 mg and was comparably safe
In subjects with mildly or moderately impaired renal function however febuxostat 40 mg daily was significantly more effective in lowering sUA than allopurinol
At the doses studied safety of febuxostat and allopurinol including CV safety was comparable
Febuxostat at 40 mg or 80 mg daily offers a well-tolerated UL alternative to allopurinol particularly for patients with mild or moderate renal impairment
Study limitations
The study does not address the efficacy of febuxostat compared with allopurinol in reducing clinically meaningful acute flares of gout
No mention is made of long-term cost-effectiveness of therapy
Additionally this study does not address the efficacy of febuxostat compared with allopurinol dosing that is more aggressive (ie gt 300 mg daily)
Allopurinol dosing was not titrated
The study population was not similar to the general population (majority of patients were white males)
Possible funding bias
Uloric Related Current Clinical
Trials
References
Dalbeth N Gracey E Pool B et al Identification of dairy fractions with anti-inflammatory properties in models of acute gout Ann
Rheum Dis 2010 69766ndash769
Choi HK Willett W Curhan G Coffee consumption and risk of incident gout in men a prospective study Arthritis Rheum 2007 562049ndash
2055
Hak AE Curhan GC Grodstein F Choi HK Menopause postmenopausal hormone use and risk of incident gout Ann Rheum Dis 2010
691305ndash1309
Becker MA Schumacher HR Wortmann RL et al (December 2005) Febuxostat compared with allopurinol in patients with hyperuricemia
and gout N Engl J Med 353 (23) 2450ndash61
Sarawate CA Patel PA Schumacher HR Yang W Brewer KK Bakst AW Serum urate levels and gout flares analysis from managed care
data J Clin Rheumatol 2006 1261-65
Schumacher HR Jr Becker MA Lloyd E MacDonald PA Lademacher C Febuxostat in the treatment of gout 5-yr findings of the FOCUS
efficacy and safety study Rheumatology (Oxford) 2009 48188-194
14 Becker MA Schumacher HR MacDonald PA Lloyd E Lademacher C Clinical efficacy and safety of successful long-term urate
lowering with febuxostat or allopurinol in subjects with gout J Rheumatol 2009 361273-1278
2012 ACR guidelines for management of gout
Uptodate
Medcape
Statistical Power
Power
The probability that the study will support the research hypothesis if it is true
1 Sample size (n)
2 Effect Size (d)
3 Significance Level (α)
4 Power (β)
As effect size increases power increases
As sample size increases power increases
As significance level increases power increases
Resources
httpwwwncbinlmnihgovpmcarticlesPMC3409926
httpswwwsealedenvelopecompowerbinary-superiority
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
Definition
Gout is an inflammatory arthritis associated
with hyperuricemia resulting from
deposition of monosodium urate crystals in
joint tendons and surrounding tissue
Risk factors for gout
Hyperuricemia is the most important risk factor for the
development of gout with the likelihood of developing
gout rising exponentially in line with serum urate levels
Despite this strong association the majority of patients
with hyperuricemia do not develop gout the annual
incidence of gout is estimated to be only 5 in patients
with levels of serum urate above 9 mgdl
Mechanisms of hyperuricemia and gout
Other risk factors
Hypertension hypertriglyceridemia
hypercholesterolemia diabetes and obesity are also
each associated with higher risk of incident gout andor
gout flare
Gout is extremely uncommon in premenopausal women
but postmenopausal women are at risk
Studies have indicated that menopause especially at an
earlier age increased the risk of gout in women
whereas post menopausal hormone therapy modestly
reduced risk of gout
Clinical gout is about five times more common in men
than in women
MANAGEMENT OF
GOUT
DRUGS USED IN GOUT AND THEIR MECHANISM OF ACTION
2012 ACR Management Guidelines
Lifestyle Modification for all patients with gout
Xanthine Oxidase Inhibitor (XOI) first-line urate-lowering
pharmacologic therapy
Target sUA lt6 at minimum sUA lt5 better
Continue prophylaxis for 3 (no tophi) ndash 6 months (tophi)
after achieving target sUA
2012 ACR Management Guidelines
Consider HLA screening for HLA-B5801 in certain populations considered high risk for allopurinol hypersensitivity syndrome
Koreans with stage 3 CKD or worse
Han Chinese
Thai descent
Combination oral ULT with 1 XOI agent and 1 uricosuric agent is appropriate when sUA not at target by XOI alone
Pegloticase appropriate for severe refractory disease or intolerance of standard regimens (Pegloticase is a porcine uricase which was approved by the FDA in September 2010 for the treatment of gout in patients who had failed conventional therapy)
2012 ACR Management Guidelines for
Acute Gouty Arthritis
The choice of pharmacologic agent depends on severity of the attack
Monotherapy for mildmoderate attack
Combination therapy for severe attack or those refractory to monotherapy
Acceptable combination therapy approaches include
Colchicine and NSAIDS
Oral steroids and colchicine
Intra-articular steroids with all other modalities
Continue current therapy during flare
Patient education on signs of flare for self treatment
Indications for pharmacological
treatment of gout
Any patient with established diagnosis of gouty arthritis
Tophus or tophi by clinical exam or imaging study
Frequent attacks of gouty arthritis (gt= 2 attacksyr)
CKD stage 2 or worse
Past urolithiasis
23
Gout Management Approach
bullTreat acute flare rapidly with anti-
inflammatory agent
bullInitiate urate-lowering therapy to
achieve sUA lt6
bullUse concomitant anti-inflammatory
prophylaxis for up to 6 mo to prevent
mobilization flares
INITIATE(acute flare)
RESOLVE(urate-lowering therapy)
bullContinue urate lowering therapy
to control flares and avoid crystal
deposition
bullProphylaxis use for at least 3-6
months until sUA normalizes
MAINTAIN(treatment to control sUA)
24
Allopurinol vs Febuxostat
Allopurinol Febuxostat (Uloric)
FDA-approved 1966 FDA-approved 2009
Purine-selective XO Inhibitor Non-Purine Selective XO
Inhibitor
Prevents uric acid production Prevents uric acid production
Renal Metabolism Liver Metabolism
FEBUXOSTAT
For treatment of hyperuricemia in patients with gout
febuxostat is recommended at 40 mg or 80 mg once daily and
can be increased to 120 mg once daily if clinically indicated
The adverse effects associated with febuxostat therapy
include nausea diarrhea arthralgia headache increased
hepatic serum enzyme levels and rash
The manufacturer recommends liver function monitoring on
initiation of therapy at two and four months after initiation
and periodically thereafter
FEBUXOSTAT
Febuxostat is US Food and Drug Administration pregnancy
category C2
Febuxostat is contraindicated with concomitant use of
theophylline and chemotherapeutic agents namely
azathioprine and 6- mercaptopurine because it could
increase blood plasma concentrations of these drugs and
therefore their toxicity
Dosage adjustments are unnecessary for mild to moderate
renal or hepatic impairment
A one-month supply of 40 or 80-mg febuxostat costs
$28243 This price far exceeds the cost of allopurinol
which is $2424 for 100 100 mg tablets
CrCl (mLmin)
Maintenance Dose of
Allopurinol
0 100mg every 3d
10 100mg every 2d
20 100mg
40 150mg
60 200mg
80 250mg
100 300mg
120 350mg
140 400mg
Maintenance Doses of Allopurinol for
Adults based on CrCl
28
Hande KR et al Am J Med 1984
Stage 1 renal damage with
normal GFR
(GFR gt 90 mlmin)
Stage 2 Mild CKD (GFR = 60-
89 mlmin)
Stage 3 Moderate CKD (GFR
= 30-59 mlmin)
Stage 4 Severe CKD (GFR =
15-29 mlmin)
Stage 5 End Stage CKD (GFR
lt15 mlmin)
Allopurinol Hypersensitivity
Syndrome
2 of all allopurinol users develop cutaneous rash
Frequency of hypersensitivity 1 in 260
DRESS syndrome
Drug Reaction Eosinophilia Systemic Symptoms
20 mortality rate
Life threatening toxicity vasculitis rash eosinophilia hepatitis progressive renal failure
Treatment early recognition withdrawal of drug supportive care Steroids N-acetyl-cysteine dialysis prn
29
Markel A IMAJ 2005
Terkeltaub RA in Primer on the Rheumatic Disease 13th ed 2008
The urate lowering efficacy and safety
of febuxostat in the treatment of the
hyperuricemia of gout
The CONFIRMS trial
Becker MA Schumacher HR Espinoza LR et al The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemia of gout the CONFIRMS trial Arthritis Res
Ther 201012(2)R63
Many long and short-term clinical trials have
proved the efficacy of Febuxostat in the treatment
of gout and lowering uric acid levels In these
studies Febuxostat was found to be superior to
allopurinol in reducing the serum uric acid levels
Some notable landmark clinical trials are FACT
APEX EXCEL FOCUS and CONFIRMS
Febuxostat versus Allopurinol Controlled Trial
(FACT) 2005
52 week randomized double-blind multicenter clinical trial that compared the safety and efficacy of febuxostat with allopurinol
760 patients with gout and a sUA gt80 mgdl were randomly assigned to receive either febuxostat 80 or 120mg or allopurinol 300mg once daily for 52 weeks
The primary endpoint was the proportion of patients to achieve a sUA concentration below 60 mgdl at the last three monthly measurements
The primary endpoint was achieved in 53 of patients receiving 80 mg febuxostat 62 of patients receiving 120mg and 21 of those receiving allopurinol (p lt0001 for each febuxostat group compared with allopurinol)
There was no statistical significance in the change in tophi size and number or the incidence of gout flare between the groups
Allopurinol Placebo controlled Efficacy study
of febuxostat (APEX) 2008
28 week randomized double-blind study of 1072 patients comparing the safety and efficacy of febuxostat allopurinol and placebo
Patients were randomized to a once daily fixed dose of placebo febuxostat 80mg120mg or 240 mg or allopurinol 300mg or 100mg depending on their baseline serum creatinine (le15 mgdl or ge16 to lt20 mgdl respectively)
After 1 year of treatment 82 of the patients in all febuxostat groups achieved sUA levels below 60 mgdl compared with 39 of the patients in both allopurinol groups In groups with moderate renal impairment the primary endpoint was achieved by 44 receiving febuxostat 80mg 45 receiving 120mg and 60 receiving 240mg compared with 0 in the allopurinol and placebo groups
However clinical endpoints were not statistically significant
The number of patients with moderate renal impairment was small
Febuxostat Comparative Extension Long-Term
study (EXCEL) 2009
160 week extension study for patients completing FACT and APEX
The studyrsquos aim was to determine long-term efficacy in sUA
lowering clinical benefits and safety of febuxostat or allopurinol
1086 patients were enrolled to receive fixed daily doses of
febuxostat 80mg or 120 mg or allopurinol 300 mg
After the first month of treatment nearly 80 of patients receiving
either febuxostat dose achieved sUA less than 6 mgdl compared
with only 46 of subjects on allopurinol There was no difference in
gout flare incidence and tophi reduction between the groups
Overall adverse events did not show significant differences among
groups
Febuxostat Open Label of Urate-Lowering
Efficacy and Safety (FOCUS) 2009
The FOCUS trial was a 5-year extension study that
assessed reduction and maintenance of sUA levels below
60 mgdl as the primary efficacy endpoint A total of
116 patients were initially enrolled to receive a dose of
80mg febuxostat with dose adjustment to either 40 or
120mg between weeks 4 and 24 93 maintained a sUA
level below 60 mgdl at 5 years
Objectives of CONFIRMS trial
The three-fold objectives of this Phase 3 double-blind RCT study were
1) To compare the UL efficacy of febuxostat at a dose of 40 mg with that of allopurinol at doses most commonly utilized in clinical practice
2) To evaluate UL efficacies of 80 mg and 40 mg daily doses of febuxostat compared with that of allopurinol in subjects with mild or moderate renal impairment
3) To gain prospective uniformly reviewed information regarding the safety of these agents particularly their comparative CV safety
Materials and methods
Subjects aged 18 to 85 years with a diagnosis of gout fulfilling American Rheumatology Association preliminary criteria and sUA ge 80 mgdL were eligible for enrollment
Subjects were enrolled at 324 sites in the United States
IRB approval was obtained and all the subjects provided written informed consent
At least 35 of subjects enrolled were to have mild or moderate renal impairment defined as baseline estimated creatinine clearance (eCLcr) of 60 to 89 mlminutes or 30 to 59 mlminutes
Subjects successfully completing either of the previously
reported long-term open-label febuxostat or
febuxostatallopurinol extension studies were also eligible for
enrollment
Exclusion criteria secondary hyperuricemia (for example
due to myeloproliferative disorder) xanthinuria severe renal
impairment (eCLcr lt30 mlminutes) alanine
aminotransferase and aspartate aminotransferase values gt15
times the upper limit of normal consumption of more than 14
alcoholic drinks per week or a history of alcoholism or drug
abuse within five years or a medical condition that in the
investigators opinion would interfere with treatment safety
or adherence to the protocol
Baseline characteristics of randomized subjects
Baseline characteristics of randomized subjects (cont)
Baseline characteristics of randomized subjects (cont)
2269 Subjects were randomized 111 on Day 1 to
receive daily febuxostat 40 mg febuxostat 80 mg or
allopurinol Among subjects randomized to allopurinol
those with normal renal function or mild renal
impairment received 300 mg daily and those with
moderate renal impairment received 200 mg
Throughout the subsequent six-month treatment period for all subjects prophylaxis for gout flares was given either as colchicine 06 mg daily or naproxen 250 mg twice daily All subjects receiving naproxen prophylaxis also received lansoprazole 15 mg daily
Choice of prophylaxis regimen was made by the investigator and subject taking into account prior drug tolerance and prophylaxis experience
In addition subjects with eCLcr lt50 mlminute were not to receive naproxen
Gout flares were regarded as expected gout manifestations rather than as AEs
The primary efficacy endpoint was the proportion of
subjects in each treatment group with sUA lt60 mgdL
at the final visit
Secondary efficacy variables included
1) The proportion of subjects with mild or moderate
renal impairment and final sUA lt60 mgdL
2) The proportion of subjects with sUA lt60 mgdL lt50
mgdL and lt40 mgdL at each visit
Efficacy analysisResults
Primary efficacy endpoint
1) The proportions of subjects achieving a final visit sUA lt60
mgdL were 452 671 and 421 in the febuxostat 40 mg
febuxostat 80 mg and allopurinol groups respectively
2) UL by febuxostat 40 mg was non-inferior to that by
allopurinol but the difference in the response rates between
the two groups (31 95 CI -19 to 81) was not significant
3) However the greater UL response rate with febuxostat 80 mg
compared with either febuxostat 40 mg (219) or allopurinol
(249) was significant (P lt 0001)
Secondary efficacy endpoints
Among subjects with any (mild or moderate) renal
impairment the UL response rate in the febuxostat 80
mg group (716 360503) significantly exceeded those
observed in the febuxostat 40 mg (497 238479) and
allopurinol (423 212501) groups (P le 0001 for each
comparison)
In addition among the total group of subjects with
renal impairment the UL response rate in the
febuxostat 40 mg group was significantly higher than
that in the allopurinol 300200 mg group (P = 0021)
At any sUA endpoint (lt60 mgdL lt50 mgdL or lt40 mgdL) and at any scheduled visit a significantly higher proportion of subjects receiving febuxostat 80 mg achieved the target endpoint than subjects receiving febuxostat 40 mg or allopurinol (P lt 0001)
Greater proportion of subjects in the febuxostat 40 mg group than the allopurinol group achieved sUAlt60 mgdL (at Month 2 visit P = 0031) and lt50 mgdL (at two- and six month visits P le 005) but significant differences were not seen at other visits including the final visit
Effect of baseline characteristic on treatment response
Adverse events
Adverse events
CONCLUSIONS
Results of the CONFIRMS trial establish equivalent UL efficacy for febuxostat 40 mg daily and allopurinol 300200 mg daily
At all levels of renal function studied UL efficacy of febuxostat 80 mg daily was superior to that of febuxostat 40 mg or allopurinol 300200 mg and was comparably safe
In subjects with mildly or moderately impaired renal function however febuxostat 40 mg daily was significantly more effective in lowering sUA than allopurinol
At the doses studied safety of febuxostat and allopurinol including CV safety was comparable
Febuxostat at 40 mg or 80 mg daily offers a well-tolerated UL alternative to allopurinol particularly for patients with mild or moderate renal impairment
Study limitations
The study does not address the efficacy of febuxostat compared with allopurinol in reducing clinically meaningful acute flares of gout
No mention is made of long-term cost-effectiveness of therapy
Additionally this study does not address the efficacy of febuxostat compared with allopurinol dosing that is more aggressive (ie gt 300 mg daily)
Allopurinol dosing was not titrated
The study population was not similar to the general population (majority of patients were white males)
Possible funding bias
Uloric Related Current Clinical
Trials
References
Dalbeth N Gracey E Pool B et al Identification of dairy fractions with anti-inflammatory properties in models of acute gout Ann
Rheum Dis 2010 69766ndash769
Choi HK Willett W Curhan G Coffee consumption and risk of incident gout in men a prospective study Arthritis Rheum 2007 562049ndash
2055
Hak AE Curhan GC Grodstein F Choi HK Menopause postmenopausal hormone use and risk of incident gout Ann Rheum Dis 2010
691305ndash1309
Becker MA Schumacher HR Wortmann RL et al (December 2005) Febuxostat compared with allopurinol in patients with hyperuricemia
and gout N Engl J Med 353 (23) 2450ndash61
Sarawate CA Patel PA Schumacher HR Yang W Brewer KK Bakst AW Serum urate levels and gout flares analysis from managed care
data J Clin Rheumatol 2006 1261-65
Schumacher HR Jr Becker MA Lloyd E MacDonald PA Lademacher C Febuxostat in the treatment of gout 5-yr findings of the FOCUS
efficacy and safety study Rheumatology (Oxford) 2009 48188-194
14 Becker MA Schumacher HR MacDonald PA Lloyd E Lademacher C Clinical efficacy and safety of successful long-term urate
lowering with febuxostat or allopurinol in subjects with gout J Rheumatol 2009 361273-1278
2012 ACR guidelines for management of gout
Uptodate
Medcape
Statistical Power
Power
The probability that the study will support the research hypothesis if it is true
1 Sample size (n)
2 Effect Size (d)
3 Significance Level (α)
4 Power (β)
As effect size increases power increases
As sample size increases power increases
As significance level increases power increases
Resources
httpwwwncbinlmnihgovpmcarticlesPMC3409926
httpswwwsealedenvelopecompowerbinary-superiority
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
Risk factors for gout
Hyperuricemia is the most important risk factor for the
development of gout with the likelihood of developing
gout rising exponentially in line with serum urate levels
Despite this strong association the majority of patients
with hyperuricemia do not develop gout the annual
incidence of gout is estimated to be only 5 in patients
with levels of serum urate above 9 mgdl
Mechanisms of hyperuricemia and gout
Other risk factors
Hypertension hypertriglyceridemia
hypercholesterolemia diabetes and obesity are also
each associated with higher risk of incident gout andor
gout flare
Gout is extremely uncommon in premenopausal women
but postmenopausal women are at risk
Studies have indicated that menopause especially at an
earlier age increased the risk of gout in women
whereas post menopausal hormone therapy modestly
reduced risk of gout
Clinical gout is about five times more common in men
than in women
MANAGEMENT OF
GOUT
DRUGS USED IN GOUT AND THEIR MECHANISM OF ACTION
2012 ACR Management Guidelines
Lifestyle Modification for all patients with gout
Xanthine Oxidase Inhibitor (XOI) first-line urate-lowering
pharmacologic therapy
Target sUA lt6 at minimum sUA lt5 better
Continue prophylaxis for 3 (no tophi) ndash 6 months (tophi)
after achieving target sUA
2012 ACR Management Guidelines
Consider HLA screening for HLA-B5801 in certain populations considered high risk for allopurinol hypersensitivity syndrome
Koreans with stage 3 CKD or worse
Han Chinese
Thai descent
Combination oral ULT with 1 XOI agent and 1 uricosuric agent is appropriate when sUA not at target by XOI alone
Pegloticase appropriate for severe refractory disease or intolerance of standard regimens (Pegloticase is a porcine uricase which was approved by the FDA in September 2010 for the treatment of gout in patients who had failed conventional therapy)
2012 ACR Management Guidelines for
Acute Gouty Arthritis
The choice of pharmacologic agent depends on severity of the attack
Monotherapy for mildmoderate attack
Combination therapy for severe attack or those refractory to monotherapy
Acceptable combination therapy approaches include
Colchicine and NSAIDS
Oral steroids and colchicine
Intra-articular steroids with all other modalities
Continue current therapy during flare
Patient education on signs of flare for self treatment
Indications for pharmacological
treatment of gout
Any patient with established diagnosis of gouty arthritis
Tophus or tophi by clinical exam or imaging study
Frequent attacks of gouty arthritis (gt= 2 attacksyr)
CKD stage 2 or worse
Past urolithiasis
23
Gout Management Approach
bullTreat acute flare rapidly with anti-
inflammatory agent
bullInitiate urate-lowering therapy to
achieve sUA lt6
bullUse concomitant anti-inflammatory
prophylaxis for up to 6 mo to prevent
mobilization flares
INITIATE(acute flare)
RESOLVE(urate-lowering therapy)
bullContinue urate lowering therapy
to control flares and avoid crystal
deposition
bullProphylaxis use for at least 3-6
months until sUA normalizes
MAINTAIN(treatment to control sUA)
24
Allopurinol vs Febuxostat
Allopurinol Febuxostat (Uloric)
FDA-approved 1966 FDA-approved 2009
Purine-selective XO Inhibitor Non-Purine Selective XO
Inhibitor
Prevents uric acid production Prevents uric acid production
Renal Metabolism Liver Metabolism
FEBUXOSTAT
For treatment of hyperuricemia in patients with gout
febuxostat is recommended at 40 mg or 80 mg once daily and
can be increased to 120 mg once daily if clinically indicated
The adverse effects associated with febuxostat therapy
include nausea diarrhea arthralgia headache increased
hepatic serum enzyme levels and rash
The manufacturer recommends liver function monitoring on
initiation of therapy at two and four months after initiation
and periodically thereafter
FEBUXOSTAT
Febuxostat is US Food and Drug Administration pregnancy
category C2
Febuxostat is contraindicated with concomitant use of
theophylline and chemotherapeutic agents namely
azathioprine and 6- mercaptopurine because it could
increase blood plasma concentrations of these drugs and
therefore their toxicity
Dosage adjustments are unnecessary for mild to moderate
renal or hepatic impairment
A one-month supply of 40 or 80-mg febuxostat costs
$28243 This price far exceeds the cost of allopurinol
which is $2424 for 100 100 mg tablets
CrCl (mLmin)
Maintenance Dose of
Allopurinol
0 100mg every 3d
10 100mg every 2d
20 100mg
40 150mg
60 200mg
80 250mg
100 300mg
120 350mg
140 400mg
Maintenance Doses of Allopurinol for
Adults based on CrCl
28
Hande KR et al Am J Med 1984
Stage 1 renal damage with
normal GFR
(GFR gt 90 mlmin)
Stage 2 Mild CKD (GFR = 60-
89 mlmin)
Stage 3 Moderate CKD (GFR
= 30-59 mlmin)
Stage 4 Severe CKD (GFR =
15-29 mlmin)
Stage 5 End Stage CKD (GFR
lt15 mlmin)
Allopurinol Hypersensitivity
Syndrome
2 of all allopurinol users develop cutaneous rash
Frequency of hypersensitivity 1 in 260
DRESS syndrome
Drug Reaction Eosinophilia Systemic Symptoms
20 mortality rate
Life threatening toxicity vasculitis rash eosinophilia hepatitis progressive renal failure
Treatment early recognition withdrawal of drug supportive care Steroids N-acetyl-cysteine dialysis prn
29
Markel A IMAJ 2005
Terkeltaub RA in Primer on the Rheumatic Disease 13th ed 2008
The urate lowering efficacy and safety
of febuxostat in the treatment of the
hyperuricemia of gout
The CONFIRMS trial
Becker MA Schumacher HR Espinoza LR et al The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemia of gout the CONFIRMS trial Arthritis Res
Ther 201012(2)R63
Many long and short-term clinical trials have
proved the efficacy of Febuxostat in the treatment
of gout and lowering uric acid levels In these
studies Febuxostat was found to be superior to
allopurinol in reducing the serum uric acid levels
Some notable landmark clinical trials are FACT
APEX EXCEL FOCUS and CONFIRMS
Febuxostat versus Allopurinol Controlled Trial
(FACT) 2005
52 week randomized double-blind multicenter clinical trial that compared the safety and efficacy of febuxostat with allopurinol
760 patients with gout and a sUA gt80 mgdl were randomly assigned to receive either febuxostat 80 or 120mg or allopurinol 300mg once daily for 52 weeks
The primary endpoint was the proportion of patients to achieve a sUA concentration below 60 mgdl at the last three monthly measurements
The primary endpoint was achieved in 53 of patients receiving 80 mg febuxostat 62 of patients receiving 120mg and 21 of those receiving allopurinol (p lt0001 for each febuxostat group compared with allopurinol)
There was no statistical significance in the change in tophi size and number or the incidence of gout flare between the groups
Allopurinol Placebo controlled Efficacy study
of febuxostat (APEX) 2008
28 week randomized double-blind study of 1072 patients comparing the safety and efficacy of febuxostat allopurinol and placebo
Patients were randomized to a once daily fixed dose of placebo febuxostat 80mg120mg or 240 mg or allopurinol 300mg or 100mg depending on their baseline serum creatinine (le15 mgdl or ge16 to lt20 mgdl respectively)
After 1 year of treatment 82 of the patients in all febuxostat groups achieved sUA levels below 60 mgdl compared with 39 of the patients in both allopurinol groups In groups with moderate renal impairment the primary endpoint was achieved by 44 receiving febuxostat 80mg 45 receiving 120mg and 60 receiving 240mg compared with 0 in the allopurinol and placebo groups
However clinical endpoints were not statistically significant
The number of patients with moderate renal impairment was small
Febuxostat Comparative Extension Long-Term
study (EXCEL) 2009
160 week extension study for patients completing FACT and APEX
The studyrsquos aim was to determine long-term efficacy in sUA
lowering clinical benefits and safety of febuxostat or allopurinol
1086 patients were enrolled to receive fixed daily doses of
febuxostat 80mg or 120 mg or allopurinol 300 mg
After the first month of treatment nearly 80 of patients receiving
either febuxostat dose achieved sUA less than 6 mgdl compared
with only 46 of subjects on allopurinol There was no difference in
gout flare incidence and tophi reduction between the groups
Overall adverse events did not show significant differences among
groups
Febuxostat Open Label of Urate-Lowering
Efficacy and Safety (FOCUS) 2009
The FOCUS trial was a 5-year extension study that
assessed reduction and maintenance of sUA levels below
60 mgdl as the primary efficacy endpoint A total of
116 patients were initially enrolled to receive a dose of
80mg febuxostat with dose adjustment to either 40 or
120mg between weeks 4 and 24 93 maintained a sUA
level below 60 mgdl at 5 years
Objectives of CONFIRMS trial
The three-fold objectives of this Phase 3 double-blind RCT study were
1) To compare the UL efficacy of febuxostat at a dose of 40 mg with that of allopurinol at doses most commonly utilized in clinical practice
2) To evaluate UL efficacies of 80 mg and 40 mg daily doses of febuxostat compared with that of allopurinol in subjects with mild or moderate renal impairment
3) To gain prospective uniformly reviewed information regarding the safety of these agents particularly their comparative CV safety
Materials and methods
Subjects aged 18 to 85 years with a diagnosis of gout fulfilling American Rheumatology Association preliminary criteria and sUA ge 80 mgdL were eligible for enrollment
Subjects were enrolled at 324 sites in the United States
IRB approval was obtained and all the subjects provided written informed consent
At least 35 of subjects enrolled were to have mild or moderate renal impairment defined as baseline estimated creatinine clearance (eCLcr) of 60 to 89 mlminutes or 30 to 59 mlminutes
Subjects successfully completing either of the previously
reported long-term open-label febuxostat or
febuxostatallopurinol extension studies were also eligible for
enrollment
Exclusion criteria secondary hyperuricemia (for example
due to myeloproliferative disorder) xanthinuria severe renal
impairment (eCLcr lt30 mlminutes) alanine
aminotransferase and aspartate aminotransferase values gt15
times the upper limit of normal consumption of more than 14
alcoholic drinks per week or a history of alcoholism or drug
abuse within five years or a medical condition that in the
investigators opinion would interfere with treatment safety
or adherence to the protocol
Baseline characteristics of randomized subjects
Baseline characteristics of randomized subjects (cont)
Baseline characteristics of randomized subjects (cont)
2269 Subjects were randomized 111 on Day 1 to
receive daily febuxostat 40 mg febuxostat 80 mg or
allopurinol Among subjects randomized to allopurinol
those with normal renal function or mild renal
impairment received 300 mg daily and those with
moderate renal impairment received 200 mg
Throughout the subsequent six-month treatment period for all subjects prophylaxis for gout flares was given either as colchicine 06 mg daily or naproxen 250 mg twice daily All subjects receiving naproxen prophylaxis also received lansoprazole 15 mg daily
Choice of prophylaxis regimen was made by the investigator and subject taking into account prior drug tolerance and prophylaxis experience
In addition subjects with eCLcr lt50 mlminute were not to receive naproxen
Gout flares were regarded as expected gout manifestations rather than as AEs
The primary efficacy endpoint was the proportion of
subjects in each treatment group with sUA lt60 mgdL
at the final visit
Secondary efficacy variables included
1) The proportion of subjects with mild or moderate
renal impairment and final sUA lt60 mgdL
2) The proportion of subjects with sUA lt60 mgdL lt50
mgdL and lt40 mgdL at each visit
Efficacy analysisResults
Primary efficacy endpoint
1) The proportions of subjects achieving a final visit sUA lt60
mgdL were 452 671 and 421 in the febuxostat 40 mg
febuxostat 80 mg and allopurinol groups respectively
2) UL by febuxostat 40 mg was non-inferior to that by
allopurinol but the difference in the response rates between
the two groups (31 95 CI -19 to 81) was not significant
3) However the greater UL response rate with febuxostat 80 mg
compared with either febuxostat 40 mg (219) or allopurinol
(249) was significant (P lt 0001)
Secondary efficacy endpoints
Among subjects with any (mild or moderate) renal
impairment the UL response rate in the febuxostat 80
mg group (716 360503) significantly exceeded those
observed in the febuxostat 40 mg (497 238479) and
allopurinol (423 212501) groups (P le 0001 for each
comparison)
In addition among the total group of subjects with
renal impairment the UL response rate in the
febuxostat 40 mg group was significantly higher than
that in the allopurinol 300200 mg group (P = 0021)
At any sUA endpoint (lt60 mgdL lt50 mgdL or lt40 mgdL) and at any scheduled visit a significantly higher proportion of subjects receiving febuxostat 80 mg achieved the target endpoint than subjects receiving febuxostat 40 mg or allopurinol (P lt 0001)
Greater proportion of subjects in the febuxostat 40 mg group than the allopurinol group achieved sUAlt60 mgdL (at Month 2 visit P = 0031) and lt50 mgdL (at two- and six month visits P le 005) but significant differences were not seen at other visits including the final visit
Effect of baseline characteristic on treatment response
Adverse events
Adverse events
CONCLUSIONS
Results of the CONFIRMS trial establish equivalent UL efficacy for febuxostat 40 mg daily and allopurinol 300200 mg daily
At all levels of renal function studied UL efficacy of febuxostat 80 mg daily was superior to that of febuxostat 40 mg or allopurinol 300200 mg and was comparably safe
In subjects with mildly or moderately impaired renal function however febuxostat 40 mg daily was significantly more effective in lowering sUA than allopurinol
At the doses studied safety of febuxostat and allopurinol including CV safety was comparable
Febuxostat at 40 mg or 80 mg daily offers a well-tolerated UL alternative to allopurinol particularly for patients with mild or moderate renal impairment
Study limitations
The study does not address the efficacy of febuxostat compared with allopurinol in reducing clinically meaningful acute flares of gout
No mention is made of long-term cost-effectiveness of therapy
Additionally this study does not address the efficacy of febuxostat compared with allopurinol dosing that is more aggressive (ie gt 300 mg daily)
Allopurinol dosing was not titrated
The study population was not similar to the general population (majority of patients were white males)
Possible funding bias
Uloric Related Current Clinical
Trials
References
Dalbeth N Gracey E Pool B et al Identification of dairy fractions with anti-inflammatory properties in models of acute gout Ann
Rheum Dis 2010 69766ndash769
Choi HK Willett W Curhan G Coffee consumption and risk of incident gout in men a prospective study Arthritis Rheum 2007 562049ndash
2055
Hak AE Curhan GC Grodstein F Choi HK Menopause postmenopausal hormone use and risk of incident gout Ann Rheum Dis 2010
691305ndash1309
Becker MA Schumacher HR Wortmann RL et al (December 2005) Febuxostat compared with allopurinol in patients with hyperuricemia
and gout N Engl J Med 353 (23) 2450ndash61
Sarawate CA Patel PA Schumacher HR Yang W Brewer KK Bakst AW Serum urate levels and gout flares analysis from managed care
data J Clin Rheumatol 2006 1261-65
Schumacher HR Jr Becker MA Lloyd E MacDonald PA Lademacher C Febuxostat in the treatment of gout 5-yr findings of the FOCUS
efficacy and safety study Rheumatology (Oxford) 2009 48188-194
14 Becker MA Schumacher HR MacDonald PA Lloyd E Lademacher C Clinical efficacy and safety of successful long-term urate
lowering with febuxostat or allopurinol in subjects with gout J Rheumatol 2009 361273-1278
2012 ACR guidelines for management of gout
Uptodate
Medcape
Statistical Power
Power
The probability that the study will support the research hypothesis if it is true
1 Sample size (n)
2 Effect Size (d)
3 Significance Level (α)
4 Power (β)
As effect size increases power increases
As sample size increases power increases
As significance level increases power increases
Resources
httpwwwncbinlmnihgovpmcarticlesPMC3409926
httpswwwsealedenvelopecompowerbinary-superiority
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
Mechanisms of hyperuricemia and gout
Other risk factors
Hypertension hypertriglyceridemia
hypercholesterolemia diabetes and obesity are also
each associated with higher risk of incident gout andor
gout flare
Gout is extremely uncommon in premenopausal women
but postmenopausal women are at risk
Studies have indicated that menopause especially at an
earlier age increased the risk of gout in women
whereas post menopausal hormone therapy modestly
reduced risk of gout
Clinical gout is about five times more common in men
than in women
MANAGEMENT OF
GOUT
DRUGS USED IN GOUT AND THEIR MECHANISM OF ACTION
2012 ACR Management Guidelines
Lifestyle Modification for all patients with gout
Xanthine Oxidase Inhibitor (XOI) first-line urate-lowering
pharmacologic therapy
Target sUA lt6 at minimum sUA lt5 better
Continue prophylaxis for 3 (no tophi) ndash 6 months (tophi)
after achieving target sUA
2012 ACR Management Guidelines
Consider HLA screening for HLA-B5801 in certain populations considered high risk for allopurinol hypersensitivity syndrome
Koreans with stage 3 CKD or worse
Han Chinese
Thai descent
Combination oral ULT with 1 XOI agent and 1 uricosuric agent is appropriate when sUA not at target by XOI alone
Pegloticase appropriate for severe refractory disease or intolerance of standard regimens (Pegloticase is a porcine uricase which was approved by the FDA in September 2010 for the treatment of gout in patients who had failed conventional therapy)
2012 ACR Management Guidelines for
Acute Gouty Arthritis
The choice of pharmacologic agent depends on severity of the attack
Monotherapy for mildmoderate attack
Combination therapy for severe attack or those refractory to monotherapy
Acceptable combination therapy approaches include
Colchicine and NSAIDS
Oral steroids and colchicine
Intra-articular steroids with all other modalities
Continue current therapy during flare
Patient education on signs of flare for self treatment
Indications for pharmacological
treatment of gout
Any patient with established diagnosis of gouty arthritis
Tophus or tophi by clinical exam or imaging study
Frequent attacks of gouty arthritis (gt= 2 attacksyr)
CKD stage 2 or worse
Past urolithiasis
23
Gout Management Approach
bullTreat acute flare rapidly with anti-
inflammatory agent
bullInitiate urate-lowering therapy to
achieve sUA lt6
bullUse concomitant anti-inflammatory
prophylaxis for up to 6 mo to prevent
mobilization flares
INITIATE(acute flare)
RESOLVE(urate-lowering therapy)
bullContinue urate lowering therapy
to control flares and avoid crystal
deposition
bullProphylaxis use for at least 3-6
months until sUA normalizes
MAINTAIN(treatment to control sUA)
24
Allopurinol vs Febuxostat
Allopurinol Febuxostat (Uloric)
FDA-approved 1966 FDA-approved 2009
Purine-selective XO Inhibitor Non-Purine Selective XO
Inhibitor
Prevents uric acid production Prevents uric acid production
Renal Metabolism Liver Metabolism
FEBUXOSTAT
For treatment of hyperuricemia in patients with gout
febuxostat is recommended at 40 mg or 80 mg once daily and
can be increased to 120 mg once daily if clinically indicated
The adverse effects associated with febuxostat therapy
include nausea diarrhea arthralgia headache increased
hepatic serum enzyme levels and rash
The manufacturer recommends liver function monitoring on
initiation of therapy at two and four months after initiation
and periodically thereafter
FEBUXOSTAT
Febuxostat is US Food and Drug Administration pregnancy
category C2
Febuxostat is contraindicated with concomitant use of
theophylline and chemotherapeutic agents namely
azathioprine and 6- mercaptopurine because it could
increase blood plasma concentrations of these drugs and
therefore their toxicity
Dosage adjustments are unnecessary for mild to moderate
renal or hepatic impairment
A one-month supply of 40 or 80-mg febuxostat costs
$28243 This price far exceeds the cost of allopurinol
which is $2424 for 100 100 mg tablets
CrCl (mLmin)
Maintenance Dose of
Allopurinol
0 100mg every 3d
10 100mg every 2d
20 100mg
40 150mg
60 200mg
80 250mg
100 300mg
120 350mg
140 400mg
Maintenance Doses of Allopurinol for
Adults based on CrCl
28
Hande KR et al Am J Med 1984
Stage 1 renal damage with
normal GFR
(GFR gt 90 mlmin)
Stage 2 Mild CKD (GFR = 60-
89 mlmin)
Stage 3 Moderate CKD (GFR
= 30-59 mlmin)
Stage 4 Severe CKD (GFR =
15-29 mlmin)
Stage 5 End Stage CKD (GFR
lt15 mlmin)
Allopurinol Hypersensitivity
Syndrome
2 of all allopurinol users develop cutaneous rash
Frequency of hypersensitivity 1 in 260
DRESS syndrome
Drug Reaction Eosinophilia Systemic Symptoms
20 mortality rate
Life threatening toxicity vasculitis rash eosinophilia hepatitis progressive renal failure
Treatment early recognition withdrawal of drug supportive care Steroids N-acetyl-cysteine dialysis prn
29
Markel A IMAJ 2005
Terkeltaub RA in Primer on the Rheumatic Disease 13th ed 2008
The urate lowering efficacy and safety
of febuxostat in the treatment of the
hyperuricemia of gout
The CONFIRMS trial
Becker MA Schumacher HR Espinoza LR et al The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemia of gout the CONFIRMS trial Arthritis Res
Ther 201012(2)R63
Many long and short-term clinical trials have
proved the efficacy of Febuxostat in the treatment
of gout and lowering uric acid levels In these
studies Febuxostat was found to be superior to
allopurinol in reducing the serum uric acid levels
Some notable landmark clinical trials are FACT
APEX EXCEL FOCUS and CONFIRMS
Febuxostat versus Allopurinol Controlled Trial
(FACT) 2005
52 week randomized double-blind multicenter clinical trial that compared the safety and efficacy of febuxostat with allopurinol
760 patients with gout and a sUA gt80 mgdl were randomly assigned to receive either febuxostat 80 or 120mg or allopurinol 300mg once daily for 52 weeks
The primary endpoint was the proportion of patients to achieve a sUA concentration below 60 mgdl at the last three monthly measurements
The primary endpoint was achieved in 53 of patients receiving 80 mg febuxostat 62 of patients receiving 120mg and 21 of those receiving allopurinol (p lt0001 for each febuxostat group compared with allopurinol)
There was no statistical significance in the change in tophi size and number or the incidence of gout flare between the groups
Allopurinol Placebo controlled Efficacy study
of febuxostat (APEX) 2008
28 week randomized double-blind study of 1072 patients comparing the safety and efficacy of febuxostat allopurinol and placebo
Patients were randomized to a once daily fixed dose of placebo febuxostat 80mg120mg or 240 mg or allopurinol 300mg or 100mg depending on their baseline serum creatinine (le15 mgdl or ge16 to lt20 mgdl respectively)
After 1 year of treatment 82 of the patients in all febuxostat groups achieved sUA levels below 60 mgdl compared with 39 of the patients in both allopurinol groups In groups with moderate renal impairment the primary endpoint was achieved by 44 receiving febuxostat 80mg 45 receiving 120mg and 60 receiving 240mg compared with 0 in the allopurinol and placebo groups
However clinical endpoints were not statistically significant
The number of patients with moderate renal impairment was small
Febuxostat Comparative Extension Long-Term
study (EXCEL) 2009
160 week extension study for patients completing FACT and APEX
The studyrsquos aim was to determine long-term efficacy in sUA
lowering clinical benefits and safety of febuxostat or allopurinol
1086 patients were enrolled to receive fixed daily doses of
febuxostat 80mg or 120 mg or allopurinol 300 mg
After the first month of treatment nearly 80 of patients receiving
either febuxostat dose achieved sUA less than 6 mgdl compared
with only 46 of subjects on allopurinol There was no difference in
gout flare incidence and tophi reduction between the groups
Overall adverse events did not show significant differences among
groups
Febuxostat Open Label of Urate-Lowering
Efficacy and Safety (FOCUS) 2009
The FOCUS trial was a 5-year extension study that
assessed reduction and maintenance of sUA levels below
60 mgdl as the primary efficacy endpoint A total of
116 patients were initially enrolled to receive a dose of
80mg febuxostat with dose adjustment to either 40 or
120mg between weeks 4 and 24 93 maintained a sUA
level below 60 mgdl at 5 years
Objectives of CONFIRMS trial
The three-fold objectives of this Phase 3 double-blind RCT study were
1) To compare the UL efficacy of febuxostat at a dose of 40 mg with that of allopurinol at doses most commonly utilized in clinical practice
2) To evaluate UL efficacies of 80 mg and 40 mg daily doses of febuxostat compared with that of allopurinol in subjects with mild or moderate renal impairment
3) To gain prospective uniformly reviewed information regarding the safety of these agents particularly their comparative CV safety
Materials and methods
Subjects aged 18 to 85 years with a diagnosis of gout fulfilling American Rheumatology Association preliminary criteria and sUA ge 80 mgdL were eligible for enrollment
Subjects were enrolled at 324 sites in the United States
IRB approval was obtained and all the subjects provided written informed consent
At least 35 of subjects enrolled were to have mild or moderate renal impairment defined as baseline estimated creatinine clearance (eCLcr) of 60 to 89 mlminutes or 30 to 59 mlminutes
Subjects successfully completing either of the previously
reported long-term open-label febuxostat or
febuxostatallopurinol extension studies were also eligible for
enrollment
Exclusion criteria secondary hyperuricemia (for example
due to myeloproliferative disorder) xanthinuria severe renal
impairment (eCLcr lt30 mlminutes) alanine
aminotransferase and aspartate aminotransferase values gt15
times the upper limit of normal consumption of more than 14
alcoholic drinks per week or a history of alcoholism or drug
abuse within five years or a medical condition that in the
investigators opinion would interfere with treatment safety
or adherence to the protocol
Baseline characteristics of randomized subjects
Baseline characteristics of randomized subjects (cont)
Baseline characteristics of randomized subjects (cont)
2269 Subjects were randomized 111 on Day 1 to
receive daily febuxostat 40 mg febuxostat 80 mg or
allopurinol Among subjects randomized to allopurinol
those with normal renal function or mild renal
impairment received 300 mg daily and those with
moderate renal impairment received 200 mg
Throughout the subsequent six-month treatment period for all subjects prophylaxis for gout flares was given either as colchicine 06 mg daily or naproxen 250 mg twice daily All subjects receiving naproxen prophylaxis also received lansoprazole 15 mg daily
Choice of prophylaxis regimen was made by the investigator and subject taking into account prior drug tolerance and prophylaxis experience
In addition subjects with eCLcr lt50 mlminute were not to receive naproxen
Gout flares were regarded as expected gout manifestations rather than as AEs
The primary efficacy endpoint was the proportion of
subjects in each treatment group with sUA lt60 mgdL
at the final visit
Secondary efficacy variables included
1) The proportion of subjects with mild or moderate
renal impairment and final sUA lt60 mgdL
2) The proportion of subjects with sUA lt60 mgdL lt50
mgdL and lt40 mgdL at each visit
Efficacy analysisResults
Primary efficacy endpoint
1) The proportions of subjects achieving a final visit sUA lt60
mgdL were 452 671 and 421 in the febuxostat 40 mg
febuxostat 80 mg and allopurinol groups respectively
2) UL by febuxostat 40 mg was non-inferior to that by
allopurinol but the difference in the response rates between
the two groups (31 95 CI -19 to 81) was not significant
3) However the greater UL response rate with febuxostat 80 mg
compared with either febuxostat 40 mg (219) or allopurinol
(249) was significant (P lt 0001)
Secondary efficacy endpoints
Among subjects with any (mild or moderate) renal
impairment the UL response rate in the febuxostat 80
mg group (716 360503) significantly exceeded those
observed in the febuxostat 40 mg (497 238479) and
allopurinol (423 212501) groups (P le 0001 for each
comparison)
In addition among the total group of subjects with
renal impairment the UL response rate in the
febuxostat 40 mg group was significantly higher than
that in the allopurinol 300200 mg group (P = 0021)
At any sUA endpoint (lt60 mgdL lt50 mgdL or lt40 mgdL) and at any scheduled visit a significantly higher proportion of subjects receiving febuxostat 80 mg achieved the target endpoint than subjects receiving febuxostat 40 mg or allopurinol (P lt 0001)
Greater proportion of subjects in the febuxostat 40 mg group than the allopurinol group achieved sUAlt60 mgdL (at Month 2 visit P = 0031) and lt50 mgdL (at two- and six month visits P le 005) but significant differences were not seen at other visits including the final visit
Effect of baseline characteristic on treatment response
Adverse events
Adverse events
CONCLUSIONS
Results of the CONFIRMS trial establish equivalent UL efficacy for febuxostat 40 mg daily and allopurinol 300200 mg daily
At all levels of renal function studied UL efficacy of febuxostat 80 mg daily was superior to that of febuxostat 40 mg or allopurinol 300200 mg and was comparably safe
In subjects with mildly or moderately impaired renal function however febuxostat 40 mg daily was significantly more effective in lowering sUA than allopurinol
At the doses studied safety of febuxostat and allopurinol including CV safety was comparable
Febuxostat at 40 mg or 80 mg daily offers a well-tolerated UL alternative to allopurinol particularly for patients with mild or moderate renal impairment
Study limitations
The study does not address the efficacy of febuxostat compared with allopurinol in reducing clinically meaningful acute flares of gout
No mention is made of long-term cost-effectiveness of therapy
Additionally this study does not address the efficacy of febuxostat compared with allopurinol dosing that is more aggressive (ie gt 300 mg daily)
Allopurinol dosing was not titrated
The study population was not similar to the general population (majority of patients were white males)
Possible funding bias
Uloric Related Current Clinical
Trials
References
Dalbeth N Gracey E Pool B et al Identification of dairy fractions with anti-inflammatory properties in models of acute gout Ann
Rheum Dis 2010 69766ndash769
Choi HK Willett W Curhan G Coffee consumption and risk of incident gout in men a prospective study Arthritis Rheum 2007 562049ndash
2055
Hak AE Curhan GC Grodstein F Choi HK Menopause postmenopausal hormone use and risk of incident gout Ann Rheum Dis 2010
691305ndash1309
Becker MA Schumacher HR Wortmann RL et al (December 2005) Febuxostat compared with allopurinol in patients with hyperuricemia
and gout N Engl J Med 353 (23) 2450ndash61
Sarawate CA Patel PA Schumacher HR Yang W Brewer KK Bakst AW Serum urate levels and gout flares analysis from managed care
data J Clin Rheumatol 2006 1261-65
Schumacher HR Jr Becker MA Lloyd E MacDonald PA Lademacher C Febuxostat in the treatment of gout 5-yr findings of the FOCUS
efficacy and safety study Rheumatology (Oxford) 2009 48188-194
14 Becker MA Schumacher HR MacDonald PA Lloyd E Lademacher C Clinical efficacy and safety of successful long-term urate
lowering with febuxostat or allopurinol in subjects with gout J Rheumatol 2009 361273-1278
2012 ACR guidelines for management of gout
Uptodate
Medcape
Statistical Power
Power
The probability that the study will support the research hypothesis if it is true
1 Sample size (n)
2 Effect Size (d)
3 Significance Level (α)
4 Power (β)
As effect size increases power increases
As sample size increases power increases
As significance level increases power increases
Resources
httpwwwncbinlmnihgovpmcarticlesPMC3409926
httpswwwsealedenvelopecompowerbinary-superiority
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
Other risk factors
Hypertension hypertriglyceridemia
hypercholesterolemia diabetes and obesity are also
each associated with higher risk of incident gout andor
gout flare
Gout is extremely uncommon in premenopausal women
but postmenopausal women are at risk
Studies have indicated that menopause especially at an
earlier age increased the risk of gout in women
whereas post menopausal hormone therapy modestly
reduced risk of gout
Clinical gout is about five times more common in men
than in women
MANAGEMENT OF
GOUT
DRUGS USED IN GOUT AND THEIR MECHANISM OF ACTION
2012 ACR Management Guidelines
Lifestyle Modification for all patients with gout
Xanthine Oxidase Inhibitor (XOI) first-line urate-lowering
pharmacologic therapy
Target sUA lt6 at minimum sUA lt5 better
Continue prophylaxis for 3 (no tophi) ndash 6 months (tophi)
after achieving target sUA
2012 ACR Management Guidelines
Consider HLA screening for HLA-B5801 in certain populations considered high risk for allopurinol hypersensitivity syndrome
Koreans with stage 3 CKD or worse
Han Chinese
Thai descent
Combination oral ULT with 1 XOI agent and 1 uricosuric agent is appropriate when sUA not at target by XOI alone
Pegloticase appropriate for severe refractory disease or intolerance of standard regimens (Pegloticase is a porcine uricase which was approved by the FDA in September 2010 for the treatment of gout in patients who had failed conventional therapy)
2012 ACR Management Guidelines for
Acute Gouty Arthritis
The choice of pharmacologic agent depends on severity of the attack
Monotherapy for mildmoderate attack
Combination therapy for severe attack or those refractory to monotherapy
Acceptable combination therapy approaches include
Colchicine and NSAIDS
Oral steroids and colchicine
Intra-articular steroids with all other modalities
Continue current therapy during flare
Patient education on signs of flare for self treatment
Indications for pharmacological
treatment of gout
Any patient with established diagnosis of gouty arthritis
Tophus or tophi by clinical exam or imaging study
Frequent attacks of gouty arthritis (gt= 2 attacksyr)
CKD stage 2 or worse
Past urolithiasis
23
Gout Management Approach
bullTreat acute flare rapidly with anti-
inflammatory agent
bullInitiate urate-lowering therapy to
achieve sUA lt6
bullUse concomitant anti-inflammatory
prophylaxis for up to 6 mo to prevent
mobilization flares
INITIATE(acute flare)
RESOLVE(urate-lowering therapy)
bullContinue urate lowering therapy
to control flares and avoid crystal
deposition
bullProphylaxis use for at least 3-6
months until sUA normalizes
MAINTAIN(treatment to control sUA)
24
Allopurinol vs Febuxostat
Allopurinol Febuxostat (Uloric)
FDA-approved 1966 FDA-approved 2009
Purine-selective XO Inhibitor Non-Purine Selective XO
Inhibitor
Prevents uric acid production Prevents uric acid production
Renal Metabolism Liver Metabolism
FEBUXOSTAT
For treatment of hyperuricemia in patients with gout
febuxostat is recommended at 40 mg or 80 mg once daily and
can be increased to 120 mg once daily if clinically indicated
The adverse effects associated with febuxostat therapy
include nausea diarrhea arthralgia headache increased
hepatic serum enzyme levels and rash
The manufacturer recommends liver function monitoring on
initiation of therapy at two and four months after initiation
and periodically thereafter
FEBUXOSTAT
Febuxostat is US Food and Drug Administration pregnancy
category C2
Febuxostat is contraindicated with concomitant use of
theophylline and chemotherapeutic agents namely
azathioprine and 6- mercaptopurine because it could
increase blood plasma concentrations of these drugs and
therefore their toxicity
Dosage adjustments are unnecessary for mild to moderate
renal or hepatic impairment
A one-month supply of 40 or 80-mg febuxostat costs
$28243 This price far exceeds the cost of allopurinol
which is $2424 for 100 100 mg tablets
CrCl (mLmin)
Maintenance Dose of
Allopurinol
0 100mg every 3d
10 100mg every 2d
20 100mg
40 150mg
60 200mg
80 250mg
100 300mg
120 350mg
140 400mg
Maintenance Doses of Allopurinol for
Adults based on CrCl
28
Hande KR et al Am J Med 1984
Stage 1 renal damage with
normal GFR
(GFR gt 90 mlmin)
Stage 2 Mild CKD (GFR = 60-
89 mlmin)
Stage 3 Moderate CKD (GFR
= 30-59 mlmin)
Stage 4 Severe CKD (GFR =
15-29 mlmin)
Stage 5 End Stage CKD (GFR
lt15 mlmin)
Allopurinol Hypersensitivity
Syndrome
2 of all allopurinol users develop cutaneous rash
Frequency of hypersensitivity 1 in 260
DRESS syndrome
Drug Reaction Eosinophilia Systemic Symptoms
20 mortality rate
Life threatening toxicity vasculitis rash eosinophilia hepatitis progressive renal failure
Treatment early recognition withdrawal of drug supportive care Steroids N-acetyl-cysteine dialysis prn
29
Markel A IMAJ 2005
Terkeltaub RA in Primer on the Rheumatic Disease 13th ed 2008
The urate lowering efficacy and safety
of febuxostat in the treatment of the
hyperuricemia of gout
The CONFIRMS trial
Becker MA Schumacher HR Espinoza LR et al The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemia of gout the CONFIRMS trial Arthritis Res
Ther 201012(2)R63
Many long and short-term clinical trials have
proved the efficacy of Febuxostat in the treatment
of gout and lowering uric acid levels In these
studies Febuxostat was found to be superior to
allopurinol in reducing the serum uric acid levels
Some notable landmark clinical trials are FACT
APEX EXCEL FOCUS and CONFIRMS
Febuxostat versus Allopurinol Controlled Trial
(FACT) 2005
52 week randomized double-blind multicenter clinical trial that compared the safety and efficacy of febuxostat with allopurinol
760 patients with gout and a sUA gt80 mgdl were randomly assigned to receive either febuxostat 80 or 120mg or allopurinol 300mg once daily for 52 weeks
The primary endpoint was the proportion of patients to achieve a sUA concentration below 60 mgdl at the last three monthly measurements
The primary endpoint was achieved in 53 of patients receiving 80 mg febuxostat 62 of patients receiving 120mg and 21 of those receiving allopurinol (p lt0001 for each febuxostat group compared with allopurinol)
There was no statistical significance in the change in tophi size and number or the incidence of gout flare between the groups
Allopurinol Placebo controlled Efficacy study
of febuxostat (APEX) 2008
28 week randomized double-blind study of 1072 patients comparing the safety and efficacy of febuxostat allopurinol and placebo
Patients were randomized to a once daily fixed dose of placebo febuxostat 80mg120mg or 240 mg or allopurinol 300mg or 100mg depending on their baseline serum creatinine (le15 mgdl or ge16 to lt20 mgdl respectively)
After 1 year of treatment 82 of the patients in all febuxostat groups achieved sUA levels below 60 mgdl compared with 39 of the patients in both allopurinol groups In groups with moderate renal impairment the primary endpoint was achieved by 44 receiving febuxostat 80mg 45 receiving 120mg and 60 receiving 240mg compared with 0 in the allopurinol and placebo groups
However clinical endpoints were not statistically significant
The number of patients with moderate renal impairment was small
Febuxostat Comparative Extension Long-Term
study (EXCEL) 2009
160 week extension study for patients completing FACT and APEX
The studyrsquos aim was to determine long-term efficacy in sUA
lowering clinical benefits and safety of febuxostat or allopurinol
1086 patients were enrolled to receive fixed daily doses of
febuxostat 80mg or 120 mg or allopurinol 300 mg
After the first month of treatment nearly 80 of patients receiving
either febuxostat dose achieved sUA less than 6 mgdl compared
with only 46 of subjects on allopurinol There was no difference in
gout flare incidence and tophi reduction between the groups
Overall adverse events did not show significant differences among
groups
Febuxostat Open Label of Urate-Lowering
Efficacy and Safety (FOCUS) 2009
The FOCUS trial was a 5-year extension study that
assessed reduction and maintenance of sUA levels below
60 mgdl as the primary efficacy endpoint A total of
116 patients were initially enrolled to receive a dose of
80mg febuxostat with dose adjustment to either 40 or
120mg between weeks 4 and 24 93 maintained a sUA
level below 60 mgdl at 5 years
Objectives of CONFIRMS trial
The three-fold objectives of this Phase 3 double-blind RCT study were
1) To compare the UL efficacy of febuxostat at a dose of 40 mg with that of allopurinol at doses most commonly utilized in clinical practice
2) To evaluate UL efficacies of 80 mg and 40 mg daily doses of febuxostat compared with that of allopurinol in subjects with mild or moderate renal impairment
3) To gain prospective uniformly reviewed information regarding the safety of these agents particularly their comparative CV safety
Materials and methods
Subjects aged 18 to 85 years with a diagnosis of gout fulfilling American Rheumatology Association preliminary criteria and sUA ge 80 mgdL were eligible for enrollment
Subjects were enrolled at 324 sites in the United States
IRB approval was obtained and all the subjects provided written informed consent
At least 35 of subjects enrolled were to have mild or moderate renal impairment defined as baseline estimated creatinine clearance (eCLcr) of 60 to 89 mlminutes or 30 to 59 mlminutes
Subjects successfully completing either of the previously
reported long-term open-label febuxostat or
febuxostatallopurinol extension studies were also eligible for
enrollment
Exclusion criteria secondary hyperuricemia (for example
due to myeloproliferative disorder) xanthinuria severe renal
impairment (eCLcr lt30 mlminutes) alanine
aminotransferase and aspartate aminotransferase values gt15
times the upper limit of normal consumption of more than 14
alcoholic drinks per week or a history of alcoholism or drug
abuse within five years or a medical condition that in the
investigators opinion would interfere with treatment safety
or adherence to the protocol
Baseline characteristics of randomized subjects
Baseline characteristics of randomized subjects (cont)
Baseline characteristics of randomized subjects (cont)
2269 Subjects were randomized 111 on Day 1 to
receive daily febuxostat 40 mg febuxostat 80 mg or
allopurinol Among subjects randomized to allopurinol
those with normal renal function or mild renal
impairment received 300 mg daily and those with
moderate renal impairment received 200 mg
Throughout the subsequent six-month treatment period for all subjects prophylaxis for gout flares was given either as colchicine 06 mg daily or naproxen 250 mg twice daily All subjects receiving naproxen prophylaxis also received lansoprazole 15 mg daily
Choice of prophylaxis regimen was made by the investigator and subject taking into account prior drug tolerance and prophylaxis experience
In addition subjects with eCLcr lt50 mlminute were not to receive naproxen
Gout flares were regarded as expected gout manifestations rather than as AEs
The primary efficacy endpoint was the proportion of
subjects in each treatment group with sUA lt60 mgdL
at the final visit
Secondary efficacy variables included
1) The proportion of subjects with mild or moderate
renal impairment and final sUA lt60 mgdL
2) The proportion of subjects with sUA lt60 mgdL lt50
mgdL and lt40 mgdL at each visit
Efficacy analysisResults
Primary efficacy endpoint
1) The proportions of subjects achieving a final visit sUA lt60
mgdL were 452 671 and 421 in the febuxostat 40 mg
febuxostat 80 mg and allopurinol groups respectively
2) UL by febuxostat 40 mg was non-inferior to that by
allopurinol but the difference in the response rates between
the two groups (31 95 CI -19 to 81) was not significant
3) However the greater UL response rate with febuxostat 80 mg
compared with either febuxostat 40 mg (219) or allopurinol
(249) was significant (P lt 0001)
Secondary efficacy endpoints
Among subjects with any (mild or moderate) renal
impairment the UL response rate in the febuxostat 80
mg group (716 360503) significantly exceeded those
observed in the febuxostat 40 mg (497 238479) and
allopurinol (423 212501) groups (P le 0001 for each
comparison)
In addition among the total group of subjects with
renal impairment the UL response rate in the
febuxostat 40 mg group was significantly higher than
that in the allopurinol 300200 mg group (P = 0021)
At any sUA endpoint (lt60 mgdL lt50 mgdL or lt40 mgdL) and at any scheduled visit a significantly higher proportion of subjects receiving febuxostat 80 mg achieved the target endpoint than subjects receiving febuxostat 40 mg or allopurinol (P lt 0001)
Greater proportion of subjects in the febuxostat 40 mg group than the allopurinol group achieved sUAlt60 mgdL (at Month 2 visit P = 0031) and lt50 mgdL (at two- and six month visits P le 005) but significant differences were not seen at other visits including the final visit
Effect of baseline characteristic on treatment response
Adverse events
Adverse events
CONCLUSIONS
Results of the CONFIRMS trial establish equivalent UL efficacy for febuxostat 40 mg daily and allopurinol 300200 mg daily
At all levels of renal function studied UL efficacy of febuxostat 80 mg daily was superior to that of febuxostat 40 mg or allopurinol 300200 mg and was comparably safe
In subjects with mildly or moderately impaired renal function however febuxostat 40 mg daily was significantly more effective in lowering sUA than allopurinol
At the doses studied safety of febuxostat and allopurinol including CV safety was comparable
Febuxostat at 40 mg or 80 mg daily offers a well-tolerated UL alternative to allopurinol particularly for patients with mild or moderate renal impairment
Study limitations
The study does not address the efficacy of febuxostat compared with allopurinol in reducing clinically meaningful acute flares of gout
No mention is made of long-term cost-effectiveness of therapy
Additionally this study does not address the efficacy of febuxostat compared with allopurinol dosing that is more aggressive (ie gt 300 mg daily)
Allopurinol dosing was not titrated
The study population was not similar to the general population (majority of patients were white males)
Possible funding bias
Uloric Related Current Clinical
Trials
References
Dalbeth N Gracey E Pool B et al Identification of dairy fractions with anti-inflammatory properties in models of acute gout Ann
Rheum Dis 2010 69766ndash769
Choi HK Willett W Curhan G Coffee consumption and risk of incident gout in men a prospective study Arthritis Rheum 2007 562049ndash
2055
Hak AE Curhan GC Grodstein F Choi HK Menopause postmenopausal hormone use and risk of incident gout Ann Rheum Dis 2010
691305ndash1309
Becker MA Schumacher HR Wortmann RL et al (December 2005) Febuxostat compared with allopurinol in patients with hyperuricemia
and gout N Engl J Med 353 (23) 2450ndash61
Sarawate CA Patel PA Schumacher HR Yang W Brewer KK Bakst AW Serum urate levels and gout flares analysis from managed care
data J Clin Rheumatol 2006 1261-65
Schumacher HR Jr Becker MA Lloyd E MacDonald PA Lademacher C Febuxostat in the treatment of gout 5-yr findings of the FOCUS
efficacy and safety study Rheumatology (Oxford) 2009 48188-194
14 Becker MA Schumacher HR MacDonald PA Lloyd E Lademacher C Clinical efficacy and safety of successful long-term urate
lowering with febuxostat or allopurinol in subjects with gout J Rheumatol 2009 361273-1278
2012 ACR guidelines for management of gout
Uptodate
Medcape
Statistical Power
Power
The probability that the study will support the research hypothesis if it is true
1 Sample size (n)
2 Effect Size (d)
3 Significance Level (α)
4 Power (β)
As effect size increases power increases
As sample size increases power increases
As significance level increases power increases
Resources
httpwwwncbinlmnihgovpmcarticlesPMC3409926
httpswwwsealedenvelopecompowerbinary-superiority
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
Gout is extremely uncommon in premenopausal women
but postmenopausal women are at risk
Studies have indicated that menopause especially at an
earlier age increased the risk of gout in women
whereas post menopausal hormone therapy modestly
reduced risk of gout
Clinical gout is about five times more common in men
than in women
MANAGEMENT OF
GOUT
DRUGS USED IN GOUT AND THEIR MECHANISM OF ACTION
2012 ACR Management Guidelines
Lifestyle Modification for all patients with gout
Xanthine Oxidase Inhibitor (XOI) first-line urate-lowering
pharmacologic therapy
Target sUA lt6 at minimum sUA lt5 better
Continue prophylaxis for 3 (no tophi) ndash 6 months (tophi)
after achieving target sUA
2012 ACR Management Guidelines
Consider HLA screening for HLA-B5801 in certain populations considered high risk for allopurinol hypersensitivity syndrome
Koreans with stage 3 CKD or worse
Han Chinese
Thai descent
Combination oral ULT with 1 XOI agent and 1 uricosuric agent is appropriate when sUA not at target by XOI alone
Pegloticase appropriate for severe refractory disease or intolerance of standard regimens (Pegloticase is a porcine uricase which was approved by the FDA in September 2010 for the treatment of gout in patients who had failed conventional therapy)
2012 ACR Management Guidelines for
Acute Gouty Arthritis
The choice of pharmacologic agent depends on severity of the attack
Monotherapy for mildmoderate attack
Combination therapy for severe attack or those refractory to monotherapy
Acceptable combination therapy approaches include
Colchicine and NSAIDS
Oral steroids and colchicine
Intra-articular steroids with all other modalities
Continue current therapy during flare
Patient education on signs of flare for self treatment
Indications for pharmacological
treatment of gout
Any patient with established diagnosis of gouty arthritis
Tophus or tophi by clinical exam or imaging study
Frequent attacks of gouty arthritis (gt= 2 attacksyr)
CKD stage 2 or worse
Past urolithiasis
23
Gout Management Approach
bullTreat acute flare rapidly with anti-
inflammatory agent
bullInitiate urate-lowering therapy to
achieve sUA lt6
bullUse concomitant anti-inflammatory
prophylaxis for up to 6 mo to prevent
mobilization flares
INITIATE(acute flare)
RESOLVE(urate-lowering therapy)
bullContinue urate lowering therapy
to control flares and avoid crystal
deposition
bullProphylaxis use for at least 3-6
months until sUA normalizes
MAINTAIN(treatment to control sUA)
24
Allopurinol vs Febuxostat
Allopurinol Febuxostat (Uloric)
FDA-approved 1966 FDA-approved 2009
Purine-selective XO Inhibitor Non-Purine Selective XO
Inhibitor
Prevents uric acid production Prevents uric acid production
Renal Metabolism Liver Metabolism
FEBUXOSTAT
For treatment of hyperuricemia in patients with gout
febuxostat is recommended at 40 mg or 80 mg once daily and
can be increased to 120 mg once daily if clinically indicated
The adverse effects associated with febuxostat therapy
include nausea diarrhea arthralgia headache increased
hepatic serum enzyme levels and rash
The manufacturer recommends liver function monitoring on
initiation of therapy at two and four months after initiation
and periodically thereafter
FEBUXOSTAT
Febuxostat is US Food and Drug Administration pregnancy
category C2
Febuxostat is contraindicated with concomitant use of
theophylline and chemotherapeutic agents namely
azathioprine and 6- mercaptopurine because it could
increase blood plasma concentrations of these drugs and
therefore their toxicity
Dosage adjustments are unnecessary for mild to moderate
renal or hepatic impairment
A one-month supply of 40 or 80-mg febuxostat costs
$28243 This price far exceeds the cost of allopurinol
which is $2424 for 100 100 mg tablets
CrCl (mLmin)
Maintenance Dose of
Allopurinol
0 100mg every 3d
10 100mg every 2d
20 100mg
40 150mg
60 200mg
80 250mg
100 300mg
120 350mg
140 400mg
Maintenance Doses of Allopurinol for
Adults based on CrCl
28
Hande KR et al Am J Med 1984
Stage 1 renal damage with
normal GFR
(GFR gt 90 mlmin)
Stage 2 Mild CKD (GFR = 60-
89 mlmin)
Stage 3 Moderate CKD (GFR
= 30-59 mlmin)
Stage 4 Severe CKD (GFR =
15-29 mlmin)
Stage 5 End Stage CKD (GFR
lt15 mlmin)
Allopurinol Hypersensitivity
Syndrome
2 of all allopurinol users develop cutaneous rash
Frequency of hypersensitivity 1 in 260
DRESS syndrome
Drug Reaction Eosinophilia Systemic Symptoms
20 mortality rate
Life threatening toxicity vasculitis rash eosinophilia hepatitis progressive renal failure
Treatment early recognition withdrawal of drug supportive care Steroids N-acetyl-cysteine dialysis prn
29
Markel A IMAJ 2005
Terkeltaub RA in Primer on the Rheumatic Disease 13th ed 2008
The urate lowering efficacy and safety
of febuxostat in the treatment of the
hyperuricemia of gout
The CONFIRMS trial
Becker MA Schumacher HR Espinoza LR et al The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemia of gout the CONFIRMS trial Arthritis Res
Ther 201012(2)R63
Many long and short-term clinical trials have
proved the efficacy of Febuxostat in the treatment
of gout and lowering uric acid levels In these
studies Febuxostat was found to be superior to
allopurinol in reducing the serum uric acid levels
Some notable landmark clinical trials are FACT
APEX EXCEL FOCUS and CONFIRMS
Febuxostat versus Allopurinol Controlled Trial
(FACT) 2005
52 week randomized double-blind multicenter clinical trial that compared the safety and efficacy of febuxostat with allopurinol
760 patients with gout and a sUA gt80 mgdl were randomly assigned to receive either febuxostat 80 or 120mg or allopurinol 300mg once daily for 52 weeks
The primary endpoint was the proportion of patients to achieve a sUA concentration below 60 mgdl at the last three monthly measurements
The primary endpoint was achieved in 53 of patients receiving 80 mg febuxostat 62 of patients receiving 120mg and 21 of those receiving allopurinol (p lt0001 for each febuxostat group compared with allopurinol)
There was no statistical significance in the change in tophi size and number or the incidence of gout flare between the groups
Allopurinol Placebo controlled Efficacy study
of febuxostat (APEX) 2008
28 week randomized double-blind study of 1072 patients comparing the safety and efficacy of febuxostat allopurinol and placebo
Patients were randomized to a once daily fixed dose of placebo febuxostat 80mg120mg or 240 mg or allopurinol 300mg or 100mg depending on their baseline serum creatinine (le15 mgdl or ge16 to lt20 mgdl respectively)
After 1 year of treatment 82 of the patients in all febuxostat groups achieved sUA levels below 60 mgdl compared with 39 of the patients in both allopurinol groups In groups with moderate renal impairment the primary endpoint was achieved by 44 receiving febuxostat 80mg 45 receiving 120mg and 60 receiving 240mg compared with 0 in the allopurinol and placebo groups
However clinical endpoints were not statistically significant
The number of patients with moderate renal impairment was small
Febuxostat Comparative Extension Long-Term
study (EXCEL) 2009
160 week extension study for patients completing FACT and APEX
The studyrsquos aim was to determine long-term efficacy in sUA
lowering clinical benefits and safety of febuxostat or allopurinol
1086 patients were enrolled to receive fixed daily doses of
febuxostat 80mg or 120 mg or allopurinol 300 mg
After the first month of treatment nearly 80 of patients receiving
either febuxostat dose achieved sUA less than 6 mgdl compared
with only 46 of subjects on allopurinol There was no difference in
gout flare incidence and tophi reduction between the groups
Overall adverse events did not show significant differences among
groups
Febuxostat Open Label of Urate-Lowering
Efficacy and Safety (FOCUS) 2009
The FOCUS trial was a 5-year extension study that
assessed reduction and maintenance of sUA levels below
60 mgdl as the primary efficacy endpoint A total of
116 patients were initially enrolled to receive a dose of
80mg febuxostat with dose adjustment to either 40 or
120mg between weeks 4 and 24 93 maintained a sUA
level below 60 mgdl at 5 years
Objectives of CONFIRMS trial
The three-fold objectives of this Phase 3 double-blind RCT study were
1) To compare the UL efficacy of febuxostat at a dose of 40 mg with that of allopurinol at doses most commonly utilized in clinical practice
2) To evaluate UL efficacies of 80 mg and 40 mg daily doses of febuxostat compared with that of allopurinol in subjects with mild or moderate renal impairment
3) To gain prospective uniformly reviewed information regarding the safety of these agents particularly their comparative CV safety
Materials and methods
Subjects aged 18 to 85 years with a diagnosis of gout fulfilling American Rheumatology Association preliminary criteria and sUA ge 80 mgdL were eligible for enrollment
Subjects were enrolled at 324 sites in the United States
IRB approval was obtained and all the subjects provided written informed consent
At least 35 of subjects enrolled were to have mild or moderate renal impairment defined as baseline estimated creatinine clearance (eCLcr) of 60 to 89 mlminutes or 30 to 59 mlminutes
Subjects successfully completing either of the previously
reported long-term open-label febuxostat or
febuxostatallopurinol extension studies were also eligible for
enrollment
Exclusion criteria secondary hyperuricemia (for example
due to myeloproliferative disorder) xanthinuria severe renal
impairment (eCLcr lt30 mlminutes) alanine
aminotransferase and aspartate aminotransferase values gt15
times the upper limit of normal consumption of more than 14
alcoholic drinks per week or a history of alcoholism or drug
abuse within five years or a medical condition that in the
investigators opinion would interfere with treatment safety
or adherence to the protocol
Baseline characteristics of randomized subjects
Baseline characteristics of randomized subjects (cont)
Baseline characteristics of randomized subjects (cont)
2269 Subjects were randomized 111 on Day 1 to
receive daily febuxostat 40 mg febuxostat 80 mg or
allopurinol Among subjects randomized to allopurinol
those with normal renal function or mild renal
impairment received 300 mg daily and those with
moderate renal impairment received 200 mg
Throughout the subsequent six-month treatment period for all subjects prophylaxis for gout flares was given either as colchicine 06 mg daily or naproxen 250 mg twice daily All subjects receiving naproxen prophylaxis also received lansoprazole 15 mg daily
Choice of prophylaxis regimen was made by the investigator and subject taking into account prior drug tolerance and prophylaxis experience
In addition subjects with eCLcr lt50 mlminute were not to receive naproxen
Gout flares were regarded as expected gout manifestations rather than as AEs
The primary efficacy endpoint was the proportion of
subjects in each treatment group with sUA lt60 mgdL
at the final visit
Secondary efficacy variables included
1) The proportion of subjects with mild or moderate
renal impairment and final sUA lt60 mgdL
2) The proportion of subjects with sUA lt60 mgdL lt50
mgdL and lt40 mgdL at each visit
Efficacy analysisResults
Primary efficacy endpoint
1) The proportions of subjects achieving a final visit sUA lt60
mgdL were 452 671 and 421 in the febuxostat 40 mg
febuxostat 80 mg and allopurinol groups respectively
2) UL by febuxostat 40 mg was non-inferior to that by
allopurinol but the difference in the response rates between
the two groups (31 95 CI -19 to 81) was not significant
3) However the greater UL response rate with febuxostat 80 mg
compared with either febuxostat 40 mg (219) or allopurinol
(249) was significant (P lt 0001)
Secondary efficacy endpoints
Among subjects with any (mild or moderate) renal
impairment the UL response rate in the febuxostat 80
mg group (716 360503) significantly exceeded those
observed in the febuxostat 40 mg (497 238479) and
allopurinol (423 212501) groups (P le 0001 for each
comparison)
In addition among the total group of subjects with
renal impairment the UL response rate in the
febuxostat 40 mg group was significantly higher than
that in the allopurinol 300200 mg group (P = 0021)
At any sUA endpoint (lt60 mgdL lt50 mgdL or lt40 mgdL) and at any scheduled visit a significantly higher proportion of subjects receiving febuxostat 80 mg achieved the target endpoint than subjects receiving febuxostat 40 mg or allopurinol (P lt 0001)
Greater proportion of subjects in the febuxostat 40 mg group than the allopurinol group achieved sUAlt60 mgdL (at Month 2 visit P = 0031) and lt50 mgdL (at two- and six month visits P le 005) but significant differences were not seen at other visits including the final visit
Effect of baseline characteristic on treatment response
Adverse events
Adverse events
CONCLUSIONS
Results of the CONFIRMS trial establish equivalent UL efficacy for febuxostat 40 mg daily and allopurinol 300200 mg daily
At all levels of renal function studied UL efficacy of febuxostat 80 mg daily was superior to that of febuxostat 40 mg or allopurinol 300200 mg and was comparably safe
In subjects with mildly or moderately impaired renal function however febuxostat 40 mg daily was significantly more effective in lowering sUA than allopurinol
At the doses studied safety of febuxostat and allopurinol including CV safety was comparable
Febuxostat at 40 mg or 80 mg daily offers a well-tolerated UL alternative to allopurinol particularly for patients with mild or moderate renal impairment
Study limitations
The study does not address the efficacy of febuxostat compared with allopurinol in reducing clinically meaningful acute flares of gout
No mention is made of long-term cost-effectiveness of therapy
Additionally this study does not address the efficacy of febuxostat compared with allopurinol dosing that is more aggressive (ie gt 300 mg daily)
Allopurinol dosing was not titrated
The study population was not similar to the general population (majority of patients were white males)
Possible funding bias
Uloric Related Current Clinical
Trials
References
Dalbeth N Gracey E Pool B et al Identification of dairy fractions with anti-inflammatory properties in models of acute gout Ann
Rheum Dis 2010 69766ndash769
Choi HK Willett W Curhan G Coffee consumption and risk of incident gout in men a prospective study Arthritis Rheum 2007 562049ndash
2055
Hak AE Curhan GC Grodstein F Choi HK Menopause postmenopausal hormone use and risk of incident gout Ann Rheum Dis 2010
691305ndash1309
Becker MA Schumacher HR Wortmann RL et al (December 2005) Febuxostat compared with allopurinol in patients with hyperuricemia
and gout N Engl J Med 353 (23) 2450ndash61
Sarawate CA Patel PA Schumacher HR Yang W Brewer KK Bakst AW Serum urate levels and gout flares analysis from managed care
data J Clin Rheumatol 2006 1261-65
Schumacher HR Jr Becker MA Lloyd E MacDonald PA Lademacher C Febuxostat in the treatment of gout 5-yr findings of the FOCUS
efficacy and safety study Rheumatology (Oxford) 2009 48188-194
14 Becker MA Schumacher HR MacDonald PA Lloyd E Lademacher C Clinical efficacy and safety of successful long-term urate
lowering with febuxostat or allopurinol in subjects with gout J Rheumatol 2009 361273-1278
2012 ACR guidelines for management of gout
Uptodate
Medcape
Statistical Power
Power
The probability that the study will support the research hypothesis if it is true
1 Sample size (n)
2 Effect Size (d)
3 Significance Level (α)
4 Power (β)
As effect size increases power increases
As sample size increases power increases
As significance level increases power increases
Resources
httpwwwncbinlmnihgovpmcarticlesPMC3409926
httpswwwsealedenvelopecompowerbinary-superiority
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
MANAGEMENT OF
GOUT
DRUGS USED IN GOUT AND THEIR MECHANISM OF ACTION
2012 ACR Management Guidelines
Lifestyle Modification for all patients with gout
Xanthine Oxidase Inhibitor (XOI) first-line urate-lowering
pharmacologic therapy
Target sUA lt6 at minimum sUA lt5 better
Continue prophylaxis for 3 (no tophi) ndash 6 months (tophi)
after achieving target sUA
2012 ACR Management Guidelines
Consider HLA screening for HLA-B5801 in certain populations considered high risk for allopurinol hypersensitivity syndrome
Koreans with stage 3 CKD or worse
Han Chinese
Thai descent
Combination oral ULT with 1 XOI agent and 1 uricosuric agent is appropriate when sUA not at target by XOI alone
Pegloticase appropriate for severe refractory disease or intolerance of standard regimens (Pegloticase is a porcine uricase which was approved by the FDA in September 2010 for the treatment of gout in patients who had failed conventional therapy)
2012 ACR Management Guidelines for
Acute Gouty Arthritis
The choice of pharmacologic agent depends on severity of the attack
Monotherapy for mildmoderate attack
Combination therapy for severe attack or those refractory to monotherapy
Acceptable combination therapy approaches include
Colchicine and NSAIDS
Oral steroids and colchicine
Intra-articular steroids with all other modalities
Continue current therapy during flare
Patient education on signs of flare for self treatment
Indications for pharmacological
treatment of gout
Any patient with established diagnosis of gouty arthritis
Tophus or tophi by clinical exam or imaging study
Frequent attacks of gouty arthritis (gt= 2 attacksyr)
CKD stage 2 or worse
Past urolithiasis
23
Gout Management Approach
bullTreat acute flare rapidly with anti-
inflammatory agent
bullInitiate urate-lowering therapy to
achieve sUA lt6
bullUse concomitant anti-inflammatory
prophylaxis for up to 6 mo to prevent
mobilization flares
INITIATE(acute flare)
RESOLVE(urate-lowering therapy)
bullContinue urate lowering therapy
to control flares and avoid crystal
deposition
bullProphylaxis use for at least 3-6
months until sUA normalizes
MAINTAIN(treatment to control sUA)
24
Allopurinol vs Febuxostat
Allopurinol Febuxostat (Uloric)
FDA-approved 1966 FDA-approved 2009
Purine-selective XO Inhibitor Non-Purine Selective XO
Inhibitor
Prevents uric acid production Prevents uric acid production
Renal Metabolism Liver Metabolism
FEBUXOSTAT
For treatment of hyperuricemia in patients with gout
febuxostat is recommended at 40 mg or 80 mg once daily and
can be increased to 120 mg once daily if clinically indicated
The adverse effects associated with febuxostat therapy
include nausea diarrhea arthralgia headache increased
hepatic serum enzyme levels and rash
The manufacturer recommends liver function monitoring on
initiation of therapy at two and four months after initiation
and periodically thereafter
FEBUXOSTAT
Febuxostat is US Food and Drug Administration pregnancy
category C2
Febuxostat is contraindicated with concomitant use of
theophylline and chemotherapeutic agents namely
azathioprine and 6- mercaptopurine because it could
increase blood plasma concentrations of these drugs and
therefore their toxicity
Dosage adjustments are unnecessary for mild to moderate
renal or hepatic impairment
A one-month supply of 40 or 80-mg febuxostat costs
$28243 This price far exceeds the cost of allopurinol
which is $2424 for 100 100 mg tablets
CrCl (mLmin)
Maintenance Dose of
Allopurinol
0 100mg every 3d
10 100mg every 2d
20 100mg
40 150mg
60 200mg
80 250mg
100 300mg
120 350mg
140 400mg
Maintenance Doses of Allopurinol for
Adults based on CrCl
28
Hande KR et al Am J Med 1984
Stage 1 renal damage with
normal GFR
(GFR gt 90 mlmin)
Stage 2 Mild CKD (GFR = 60-
89 mlmin)
Stage 3 Moderate CKD (GFR
= 30-59 mlmin)
Stage 4 Severe CKD (GFR =
15-29 mlmin)
Stage 5 End Stage CKD (GFR
lt15 mlmin)
Allopurinol Hypersensitivity
Syndrome
2 of all allopurinol users develop cutaneous rash
Frequency of hypersensitivity 1 in 260
DRESS syndrome
Drug Reaction Eosinophilia Systemic Symptoms
20 mortality rate
Life threatening toxicity vasculitis rash eosinophilia hepatitis progressive renal failure
Treatment early recognition withdrawal of drug supportive care Steroids N-acetyl-cysteine dialysis prn
29
Markel A IMAJ 2005
Terkeltaub RA in Primer on the Rheumatic Disease 13th ed 2008
The urate lowering efficacy and safety
of febuxostat in the treatment of the
hyperuricemia of gout
The CONFIRMS trial
Becker MA Schumacher HR Espinoza LR et al The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemia of gout the CONFIRMS trial Arthritis Res
Ther 201012(2)R63
Many long and short-term clinical trials have
proved the efficacy of Febuxostat in the treatment
of gout and lowering uric acid levels In these
studies Febuxostat was found to be superior to
allopurinol in reducing the serum uric acid levels
Some notable landmark clinical trials are FACT
APEX EXCEL FOCUS and CONFIRMS
Febuxostat versus Allopurinol Controlled Trial
(FACT) 2005
52 week randomized double-blind multicenter clinical trial that compared the safety and efficacy of febuxostat with allopurinol
760 patients with gout and a sUA gt80 mgdl were randomly assigned to receive either febuxostat 80 or 120mg or allopurinol 300mg once daily for 52 weeks
The primary endpoint was the proportion of patients to achieve a sUA concentration below 60 mgdl at the last three monthly measurements
The primary endpoint was achieved in 53 of patients receiving 80 mg febuxostat 62 of patients receiving 120mg and 21 of those receiving allopurinol (p lt0001 for each febuxostat group compared with allopurinol)
There was no statistical significance in the change in tophi size and number or the incidence of gout flare between the groups
Allopurinol Placebo controlled Efficacy study
of febuxostat (APEX) 2008
28 week randomized double-blind study of 1072 patients comparing the safety and efficacy of febuxostat allopurinol and placebo
Patients were randomized to a once daily fixed dose of placebo febuxostat 80mg120mg or 240 mg or allopurinol 300mg or 100mg depending on their baseline serum creatinine (le15 mgdl or ge16 to lt20 mgdl respectively)
After 1 year of treatment 82 of the patients in all febuxostat groups achieved sUA levels below 60 mgdl compared with 39 of the patients in both allopurinol groups In groups with moderate renal impairment the primary endpoint was achieved by 44 receiving febuxostat 80mg 45 receiving 120mg and 60 receiving 240mg compared with 0 in the allopurinol and placebo groups
However clinical endpoints were not statistically significant
The number of patients with moderate renal impairment was small
Febuxostat Comparative Extension Long-Term
study (EXCEL) 2009
160 week extension study for patients completing FACT and APEX
The studyrsquos aim was to determine long-term efficacy in sUA
lowering clinical benefits and safety of febuxostat or allopurinol
1086 patients were enrolled to receive fixed daily doses of
febuxostat 80mg or 120 mg or allopurinol 300 mg
After the first month of treatment nearly 80 of patients receiving
either febuxostat dose achieved sUA less than 6 mgdl compared
with only 46 of subjects on allopurinol There was no difference in
gout flare incidence and tophi reduction between the groups
Overall adverse events did not show significant differences among
groups
Febuxostat Open Label of Urate-Lowering
Efficacy and Safety (FOCUS) 2009
The FOCUS trial was a 5-year extension study that
assessed reduction and maintenance of sUA levels below
60 mgdl as the primary efficacy endpoint A total of
116 patients were initially enrolled to receive a dose of
80mg febuxostat with dose adjustment to either 40 or
120mg between weeks 4 and 24 93 maintained a sUA
level below 60 mgdl at 5 years
Objectives of CONFIRMS trial
The three-fold objectives of this Phase 3 double-blind RCT study were
1) To compare the UL efficacy of febuxostat at a dose of 40 mg with that of allopurinol at doses most commonly utilized in clinical practice
2) To evaluate UL efficacies of 80 mg and 40 mg daily doses of febuxostat compared with that of allopurinol in subjects with mild or moderate renal impairment
3) To gain prospective uniformly reviewed information regarding the safety of these agents particularly their comparative CV safety
Materials and methods
Subjects aged 18 to 85 years with a diagnosis of gout fulfilling American Rheumatology Association preliminary criteria and sUA ge 80 mgdL were eligible for enrollment
Subjects were enrolled at 324 sites in the United States
IRB approval was obtained and all the subjects provided written informed consent
At least 35 of subjects enrolled were to have mild or moderate renal impairment defined as baseline estimated creatinine clearance (eCLcr) of 60 to 89 mlminutes or 30 to 59 mlminutes
Subjects successfully completing either of the previously
reported long-term open-label febuxostat or
febuxostatallopurinol extension studies were also eligible for
enrollment
Exclusion criteria secondary hyperuricemia (for example
due to myeloproliferative disorder) xanthinuria severe renal
impairment (eCLcr lt30 mlminutes) alanine
aminotransferase and aspartate aminotransferase values gt15
times the upper limit of normal consumption of more than 14
alcoholic drinks per week or a history of alcoholism or drug
abuse within five years or a medical condition that in the
investigators opinion would interfere with treatment safety
or adherence to the protocol
Baseline characteristics of randomized subjects
Baseline characteristics of randomized subjects (cont)
Baseline characteristics of randomized subjects (cont)
2269 Subjects were randomized 111 on Day 1 to
receive daily febuxostat 40 mg febuxostat 80 mg or
allopurinol Among subjects randomized to allopurinol
those with normal renal function or mild renal
impairment received 300 mg daily and those with
moderate renal impairment received 200 mg
Throughout the subsequent six-month treatment period for all subjects prophylaxis for gout flares was given either as colchicine 06 mg daily or naproxen 250 mg twice daily All subjects receiving naproxen prophylaxis also received lansoprazole 15 mg daily
Choice of prophylaxis regimen was made by the investigator and subject taking into account prior drug tolerance and prophylaxis experience
In addition subjects with eCLcr lt50 mlminute were not to receive naproxen
Gout flares were regarded as expected gout manifestations rather than as AEs
The primary efficacy endpoint was the proportion of
subjects in each treatment group with sUA lt60 mgdL
at the final visit
Secondary efficacy variables included
1) The proportion of subjects with mild or moderate
renal impairment and final sUA lt60 mgdL
2) The proportion of subjects with sUA lt60 mgdL lt50
mgdL and lt40 mgdL at each visit
Efficacy analysisResults
Primary efficacy endpoint
1) The proportions of subjects achieving a final visit sUA lt60
mgdL were 452 671 and 421 in the febuxostat 40 mg
febuxostat 80 mg and allopurinol groups respectively
2) UL by febuxostat 40 mg was non-inferior to that by
allopurinol but the difference in the response rates between
the two groups (31 95 CI -19 to 81) was not significant
3) However the greater UL response rate with febuxostat 80 mg
compared with either febuxostat 40 mg (219) or allopurinol
(249) was significant (P lt 0001)
Secondary efficacy endpoints
Among subjects with any (mild or moderate) renal
impairment the UL response rate in the febuxostat 80
mg group (716 360503) significantly exceeded those
observed in the febuxostat 40 mg (497 238479) and
allopurinol (423 212501) groups (P le 0001 for each
comparison)
In addition among the total group of subjects with
renal impairment the UL response rate in the
febuxostat 40 mg group was significantly higher than
that in the allopurinol 300200 mg group (P = 0021)
At any sUA endpoint (lt60 mgdL lt50 mgdL or lt40 mgdL) and at any scheduled visit a significantly higher proportion of subjects receiving febuxostat 80 mg achieved the target endpoint than subjects receiving febuxostat 40 mg or allopurinol (P lt 0001)
Greater proportion of subjects in the febuxostat 40 mg group than the allopurinol group achieved sUAlt60 mgdL (at Month 2 visit P = 0031) and lt50 mgdL (at two- and six month visits P le 005) but significant differences were not seen at other visits including the final visit
Effect of baseline characteristic on treatment response
Adverse events
Adverse events
CONCLUSIONS
Results of the CONFIRMS trial establish equivalent UL efficacy for febuxostat 40 mg daily and allopurinol 300200 mg daily
At all levels of renal function studied UL efficacy of febuxostat 80 mg daily was superior to that of febuxostat 40 mg or allopurinol 300200 mg and was comparably safe
In subjects with mildly or moderately impaired renal function however febuxostat 40 mg daily was significantly more effective in lowering sUA than allopurinol
At the doses studied safety of febuxostat and allopurinol including CV safety was comparable
Febuxostat at 40 mg or 80 mg daily offers a well-tolerated UL alternative to allopurinol particularly for patients with mild or moderate renal impairment
Study limitations
The study does not address the efficacy of febuxostat compared with allopurinol in reducing clinically meaningful acute flares of gout
No mention is made of long-term cost-effectiveness of therapy
Additionally this study does not address the efficacy of febuxostat compared with allopurinol dosing that is more aggressive (ie gt 300 mg daily)
Allopurinol dosing was not titrated
The study population was not similar to the general population (majority of patients were white males)
Possible funding bias
Uloric Related Current Clinical
Trials
References
Dalbeth N Gracey E Pool B et al Identification of dairy fractions with anti-inflammatory properties in models of acute gout Ann
Rheum Dis 2010 69766ndash769
Choi HK Willett W Curhan G Coffee consumption and risk of incident gout in men a prospective study Arthritis Rheum 2007 562049ndash
2055
Hak AE Curhan GC Grodstein F Choi HK Menopause postmenopausal hormone use and risk of incident gout Ann Rheum Dis 2010
691305ndash1309
Becker MA Schumacher HR Wortmann RL et al (December 2005) Febuxostat compared with allopurinol in patients with hyperuricemia
and gout N Engl J Med 353 (23) 2450ndash61
Sarawate CA Patel PA Schumacher HR Yang W Brewer KK Bakst AW Serum urate levels and gout flares analysis from managed care
data J Clin Rheumatol 2006 1261-65
Schumacher HR Jr Becker MA Lloyd E MacDonald PA Lademacher C Febuxostat in the treatment of gout 5-yr findings of the FOCUS
efficacy and safety study Rheumatology (Oxford) 2009 48188-194
14 Becker MA Schumacher HR MacDonald PA Lloyd E Lademacher C Clinical efficacy and safety of successful long-term urate
lowering with febuxostat or allopurinol in subjects with gout J Rheumatol 2009 361273-1278
2012 ACR guidelines for management of gout
Uptodate
Medcape
Statistical Power
Power
The probability that the study will support the research hypothesis if it is true
1 Sample size (n)
2 Effect Size (d)
3 Significance Level (α)
4 Power (β)
As effect size increases power increases
As sample size increases power increases
As significance level increases power increases
Resources
httpwwwncbinlmnihgovpmcarticlesPMC3409926
httpswwwsealedenvelopecompowerbinary-superiority
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
DRUGS USED IN GOUT AND THEIR MECHANISM OF ACTION
2012 ACR Management Guidelines
Lifestyle Modification for all patients with gout
Xanthine Oxidase Inhibitor (XOI) first-line urate-lowering
pharmacologic therapy
Target sUA lt6 at minimum sUA lt5 better
Continue prophylaxis for 3 (no tophi) ndash 6 months (tophi)
after achieving target sUA
2012 ACR Management Guidelines
Consider HLA screening for HLA-B5801 in certain populations considered high risk for allopurinol hypersensitivity syndrome
Koreans with stage 3 CKD or worse
Han Chinese
Thai descent
Combination oral ULT with 1 XOI agent and 1 uricosuric agent is appropriate when sUA not at target by XOI alone
Pegloticase appropriate for severe refractory disease or intolerance of standard regimens (Pegloticase is a porcine uricase which was approved by the FDA in September 2010 for the treatment of gout in patients who had failed conventional therapy)
2012 ACR Management Guidelines for
Acute Gouty Arthritis
The choice of pharmacologic agent depends on severity of the attack
Monotherapy for mildmoderate attack
Combination therapy for severe attack or those refractory to monotherapy
Acceptable combination therapy approaches include
Colchicine and NSAIDS
Oral steroids and colchicine
Intra-articular steroids with all other modalities
Continue current therapy during flare
Patient education on signs of flare for self treatment
Indications for pharmacological
treatment of gout
Any patient with established diagnosis of gouty arthritis
Tophus or tophi by clinical exam or imaging study
Frequent attacks of gouty arthritis (gt= 2 attacksyr)
CKD stage 2 or worse
Past urolithiasis
23
Gout Management Approach
bullTreat acute flare rapidly with anti-
inflammatory agent
bullInitiate urate-lowering therapy to
achieve sUA lt6
bullUse concomitant anti-inflammatory
prophylaxis for up to 6 mo to prevent
mobilization flares
INITIATE(acute flare)
RESOLVE(urate-lowering therapy)
bullContinue urate lowering therapy
to control flares and avoid crystal
deposition
bullProphylaxis use for at least 3-6
months until sUA normalizes
MAINTAIN(treatment to control sUA)
24
Allopurinol vs Febuxostat
Allopurinol Febuxostat (Uloric)
FDA-approved 1966 FDA-approved 2009
Purine-selective XO Inhibitor Non-Purine Selective XO
Inhibitor
Prevents uric acid production Prevents uric acid production
Renal Metabolism Liver Metabolism
FEBUXOSTAT
For treatment of hyperuricemia in patients with gout
febuxostat is recommended at 40 mg or 80 mg once daily and
can be increased to 120 mg once daily if clinically indicated
The adverse effects associated with febuxostat therapy
include nausea diarrhea arthralgia headache increased
hepatic serum enzyme levels and rash
The manufacturer recommends liver function monitoring on
initiation of therapy at two and four months after initiation
and periodically thereafter
FEBUXOSTAT
Febuxostat is US Food and Drug Administration pregnancy
category C2
Febuxostat is contraindicated with concomitant use of
theophylline and chemotherapeutic agents namely
azathioprine and 6- mercaptopurine because it could
increase blood plasma concentrations of these drugs and
therefore their toxicity
Dosage adjustments are unnecessary for mild to moderate
renal or hepatic impairment
A one-month supply of 40 or 80-mg febuxostat costs
$28243 This price far exceeds the cost of allopurinol
which is $2424 for 100 100 mg tablets
CrCl (mLmin)
Maintenance Dose of
Allopurinol
0 100mg every 3d
10 100mg every 2d
20 100mg
40 150mg
60 200mg
80 250mg
100 300mg
120 350mg
140 400mg
Maintenance Doses of Allopurinol for
Adults based on CrCl
28
Hande KR et al Am J Med 1984
Stage 1 renal damage with
normal GFR
(GFR gt 90 mlmin)
Stage 2 Mild CKD (GFR = 60-
89 mlmin)
Stage 3 Moderate CKD (GFR
= 30-59 mlmin)
Stage 4 Severe CKD (GFR =
15-29 mlmin)
Stage 5 End Stage CKD (GFR
lt15 mlmin)
Allopurinol Hypersensitivity
Syndrome
2 of all allopurinol users develop cutaneous rash
Frequency of hypersensitivity 1 in 260
DRESS syndrome
Drug Reaction Eosinophilia Systemic Symptoms
20 mortality rate
Life threatening toxicity vasculitis rash eosinophilia hepatitis progressive renal failure
Treatment early recognition withdrawal of drug supportive care Steroids N-acetyl-cysteine dialysis prn
29
Markel A IMAJ 2005
Terkeltaub RA in Primer on the Rheumatic Disease 13th ed 2008
The urate lowering efficacy and safety
of febuxostat in the treatment of the
hyperuricemia of gout
The CONFIRMS trial
Becker MA Schumacher HR Espinoza LR et al The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemia of gout the CONFIRMS trial Arthritis Res
Ther 201012(2)R63
Many long and short-term clinical trials have
proved the efficacy of Febuxostat in the treatment
of gout and lowering uric acid levels In these
studies Febuxostat was found to be superior to
allopurinol in reducing the serum uric acid levels
Some notable landmark clinical trials are FACT
APEX EXCEL FOCUS and CONFIRMS
Febuxostat versus Allopurinol Controlled Trial
(FACT) 2005
52 week randomized double-blind multicenter clinical trial that compared the safety and efficacy of febuxostat with allopurinol
760 patients with gout and a sUA gt80 mgdl were randomly assigned to receive either febuxostat 80 or 120mg or allopurinol 300mg once daily for 52 weeks
The primary endpoint was the proportion of patients to achieve a sUA concentration below 60 mgdl at the last three monthly measurements
The primary endpoint was achieved in 53 of patients receiving 80 mg febuxostat 62 of patients receiving 120mg and 21 of those receiving allopurinol (p lt0001 for each febuxostat group compared with allopurinol)
There was no statistical significance in the change in tophi size and number or the incidence of gout flare between the groups
Allopurinol Placebo controlled Efficacy study
of febuxostat (APEX) 2008
28 week randomized double-blind study of 1072 patients comparing the safety and efficacy of febuxostat allopurinol and placebo
Patients were randomized to a once daily fixed dose of placebo febuxostat 80mg120mg or 240 mg or allopurinol 300mg or 100mg depending on their baseline serum creatinine (le15 mgdl or ge16 to lt20 mgdl respectively)
After 1 year of treatment 82 of the patients in all febuxostat groups achieved sUA levels below 60 mgdl compared with 39 of the patients in both allopurinol groups In groups with moderate renal impairment the primary endpoint was achieved by 44 receiving febuxostat 80mg 45 receiving 120mg and 60 receiving 240mg compared with 0 in the allopurinol and placebo groups
However clinical endpoints were not statistically significant
The number of patients with moderate renal impairment was small
Febuxostat Comparative Extension Long-Term
study (EXCEL) 2009
160 week extension study for patients completing FACT and APEX
The studyrsquos aim was to determine long-term efficacy in sUA
lowering clinical benefits and safety of febuxostat or allopurinol
1086 patients were enrolled to receive fixed daily doses of
febuxostat 80mg or 120 mg or allopurinol 300 mg
After the first month of treatment nearly 80 of patients receiving
either febuxostat dose achieved sUA less than 6 mgdl compared
with only 46 of subjects on allopurinol There was no difference in
gout flare incidence and tophi reduction between the groups
Overall adverse events did not show significant differences among
groups
Febuxostat Open Label of Urate-Lowering
Efficacy and Safety (FOCUS) 2009
The FOCUS trial was a 5-year extension study that
assessed reduction and maintenance of sUA levels below
60 mgdl as the primary efficacy endpoint A total of
116 patients were initially enrolled to receive a dose of
80mg febuxostat with dose adjustment to either 40 or
120mg between weeks 4 and 24 93 maintained a sUA
level below 60 mgdl at 5 years
Objectives of CONFIRMS trial
The three-fold objectives of this Phase 3 double-blind RCT study were
1) To compare the UL efficacy of febuxostat at a dose of 40 mg with that of allopurinol at doses most commonly utilized in clinical practice
2) To evaluate UL efficacies of 80 mg and 40 mg daily doses of febuxostat compared with that of allopurinol in subjects with mild or moderate renal impairment
3) To gain prospective uniformly reviewed information regarding the safety of these agents particularly their comparative CV safety
Materials and methods
Subjects aged 18 to 85 years with a diagnosis of gout fulfilling American Rheumatology Association preliminary criteria and sUA ge 80 mgdL were eligible for enrollment
Subjects were enrolled at 324 sites in the United States
IRB approval was obtained and all the subjects provided written informed consent
At least 35 of subjects enrolled were to have mild or moderate renal impairment defined as baseline estimated creatinine clearance (eCLcr) of 60 to 89 mlminutes or 30 to 59 mlminutes
Subjects successfully completing either of the previously
reported long-term open-label febuxostat or
febuxostatallopurinol extension studies were also eligible for
enrollment
Exclusion criteria secondary hyperuricemia (for example
due to myeloproliferative disorder) xanthinuria severe renal
impairment (eCLcr lt30 mlminutes) alanine
aminotransferase and aspartate aminotransferase values gt15
times the upper limit of normal consumption of more than 14
alcoholic drinks per week or a history of alcoholism or drug
abuse within five years or a medical condition that in the
investigators opinion would interfere with treatment safety
or adherence to the protocol
Baseline characteristics of randomized subjects
Baseline characteristics of randomized subjects (cont)
Baseline characteristics of randomized subjects (cont)
2269 Subjects were randomized 111 on Day 1 to
receive daily febuxostat 40 mg febuxostat 80 mg or
allopurinol Among subjects randomized to allopurinol
those with normal renal function or mild renal
impairment received 300 mg daily and those with
moderate renal impairment received 200 mg
Throughout the subsequent six-month treatment period for all subjects prophylaxis for gout flares was given either as colchicine 06 mg daily or naproxen 250 mg twice daily All subjects receiving naproxen prophylaxis also received lansoprazole 15 mg daily
Choice of prophylaxis regimen was made by the investigator and subject taking into account prior drug tolerance and prophylaxis experience
In addition subjects with eCLcr lt50 mlminute were not to receive naproxen
Gout flares were regarded as expected gout manifestations rather than as AEs
The primary efficacy endpoint was the proportion of
subjects in each treatment group with sUA lt60 mgdL
at the final visit
Secondary efficacy variables included
1) The proportion of subjects with mild or moderate
renal impairment and final sUA lt60 mgdL
2) The proportion of subjects with sUA lt60 mgdL lt50
mgdL and lt40 mgdL at each visit
Efficacy analysisResults
Primary efficacy endpoint
1) The proportions of subjects achieving a final visit sUA lt60
mgdL were 452 671 and 421 in the febuxostat 40 mg
febuxostat 80 mg and allopurinol groups respectively
2) UL by febuxostat 40 mg was non-inferior to that by
allopurinol but the difference in the response rates between
the two groups (31 95 CI -19 to 81) was not significant
3) However the greater UL response rate with febuxostat 80 mg
compared with either febuxostat 40 mg (219) or allopurinol
(249) was significant (P lt 0001)
Secondary efficacy endpoints
Among subjects with any (mild or moderate) renal
impairment the UL response rate in the febuxostat 80
mg group (716 360503) significantly exceeded those
observed in the febuxostat 40 mg (497 238479) and
allopurinol (423 212501) groups (P le 0001 for each
comparison)
In addition among the total group of subjects with
renal impairment the UL response rate in the
febuxostat 40 mg group was significantly higher than
that in the allopurinol 300200 mg group (P = 0021)
At any sUA endpoint (lt60 mgdL lt50 mgdL or lt40 mgdL) and at any scheduled visit a significantly higher proportion of subjects receiving febuxostat 80 mg achieved the target endpoint than subjects receiving febuxostat 40 mg or allopurinol (P lt 0001)
Greater proportion of subjects in the febuxostat 40 mg group than the allopurinol group achieved sUAlt60 mgdL (at Month 2 visit P = 0031) and lt50 mgdL (at two- and six month visits P le 005) but significant differences were not seen at other visits including the final visit
Effect of baseline characteristic on treatment response
Adverse events
Adverse events
CONCLUSIONS
Results of the CONFIRMS trial establish equivalent UL efficacy for febuxostat 40 mg daily and allopurinol 300200 mg daily
At all levels of renal function studied UL efficacy of febuxostat 80 mg daily was superior to that of febuxostat 40 mg or allopurinol 300200 mg and was comparably safe
In subjects with mildly or moderately impaired renal function however febuxostat 40 mg daily was significantly more effective in lowering sUA than allopurinol
At the doses studied safety of febuxostat and allopurinol including CV safety was comparable
Febuxostat at 40 mg or 80 mg daily offers a well-tolerated UL alternative to allopurinol particularly for patients with mild or moderate renal impairment
Study limitations
The study does not address the efficacy of febuxostat compared with allopurinol in reducing clinically meaningful acute flares of gout
No mention is made of long-term cost-effectiveness of therapy
Additionally this study does not address the efficacy of febuxostat compared with allopurinol dosing that is more aggressive (ie gt 300 mg daily)
Allopurinol dosing was not titrated
The study population was not similar to the general population (majority of patients were white males)
Possible funding bias
Uloric Related Current Clinical
Trials
References
Dalbeth N Gracey E Pool B et al Identification of dairy fractions with anti-inflammatory properties in models of acute gout Ann
Rheum Dis 2010 69766ndash769
Choi HK Willett W Curhan G Coffee consumption and risk of incident gout in men a prospective study Arthritis Rheum 2007 562049ndash
2055
Hak AE Curhan GC Grodstein F Choi HK Menopause postmenopausal hormone use and risk of incident gout Ann Rheum Dis 2010
691305ndash1309
Becker MA Schumacher HR Wortmann RL et al (December 2005) Febuxostat compared with allopurinol in patients with hyperuricemia
and gout N Engl J Med 353 (23) 2450ndash61
Sarawate CA Patel PA Schumacher HR Yang W Brewer KK Bakst AW Serum urate levels and gout flares analysis from managed care
data J Clin Rheumatol 2006 1261-65
Schumacher HR Jr Becker MA Lloyd E MacDonald PA Lademacher C Febuxostat in the treatment of gout 5-yr findings of the FOCUS
efficacy and safety study Rheumatology (Oxford) 2009 48188-194
14 Becker MA Schumacher HR MacDonald PA Lloyd E Lademacher C Clinical efficacy and safety of successful long-term urate
lowering with febuxostat or allopurinol in subjects with gout J Rheumatol 2009 361273-1278
2012 ACR guidelines for management of gout
Uptodate
Medcape
Statistical Power
Power
The probability that the study will support the research hypothesis if it is true
1 Sample size (n)
2 Effect Size (d)
3 Significance Level (α)
4 Power (β)
As effect size increases power increases
As sample size increases power increases
As significance level increases power increases
Resources
httpwwwncbinlmnihgovpmcarticlesPMC3409926
httpswwwsealedenvelopecompowerbinary-superiority
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
2012 ACR Management Guidelines
Lifestyle Modification for all patients with gout
Xanthine Oxidase Inhibitor (XOI) first-line urate-lowering
pharmacologic therapy
Target sUA lt6 at minimum sUA lt5 better
Continue prophylaxis for 3 (no tophi) ndash 6 months (tophi)
after achieving target sUA
2012 ACR Management Guidelines
Consider HLA screening for HLA-B5801 in certain populations considered high risk for allopurinol hypersensitivity syndrome
Koreans with stage 3 CKD or worse
Han Chinese
Thai descent
Combination oral ULT with 1 XOI agent and 1 uricosuric agent is appropriate when sUA not at target by XOI alone
Pegloticase appropriate for severe refractory disease or intolerance of standard regimens (Pegloticase is a porcine uricase which was approved by the FDA in September 2010 for the treatment of gout in patients who had failed conventional therapy)
2012 ACR Management Guidelines for
Acute Gouty Arthritis
The choice of pharmacologic agent depends on severity of the attack
Monotherapy for mildmoderate attack
Combination therapy for severe attack or those refractory to monotherapy
Acceptable combination therapy approaches include
Colchicine and NSAIDS
Oral steroids and colchicine
Intra-articular steroids with all other modalities
Continue current therapy during flare
Patient education on signs of flare for self treatment
Indications for pharmacological
treatment of gout
Any patient with established diagnosis of gouty arthritis
Tophus or tophi by clinical exam or imaging study
Frequent attacks of gouty arthritis (gt= 2 attacksyr)
CKD stage 2 or worse
Past urolithiasis
23
Gout Management Approach
bullTreat acute flare rapidly with anti-
inflammatory agent
bullInitiate urate-lowering therapy to
achieve sUA lt6
bullUse concomitant anti-inflammatory
prophylaxis for up to 6 mo to prevent
mobilization flares
INITIATE(acute flare)
RESOLVE(urate-lowering therapy)
bullContinue urate lowering therapy
to control flares and avoid crystal
deposition
bullProphylaxis use for at least 3-6
months until sUA normalizes
MAINTAIN(treatment to control sUA)
24
Allopurinol vs Febuxostat
Allopurinol Febuxostat (Uloric)
FDA-approved 1966 FDA-approved 2009
Purine-selective XO Inhibitor Non-Purine Selective XO
Inhibitor
Prevents uric acid production Prevents uric acid production
Renal Metabolism Liver Metabolism
FEBUXOSTAT
For treatment of hyperuricemia in patients with gout
febuxostat is recommended at 40 mg or 80 mg once daily and
can be increased to 120 mg once daily if clinically indicated
The adverse effects associated with febuxostat therapy
include nausea diarrhea arthralgia headache increased
hepatic serum enzyme levels and rash
The manufacturer recommends liver function monitoring on
initiation of therapy at two and four months after initiation
and periodically thereafter
FEBUXOSTAT
Febuxostat is US Food and Drug Administration pregnancy
category C2
Febuxostat is contraindicated with concomitant use of
theophylline and chemotherapeutic agents namely
azathioprine and 6- mercaptopurine because it could
increase blood plasma concentrations of these drugs and
therefore their toxicity
Dosage adjustments are unnecessary for mild to moderate
renal or hepatic impairment
A one-month supply of 40 or 80-mg febuxostat costs
$28243 This price far exceeds the cost of allopurinol
which is $2424 for 100 100 mg tablets
CrCl (mLmin)
Maintenance Dose of
Allopurinol
0 100mg every 3d
10 100mg every 2d
20 100mg
40 150mg
60 200mg
80 250mg
100 300mg
120 350mg
140 400mg
Maintenance Doses of Allopurinol for
Adults based on CrCl
28
Hande KR et al Am J Med 1984
Stage 1 renal damage with
normal GFR
(GFR gt 90 mlmin)
Stage 2 Mild CKD (GFR = 60-
89 mlmin)
Stage 3 Moderate CKD (GFR
= 30-59 mlmin)
Stage 4 Severe CKD (GFR =
15-29 mlmin)
Stage 5 End Stage CKD (GFR
lt15 mlmin)
Allopurinol Hypersensitivity
Syndrome
2 of all allopurinol users develop cutaneous rash
Frequency of hypersensitivity 1 in 260
DRESS syndrome
Drug Reaction Eosinophilia Systemic Symptoms
20 mortality rate
Life threatening toxicity vasculitis rash eosinophilia hepatitis progressive renal failure
Treatment early recognition withdrawal of drug supportive care Steroids N-acetyl-cysteine dialysis prn
29
Markel A IMAJ 2005
Terkeltaub RA in Primer on the Rheumatic Disease 13th ed 2008
The urate lowering efficacy and safety
of febuxostat in the treatment of the
hyperuricemia of gout
The CONFIRMS trial
Becker MA Schumacher HR Espinoza LR et al The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemia of gout the CONFIRMS trial Arthritis Res
Ther 201012(2)R63
Many long and short-term clinical trials have
proved the efficacy of Febuxostat in the treatment
of gout and lowering uric acid levels In these
studies Febuxostat was found to be superior to
allopurinol in reducing the serum uric acid levels
Some notable landmark clinical trials are FACT
APEX EXCEL FOCUS and CONFIRMS
Febuxostat versus Allopurinol Controlled Trial
(FACT) 2005
52 week randomized double-blind multicenter clinical trial that compared the safety and efficacy of febuxostat with allopurinol
760 patients with gout and a sUA gt80 mgdl were randomly assigned to receive either febuxostat 80 or 120mg or allopurinol 300mg once daily for 52 weeks
The primary endpoint was the proportion of patients to achieve a sUA concentration below 60 mgdl at the last three monthly measurements
The primary endpoint was achieved in 53 of patients receiving 80 mg febuxostat 62 of patients receiving 120mg and 21 of those receiving allopurinol (p lt0001 for each febuxostat group compared with allopurinol)
There was no statistical significance in the change in tophi size and number or the incidence of gout flare between the groups
Allopurinol Placebo controlled Efficacy study
of febuxostat (APEX) 2008
28 week randomized double-blind study of 1072 patients comparing the safety and efficacy of febuxostat allopurinol and placebo
Patients were randomized to a once daily fixed dose of placebo febuxostat 80mg120mg or 240 mg or allopurinol 300mg or 100mg depending on their baseline serum creatinine (le15 mgdl or ge16 to lt20 mgdl respectively)
After 1 year of treatment 82 of the patients in all febuxostat groups achieved sUA levels below 60 mgdl compared with 39 of the patients in both allopurinol groups In groups with moderate renal impairment the primary endpoint was achieved by 44 receiving febuxostat 80mg 45 receiving 120mg and 60 receiving 240mg compared with 0 in the allopurinol and placebo groups
However clinical endpoints were not statistically significant
The number of patients with moderate renal impairment was small
Febuxostat Comparative Extension Long-Term
study (EXCEL) 2009
160 week extension study for patients completing FACT and APEX
The studyrsquos aim was to determine long-term efficacy in sUA
lowering clinical benefits and safety of febuxostat or allopurinol
1086 patients were enrolled to receive fixed daily doses of
febuxostat 80mg or 120 mg or allopurinol 300 mg
After the first month of treatment nearly 80 of patients receiving
either febuxostat dose achieved sUA less than 6 mgdl compared
with only 46 of subjects on allopurinol There was no difference in
gout flare incidence and tophi reduction between the groups
Overall adverse events did not show significant differences among
groups
Febuxostat Open Label of Urate-Lowering
Efficacy and Safety (FOCUS) 2009
The FOCUS trial was a 5-year extension study that
assessed reduction and maintenance of sUA levels below
60 mgdl as the primary efficacy endpoint A total of
116 patients were initially enrolled to receive a dose of
80mg febuxostat with dose adjustment to either 40 or
120mg between weeks 4 and 24 93 maintained a sUA
level below 60 mgdl at 5 years
Objectives of CONFIRMS trial
The three-fold objectives of this Phase 3 double-blind RCT study were
1) To compare the UL efficacy of febuxostat at a dose of 40 mg with that of allopurinol at doses most commonly utilized in clinical practice
2) To evaluate UL efficacies of 80 mg and 40 mg daily doses of febuxostat compared with that of allopurinol in subjects with mild or moderate renal impairment
3) To gain prospective uniformly reviewed information regarding the safety of these agents particularly their comparative CV safety
Materials and methods
Subjects aged 18 to 85 years with a diagnosis of gout fulfilling American Rheumatology Association preliminary criteria and sUA ge 80 mgdL were eligible for enrollment
Subjects were enrolled at 324 sites in the United States
IRB approval was obtained and all the subjects provided written informed consent
At least 35 of subjects enrolled were to have mild or moderate renal impairment defined as baseline estimated creatinine clearance (eCLcr) of 60 to 89 mlminutes or 30 to 59 mlminutes
Subjects successfully completing either of the previously
reported long-term open-label febuxostat or
febuxostatallopurinol extension studies were also eligible for
enrollment
Exclusion criteria secondary hyperuricemia (for example
due to myeloproliferative disorder) xanthinuria severe renal
impairment (eCLcr lt30 mlminutes) alanine
aminotransferase and aspartate aminotransferase values gt15
times the upper limit of normal consumption of more than 14
alcoholic drinks per week or a history of alcoholism or drug
abuse within five years or a medical condition that in the
investigators opinion would interfere with treatment safety
or adherence to the protocol
Baseline characteristics of randomized subjects
Baseline characteristics of randomized subjects (cont)
Baseline characteristics of randomized subjects (cont)
2269 Subjects were randomized 111 on Day 1 to
receive daily febuxostat 40 mg febuxostat 80 mg or
allopurinol Among subjects randomized to allopurinol
those with normal renal function or mild renal
impairment received 300 mg daily and those with
moderate renal impairment received 200 mg
Throughout the subsequent six-month treatment period for all subjects prophylaxis for gout flares was given either as colchicine 06 mg daily or naproxen 250 mg twice daily All subjects receiving naproxen prophylaxis also received lansoprazole 15 mg daily
Choice of prophylaxis regimen was made by the investigator and subject taking into account prior drug tolerance and prophylaxis experience
In addition subjects with eCLcr lt50 mlminute were not to receive naproxen
Gout flares were regarded as expected gout manifestations rather than as AEs
The primary efficacy endpoint was the proportion of
subjects in each treatment group with sUA lt60 mgdL
at the final visit
Secondary efficacy variables included
1) The proportion of subjects with mild or moderate
renal impairment and final sUA lt60 mgdL
2) The proportion of subjects with sUA lt60 mgdL lt50
mgdL and lt40 mgdL at each visit
Efficacy analysisResults
Primary efficacy endpoint
1) The proportions of subjects achieving a final visit sUA lt60
mgdL were 452 671 and 421 in the febuxostat 40 mg
febuxostat 80 mg and allopurinol groups respectively
2) UL by febuxostat 40 mg was non-inferior to that by
allopurinol but the difference in the response rates between
the two groups (31 95 CI -19 to 81) was not significant
3) However the greater UL response rate with febuxostat 80 mg
compared with either febuxostat 40 mg (219) or allopurinol
(249) was significant (P lt 0001)
Secondary efficacy endpoints
Among subjects with any (mild or moderate) renal
impairment the UL response rate in the febuxostat 80
mg group (716 360503) significantly exceeded those
observed in the febuxostat 40 mg (497 238479) and
allopurinol (423 212501) groups (P le 0001 for each
comparison)
In addition among the total group of subjects with
renal impairment the UL response rate in the
febuxostat 40 mg group was significantly higher than
that in the allopurinol 300200 mg group (P = 0021)
At any sUA endpoint (lt60 mgdL lt50 mgdL or lt40 mgdL) and at any scheduled visit a significantly higher proportion of subjects receiving febuxostat 80 mg achieved the target endpoint than subjects receiving febuxostat 40 mg or allopurinol (P lt 0001)
Greater proportion of subjects in the febuxostat 40 mg group than the allopurinol group achieved sUAlt60 mgdL (at Month 2 visit P = 0031) and lt50 mgdL (at two- and six month visits P le 005) but significant differences were not seen at other visits including the final visit
Effect of baseline characteristic on treatment response
Adverse events
Adverse events
CONCLUSIONS
Results of the CONFIRMS trial establish equivalent UL efficacy for febuxostat 40 mg daily and allopurinol 300200 mg daily
At all levels of renal function studied UL efficacy of febuxostat 80 mg daily was superior to that of febuxostat 40 mg or allopurinol 300200 mg and was comparably safe
In subjects with mildly or moderately impaired renal function however febuxostat 40 mg daily was significantly more effective in lowering sUA than allopurinol
At the doses studied safety of febuxostat and allopurinol including CV safety was comparable
Febuxostat at 40 mg or 80 mg daily offers a well-tolerated UL alternative to allopurinol particularly for patients with mild or moderate renal impairment
Study limitations
The study does not address the efficacy of febuxostat compared with allopurinol in reducing clinically meaningful acute flares of gout
No mention is made of long-term cost-effectiveness of therapy
Additionally this study does not address the efficacy of febuxostat compared with allopurinol dosing that is more aggressive (ie gt 300 mg daily)
Allopurinol dosing was not titrated
The study population was not similar to the general population (majority of patients were white males)
Possible funding bias
Uloric Related Current Clinical
Trials
References
Dalbeth N Gracey E Pool B et al Identification of dairy fractions with anti-inflammatory properties in models of acute gout Ann
Rheum Dis 2010 69766ndash769
Choi HK Willett W Curhan G Coffee consumption and risk of incident gout in men a prospective study Arthritis Rheum 2007 562049ndash
2055
Hak AE Curhan GC Grodstein F Choi HK Menopause postmenopausal hormone use and risk of incident gout Ann Rheum Dis 2010
691305ndash1309
Becker MA Schumacher HR Wortmann RL et al (December 2005) Febuxostat compared with allopurinol in patients with hyperuricemia
and gout N Engl J Med 353 (23) 2450ndash61
Sarawate CA Patel PA Schumacher HR Yang W Brewer KK Bakst AW Serum urate levels and gout flares analysis from managed care
data J Clin Rheumatol 2006 1261-65
Schumacher HR Jr Becker MA Lloyd E MacDonald PA Lademacher C Febuxostat in the treatment of gout 5-yr findings of the FOCUS
efficacy and safety study Rheumatology (Oxford) 2009 48188-194
14 Becker MA Schumacher HR MacDonald PA Lloyd E Lademacher C Clinical efficacy and safety of successful long-term urate
lowering with febuxostat or allopurinol in subjects with gout J Rheumatol 2009 361273-1278
2012 ACR guidelines for management of gout
Uptodate
Medcape
Statistical Power
Power
The probability that the study will support the research hypothesis if it is true
1 Sample size (n)
2 Effect Size (d)
3 Significance Level (α)
4 Power (β)
As effect size increases power increases
As sample size increases power increases
As significance level increases power increases
Resources
httpwwwncbinlmnihgovpmcarticlesPMC3409926
httpswwwsealedenvelopecompowerbinary-superiority
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
2012 ACR Management Guidelines
Consider HLA screening for HLA-B5801 in certain populations considered high risk for allopurinol hypersensitivity syndrome
Koreans with stage 3 CKD or worse
Han Chinese
Thai descent
Combination oral ULT with 1 XOI agent and 1 uricosuric agent is appropriate when sUA not at target by XOI alone
Pegloticase appropriate for severe refractory disease or intolerance of standard regimens (Pegloticase is a porcine uricase which was approved by the FDA in September 2010 for the treatment of gout in patients who had failed conventional therapy)
2012 ACR Management Guidelines for
Acute Gouty Arthritis
The choice of pharmacologic agent depends on severity of the attack
Monotherapy for mildmoderate attack
Combination therapy for severe attack or those refractory to monotherapy
Acceptable combination therapy approaches include
Colchicine and NSAIDS
Oral steroids and colchicine
Intra-articular steroids with all other modalities
Continue current therapy during flare
Patient education on signs of flare for self treatment
Indications for pharmacological
treatment of gout
Any patient with established diagnosis of gouty arthritis
Tophus or tophi by clinical exam or imaging study
Frequent attacks of gouty arthritis (gt= 2 attacksyr)
CKD stage 2 or worse
Past urolithiasis
23
Gout Management Approach
bullTreat acute flare rapidly with anti-
inflammatory agent
bullInitiate urate-lowering therapy to
achieve sUA lt6
bullUse concomitant anti-inflammatory
prophylaxis for up to 6 mo to prevent
mobilization flares
INITIATE(acute flare)
RESOLVE(urate-lowering therapy)
bullContinue urate lowering therapy
to control flares and avoid crystal
deposition
bullProphylaxis use for at least 3-6
months until sUA normalizes
MAINTAIN(treatment to control sUA)
24
Allopurinol vs Febuxostat
Allopurinol Febuxostat (Uloric)
FDA-approved 1966 FDA-approved 2009
Purine-selective XO Inhibitor Non-Purine Selective XO
Inhibitor
Prevents uric acid production Prevents uric acid production
Renal Metabolism Liver Metabolism
FEBUXOSTAT
For treatment of hyperuricemia in patients with gout
febuxostat is recommended at 40 mg or 80 mg once daily and
can be increased to 120 mg once daily if clinically indicated
The adverse effects associated with febuxostat therapy
include nausea diarrhea arthralgia headache increased
hepatic serum enzyme levels and rash
The manufacturer recommends liver function monitoring on
initiation of therapy at two and four months after initiation
and periodically thereafter
FEBUXOSTAT
Febuxostat is US Food and Drug Administration pregnancy
category C2
Febuxostat is contraindicated with concomitant use of
theophylline and chemotherapeutic agents namely
azathioprine and 6- mercaptopurine because it could
increase blood plasma concentrations of these drugs and
therefore their toxicity
Dosage adjustments are unnecessary for mild to moderate
renal or hepatic impairment
A one-month supply of 40 or 80-mg febuxostat costs
$28243 This price far exceeds the cost of allopurinol
which is $2424 for 100 100 mg tablets
CrCl (mLmin)
Maintenance Dose of
Allopurinol
0 100mg every 3d
10 100mg every 2d
20 100mg
40 150mg
60 200mg
80 250mg
100 300mg
120 350mg
140 400mg
Maintenance Doses of Allopurinol for
Adults based on CrCl
28
Hande KR et al Am J Med 1984
Stage 1 renal damage with
normal GFR
(GFR gt 90 mlmin)
Stage 2 Mild CKD (GFR = 60-
89 mlmin)
Stage 3 Moderate CKD (GFR
= 30-59 mlmin)
Stage 4 Severe CKD (GFR =
15-29 mlmin)
Stage 5 End Stage CKD (GFR
lt15 mlmin)
Allopurinol Hypersensitivity
Syndrome
2 of all allopurinol users develop cutaneous rash
Frequency of hypersensitivity 1 in 260
DRESS syndrome
Drug Reaction Eosinophilia Systemic Symptoms
20 mortality rate
Life threatening toxicity vasculitis rash eosinophilia hepatitis progressive renal failure
Treatment early recognition withdrawal of drug supportive care Steroids N-acetyl-cysteine dialysis prn
29
Markel A IMAJ 2005
Terkeltaub RA in Primer on the Rheumatic Disease 13th ed 2008
The urate lowering efficacy and safety
of febuxostat in the treatment of the
hyperuricemia of gout
The CONFIRMS trial
Becker MA Schumacher HR Espinoza LR et al The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemia of gout the CONFIRMS trial Arthritis Res
Ther 201012(2)R63
Many long and short-term clinical trials have
proved the efficacy of Febuxostat in the treatment
of gout and lowering uric acid levels In these
studies Febuxostat was found to be superior to
allopurinol in reducing the serum uric acid levels
Some notable landmark clinical trials are FACT
APEX EXCEL FOCUS and CONFIRMS
Febuxostat versus Allopurinol Controlled Trial
(FACT) 2005
52 week randomized double-blind multicenter clinical trial that compared the safety and efficacy of febuxostat with allopurinol
760 patients with gout and a sUA gt80 mgdl were randomly assigned to receive either febuxostat 80 or 120mg or allopurinol 300mg once daily for 52 weeks
The primary endpoint was the proportion of patients to achieve a sUA concentration below 60 mgdl at the last three monthly measurements
The primary endpoint was achieved in 53 of patients receiving 80 mg febuxostat 62 of patients receiving 120mg and 21 of those receiving allopurinol (p lt0001 for each febuxostat group compared with allopurinol)
There was no statistical significance in the change in tophi size and number or the incidence of gout flare between the groups
Allopurinol Placebo controlled Efficacy study
of febuxostat (APEX) 2008
28 week randomized double-blind study of 1072 patients comparing the safety and efficacy of febuxostat allopurinol and placebo
Patients were randomized to a once daily fixed dose of placebo febuxostat 80mg120mg or 240 mg or allopurinol 300mg or 100mg depending on their baseline serum creatinine (le15 mgdl or ge16 to lt20 mgdl respectively)
After 1 year of treatment 82 of the patients in all febuxostat groups achieved sUA levels below 60 mgdl compared with 39 of the patients in both allopurinol groups In groups with moderate renal impairment the primary endpoint was achieved by 44 receiving febuxostat 80mg 45 receiving 120mg and 60 receiving 240mg compared with 0 in the allopurinol and placebo groups
However clinical endpoints were not statistically significant
The number of patients with moderate renal impairment was small
Febuxostat Comparative Extension Long-Term
study (EXCEL) 2009
160 week extension study for patients completing FACT and APEX
The studyrsquos aim was to determine long-term efficacy in sUA
lowering clinical benefits and safety of febuxostat or allopurinol
1086 patients were enrolled to receive fixed daily doses of
febuxostat 80mg or 120 mg or allopurinol 300 mg
After the first month of treatment nearly 80 of patients receiving
either febuxostat dose achieved sUA less than 6 mgdl compared
with only 46 of subjects on allopurinol There was no difference in
gout flare incidence and tophi reduction between the groups
Overall adverse events did not show significant differences among
groups
Febuxostat Open Label of Urate-Lowering
Efficacy and Safety (FOCUS) 2009
The FOCUS trial was a 5-year extension study that
assessed reduction and maintenance of sUA levels below
60 mgdl as the primary efficacy endpoint A total of
116 patients were initially enrolled to receive a dose of
80mg febuxostat with dose adjustment to either 40 or
120mg between weeks 4 and 24 93 maintained a sUA
level below 60 mgdl at 5 years
Objectives of CONFIRMS trial
The three-fold objectives of this Phase 3 double-blind RCT study were
1) To compare the UL efficacy of febuxostat at a dose of 40 mg with that of allopurinol at doses most commonly utilized in clinical practice
2) To evaluate UL efficacies of 80 mg and 40 mg daily doses of febuxostat compared with that of allopurinol in subjects with mild or moderate renal impairment
3) To gain prospective uniformly reviewed information regarding the safety of these agents particularly their comparative CV safety
Materials and methods
Subjects aged 18 to 85 years with a diagnosis of gout fulfilling American Rheumatology Association preliminary criteria and sUA ge 80 mgdL were eligible for enrollment
Subjects were enrolled at 324 sites in the United States
IRB approval was obtained and all the subjects provided written informed consent
At least 35 of subjects enrolled were to have mild or moderate renal impairment defined as baseline estimated creatinine clearance (eCLcr) of 60 to 89 mlminutes or 30 to 59 mlminutes
Subjects successfully completing either of the previously
reported long-term open-label febuxostat or
febuxostatallopurinol extension studies were also eligible for
enrollment
Exclusion criteria secondary hyperuricemia (for example
due to myeloproliferative disorder) xanthinuria severe renal
impairment (eCLcr lt30 mlminutes) alanine
aminotransferase and aspartate aminotransferase values gt15
times the upper limit of normal consumption of more than 14
alcoholic drinks per week or a history of alcoholism or drug
abuse within five years or a medical condition that in the
investigators opinion would interfere with treatment safety
or adherence to the protocol
Baseline characteristics of randomized subjects
Baseline characteristics of randomized subjects (cont)
Baseline characteristics of randomized subjects (cont)
2269 Subjects were randomized 111 on Day 1 to
receive daily febuxostat 40 mg febuxostat 80 mg or
allopurinol Among subjects randomized to allopurinol
those with normal renal function or mild renal
impairment received 300 mg daily and those with
moderate renal impairment received 200 mg
Throughout the subsequent six-month treatment period for all subjects prophylaxis for gout flares was given either as colchicine 06 mg daily or naproxen 250 mg twice daily All subjects receiving naproxen prophylaxis also received lansoprazole 15 mg daily
Choice of prophylaxis regimen was made by the investigator and subject taking into account prior drug tolerance and prophylaxis experience
In addition subjects with eCLcr lt50 mlminute were not to receive naproxen
Gout flares were regarded as expected gout manifestations rather than as AEs
The primary efficacy endpoint was the proportion of
subjects in each treatment group with sUA lt60 mgdL
at the final visit
Secondary efficacy variables included
1) The proportion of subjects with mild or moderate
renal impairment and final sUA lt60 mgdL
2) The proportion of subjects with sUA lt60 mgdL lt50
mgdL and lt40 mgdL at each visit
Efficacy analysisResults
Primary efficacy endpoint
1) The proportions of subjects achieving a final visit sUA lt60
mgdL were 452 671 and 421 in the febuxostat 40 mg
febuxostat 80 mg and allopurinol groups respectively
2) UL by febuxostat 40 mg was non-inferior to that by
allopurinol but the difference in the response rates between
the two groups (31 95 CI -19 to 81) was not significant
3) However the greater UL response rate with febuxostat 80 mg
compared with either febuxostat 40 mg (219) or allopurinol
(249) was significant (P lt 0001)
Secondary efficacy endpoints
Among subjects with any (mild or moderate) renal
impairment the UL response rate in the febuxostat 80
mg group (716 360503) significantly exceeded those
observed in the febuxostat 40 mg (497 238479) and
allopurinol (423 212501) groups (P le 0001 for each
comparison)
In addition among the total group of subjects with
renal impairment the UL response rate in the
febuxostat 40 mg group was significantly higher than
that in the allopurinol 300200 mg group (P = 0021)
At any sUA endpoint (lt60 mgdL lt50 mgdL or lt40 mgdL) and at any scheduled visit a significantly higher proportion of subjects receiving febuxostat 80 mg achieved the target endpoint than subjects receiving febuxostat 40 mg or allopurinol (P lt 0001)
Greater proportion of subjects in the febuxostat 40 mg group than the allopurinol group achieved sUAlt60 mgdL (at Month 2 visit P = 0031) and lt50 mgdL (at two- and six month visits P le 005) but significant differences were not seen at other visits including the final visit
Effect of baseline characteristic on treatment response
Adverse events
Adverse events
CONCLUSIONS
Results of the CONFIRMS trial establish equivalent UL efficacy for febuxostat 40 mg daily and allopurinol 300200 mg daily
At all levels of renal function studied UL efficacy of febuxostat 80 mg daily was superior to that of febuxostat 40 mg or allopurinol 300200 mg and was comparably safe
In subjects with mildly or moderately impaired renal function however febuxostat 40 mg daily was significantly more effective in lowering sUA than allopurinol
At the doses studied safety of febuxostat and allopurinol including CV safety was comparable
Febuxostat at 40 mg or 80 mg daily offers a well-tolerated UL alternative to allopurinol particularly for patients with mild or moderate renal impairment
Study limitations
The study does not address the efficacy of febuxostat compared with allopurinol in reducing clinically meaningful acute flares of gout
No mention is made of long-term cost-effectiveness of therapy
Additionally this study does not address the efficacy of febuxostat compared with allopurinol dosing that is more aggressive (ie gt 300 mg daily)
Allopurinol dosing was not titrated
The study population was not similar to the general population (majority of patients were white males)
Possible funding bias
Uloric Related Current Clinical
Trials
References
Dalbeth N Gracey E Pool B et al Identification of dairy fractions with anti-inflammatory properties in models of acute gout Ann
Rheum Dis 2010 69766ndash769
Choi HK Willett W Curhan G Coffee consumption and risk of incident gout in men a prospective study Arthritis Rheum 2007 562049ndash
2055
Hak AE Curhan GC Grodstein F Choi HK Menopause postmenopausal hormone use and risk of incident gout Ann Rheum Dis 2010
691305ndash1309
Becker MA Schumacher HR Wortmann RL et al (December 2005) Febuxostat compared with allopurinol in patients with hyperuricemia
and gout N Engl J Med 353 (23) 2450ndash61
Sarawate CA Patel PA Schumacher HR Yang W Brewer KK Bakst AW Serum urate levels and gout flares analysis from managed care
data J Clin Rheumatol 2006 1261-65
Schumacher HR Jr Becker MA Lloyd E MacDonald PA Lademacher C Febuxostat in the treatment of gout 5-yr findings of the FOCUS
efficacy and safety study Rheumatology (Oxford) 2009 48188-194
14 Becker MA Schumacher HR MacDonald PA Lloyd E Lademacher C Clinical efficacy and safety of successful long-term urate
lowering with febuxostat or allopurinol in subjects with gout J Rheumatol 2009 361273-1278
2012 ACR guidelines for management of gout
Uptodate
Medcape
Statistical Power
Power
The probability that the study will support the research hypothesis if it is true
1 Sample size (n)
2 Effect Size (d)
3 Significance Level (α)
4 Power (β)
As effect size increases power increases
As sample size increases power increases
As significance level increases power increases
Resources
httpwwwncbinlmnihgovpmcarticlesPMC3409926
httpswwwsealedenvelopecompowerbinary-superiority
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
2012 ACR Management Guidelines for
Acute Gouty Arthritis
The choice of pharmacologic agent depends on severity of the attack
Monotherapy for mildmoderate attack
Combination therapy for severe attack or those refractory to monotherapy
Acceptable combination therapy approaches include
Colchicine and NSAIDS
Oral steroids and colchicine
Intra-articular steroids with all other modalities
Continue current therapy during flare
Patient education on signs of flare for self treatment
Indications for pharmacological
treatment of gout
Any patient with established diagnosis of gouty arthritis
Tophus or tophi by clinical exam or imaging study
Frequent attacks of gouty arthritis (gt= 2 attacksyr)
CKD stage 2 or worse
Past urolithiasis
23
Gout Management Approach
bullTreat acute flare rapidly with anti-
inflammatory agent
bullInitiate urate-lowering therapy to
achieve sUA lt6
bullUse concomitant anti-inflammatory
prophylaxis for up to 6 mo to prevent
mobilization flares
INITIATE(acute flare)
RESOLVE(urate-lowering therapy)
bullContinue urate lowering therapy
to control flares and avoid crystal
deposition
bullProphylaxis use for at least 3-6
months until sUA normalizes
MAINTAIN(treatment to control sUA)
24
Allopurinol vs Febuxostat
Allopurinol Febuxostat (Uloric)
FDA-approved 1966 FDA-approved 2009
Purine-selective XO Inhibitor Non-Purine Selective XO
Inhibitor
Prevents uric acid production Prevents uric acid production
Renal Metabolism Liver Metabolism
FEBUXOSTAT
For treatment of hyperuricemia in patients with gout
febuxostat is recommended at 40 mg or 80 mg once daily and
can be increased to 120 mg once daily if clinically indicated
The adverse effects associated with febuxostat therapy
include nausea diarrhea arthralgia headache increased
hepatic serum enzyme levels and rash
The manufacturer recommends liver function monitoring on
initiation of therapy at two and four months after initiation
and periodically thereafter
FEBUXOSTAT
Febuxostat is US Food and Drug Administration pregnancy
category C2
Febuxostat is contraindicated with concomitant use of
theophylline and chemotherapeutic agents namely
azathioprine and 6- mercaptopurine because it could
increase blood plasma concentrations of these drugs and
therefore their toxicity
Dosage adjustments are unnecessary for mild to moderate
renal or hepatic impairment
A one-month supply of 40 or 80-mg febuxostat costs
$28243 This price far exceeds the cost of allopurinol
which is $2424 for 100 100 mg tablets
CrCl (mLmin)
Maintenance Dose of
Allopurinol
0 100mg every 3d
10 100mg every 2d
20 100mg
40 150mg
60 200mg
80 250mg
100 300mg
120 350mg
140 400mg
Maintenance Doses of Allopurinol for
Adults based on CrCl
28
Hande KR et al Am J Med 1984
Stage 1 renal damage with
normal GFR
(GFR gt 90 mlmin)
Stage 2 Mild CKD (GFR = 60-
89 mlmin)
Stage 3 Moderate CKD (GFR
= 30-59 mlmin)
Stage 4 Severe CKD (GFR =
15-29 mlmin)
Stage 5 End Stage CKD (GFR
lt15 mlmin)
Allopurinol Hypersensitivity
Syndrome
2 of all allopurinol users develop cutaneous rash
Frequency of hypersensitivity 1 in 260
DRESS syndrome
Drug Reaction Eosinophilia Systemic Symptoms
20 mortality rate
Life threatening toxicity vasculitis rash eosinophilia hepatitis progressive renal failure
Treatment early recognition withdrawal of drug supportive care Steroids N-acetyl-cysteine dialysis prn
29
Markel A IMAJ 2005
Terkeltaub RA in Primer on the Rheumatic Disease 13th ed 2008
The urate lowering efficacy and safety
of febuxostat in the treatment of the
hyperuricemia of gout
The CONFIRMS trial
Becker MA Schumacher HR Espinoza LR et al The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemia of gout the CONFIRMS trial Arthritis Res
Ther 201012(2)R63
Many long and short-term clinical trials have
proved the efficacy of Febuxostat in the treatment
of gout and lowering uric acid levels In these
studies Febuxostat was found to be superior to
allopurinol in reducing the serum uric acid levels
Some notable landmark clinical trials are FACT
APEX EXCEL FOCUS and CONFIRMS
Febuxostat versus Allopurinol Controlled Trial
(FACT) 2005
52 week randomized double-blind multicenter clinical trial that compared the safety and efficacy of febuxostat with allopurinol
760 patients with gout and a sUA gt80 mgdl were randomly assigned to receive either febuxostat 80 or 120mg or allopurinol 300mg once daily for 52 weeks
The primary endpoint was the proportion of patients to achieve a sUA concentration below 60 mgdl at the last three monthly measurements
The primary endpoint was achieved in 53 of patients receiving 80 mg febuxostat 62 of patients receiving 120mg and 21 of those receiving allopurinol (p lt0001 for each febuxostat group compared with allopurinol)
There was no statistical significance in the change in tophi size and number or the incidence of gout flare between the groups
Allopurinol Placebo controlled Efficacy study
of febuxostat (APEX) 2008
28 week randomized double-blind study of 1072 patients comparing the safety and efficacy of febuxostat allopurinol and placebo
Patients were randomized to a once daily fixed dose of placebo febuxostat 80mg120mg or 240 mg or allopurinol 300mg or 100mg depending on their baseline serum creatinine (le15 mgdl or ge16 to lt20 mgdl respectively)
After 1 year of treatment 82 of the patients in all febuxostat groups achieved sUA levels below 60 mgdl compared with 39 of the patients in both allopurinol groups In groups with moderate renal impairment the primary endpoint was achieved by 44 receiving febuxostat 80mg 45 receiving 120mg and 60 receiving 240mg compared with 0 in the allopurinol and placebo groups
However clinical endpoints were not statistically significant
The number of patients with moderate renal impairment was small
Febuxostat Comparative Extension Long-Term
study (EXCEL) 2009
160 week extension study for patients completing FACT and APEX
The studyrsquos aim was to determine long-term efficacy in sUA
lowering clinical benefits and safety of febuxostat or allopurinol
1086 patients were enrolled to receive fixed daily doses of
febuxostat 80mg or 120 mg or allopurinol 300 mg
After the first month of treatment nearly 80 of patients receiving
either febuxostat dose achieved sUA less than 6 mgdl compared
with only 46 of subjects on allopurinol There was no difference in
gout flare incidence and tophi reduction between the groups
Overall adverse events did not show significant differences among
groups
Febuxostat Open Label of Urate-Lowering
Efficacy and Safety (FOCUS) 2009
The FOCUS trial was a 5-year extension study that
assessed reduction and maintenance of sUA levels below
60 mgdl as the primary efficacy endpoint A total of
116 patients were initially enrolled to receive a dose of
80mg febuxostat with dose adjustment to either 40 or
120mg between weeks 4 and 24 93 maintained a sUA
level below 60 mgdl at 5 years
Objectives of CONFIRMS trial
The three-fold objectives of this Phase 3 double-blind RCT study were
1) To compare the UL efficacy of febuxostat at a dose of 40 mg with that of allopurinol at doses most commonly utilized in clinical practice
2) To evaluate UL efficacies of 80 mg and 40 mg daily doses of febuxostat compared with that of allopurinol in subjects with mild or moderate renal impairment
3) To gain prospective uniformly reviewed information regarding the safety of these agents particularly their comparative CV safety
Materials and methods
Subjects aged 18 to 85 years with a diagnosis of gout fulfilling American Rheumatology Association preliminary criteria and sUA ge 80 mgdL were eligible for enrollment
Subjects were enrolled at 324 sites in the United States
IRB approval was obtained and all the subjects provided written informed consent
At least 35 of subjects enrolled were to have mild or moderate renal impairment defined as baseline estimated creatinine clearance (eCLcr) of 60 to 89 mlminutes or 30 to 59 mlminutes
Subjects successfully completing either of the previously
reported long-term open-label febuxostat or
febuxostatallopurinol extension studies were also eligible for
enrollment
Exclusion criteria secondary hyperuricemia (for example
due to myeloproliferative disorder) xanthinuria severe renal
impairment (eCLcr lt30 mlminutes) alanine
aminotransferase and aspartate aminotransferase values gt15
times the upper limit of normal consumption of more than 14
alcoholic drinks per week or a history of alcoholism or drug
abuse within five years or a medical condition that in the
investigators opinion would interfere with treatment safety
or adherence to the protocol
Baseline characteristics of randomized subjects
Baseline characteristics of randomized subjects (cont)
Baseline characteristics of randomized subjects (cont)
2269 Subjects were randomized 111 on Day 1 to
receive daily febuxostat 40 mg febuxostat 80 mg or
allopurinol Among subjects randomized to allopurinol
those with normal renal function or mild renal
impairment received 300 mg daily and those with
moderate renal impairment received 200 mg
Throughout the subsequent six-month treatment period for all subjects prophylaxis for gout flares was given either as colchicine 06 mg daily or naproxen 250 mg twice daily All subjects receiving naproxen prophylaxis also received lansoprazole 15 mg daily
Choice of prophylaxis regimen was made by the investigator and subject taking into account prior drug tolerance and prophylaxis experience
In addition subjects with eCLcr lt50 mlminute were not to receive naproxen
Gout flares were regarded as expected gout manifestations rather than as AEs
The primary efficacy endpoint was the proportion of
subjects in each treatment group with sUA lt60 mgdL
at the final visit
Secondary efficacy variables included
1) The proportion of subjects with mild or moderate
renal impairment and final sUA lt60 mgdL
2) The proportion of subjects with sUA lt60 mgdL lt50
mgdL and lt40 mgdL at each visit
Efficacy analysisResults
Primary efficacy endpoint
1) The proportions of subjects achieving a final visit sUA lt60
mgdL were 452 671 and 421 in the febuxostat 40 mg
febuxostat 80 mg and allopurinol groups respectively
2) UL by febuxostat 40 mg was non-inferior to that by
allopurinol but the difference in the response rates between
the two groups (31 95 CI -19 to 81) was not significant
3) However the greater UL response rate with febuxostat 80 mg
compared with either febuxostat 40 mg (219) or allopurinol
(249) was significant (P lt 0001)
Secondary efficacy endpoints
Among subjects with any (mild or moderate) renal
impairment the UL response rate in the febuxostat 80
mg group (716 360503) significantly exceeded those
observed in the febuxostat 40 mg (497 238479) and
allopurinol (423 212501) groups (P le 0001 for each
comparison)
In addition among the total group of subjects with
renal impairment the UL response rate in the
febuxostat 40 mg group was significantly higher than
that in the allopurinol 300200 mg group (P = 0021)
At any sUA endpoint (lt60 mgdL lt50 mgdL or lt40 mgdL) and at any scheduled visit a significantly higher proportion of subjects receiving febuxostat 80 mg achieved the target endpoint than subjects receiving febuxostat 40 mg or allopurinol (P lt 0001)
Greater proportion of subjects in the febuxostat 40 mg group than the allopurinol group achieved sUAlt60 mgdL (at Month 2 visit P = 0031) and lt50 mgdL (at two- and six month visits P le 005) but significant differences were not seen at other visits including the final visit
Effect of baseline characteristic on treatment response
Adverse events
Adverse events
CONCLUSIONS
Results of the CONFIRMS trial establish equivalent UL efficacy for febuxostat 40 mg daily and allopurinol 300200 mg daily
At all levels of renal function studied UL efficacy of febuxostat 80 mg daily was superior to that of febuxostat 40 mg or allopurinol 300200 mg and was comparably safe
In subjects with mildly or moderately impaired renal function however febuxostat 40 mg daily was significantly more effective in lowering sUA than allopurinol
At the doses studied safety of febuxostat and allopurinol including CV safety was comparable
Febuxostat at 40 mg or 80 mg daily offers a well-tolerated UL alternative to allopurinol particularly for patients with mild or moderate renal impairment
Study limitations
The study does not address the efficacy of febuxostat compared with allopurinol in reducing clinically meaningful acute flares of gout
No mention is made of long-term cost-effectiveness of therapy
Additionally this study does not address the efficacy of febuxostat compared with allopurinol dosing that is more aggressive (ie gt 300 mg daily)
Allopurinol dosing was not titrated
The study population was not similar to the general population (majority of patients were white males)
Possible funding bias
Uloric Related Current Clinical
Trials
References
Dalbeth N Gracey E Pool B et al Identification of dairy fractions with anti-inflammatory properties in models of acute gout Ann
Rheum Dis 2010 69766ndash769
Choi HK Willett W Curhan G Coffee consumption and risk of incident gout in men a prospective study Arthritis Rheum 2007 562049ndash
2055
Hak AE Curhan GC Grodstein F Choi HK Menopause postmenopausal hormone use and risk of incident gout Ann Rheum Dis 2010
691305ndash1309
Becker MA Schumacher HR Wortmann RL et al (December 2005) Febuxostat compared with allopurinol in patients with hyperuricemia
and gout N Engl J Med 353 (23) 2450ndash61
Sarawate CA Patel PA Schumacher HR Yang W Brewer KK Bakst AW Serum urate levels and gout flares analysis from managed care
data J Clin Rheumatol 2006 1261-65
Schumacher HR Jr Becker MA Lloyd E MacDonald PA Lademacher C Febuxostat in the treatment of gout 5-yr findings of the FOCUS
efficacy and safety study Rheumatology (Oxford) 2009 48188-194
14 Becker MA Schumacher HR MacDonald PA Lloyd E Lademacher C Clinical efficacy and safety of successful long-term urate
lowering with febuxostat or allopurinol in subjects with gout J Rheumatol 2009 361273-1278
2012 ACR guidelines for management of gout
Uptodate
Medcape
Statistical Power
Power
The probability that the study will support the research hypothesis if it is true
1 Sample size (n)
2 Effect Size (d)
3 Significance Level (α)
4 Power (β)
As effect size increases power increases
As sample size increases power increases
As significance level increases power increases
Resources
httpwwwncbinlmnihgovpmcarticlesPMC3409926
httpswwwsealedenvelopecompowerbinary-superiority
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
Indications for pharmacological
treatment of gout
Any patient with established diagnosis of gouty arthritis
Tophus or tophi by clinical exam or imaging study
Frequent attacks of gouty arthritis (gt= 2 attacksyr)
CKD stage 2 or worse
Past urolithiasis
23
Gout Management Approach
bullTreat acute flare rapidly with anti-
inflammatory agent
bullInitiate urate-lowering therapy to
achieve sUA lt6
bullUse concomitant anti-inflammatory
prophylaxis for up to 6 mo to prevent
mobilization flares
INITIATE(acute flare)
RESOLVE(urate-lowering therapy)
bullContinue urate lowering therapy
to control flares and avoid crystal
deposition
bullProphylaxis use for at least 3-6
months until sUA normalizes
MAINTAIN(treatment to control sUA)
24
Allopurinol vs Febuxostat
Allopurinol Febuxostat (Uloric)
FDA-approved 1966 FDA-approved 2009
Purine-selective XO Inhibitor Non-Purine Selective XO
Inhibitor
Prevents uric acid production Prevents uric acid production
Renal Metabolism Liver Metabolism
FEBUXOSTAT
For treatment of hyperuricemia in patients with gout
febuxostat is recommended at 40 mg or 80 mg once daily and
can be increased to 120 mg once daily if clinically indicated
The adverse effects associated with febuxostat therapy
include nausea diarrhea arthralgia headache increased
hepatic serum enzyme levels and rash
The manufacturer recommends liver function monitoring on
initiation of therapy at two and four months after initiation
and periodically thereafter
FEBUXOSTAT
Febuxostat is US Food and Drug Administration pregnancy
category C2
Febuxostat is contraindicated with concomitant use of
theophylline and chemotherapeutic agents namely
azathioprine and 6- mercaptopurine because it could
increase blood plasma concentrations of these drugs and
therefore their toxicity
Dosage adjustments are unnecessary for mild to moderate
renal or hepatic impairment
A one-month supply of 40 or 80-mg febuxostat costs
$28243 This price far exceeds the cost of allopurinol
which is $2424 for 100 100 mg tablets
CrCl (mLmin)
Maintenance Dose of
Allopurinol
0 100mg every 3d
10 100mg every 2d
20 100mg
40 150mg
60 200mg
80 250mg
100 300mg
120 350mg
140 400mg
Maintenance Doses of Allopurinol for
Adults based on CrCl
28
Hande KR et al Am J Med 1984
Stage 1 renal damage with
normal GFR
(GFR gt 90 mlmin)
Stage 2 Mild CKD (GFR = 60-
89 mlmin)
Stage 3 Moderate CKD (GFR
= 30-59 mlmin)
Stage 4 Severe CKD (GFR =
15-29 mlmin)
Stage 5 End Stage CKD (GFR
lt15 mlmin)
Allopurinol Hypersensitivity
Syndrome
2 of all allopurinol users develop cutaneous rash
Frequency of hypersensitivity 1 in 260
DRESS syndrome
Drug Reaction Eosinophilia Systemic Symptoms
20 mortality rate
Life threatening toxicity vasculitis rash eosinophilia hepatitis progressive renal failure
Treatment early recognition withdrawal of drug supportive care Steroids N-acetyl-cysteine dialysis prn
29
Markel A IMAJ 2005
Terkeltaub RA in Primer on the Rheumatic Disease 13th ed 2008
The urate lowering efficacy and safety
of febuxostat in the treatment of the
hyperuricemia of gout
The CONFIRMS trial
Becker MA Schumacher HR Espinoza LR et al The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemia of gout the CONFIRMS trial Arthritis Res
Ther 201012(2)R63
Many long and short-term clinical trials have
proved the efficacy of Febuxostat in the treatment
of gout and lowering uric acid levels In these
studies Febuxostat was found to be superior to
allopurinol in reducing the serum uric acid levels
Some notable landmark clinical trials are FACT
APEX EXCEL FOCUS and CONFIRMS
Febuxostat versus Allopurinol Controlled Trial
(FACT) 2005
52 week randomized double-blind multicenter clinical trial that compared the safety and efficacy of febuxostat with allopurinol
760 patients with gout and a sUA gt80 mgdl were randomly assigned to receive either febuxostat 80 or 120mg or allopurinol 300mg once daily for 52 weeks
The primary endpoint was the proportion of patients to achieve a sUA concentration below 60 mgdl at the last three monthly measurements
The primary endpoint was achieved in 53 of patients receiving 80 mg febuxostat 62 of patients receiving 120mg and 21 of those receiving allopurinol (p lt0001 for each febuxostat group compared with allopurinol)
There was no statistical significance in the change in tophi size and number or the incidence of gout flare between the groups
Allopurinol Placebo controlled Efficacy study
of febuxostat (APEX) 2008
28 week randomized double-blind study of 1072 patients comparing the safety and efficacy of febuxostat allopurinol and placebo
Patients were randomized to a once daily fixed dose of placebo febuxostat 80mg120mg or 240 mg or allopurinol 300mg or 100mg depending on their baseline serum creatinine (le15 mgdl or ge16 to lt20 mgdl respectively)
After 1 year of treatment 82 of the patients in all febuxostat groups achieved sUA levels below 60 mgdl compared with 39 of the patients in both allopurinol groups In groups with moderate renal impairment the primary endpoint was achieved by 44 receiving febuxostat 80mg 45 receiving 120mg and 60 receiving 240mg compared with 0 in the allopurinol and placebo groups
However clinical endpoints were not statistically significant
The number of patients with moderate renal impairment was small
Febuxostat Comparative Extension Long-Term
study (EXCEL) 2009
160 week extension study for patients completing FACT and APEX
The studyrsquos aim was to determine long-term efficacy in sUA
lowering clinical benefits and safety of febuxostat or allopurinol
1086 patients were enrolled to receive fixed daily doses of
febuxostat 80mg or 120 mg or allopurinol 300 mg
After the first month of treatment nearly 80 of patients receiving
either febuxostat dose achieved sUA less than 6 mgdl compared
with only 46 of subjects on allopurinol There was no difference in
gout flare incidence and tophi reduction between the groups
Overall adverse events did not show significant differences among
groups
Febuxostat Open Label of Urate-Lowering
Efficacy and Safety (FOCUS) 2009
The FOCUS trial was a 5-year extension study that
assessed reduction and maintenance of sUA levels below
60 mgdl as the primary efficacy endpoint A total of
116 patients were initially enrolled to receive a dose of
80mg febuxostat with dose adjustment to either 40 or
120mg between weeks 4 and 24 93 maintained a sUA
level below 60 mgdl at 5 years
Objectives of CONFIRMS trial
The three-fold objectives of this Phase 3 double-blind RCT study were
1) To compare the UL efficacy of febuxostat at a dose of 40 mg with that of allopurinol at doses most commonly utilized in clinical practice
2) To evaluate UL efficacies of 80 mg and 40 mg daily doses of febuxostat compared with that of allopurinol in subjects with mild or moderate renal impairment
3) To gain prospective uniformly reviewed information regarding the safety of these agents particularly their comparative CV safety
Materials and methods
Subjects aged 18 to 85 years with a diagnosis of gout fulfilling American Rheumatology Association preliminary criteria and sUA ge 80 mgdL were eligible for enrollment
Subjects were enrolled at 324 sites in the United States
IRB approval was obtained and all the subjects provided written informed consent
At least 35 of subjects enrolled were to have mild or moderate renal impairment defined as baseline estimated creatinine clearance (eCLcr) of 60 to 89 mlminutes or 30 to 59 mlminutes
Subjects successfully completing either of the previously
reported long-term open-label febuxostat or
febuxostatallopurinol extension studies were also eligible for
enrollment
Exclusion criteria secondary hyperuricemia (for example
due to myeloproliferative disorder) xanthinuria severe renal
impairment (eCLcr lt30 mlminutes) alanine
aminotransferase and aspartate aminotransferase values gt15
times the upper limit of normal consumption of more than 14
alcoholic drinks per week or a history of alcoholism or drug
abuse within five years or a medical condition that in the
investigators opinion would interfere with treatment safety
or adherence to the protocol
Baseline characteristics of randomized subjects
Baseline characteristics of randomized subjects (cont)
Baseline characteristics of randomized subjects (cont)
2269 Subjects were randomized 111 on Day 1 to
receive daily febuxostat 40 mg febuxostat 80 mg or
allopurinol Among subjects randomized to allopurinol
those with normal renal function or mild renal
impairment received 300 mg daily and those with
moderate renal impairment received 200 mg
Throughout the subsequent six-month treatment period for all subjects prophylaxis for gout flares was given either as colchicine 06 mg daily or naproxen 250 mg twice daily All subjects receiving naproxen prophylaxis also received lansoprazole 15 mg daily
Choice of prophylaxis regimen was made by the investigator and subject taking into account prior drug tolerance and prophylaxis experience
In addition subjects with eCLcr lt50 mlminute were not to receive naproxen
Gout flares were regarded as expected gout manifestations rather than as AEs
The primary efficacy endpoint was the proportion of
subjects in each treatment group with sUA lt60 mgdL
at the final visit
Secondary efficacy variables included
1) The proportion of subjects with mild or moderate
renal impairment and final sUA lt60 mgdL
2) The proportion of subjects with sUA lt60 mgdL lt50
mgdL and lt40 mgdL at each visit
Efficacy analysisResults
Primary efficacy endpoint
1) The proportions of subjects achieving a final visit sUA lt60
mgdL were 452 671 and 421 in the febuxostat 40 mg
febuxostat 80 mg and allopurinol groups respectively
2) UL by febuxostat 40 mg was non-inferior to that by
allopurinol but the difference in the response rates between
the two groups (31 95 CI -19 to 81) was not significant
3) However the greater UL response rate with febuxostat 80 mg
compared with either febuxostat 40 mg (219) or allopurinol
(249) was significant (P lt 0001)
Secondary efficacy endpoints
Among subjects with any (mild or moderate) renal
impairment the UL response rate in the febuxostat 80
mg group (716 360503) significantly exceeded those
observed in the febuxostat 40 mg (497 238479) and
allopurinol (423 212501) groups (P le 0001 for each
comparison)
In addition among the total group of subjects with
renal impairment the UL response rate in the
febuxostat 40 mg group was significantly higher than
that in the allopurinol 300200 mg group (P = 0021)
At any sUA endpoint (lt60 mgdL lt50 mgdL or lt40 mgdL) and at any scheduled visit a significantly higher proportion of subjects receiving febuxostat 80 mg achieved the target endpoint than subjects receiving febuxostat 40 mg or allopurinol (P lt 0001)
Greater proportion of subjects in the febuxostat 40 mg group than the allopurinol group achieved sUAlt60 mgdL (at Month 2 visit P = 0031) and lt50 mgdL (at two- and six month visits P le 005) but significant differences were not seen at other visits including the final visit
Effect of baseline characteristic on treatment response
Adverse events
Adverse events
CONCLUSIONS
Results of the CONFIRMS trial establish equivalent UL efficacy for febuxostat 40 mg daily and allopurinol 300200 mg daily
At all levels of renal function studied UL efficacy of febuxostat 80 mg daily was superior to that of febuxostat 40 mg or allopurinol 300200 mg and was comparably safe
In subjects with mildly or moderately impaired renal function however febuxostat 40 mg daily was significantly more effective in lowering sUA than allopurinol
At the doses studied safety of febuxostat and allopurinol including CV safety was comparable
Febuxostat at 40 mg or 80 mg daily offers a well-tolerated UL alternative to allopurinol particularly for patients with mild or moderate renal impairment
Study limitations
The study does not address the efficacy of febuxostat compared with allopurinol in reducing clinically meaningful acute flares of gout
No mention is made of long-term cost-effectiveness of therapy
Additionally this study does not address the efficacy of febuxostat compared with allopurinol dosing that is more aggressive (ie gt 300 mg daily)
Allopurinol dosing was not titrated
The study population was not similar to the general population (majority of patients were white males)
Possible funding bias
Uloric Related Current Clinical
Trials
References
Dalbeth N Gracey E Pool B et al Identification of dairy fractions with anti-inflammatory properties in models of acute gout Ann
Rheum Dis 2010 69766ndash769
Choi HK Willett W Curhan G Coffee consumption and risk of incident gout in men a prospective study Arthritis Rheum 2007 562049ndash
2055
Hak AE Curhan GC Grodstein F Choi HK Menopause postmenopausal hormone use and risk of incident gout Ann Rheum Dis 2010
691305ndash1309
Becker MA Schumacher HR Wortmann RL et al (December 2005) Febuxostat compared with allopurinol in patients with hyperuricemia
and gout N Engl J Med 353 (23) 2450ndash61
Sarawate CA Patel PA Schumacher HR Yang W Brewer KK Bakst AW Serum urate levels and gout flares analysis from managed care
data J Clin Rheumatol 2006 1261-65
Schumacher HR Jr Becker MA Lloyd E MacDonald PA Lademacher C Febuxostat in the treatment of gout 5-yr findings of the FOCUS
efficacy and safety study Rheumatology (Oxford) 2009 48188-194
14 Becker MA Schumacher HR MacDonald PA Lloyd E Lademacher C Clinical efficacy and safety of successful long-term urate
lowering with febuxostat or allopurinol in subjects with gout J Rheumatol 2009 361273-1278
2012 ACR guidelines for management of gout
Uptodate
Medcape
Statistical Power
Power
The probability that the study will support the research hypothesis if it is true
1 Sample size (n)
2 Effect Size (d)
3 Significance Level (α)
4 Power (β)
As effect size increases power increases
As sample size increases power increases
As significance level increases power increases
Resources
httpwwwncbinlmnihgovpmcarticlesPMC3409926
httpswwwsealedenvelopecompowerbinary-superiority
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
23
Gout Management Approach
bullTreat acute flare rapidly with anti-
inflammatory agent
bullInitiate urate-lowering therapy to
achieve sUA lt6
bullUse concomitant anti-inflammatory
prophylaxis for up to 6 mo to prevent
mobilization flares
INITIATE(acute flare)
RESOLVE(urate-lowering therapy)
bullContinue urate lowering therapy
to control flares and avoid crystal
deposition
bullProphylaxis use for at least 3-6
months until sUA normalizes
MAINTAIN(treatment to control sUA)
24
Allopurinol vs Febuxostat
Allopurinol Febuxostat (Uloric)
FDA-approved 1966 FDA-approved 2009
Purine-selective XO Inhibitor Non-Purine Selective XO
Inhibitor
Prevents uric acid production Prevents uric acid production
Renal Metabolism Liver Metabolism
FEBUXOSTAT
For treatment of hyperuricemia in patients with gout
febuxostat is recommended at 40 mg or 80 mg once daily and
can be increased to 120 mg once daily if clinically indicated
The adverse effects associated with febuxostat therapy
include nausea diarrhea arthralgia headache increased
hepatic serum enzyme levels and rash
The manufacturer recommends liver function monitoring on
initiation of therapy at two and four months after initiation
and periodically thereafter
FEBUXOSTAT
Febuxostat is US Food and Drug Administration pregnancy
category C2
Febuxostat is contraindicated with concomitant use of
theophylline and chemotherapeutic agents namely
azathioprine and 6- mercaptopurine because it could
increase blood plasma concentrations of these drugs and
therefore their toxicity
Dosage adjustments are unnecessary for mild to moderate
renal or hepatic impairment
A one-month supply of 40 or 80-mg febuxostat costs
$28243 This price far exceeds the cost of allopurinol
which is $2424 for 100 100 mg tablets
CrCl (mLmin)
Maintenance Dose of
Allopurinol
0 100mg every 3d
10 100mg every 2d
20 100mg
40 150mg
60 200mg
80 250mg
100 300mg
120 350mg
140 400mg
Maintenance Doses of Allopurinol for
Adults based on CrCl
28
Hande KR et al Am J Med 1984
Stage 1 renal damage with
normal GFR
(GFR gt 90 mlmin)
Stage 2 Mild CKD (GFR = 60-
89 mlmin)
Stage 3 Moderate CKD (GFR
= 30-59 mlmin)
Stage 4 Severe CKD (GFR =
15-29 mlmin)
Stage 5 End Stage CKD (GFR
lt15 mlmin)
Allopurinol Hypersensitivity
Syndrome
2 of all allopurinol users develop cutaneous rash
Frequency of hypersensitivity 1 in 260
DRESS syndrome
Drug Reaction Eosinophilia Systemic Symptoms
20 mortality rate
Life threatening toxicity vasculitis rash eosinophilia hepatitis progressive renal failure
Treatment early recognition withdrawal of drug supportive care Steroids N-acetyl-cysteine dialysis prn
29
Markel A IMAJ 2005
Terkeltaub RA in Primer on the Rheumatic Disease 13th ed 2008
The urate lowering efficacy and safety
of febuxostat in the treatment of the
hyperuricemia of gout
The CONFIRMS trial
Becker MA Schumacher HR Espinoza LR et al The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemia of gout the CONFIRMS trial Arthritis Res
Ther 201012(2)R63
Many long and short-term clinical trials have
proved the efficacy of Febuxostat in the treatment
of gout and lowering uric acid levels In these
studies Febuxostat was found to be superior to
allopurinol in reducing the serum uric acid levels
Some notable landmark clinical trials are FACT
APEX EXCEL FOCUS and CONFIRMS
Febuxostat versus Allopurinol Controlled Trial
(FACT) 2005
52 week randomized double-blind multicenter clinical trial that compared the safety and efficacy of febuxostat with allopurinol
760 patients with gout and a sUA gt80 mgdl were randomly assigned to receive either febuxostat 80 or 120mg or allopurinol 300mg once daily for 52 weeks
The primary endpoint was the proportion of patients to achieve a sUA concentration below 60 mgdl at the last three monthly measurements
The primary endpoint was achieved in 53 of patients receiving 80 mg febuxostat 62 of patients receiving 120mg and 21 of those receiving allopurinol (p lt0001 for each febuxostat group compared with allopurinol)
There was no statistical significance in the change in tophi size and number or the incidence of gout flare between the groups
Allopurinol Placebo controlled Efficacy study
of febuxostat (APEX) 2008
28 week randomized double-blind study of 1072 patients comparing the safety and efficacy of febuxostat allopurinol and placebo
Patients were randomized to a once daily fixed dose of placebo febuxostat 80mg120mg or 240 mg or allopurinol 300mg or 100mg depending on their baseline serum creatinine (le15 mgdl or ge16 to lt20 mgdl respectively)
After 1 year of treatment 82 of the patients in all febuxostat groups achieved sUA levels below 60 mgdl compared with 39 of the patients in both allopurinol groups In groups with moderate renal impairment the primary endpoint was achieved by 44 receiving febuxostat 80mg 45 receiving 120mg and 60 receiving 240mg compared with 0 in the allopurinol and placebo groups
However clinical endpoints were not statistically significant
The number of patients with moderate renal impairment was small
Febuxostat Comparative Extension Long-Term
study (EXCEL) 2009
160 week extension study for patients completing FACT and APEX
The studyrsquos aim was to determine long-term efficacy in sUA
lowering clinical benefits and safety of febuxostat or allopurinol
1086 patients were enrolled to receive fixed daily doses of
febuxostat 80mg or 120 mg or allopurinol 300 mg
After the first month of treatment nearly 80 of patients receiving
either febuxostat dose achieved sUA less than 6 mgdl compared
with only 46 of subjects on allopurinol There was no difference in
gout flare incidence and tophi reduction between the groups
Overall adverse events did not show significant differences among
groups
Febuxostat Open Label of Urate-Lowering
Efficacy and Safety (FOCUS) 2009
The FOCUS trial was a 5-year extension study that
assessed reduction and maintenance of sUA levels below
60 mgdl as the primary efficacy endpoint A total of
116 patients were initially enrolled to receive a dose of
80mg febuxostat with dose adjustment to either 40 or
120mg between weeks 4 and 24 93 maintained a sUA
level below 60 mgdl at 5 years
Objectives of CONFIRMS trial
The three-fold objectives of this Phase 3 double-blind RCT study were
1) To compare the UL efficacy of febuxostat at a dose of 40 mg with that of allopurinol at doses most commonly utilized in clinical practice
2) To evaluate UL efficacies of 80 mg and 40 mg daily doses of febuxostat compared with that of allopurinol in subjects with mild or moderate renal impairment
3) To gain prospective uniformly reviewed information regarding the safety of these agents particularly their comparative CV safety
Materials and methods
Subjects aged 18 to 85 years with a diagnosis of gout fulfilling American Rheumatology Association preliminary criteria and sUA ge 80 mgdL were eligible for enrollment
Subjects were enrolled at 324 sites in the United States
IRB approval was obtained and all the subjects provided written informed consent
At least 35 of subjects enrolled were to have mild or moderate renal impairment defined as baseline estimated creatinine clearance (eCLcr) of 60 to 89 mlminutes or 30 to 59 mlminutes
Subjects successfully completing either of the previously
reported long-term open-label febuxostat or
febuxostatallopurinol extension studies were also eligible for
enrollment
Exclusion criteria secondary hyperuricemia (for example
due to myeloproliferative disorder) xanthinuria severe renal
impairment (eCLcr lt30 mlminutes) alanine
aminotransferase and aspartate aminotransferase values gt15
times the upper limit of normal consumption of more than 14
alcoholic drinks per week or a history of alcoholism or drug
abuse within five years or a medical condition that in the
investigators opinion would interfere with treatment safety
or adherence to the protocol
Baseline characteristics of randomized subjects
Baseline characteristics of randomized subjects (cont)
Baseline characteristics of randomized subjects (cont)
2269 Subjects were randomized 111 on Day 1 to
receive daily febuxostat 40 mg febuxostat 80 mg or
allopurinol Among subjects randomized to allopurinol
those with normal renal function or mild renal
impairment received 300 mg daily and those with
moderate renal impairment received 200 mg
Throughout the subsequent six-month treatment period for all subjects prophylaxis for gout flares was given either as colchicine 06 mg daily or naproxen 250 mg twice daily All subjects receiving naproxen prophylaxis also received lansoprazole 15 mg daily
Choice of prophylaxis regimen was made by the investigator and subject taking into account prior drug tolerance and prophylaxis experience
In addition subjects with eCLcr lt50 mlminute were not to receive naproxen
Gout flares were regarded as expected gout manifestations rather than as AEs
The primary efficacy endpoint was the proportion of
subjects in each treatment group with sUA lt60 mgdL
at the final visit
Secondary efficacy variables included
1) The proportion of subjects with mild or moderate
renal impairment and final sUA lt60 mgdL
2) The proportion of subjects with sUA lt60 mgdL lt50
mgdL and lt40 mgdL at each visit
Efficacy analysisResults
Primary efficacy endpoint
1) The proportions of subjects achieving a final visit sUA lt60
mgdL were 452 671 and 421 in the febuxostat 40 mg
febuxostat 80 mg and allopurinol groups respectively
2) UL by febuxostat 40 mg was non-inferior to that by
allopurinol but the difference in the response rates between
the two groups (31 95 CI -19 to 81) was not significant
3) However the greater UL response rate with febuxostat 80 mg
compared with either febuxostat 40 mg (219) or allopurinol
(249) was significant (P lt 0001)
Secondary efficacy endpoints
Among subjects with any (mild or moderate) renal
impairment the UL response rate in the febuxostat 80
mg group (716 360503) significantly exceeded those
observed in the febuxostat 40 mg (497 238479) and
allopurinol (423 212501) groups (P le 0001 for each
comparison)
In addition among the total group of subjects with
renal impairment the UL response rate in the
febuxostat 40 mg group was significantly higher than
that in the allopurinol 300200 mg group (P = 0021)
At any sUA endpoint (lt60 mgdL lt50 mgdL or lt40 mgdL) and at any scheduled visit a significantly higher proportion of subjects receiving febuxostat 80 mg achieved the target endpoint than subjects receiving febuxostat 40 mg or allopurinol (P lt 0001)
Greater proportion of subjects in the febuxostat 40 mg group than the allopurinol group achieved sUAlt60 mgdL (at Month 2 visit P = 0031) and lt50 mgdL (at two- and six month visits P le 005) but significant differences were not seen at other visits including the final visit
Effect of baseline characteristic on treatment response
Adverse events
Adverse events
CONCLUSIONS
Results of the CONFIRMS trial establish equivalent UL efficacy for febuxostat 40 mg daily and allopurinol 300200 mg daily
At all levels of renal function studied UL efficacy of febuxostat 80 mg daily was superior to that of febuxostat 40 mg or allopurinol 300200 mg and was comparably safe
In subjects with mildly or moderately impaired renal function however febuxostat 40 mg daily was significantly more effective in lowering sUA than allopurinol
At the doses studied safety of febuxostat and allopurinol including CV safety was comparable
Febuxostat at 40 mg or 80 mg daily offers a well-tolerated UL alternative to allopurinol particularly for patients with mild or moderate renal impairment
Study limitations
The study does not address the efficacy of febuxostat compared with allopurinol in reducing clinically meaningful acute flares of gout
No mention is made of long-term cost-effectiveness of therapy
Additionally this study does not address the efficacy of febuxostat compared with allopurinol dosing that is more aggressive (ie gt 300 mg daily)
Allopurinol dosing was not titrated
The study population was not similar to the general population (majority of patients were white males)
Possible funding bias
Uloric Related Current Clinical
Trials
References
Dalbeth N Gracey E Pool B et al Identification of dairy fractions with anti-inflammatory properties in models of acute gout Ann
Rheum Dis 2010 69766ndash769
Choi HK Willett W Curhan G Coffee consumption and risk of incident gout in men a prospective study Arthritis Rheum 2007 562049ndash
2055
Hak AE Curhan GC Grodstein F Choi HK Menopause postmenopausal hormone use and risk of incident gout Ann Rheum Dis 2010
691305ndash1309
Becker MA Schumacher HR Wortmann RL et al (December 2005) Febuxostat compared with allopurinol in patients with hyperuricemia
and gout N Engl J Med 353 (23) 2450ndash61
Sarawate CA Patel PA Schumacher HR Yang W Brewer KK Bakst AW Serum urate levels and gout flares analysis from managed care
data J Clin Rheumatol 2006 1261-65
Schumacher HR Jr Becker MA Lloyd E MacDonald PA Lademacher C Febuxostat in the treatment of gout 5-yr findings of the FOCUS
efficacy and safety study Rheumatology (Oxford) 2009 48188-194
14 Becker MA Schumacher HR MacDonald PA Lloyd E Lademacher C Clinical efficacy and safety of successful long-term urate
lowering with febuxostat or allopurinol in subjects with gout J Rheumatol 2009 361273-1278
2012 ACR guidelines for management of gout
Uptodate
Medcape
Statistical Power
Power
The probability that the study will support the research hypothesis if it is true
1 Sample size (n)
2 Effect Size (d)
3 Significance Level (α)
4 Power (β)
As effect size increases power increases
As sample size increases power increases
As significance level increases power increases
Resources
httpwwwncbinlmnihgovpmcarticlesPMC3409926
httpswwwsealedenvelopecompowerbinary-superiority
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
24
Allopurinol vs Febuxostat
Allopurinol Febuxostat (Uloric)
FDA-approved 1966 FDA-approved 2009
Purine-selective XO Inhibitor Non-Purine Selective XO
Inhibitor
Prevents uric acid production Prevents uric acid production
Renal Metabolism Liver Metabolism
FEBUXOSTAT
For treatment of hyperuricemia in patients with gout
febuxostat is recommended at 40 mg or 80 mg once daily and
can be increased to 120 mg once daily if clinically indicated
The adverse effects associated with febuxostat therapy
include nausea diarrhea arthralgia headache increased
hepatic serum enzyme levels and rash
The manufacturer recommends liver function monitoring on
initiation of therapy at two and four months after initiation
and periodically thereafter
FEBUXOSTAT
Febuxostat is US Food and Drug Administration pregnancy
category C2
Febuxostat is contraindicated with concomitant use of
theophylline and chemotherapeutic agents namely
azathioprine and 6- mercaptopurine because it could
increase blood plasma concentrations of these drugs and
therefore their toxicity
Dosage adjustments are unnecessary for mild to moderate
renal or hepatic impairment
A one-month supply of 40 or 80-mg febuxostat costs
$28243 This price far exceeds the cost of allopurinol
which is $2424 for 100 100 mg tablets
CrCl (mLmin)
Maintenance Dose of
Allopurinol
0 100mg every 3d
10 100mg every 2d
20 100mg
40 150mg
60 200mg
80 250mg
100 300mg
120 350mg
140 400mg
Maintenance Doses of Allopurinol for
Adults based on CrCl
28
Hande KR et al Am J Med 1984
Stage 1 renal damage with
normal GFR
(GFR gt 90 mlmin)
Stage 2 Mild CKD (GFR = 60-
89 mlmin)
Stage 3 Moderate CKD (GFR
= 30-59 mlmin)
Stage 4 Severe CKD (GFR =
15-29 mlmin)
Stage 5 End Stage CKD (GFR
lt15 mlmin)
Allopurinol Hypersensitivity
Syndrome
2 of all allopurinol users develop cutaneous rash
Frequency of hypersensitivity 1 in 260
DRESS syndrome
Drug Reaction Eosinophilia Systemic Symptoms
20 mortality rate
Life threatening toxicity vasculitis rash eosinophilia hepatitis progressive renal failure
Treatment early recognition withdrawal of drug supportive care Steroids N-acetyl-cysteine dialysis prn
29
Markel A IMAJ 2005
Terkeltaub RA in Primer on the Rheumatic Disease 13th ed 2008
The urate lowering efficacy and safety
of febuxostat in the treatment of the
hyperuricemia of gout
The CONFIRMS trial
Becker MA Schumacher HR Espinoza LR et al The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemia of gout the CONFIRMS trial Arthritis Res
Ther 201012(2)R63
Many long and short-term clinical trials have
proved the efficacy of Febuxostat in the treatment
of gout and lowering uric acid levels In these
studies Febuxostat was found to be superior to
allopurinol in reducing the serum uric acid levels
Some notable landmark clinical trials are FACT
APEX EXCEL FOCUS and CONFIRMS
Febuxostat versus Allopurinol Controlled Trial
(FACT) 2005
52 week randomized double-blind multicenter clinical trial that compared the safety and efficacy of febuxostat with allopurinol
760 patients with gout and a sUA gt80 mgdl were randomly assigned to receive either febuxostat 80 or 120mg or allopurinol 300mg once daily for 52 weeks
The primary endpoint was the proportion of patients to achieve a sUA concentration below 60 mgdl at the last three monthly measurements
The primary endpoint was achieved in 53 of patients receiving 80 mg febuxostat 62 of patients receiving 120mg and 21 of those receiving allopurinol (p lt0001 for each febuxostat group compared with allopurinol)
There was no statistical significance in the change in tophi size and number or the incidence of gout flare between the groups
Allopurinol Placebo controlled Efficacy study
of febuxostat (APEX) 2008
28 week randomized double-blind study of 1072 patients comparing the safety and efficacy of febuxostat allopurinol and placebo
Patients were randomized to a once daily fixed dose of placebo febuxostat 80mg120mg or 240 mg or allopurinol 300mg or 100mg depending on their baseline serum creatinine (le15 mgdl or ge16 to lt20 mgdl respectively)
After 1 year of treatment 82 of the patients in all febuxostat groups achieved sUA levels below 60 mgdl compared with 39 of the patients in both allopurinol groups In groups with moderate renal impairment the primary endpoint was achieved by 44 receiving febuxostat 80mg 45 receiving 120mg and 60 receiving 240mg compared with 0 in the allopurinol and placebo groups
However clinical endpoints were not statistically significant
The number of patients with moderate renal impairment was small
Febuxostat Comparative Extension Long-Term
study (EXCEL) 2009
160 week extension study for patients completing FACT and APEX
The studyrsquos aim was to determine long-term efficacy in sUA
lowering clinical benefits and safety of febuxostat or allopurinol
1086 patients were enrolled to receive fixed daily doses of
febuxostat 80mg or 120 mg or allopurinol 300 mg
After the first month of treatment nearly 80 of patients receiving
either febuxostat dose achieved sUA less than 6 mgdl compared
with only 46 of subjects on allopurinol There was no difference in
gout flare incidence and tophi reduction between the groups
Overall adverse events did not show significant differences among
groups
Febuxostat Open Label of Urate-Lowering
Efficacy and Safety (FOCUS) 2009
The FOCUS trial was a 5-year extension study that
assessed reduction and maintenance of sUA levels below
60 mgdl as the primary efficacy endpoint A total of
116 patients were initially enrolled to receive a dose of
80mg febuxostat with dose adjustment to either 40 or
120mg between weeks 4 and 24 93 maintained a sUA
level below 60 mgdl at 5 years
Objectives of CONFIRMS trial
The three-fold objectives of this Phase 3 double-blind RCT study were
1) To compare the UL efficacy of febuxostat at a dose of 40 mg with that of allopurinol at doses most commonly utilized in clinical practice
2) To evaluate UL efficacies of 80 mg and 40 mg daily doses of febuxostat compared with that of allopurinol in subjects with mild or moderate renal impairment
3) To gain prospective uniformly reviewed information regarding the safety of these agents particularly their comparative CV safety
Materials and methods
Subjects aged 18 to 85 years with a diagnosis of gout fulfilling American Rheumatology Association preliminary criteria and sUA ge 80 mgdL were eligible for enrollment
Subjects were enrolled at 324 sites in the United States
IRB approval was obtained and all the subjects provided written informed consent
At least 35 of subjects enrolled were to have mild or moderate renal impairment defined as baseline estimated creatinine clearance (eCLcr) of 60 to 89 mlminutes or 30 to 59 mlminutes
Subjects successfully completing either of the previously
reported long-term open-label febuxostat or
febuxostatallopurinol extension studies were also eligible for
enrollment
Exclusion criteria secondary hyperuricemia (for example
due to myeloproliferative disorder) xanthinuria severe renal
impairment (eCLcr lt30 mlminutes) alanine
aminotransferase and aspartate aminotransferase values gt15
times the upper limit of normal consumption of more than 14
alcoholic drinks per week or a history of alcoholism or drug
abuse within five years or a medical condition that in the
investigators opinion would interfere with treatment safety
or adherence to the protocol
Baseline characteristics of randomized subjects
Baseline characteristics of randomized subjects (cont)
Baseline characteristics of randomized subjects (cont)
2269 Subjects were randomized 111 on Day 1 to
receive daily febuxostat 40 mg febuxostat 80 mg or
allopurinol Among subjects randomized to allopurinol
those with normal renal function or mild renal
impairment received 300 mg daily and those with
moderate renal impairment received 200 mg
Throughout the subsequent six-month treatment period for all subjects prophylaxis for gout flares was given either as colchicine 06 mg daily or naproxen 250 mg twice daily All subjects receiving naproxen prophylaxis also received lansoprazole 15 mg daily
Choice of prophylaxis regimen was made by the investigator and subject taking into account prior drug tolerance and prophylaxis experience
In addition subjects with eCLcr lt50 mlminute were not to receive naproxen
Gout flares were regarded as expected gout manifestations rather than as AEs
The primary efficacy endpoint was the proportion of
subjects in each treatment group with sUA lt60 mgdL
at the final visit
Secondary efficacy variables included
1) The proportion of subjects with mild or moderate
renal impairment and final sUA lt60 mgdL
2) The proportion of subjects with sUA lt60 mgdL lt50
mgdL and lt40 mgdL at each visit
Efficacy analysisResults
Primary efficacy endpoint
1) The proportions of subjects achieving a final visit sUA lt60
mgdL were 452 671 and 421 in the febuxostat 40 mg
febuxostat 80 mg and allopurinol groups respectively
2) UL by febuxostat 40 mg was non-inferior to that by
allopurinol but the difference in the response rates between
the two groups (31 95 CI -19 to 81) was not significant
3) However the greater UL response rate with febuxostat 80 mg
compared with either febuxostat 40 mg (219) or allopurinol
(249) was significant (P lt 0001)
Secondary efficacy endpoints
Among subjects with any (mild or moderate) renal
impairment the UL response rate in the febuxostat 80
mg group (716 360503) significantly exceeded those
observed in the febuxostat 40 mg (497 238479) and
allopurinol (423 212501) groups (P le 0001 for each
comparison)
In addition among the total group of subjects with
renal impairment the UL response rate in the
febuxostat 40 mg group was significantly higher than
that in the allopurinol 300200 mg group (P = 0021)
At any sUA endpoint (lt60 mgdL lt50 mgdL or lt40 mgdL) and at any scheduled visit a significantly higher proportion of subjects receiving febuxostat 80 mg achieved the target endpoint than subjects receiving febuxostat 40 mg or allopurinol (P lt 0001)
Greater proportion of subjects in the febuxostat 40 mg group than the allopurinol group achieved sUAlt60 mgdL (at Month 2 visit P = 0031) and lt50 mgdL (at two- and six month visits P le 005) but significant differences were not seen at other visits including the final visit
Effect of baseline characteristic on treatment response
Adverse events
Adverse events
CONCLUSIONS
Results of the CONFIRMS trial establish equivalent UL efficacy for febuxostat 40 mg daily and allopurinol 300200 mg daily
At all levels of renal function studied UL efficacy of febuxostat 80 mg daily was superior to that of febuxostat 40 mg or allopurinol 300200 mg and was comparably safe
In subjects with mildly or moderately impaired renal function however febuxostat 40 mg daily was significantly more effective in lowering sUA than allopurinol
At the doses studied safety of febuxostat and allopurinol including CV safety was comparable
Febuxostat at 40 mg or 80 mg daily offers a well-tolerated UL alternative to allopurinol particularly for patients with mild or moderate renal impairment
Study limitations
The study does not address the efficacy of febuxostat compared with allopurinol in reducing clinically meaningful acute flares of gout
No mention is made of long-term cost-effectiveness of therapy
Additionally this study does not address the efficacy of febuxostat compared with allopurinol dosing that is more aggressive (ie gt 300 mg daily)
Allopurinol dosing was not titrated
The study population was not similar to the general population (majority of patients were white males)
Possible funding bias
Uloric Related Current Clinical
Trials
References
Dalbeth N Gracey E Pool B et al Identification of dairy fractions with anti-inflammatory properties in models of acute gout Ann
Rheum Dis 2010 69766ndash769
Choi HK Willett W Curhan G Coffee consumption and risk of incident gout in men a prospective study Arthritis Rheum 2007 562049ndash
2055
Hak AE Curhan GC Grodstein F Choi HK Menopause postmenopausal hormone use and risk of incident gout Ann Rheum Dis 2010
691305ndash1309
Becker MA Schumacher HR Wortmann RL et al (December 2005) Febuxostat compared with allopurinol in patients with hyperuricemia
and gout N Engl J Med 353 (23) 2450ndash61
Sarawate CA Patel PA Schumacher HR Yang W Brewer KK Bakst AW Serum urate levels and gout flares analysis from managed care
data J Clin Rheumatol 2006 1261-65
Schumacher HR Jr Becker MA Lloyd E MacDonald PA Lademacher C Febuxostat in the treatment of gout 5-yr findings of the FOCUS
efficacy and safety study Rheumatology (Oxford) 2009 48188-194
14 Becker MA Schumacher HR MacDonald PA Lloyd E Lademacher C Clinical efficacy and safety of successful long-term urate
lowering with febuxostat or allopurinol in subjects with gout J Rheumatol 2009 361273-1278
2012 ACR guidelines for management of gout
Uptodate
Medcape
Statistical Power
Power
The probability that the study will support the research hypothesis if it is true
1 Sample size (n)
2 Effect Size (d)
3 Significance Level (α)
4 Power (β)
As effect size increases power increases
As sample size increases power increases
As significance level increases power increases
Resources
httpwwwncbinlmnihgovpmcarticlesPMC3409926
httpswwwsealedenvelopecompowerbinary-superiority
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
FEBUXOSTAT
For treatment of hyperuricemia in patients with gout
febuxostat is recommended at 40 mg or 80 mg once daily and
can be increased to 120 mg once daily if clinically indicated
The adverse effects associated with febuxostat therapy
include nausea diarrhea arthralgia headache increased
hepatic serum enzyme levels and rash
The manufacturer recommends liver function monitoring on
initiation of therapy at two and four months after initiation
and periodically thereafter
FEBUXOSTAT
Febuxostat is US Food and Drug Administration pregnancy
category C2
Febuxostat is contraindicated with concomitant use of
theophylline and chemotherapeutic agents namely
azathioprine and 6- mercaptopurine because it could
increase blood plasma concentrations of these drugs and
therefore their toxicity
Dosage adjustments are unnecessary for mild to moderate
renal or hepatic impairment
A one-month supply of 40 or 80-mg febuxostat costs
$28243 This price far exceeds the cost of allopurinol
which is $2424 for 100 100 mg tablets
CrCl (mLmin)
Maintenance Dose of
Allopurinol
0 100mg every 3d
10 100mg every 2d
20 100mg
40 150mg
60 200mg
80 250mg
100 300mg
120 350mg
140 400mg
Maintenance Doses of Allopurinol for
Adults based on CrCl
28
Hande KR et al Am J Med 1984
Stage 1 renal damage with
normal GFR
(GFR gt 90 mlmin)
Stage 2 Mild CKD (GFR = 60-
89 mlmin)
Stage 3 Moderate CKD (GFR
= 30-59 mlmin)
Stage 4 Severe CKD (GFR =
15-29 mlmin)
Stage 5 End Stage CKD (GFR
lt15 mlmin)
Allopurinol Hypersensitivity
Syndrome
2 of all allopurinol users develop cutaneous rash
Frequency of hypersensitivity 1 in 260
DRESS syndrome
Drug Reaction Eosinophilia Systemic Symptoms
20 mortality rate
Life threatening toxicity vasculitis rash eosinophilia hepatitis progressive renal failure
Treatment early recognition withdrawal of drug supportive care Steroids N-acetyl-cysteine dialysis prn
29
Markel A IMAJ 2005
Terkeltaub RA in Primer on the Rheumatic Disease 13th ed 2008
The urate lowering efficacy and safety
of febuxostat in the treatment of the
hyperuricemia of gout
The CONFIRMS trial
Becker MA Schumacher HR Espinoza LR et al The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemia of gout the CONFIRMS trial Arthritis Res
Ther 201012(2)R63
Many long and short-term clinical trials have
proved the efficacy of Febuxostat in the treatment
of gout and lowering uric acid levels In these
studies Febuxostat was found to be superior to
allopurinol in reducing the serum uric acid levels
Some notable landmark clinical trials are FACT
APEX EXCEL FOCUS and CONFIRMS
Febuxostat versus Allopurinol Controlled Trial
(FACT) 2005
52 week randomized double-blind multicenter clinical trial that compared the safety and efficacy of febuxostat with allopurinol
760 patients with gout and a sUA gt80 mgdl were randomly assigned to receive either febuxostat 80 or 120mg or allopurinol 300mg once daily for 52 weeks
The primary endpoint was the proportion of patients to achieve a sUA concentration below 60 mgdl at the last three monthly measurements
The primary endpoint was achieved in 53 of patients receiving 80 mg febuxostat 62 of patients receiving 120mg and 21 of those receiving allopurinol (p lt0001 for each febuxostat group compared with allopurinol)
There was no statistical significance in the change in tophi size and number or the incidence of gout flare between the groups
Allopurinol Placebo controlled Efficacy study
of febuxostat (APEX) 2008
28 week randomized double-blind study of 1072 patients comparing the safety and efficacy of febuxostat allopurinol and placebo
Patients were randomized to a once daily fixed dose of placebo febuxostat 80mg120mg or 240 mg or allopurinol 300mg or 100mg depending on their baseline serum creatinine (le15 mgdl or ge16 to lt20 mgdl respectively)
After 1 year of treatment 82 of the patients in all febuxostat groups achieved sUA levels below 60 mgdl compared with 39 of the patients in both allopurinol groups In groups with moderate renal impairment the primary endpoint was achieved by 44 receiving febuxostat 80mg 45 receiving 120mg and 60 receiving 240mg compared with 0 in the allopurinol and placebo groups
However clinical endpoints were not statistically significant
The number of patients with moderate renal impairment was small
Febuxostat Comparative Extension Long-Term
study (EXCEL) 2009
160 week extension study for patients completing FACT and APEX
The studyrsquos aim was to determine long-term efficacy in sUA
lowering clinical benefits and safety of febuxostat or allopurinol
1086 patients were enrolled to receive fixed daily doses of
febuxostat 80mg or 120 mg or allopurinol 300 mg
After the first month of treatment nearly 80 of patients receiving
either febuxostat dose achieved sUA less than 6 mgdl compared
with only 46 of subjects on allopurinol There was no difference in
gout flare incidence and tophi reduction between the groups
Overall adverse events did not show significant differences among
groups
Febuxostat Open Label of Urate-Lowering
Efficacy and Safety (FOCUS) 2009
The FOCUS trial was a 5-year extension study that
assessed reduction and maintenance of sUA levels below
60 mgdl as the primary efficacy endpoint A total of
116 patients were initially enrolled to receive a dose of
80mg febuxostat with dose adjustment to either 40 or
120mg between weeks 4 and 24 93 maintained a sUA
level below 60 mgdl at 5 years
Objectives of CONFIRMS trial
The three-fold objectives of this Phase 3 double-blind RCT study were
1) To compare the UL efficacy of febuxostat at a dose of 40 mg with that of allopurinol at doses most commonly utilized in clinical practice
2) To evaluate UL efficacies of 80 mg and 40 mg daily doses of febuxostat compared with that of allopurinol in subjects with mild or moderate renal impairment
3) To gain prospective uniformly reviewed information regarding the safety of these agents particularly their comparative CV safety
Materials and methods
Subjects aged 18 to 85 years with a diagnosis of gout fulfilling American Rheumatology Association preliminary criteria and sUA ge 80 mgdL were eligible for enrollment
Subjects were enrolled at 324 sites in the United States
IRB approval was obtained and all the subjects provided written informed consent
At least 35 of subjects enrolled were to have mild or moderate renal impairment defined as baseline estimated creatinine clearance (eCLcr) of 60 to 89 mlminutes or 30 to 59 mlminutes
Subjects successfully completing either of the previously
reported long-term open-label febuxostat or
febuxostatallopurinol extension studies were also eligible for
enrollment
Exclusion criteria secondary hyperuricemia (for example
due to myeloproliferative disorder) xanthinuria severe renal
impairment (eCLcr lt30 mlminutes) alanine
aminotransferase and aspartate aminotransferase values gt15
times the upper limit of normal consumption of more than 14
alcoholic drinks per week or a history of alcoholism or drug
abuse within five years or a medical condition that in the
investigators opinion would interfere with treatment safety
or adherence to the protocol
Baseline characteristics of randomized subjects
Baseline characteristics of randomized subjects (cont)
Baseline characteristics of randomized subjects (cont)
2269 Subjects were randomized 111 on Day 1 to
receive daily febuxostat 40 mg febuxostat 80 mg or
allopurinol Among subjects randomized to allopurinol
those with normal renal function or mild renal
impairment received 300 mg daily and those with
moderate renal impairment received 200 mg
Throughout the subsequent six-month treatment period for all subjects prophylaxis for gout flares was given either as colchicine 06 mg daily or naproxen 250 mg twice daily All subjects receiving naproxen prophylaxis also received lansoprazole 15 mg daily
Choice of prophylaxis regimen was made by the investigator and subject taking into account prior drug tolerance and prophylaxis experience
In addition subjects with eCLcr lt50 mlminute were not to receive naproxen
Gout flares were regarded as expected gout manifestations rather than as AEs
The primary efficacy endpoint was the proportion of
subjects in each treatment group with sUA lt60 mgdL
at the final visit
Secondary efficacy variables included
1) The proportion of subjects with mild or moderate
renal impairment and final sUA lt60 mgdL
2) The proportion of subjects with sUA lt60 mgdL lt50
mgdL and lt40 mgdL at each visit
Efficacy analysisResults
Primary efficacy endpoint
1) The proportions of subjects achieving a final visit sUA lt60
mgdL were 452 671 and 421 in the febuxostat 40 mg
febuxostat 80 mg and allopurinol groups respectively
2) UL by febuxostat 40 mg was non-inferior to that by
allopurinol but the difference in the response rates between
the two groups (31 95 CI -19 to 81) was not significant
3) However the greater UL response rate with febuxostat 80 mg
compared with either febuxostat 40 mg (219) or allopurinol
(249) was significant (P lt 0001)
Secondary efficacy endpoints
Among subjects with any (mild or moderate) renal
impairment the UL response rate in the febuxostat 80
mg group (716 360503) significantly exceeded those
observed in the febuxostat 40 mg (497 238479) and
allopurinol (423 212501) groups (P le 0001 for each
comparison)
In addition among the total group of subjects with
renal impairment the UL response rate in the
febuxostat 40 mg group was significantly higher than
that in the allopurinol 300200 mg group (P = 0021)
At any sUA endpoint (lt60 mgdL lt50 mgdL or lt40 mgdL) and at any scheduled visit a significantly higher proportion of subjects receiving febuxostat 80 mg achieved the target endpoint than subjects receiving febuxostat 40 mg or allopurinol (P lt 0001)
Greater proportion of subjects in the febuxostat 40 mg group than the allopurinol group achieved sUAlt60 mgdL (at Month 2 visit P = 0031) and lt50 mgdL (at two- and six month visits P le 005) but significant differences were not seen at other visits including the final visit
Effect of baseline characteristic on treatment response
Adverse events
Adverse events
CONCLUSIONS
Results of the CONFIRMS trial establish equivalent UL efficacy for febuxostat 40 mg daily and allopurinol 300200 mg daily
At all levels of renal function studied UL efficacy of febuxostat 80 mg daily was superior to that of febuxostat 40 mg or allopurinol 300200 mg and was comparably safe
In subjects with mildly or moderately impaired renal function however febuxostat 40 mg daily was significantly more effective in lowering sUA than allopurinol
At the doses studied safety of febuxostat and allopurinol including CV safety was comparable
Febuxostat at 40 mg or 80 mg daily offers a well-tolerated UL alternative to allopurinol particularly for patients with mild or moderate renal impairment
Study limitations
The study does not address the efficacy of febuxostat compared with allopurinol in reducing clinically meaningful acute flares of gout
No mention is made of long-term cost-effectiveness of therapy
Additionally this study does not address the efficacy of febuxostat compared with allopurinol dosing that is more aggressive (ie gt 300 mg daily)
Allopurinol dosing was not titrated
The study population was not similar to the general population (majority of patients were white males)
Possible funding bias
Uloric Related Current Clinical
Trials
References
Dalbeth N Gracey E Pool B et al Identification of dairy fractions with anti-inflammatory properties in models of acute gout Ann
Rheum Dis 2010 69766ndash769
Choi HK Willett W Curhan G Coffee consumption and risk of incident gout in men a prospective study Arthritis Rheum 2007 562049ndash
2055
Hak AE Curhan GC Grodstein F Choi HK Menopause postmenopausal hormone use and risk of incident gout Ann Rheum Dis 2010
691305ndash1309
Becker MA Schumacher HR Wortmann RL et al (December 2005) Febuxostat compared with allopurinol in patients with hyperuricemia
and gout N Engl J Med 353 (23) 2450ndash61
Sarawate CA Patel PA Schumacher HR Yang W Brewer KK Bakst AW Serum urate levels and gout flares analysis from managed care
data J Clin Rheumatol 2006 1261-65
Schumacher HR Jr Becker MA Lloyd E MacDonald PA Lademacher C Febuxostat in the treatment of gout 5-yr findings of the FOCUS
efficacy and safety study Rheumatology (Oxford) 2009 48188-194
14 Becker MA Schumacher HR MacDonald PA Lloyd E Lademacher C Clinical efficacy and safety of successful long-term urate
lowering with febuxostat or allopurinol in subjects with gout J Rheumatol 2009 361273-1278
2012 ACR guidelines for management of gout
Uptodate
Medcape
Statistical Power
Power
The probability that the study will support the research hypothesis if it is true
1 Sample size (n)
2 Effect Size (d)
3 Significance Level (α)
4 Power (β)
As effect size increases power increases
As sample size increases power increases
As significance level increases power increases
Resources
httpwwwncbinlmnihgovpmcarticlesPMC3409926
httpswwwsealedenvelopecompowerbinary-superiority
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
FEBUXOSTAT
Febuxostat is US Food and Drug Administration pregnancy
category C2
Febuxostat is contraindicated with concomitant use of
theophylline and chemotherapeutic agents namely
azathioprine and 6- mercaptopurine because it could
increase blood plasma concentrations of these drugs and
therefore their toxicity
Dosage adjustments are unnecessary for mild to moderate
renal or hepatic impairment
A one-month supply of 40 or 80-mg febuxostat costs
$28243 This price far exceeds the cost of allopurinol
which is $2424 for 100 100 mg tablets
CrCl (mLmin)
Maintenance Dose of
Allopurinol
0 100mg every 3d
10 100mg every 2d
20 100mg
40 150mg
60 200mg
80 250mg
100 300mg
120 350mg
140 400mg
Maintenance Doses of Allopurinol for
Adults based on CrCl
28
Hande KR et al Am J Med 1984
Stage 1 renal damage with
normal GFR
(GFR gt 90 mlmin)
Stage 2 Mild CKD (GFR = 60-
89 mlmin)
Stage 3 Moderate CKD (GFR
= 30-59 mlmin)
Stage 4 Severe CKD (GFR =
15-29 mlmin)
Stage 5 End Stage CKD (GFR
lt15 mlmin)
Allopurinol Hypersensitivity
Syndrome
2 of all allopurinol users develop cutaneous rash
Frequency of hypersensitivity 1 in 260
DRESS syndrome
Drug Reaction Eosinophilia Systemic Symptoms
20 mortality rate
Life threatening toxicity vasculitis rash eosinophilia hepatitis progressive renal failure
Treatment early recognition withdrawal of drug supportive care Steroids N-acetyl-cysteine dialysis prn
29
Markel A IMAJ 2005
Terkeltaub RA in Primer on the Rheumatic Disease 13th ed 2008
The urate lowering efficacy and safety
of febuxostat in the treatment of the
hyperuricemia of gout
The CONFIRMS trial
Becker MA Schumacher HR Espinoza LR et al The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemia of gout the CONFIRMS trial Arthritis Res
Ther 201012(2)R63
Many long and short-term clinical trials have
proved the efficacy of Febuxostat in the treatment
of gout and lowering uric acid levels In these
studies Febuxostat was found to be superior to
allopurinol in reducing the serum uric acid levels
Some notable landmark clinical trials are FACT
APEX EXCEL FOCUS and CONFIRMS
Febuxostat versus Allopurinol Controlled Trial
(FACT) 2005
52 week randomized double-blind multicenter clinical trial that compared the safety and efficacy of febuxostat with allopurinol
760 patients with gout and a sUA gt80 mgdl were randomly assigned to receive either febuxostat 80 or 120mg or allopurinol 300mg once daily for 52 weeks
The primary endpoint was the proportion of patients to achieve a sUA concentration below 60 mgdl at the last three monthly measurements
The primary endpoint was achieved in 53 of patients receiving 80 mg febuxostat 62 of patients receiving 120mg and 21 of those receiving allopurinol (p lt0001 for each febuxostat group compared with allopurinol)
There was no statistical significance in the change in tophi size and number or the incidence of gout flare between the groups
Allopurinol Placebo controlled Efficacy study
of febuxostat (APEX) 2008
28 week randomized double-blind study of 1072 patients comparing the safety and efficacy of febuxostat allopurinol and placebo
Patients were randomized to a once daily fixed dose of placebo febuxostat 80mg120mg or 240 mg or allopurinol 300mg or 100mg depending on their baseline serum creatinine (le15 mgdl or ge16 to lt20 mgdl respectively)
After 1 year of treatment 82 of the patients in all febuxostat groups achieved sUA levels below 60 mgdl compared with 39 of the patients in both allopurinol groups In groups with moderate renal impairment the primary endpoint was achieved by 44 receiving febuxostat 80mg 45 receiving 120mg and 60 receiving 240mg compared with 0 in the allopurinol and placebo groups
However clinical endpoints were not statistically significant
The number of patients with moderate renal impairment was small
Febuxostat Comparative Extension Long-Term
study (EXCEL) 2009
160 week extension study for patients completing FACT and APEX
The studyrsquos aim was to determine long-term efficacy in sUA
lowering clinical benefits and safety of febuxostat or allopurinol
1086 patients were enrolled to receive fixed daily doses of
febuxostat 80mg or 120 mg or allopurinol 300 mg
After the first month of treatment nearly 80 of patients receiving
either febuxostat dose achieved sUA less than 6 mgdl compared
with only 46 of subjects on allopurinol There was no difference in
gout flare incidence and tophi reduction between the groups
Overall adverse events did not show significant differences among
groups
Febuxostat Open Label of Urate-Lowering
Efficacy and Safety (FOCUS) 2009
The FOCUS trial was a 5-year extension study that
assessed reduction and maintenance of sUA levels below
60 mgdl as the primary efficacy endpoint A total of
116 patients were initially enrolled to receive a dose of
80mg febuxostat with dose adjustment to either 40 or
120mg between weeks 4 and 24 93 maintained a sUA
level below 60 mgdl at 5 years
Objectives of CONFIRMS trial
The three-fold objectives of this Phase 3 double-blind RCT study were
1) To compare the UL efficacy of febuxostat at a dose of 40 mg with that of allopurinol at doses most commonly utilized in clinical practice
2) To evaluate UL efficacies of 80 mg and 40 mg daily doses of febuxostat compared with that of allopurinol in subjects with mild or moderate renal impairment
3) To gain prospective uniformly reviewed information regarding the safety of these agents particularly their comparative CV safety
Materials and methods
Subjects aged 18 to 85 years with a diagnosis of gout fulfilling American Rheumatology Association preliminary criteria and sUA ge 80 mgdL were eligible for enrollment
Subjects were enrolled at 324 sites in the United States
IRB approval was obtained and all the subjects provided written informed consent
At least 35 of subjects enrolled were to have mild or moderate renal impairment defined as baseline estimated creatinine clearance (eCLcr) of 60 to 89 mlminutes or 30 to 59 mlminutes
Subjects successfully completing either of the previously
reported long-term open-label febuxostat or
febuxostatallopurinol extension studies were also eligible for
enrollment
Exclusion criteria secondary hyperuricemia (for example
due to myeloproliferative disorder) xanthinuria severe renal
impairment (eCLcr lt30 mlminutes) alanine
aminotransferase and aspartate aminotransferase values gt15
times the upper limit of normal consumption of more than 14
alcoholic drinks per week or a history of alcoholism or drug
abuse within five years or a medical condition that in the
investigators opinion would interfere with treatment safety
or adherence to the protocol
Baseline characteristics of randomized subjects
Baseline characteristics of randomized subjects (cont)
Baseline characteristics of randomized subjects (cont)
2269 Subjects were randomized 111 on Day 1 to
receive daily febuxostat 40 mg febuxostat 80 mg or
allopurinol Among subjects randomized to allopurinol
those with normal renal function or mild renal
impairment received 300 mg daily and those with
moderate renal impairment received 200 mg
Throughout the subsequent six-month treatment period for all subjects prophylaxis for gout flares was given either as colchicine 06 mg daily or naproxen 250 mg twice daily All subjects receiving naproxen prophylaxis also received lansoprazole 15 mg daily
Choice of prophylaxis regimen was made by the investigator and subject taking into account prior drug tolerance and prophylaxis experience
In addition subjects with eCLcr lt50 mlminute were not to receive naproxen
Gout flares were regarded as expected gout manifestations rather than as AEs
The primary efficacy endpoint was the proportion of
subjects in each treatment group with sUA lt60 mgdL
at the final visit
Secondary efficacy variables included
1) The proportion of subjects with mild or moderate
renal impairment and final sUA lt60 mgdL
2) The proportion of subjects with sUA lt60 mgdL lt50
mgdL and lt40 mgdL at each visit
Efficacy analysisResults
Primary efficacy endpoint
1) The proportions of subjects achieving a final visit sUA lt60
mgdL were 452 671 and 421 in the febuxostat 40 mg
febuxostat 80 mg and allopurinol groups respectively
2) UL by febuxostat 40 mg was non-inferior to that by
allopurinol but the difference in the response rates between
the two groups (31 95 CI -19 to 81) was not significant
3) However the greater UL response rate with febuxostat 80 mg
compared with either febuxostat 40 mg (219) or allopurinol
(249) was significant (P lt 0001)
Secondary efficacy endpoints
Among subjects with any (mild or moderate) renal
impairment the UL response rate in the febuxostat 80
mg group (716 360503) significantly exceeded those
observed in the febuxostat 40 mg (497 238479) and
allopurinol (423 212501) groups (P le 0001 for each
comparison)
In addition among the total group of subjects with
renal impairment the UL response rate in the
febuxostat 40 mg group was significantly higher than
that in the allopurinol 300200 mg group (P = 0021)
At any sUA endpoint (lt60 mgdL lt50 mgdL or lt40 mgdL) and at any scheduled visit a significantly higher proportion of subjects receiving febuxostat 80 mg achieved the target endpoint than subjects receiving febuxostat 40 mg or allopurinol (P lt 0001)
Greater proportion of subjects in the febuxostat 40 mg group than the allopurinol group achieved sUAlt60 mgdL (at Month 2 visit P = 0031) and lt50 mgdL (at two- and six month visits P le 005) but significant differences were not seen at other visits including the final visit
Effect of baseline characteristic on treatment response
Adverse events
Adverse events
CONCLUSIONS
Results of the CONFIRMS trial establish equivalent UL efficacy for febuxostat 40 mg daily and allopurinol 300200 mg daily
At all levels of renal function studied UL efficacy of febuxostat 80 mg daily was superior to that of febuxostat 40 mg or allopurinol 300200 mg and was comparably safe
In subjects with mildly or moderately impaired renal function however febuxostat 40 mg daily was significantly more effective in lowering sUA than allopurinol
At the doses studied safety of febuxostat and allopurinol including CV safety was comparable
Febuxostat at 40 mg or 80 mg daily offers a well-tolerated UL alternative to allopurinol particularly for patients with mild or moderate renal impairment
Study limitations
The study does not address the efficacy of febuxostat compared with allopurinol in reducing clinically meaningful acute flares of gout
No mention is made of long-term cost-effectiveness of therapy
Additionally this study does not address the efficacy of febuxostat compared with allopurinol dosing that is more aggressive (ie gt 300 mg daily)
Allopurinol dosing was not titrated
The study population was not similar to the general population (majority of patients were white males)
Possible funding bias
Uloric Related Current Clinical
Trials
References
Dalbeth N Gracey E Pool B et al Identification of dairy fractions with anti-inflammatory properties in models of acute gout Ann
Rheum Dis 2010 69766ndash769
Choi HK Willett W Curhan G Coffee consumption and risk of incident gout in men a prospective study Arthritis Rheum 2007 562049ndash
2055
Hak AE Curhan GC Grodstein F Choi HK Menopause postmenopausal hormone use and risk of incident gout Ann Rheum Dis 2010
691305ndash1309
Becker MA Schumacher HR Wortmann RL et al (December 2005) Febuxostat compared with allopurinol in patients with hyperuricemia
and gout N Engl J Med 353 (23) 2450ndash61
Sarawate CA Patel PA Schumacher HR Yang W Brewer KK Bakst AW Serum urate levels and gout flares analysis from managed care
data J Clin Rheumatol 2006 1261-65
Schumacher HR Jr Becker MA Lloyd E MacDonald PA Lademacher C Febuxostat in the treatment of gout 5-yr findings of the FOCUS
efficacy and safety study Rheumatology (Oxford) 2009 48188-194
14 Becker MA Schumacher HR MacDonald PA Lloyd E Lademacher C Clinical efficacy and safety of successful long-term urate
lowering with febuxostat or allopurinol in subjects with gout J Rheumatol 2009 361273-1278
2012 ACR guidelines for management of gout
Uptodate
Medcape
Statistical Power
Power
The probability that the study will support the research hypothesis if it is true
1 Sample size (n)
2 Effect Size (d)
3 Significance Level (α)
4 Power (β)
As effect size increases power increases
As sample size increases power increases
As significance level increases power increases
Resources
httpwwwncbinlmnihgovpmcarticlesPMC3409926
httpswwwsealedenvelopecompowerbinary-superiority
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
A one-month supply of 40 or 80-mg febuxostat costs
$28243 This price far exceeds the cost of allopurinol
which is $2424 for 100 100 mg tablets
CrCl (mLmin)
Maintenance Dose of
Allopurinol
0 100mg every 3d
10 100mg every 2d
20 100mg
40 150mg
60 200mg
80 250mg
100 300mg
120 350mg
140 400mg
Maintenance Doses of Allopurinol for
Adults based on CrCl
28
Hande KR et al Am J Med 1984
Stage 1 renal damage with
normal GFR
(GFR gt 90 mlmin)
Stage 2 Mild CKD (GFR = 60-
89 mlmin)
Stage 3 Moderate CKD (GFR
= 30-59 mlmin)
Stage 4 Severe CKD (GFR =
15-29 mlmin)
Stage 5 End Stage CKD (GFR
lt15 mlmin)
Allopurinol Hypersensitivity
Syndrome
2 of all allopurinol users develop cutaneous rash
Frequency of hypersensitivity 1 in 260
DRESS syndrome
Drug Reaction Eosinophilia Systemic Symptoms
20 mortality rate
Life threatening toxicity vasculitis rash eosinophilia hepatitis progressive renal failure
Treatment early recognition withdrawal of drug supportive care Steroids N-acetyl-cysteine dialysis prn
29
Markel A IMAJ 2005
Terkeltaub RA in Primer on the Rheumatic Disease 13th ed 2008
The urate lowering efficacy and safety
of febuxostat in the treatment of the
hyperuricemia of gout
The CONFIRMS trial
Becker MA Schumacher HR Espinoza LR et al The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemia of gout the CONFIRMS trial Arthritis Res
Ther 201012(2)R63
Many long and short-term clinical trials have
proved the efficacy of Febuxostat in the treatment
of gout and lowering uric acid levels In these
studies Febuxostat was found to be superior to
allopurinol in reducing the serum uric acid levels
Some notable landmark clinical trials are FACT
APEX EXCEL FOCUS and CONFIRMS
Febuxostat versus Allopurinol Controlled Trial
(FACT) 2005
52 week randomized double-blind multicenter clinical trial that compared the safety and efficacy of febuxostat with allopurinol
760 patients with gout and a sUA gt80 mgdl were randomly assigned to receive either febuxostat 80 or 120mg or allopurinol 300mg once daily for 52 weeks
The primary endpoint was the proportion of patients to achieve a sUA concentration below 60 mgdl at the last three monthly measurements
The primary endpoint was achieved in 53 of patients receiving 80 mg febuxostat 62 of patients receiving 120mg and 21 of those receiving allopurinol (p lt0001 for each febuxostat group compared with allopurinol)
There was no statistical significance in the change in tophi size and number or the incidence of gout flare between the groups
Allopurinol Placebo controlled Efficacy study
of febuxostat (APEX) 2008
28 week randomized double-blind study of 1072 patients comparing the safety and efficacy of febuxostat allopurinol and placebo
Patients were randomized to a once daily fixed dose of placebo febuxostat 80mg120mg or 240 mg or allopurinol 300mg or 100mg depending on their baseline serum creatinine (le15 mgdl or ge16 to lt20 mgdl respectively)
After 1 year of treatment 82 of the patients in all febuxostat groups achieved sUA levels below 60 mgdl compared with 39 of the patients in both allopurinol groups In groups with moderate renal impairment the primary endpoint was achieved by 44 receiving febuxostat 80mg 45 receiving 120mg and 60 receiving 240mg compared with 0 in the allopurinol and placebo groups
However clinical endpoints were not statistically significant
The number of patients with moderate renal impairment was small
Febuxostat Comparative Extension Long-Term
study (EXCEL) 2009
160 week extension study for patients completing FACT and APEX
The studyrsquos aim was to determine long-term efficacy in sUA
lowering clinical benefits and safety of febuxostat or allopurinol
1086 patients were enrolled to receive fixed daily doses of
febuxostat 80mg or 120 mg or allopurinol 300 mg
After the first month of treatment nearly 80 of patients receiving
either febuxostat dose achieved sUA less than 6 mgdl compared
with only 46 of subjects on allopurinol There was no difference in
gout flare incidence and tophi reduction between the groups
Overall adverse events did not show significant differences among
groups
Febuxostat Open Label of Urate-Lowering
Efficacy and Safety (FOCUS) 2009
The FOCUS trial was a 5-year extension study that
assessed reduction and maintenance of sUA levels below
60 mgdl as the primary efficacy endpoint A total of
116 patients were initially enrolled to receive a dose of
80mg febuxostat with dose adjustment to either 40 or
120mg between weeks 4 and 24 93 maintained a sUA
level below 60 mgdl at 5 years
Objectives of CONFIRMS trial
The three-fold objectives of this Phase 3 double-blind RCT study were
1) To compare the UL efficacy of febuxostat at a dose of 40 mg with that of allopurinol at doses most commonly utilized in clinical practice
2) To evaluate UL efficacies of 80 mg and 40 mg daily doses of febuxostat compared with that of allopurinol in subjects with mild or moderate renal impairment
3) To gain prospective uniformly reviewed information regarding the safety of these agents particularly their comparative CV safety
Materials and methods
Subjects aged 18 to 85 years with a diagnosis of gout fulfilling American Rheumatology Association preliminary criteria and sUA ge 80 mgdL were eligible for enrollment
Subjects were enrolled at 324 sites in the United States
IRB approval was obtained and all the subjects provided written informed consent
At least 35 of subjects enrolled were to have mild or moderate renal impairment defined as baseline estimated creatinine clearance (eCLcr) of 60 to 89 mlminutes or 30 to 59 mlminutes
Subjects successfully completing either of the previously
reported long-term open-label febuxostat or
febuxostatallopurinol extension studies were also eligible for
enrollment
Exclusion criteria secondary hyperuricemia (for example
due to myeloproliferative disorder) xanthinuria severe renal
impairment (eCLcr lt30 mlminutes) alanine
aminotransferase and aspartate aminotransferase values gt15
times the upper limit of normal consumption of more than 14
alcoholic drinks per week or a history of alcoholism or drug
abuse within five years or a medical condition that in the
investigators opinion would interfere with treatment safety
or adherence to the protocol
Baseline characteristics of randomized subjects
Baseline characteristics of randomized subjects (cont)
Baseline characteristics of randomized subjects (cont)
2269 Subjects were randomized 111 on Day 1 to
receive daily febuxostat 40 mg febuxostat 80 mg or
allopurinol Among subjects randomized to allopurinol
those with normal renal function or mild renal
impairment received 300 mg daily and those with
moderate renal impairment received 200 mg
Throughout the subsequent six-month treatment period for all subjects prophylaxis for gout flares was given either as colchicine 06 mg daily or naproxen 250 mg twice daily All subjects receiving naproxen prophylaxis also received lansoprazole 15 mg daily
Choice of prophylaxis regimen was made by the investigator and subject taking into account prior drug tolerance and prophylaxis experience
In addition subjects with eCLcr lt50 mlminute were not to receive naproxen
Gout flares were regarded as expected gout manifestations rather than as AEs
The primary efficacy endpoint was the proportion of
subjects in each treatment group with sUA lt60 mgdL
at the final visit
Secondary efficacy variables included
1) The proportion of subjects with mild or moderate
renal impairment and final sUA lt60 mgdL
2) The proportion of subjects with sUA lt60 mgdL lt50
mgdL and lt40 mgdL at each visit
Efficacy analysisResults
Primary efficacy endpoint
1) The proportions of subjects achieving a final visit sUA lt60
mgdL were 452 671 and 421 in the febuxostat 40 mg
febuxostat 80 mg and allopurinol groups respectively
2) UL by febuxostat 40 mg was non-inferior to that by
allopurinol but the difference in the response rates between
the two groups (31 95 CI -19 to 81) was not significant
3) However the greater UL response rate with febuxostat 80 mg
compared with either febuxostat 40 mg (219) or allopurinol
(249) was significant (P lt 0001)
Secondary efficacy endpoints
Among subjects with any (mild or moderate) renal
impairment the UL response rate in the febuxostat 80
mg group (716 360503) significantly exceeded those
observed in the febuxostat 40 mg (497 238479) and
allopurinol (423 212501) groups (P le 0001 for each
comparison)
In addition among the total group of subjects with
renal impairment the UL response rate in the
febuxostat 40 mg group was significantly higher than
that in the allopurinol 300200 mg group (P = 0021)
At any sUA endpoint (lt60 mgdL lt50 mgdL or lt40 mgdL) and at any scheduled visit a significantly higher proportion of subjects receiving febuxostat 80 mg achieved the target endpoint than subjects receiving febuxostat 40 mg or allopurinol (P lt 0001)
Greater proportion of subjects in the febuxostat 40 mg group than the allopurinol group achieved sUAlt60 mgdL (at Month 2 visit P = 0031) and lt50 mgdL (at two- and six month visits P le 005) but significant differences were not seen at other visits including the final visit
Effect of baseline characteristic on treatment response
Adverse events
Adverse events
CONCLUSIONS
Results of the CONFIRMS trial establish equivalent UL efficacy for febuxostat 40 mg daily and allopurinol 300200 mg daily
At all levels of renal function studied UL efficacy of febuxostat 80 mg daily was superior to that of febuxostat 40 mg or allopurinol 300200 mg and was comparably safe
In subjects with mildly or moderately impaired renal function however febuxostat 40 mg daily was significantly more effective in lowering sUA than allopurinol
At the doses studied safety of febuxostat and allopurinol including CV safety was comparable
Febuxostat at 40 mg or 80 mg daily offers a well-tolerated UL alternative to allopurinol particularly for patients with mild or moderate renal impairment
Study limitations
The study does not address the efficacy of febuxostat compared with allopurinol in reducing clinically meaningful acute flares of gout
No mention is made of long-term cost-effectiveness of therapy
Additionally this study does not address the efficacy of febuxostat compared with allopurinol dosing that is more aggressive (ie gt 300 mg daily)
Allopurinol dosing was not titrated
The study population was not similar to the general population (majority of patients were white males)
Possible funding bias
Uloric Related Current Clinical
Trials
References
Dalbeth N Gracey E Pool B et al Identification of dairy fractions with anti-inflammatory properties in models of acute gout Ann
Rheum Dis 2010 69766ndash769
Choi HK Willett W Curhan G Coffee consumption and risk of incident gout in men a prospective study Arthritis Rheum 2007 562049ndash
2055
Hak AE Curhan GC Grodstein F Choi HK Menopause postmenopausal hormone use and risk of incident gout Ann Rheum Dis 2010
691305ndash1309
Becker MA Schumacher HR Wortmann RL et al (December 2005) Febuxostat compared with allopurinol in patients with hyperuricemia
and gout N Engl J Med 353 (23) 2450ndash61
Sarawate CA Patel PA Schumacher HR Yang W Brewer KK Bakst AW Serum urate levels and gout flares analysis from managed care
data J Clin Rheumatol 2006 1261-65
Schumacher HR Jr Becker MA Lloyd E MacDonald PA Lademacher C Febuxostat in the treatment of gout 5-yr findings of the FOCUS
efficacy and safety study Rheumatology (Oxford) 2009 48188-194
14 Becker MA Schumacher HR MacDonald PA Lloyd E Lademacher C Clinical efficacy and safety of successful long-term urate
lowering with febuxostat or allopurinol in subjects with gout J Rheumatol 2009 361273-1278
2012 ACR guidelines for management of gout
Uptodate
Medcape
Statistical Power
Power
The probability that the study will support the research hypothesis if it is true
1 Sample size (n)
2 Effect Size (d)
3 Significance Level (α)
4 Power (β)
As effect size increases power increases
As sample size increases power increases
As significance level increases power increases
Resources
httpwwwncbinlmnihgovpmcarticlesPMC3409926
httpswwwsealedenvelopecompowerbinary-superiority
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
CrCl (mLmin)
Maintenance Dose of
Allopurinol
0 100mg every 3d
10 100mg every 2d
20 100mg
40 150mg
60 200mg
80 250mg
100 300mg
120 350mg
140 400mg
Maintenance Doses of Allopurinol for
Adults based on CrCl
28
Hande KR et al Am J Med 1984
Stage 1 renal damage with
normal GFR
(GFR gt 90 mlmin)
Stage 2 Mild CKD (GFR = 60-
89 mlmin)
Stage 3 Moderate CKD (GFR
= 30-59 mlmin)
Stage 4 Severe CKD (GFR =
15-29 mlmin)
Stage 5 End Stage CKD (GFR
lt15 mlmin)
Allopurinol Hypersensitivity
Syndrome
2 of all allopurinol users develop cutaneous rash
Frequency of hypersensitivity 1 in 260
DRESS syndrome
Drug Reaction Eosinophilia Systemic Symptoms
20 mortality rate
Life threatening toxicity vasculitis rash eosinophilia hepatitis progressive renal failure
Treatment early recognition withdrawal of drug supportive care Steroids N-acetyl-cysteine dialysis prn
29
Markel A IMAJ 2005
Terkeltaub RA in Primer on the Rheumatic Disease 13th ed 2008
The urate lowering efficacy and safety
of febuxostat in the treatment of the
hyperuricemia of gout
The CONFIRMS trial
Becker MA Schumacher HR Espinoza LR et al The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemia of gout the CONFIRMS trial Arthritis Res
Ther 201012(2)R63
Many long and short-term clinical trials have
proved the efficacy of Febuxostat in the treatment
of gout and lowering uric acid levels In these
studies Febuxostat was found to be superior to
allopurinol in reducing the serum uric acid levels
Some notable landmark clinical trials are FACT
APEX EXCEL FOCUS and CONFIRMS
Febuxostat versus Allopurinol Controlled Trial
(FACT) 2005
52 week randomized double-blind multicenter clinical trial that compared the safety and efficacy of febuxostat with allopurinol
760 patients with gout and a sUA gt80 mgdl were randomly assigned to receive either febuxostat 80 or 120mg or allopurinol 300mg once daily for 52 weeks
The primary endpoint was the proportion of patients to achieve a sUA concentration below 60 mgdl at the last three monthly measurements
The primary endpoint was achieved in 53 of patients receiving 80 mg febuxostat 62 of patients receiving 120mg and 21 of those receiving allopurinol (p lt0001 for each febuxostat group compared with allopurinol)
There was no statistical significance in the change in tophi size and number or the incidence of gout flare between the groups
Allopurinol Placebo controlled Efficacy study
of febuxostat (APEX) 2008
28 week randomized double-blind study of 1072 patients comparing the safety and efficacy of febuxostat allopurinol and placebo
Patients were randomized to a once daily fixed dose of placebo febuxostat 80mg120mg or 240 mg or allopurinol 300mg or 100mg depending on their baseline serum creatinine (le15 mgdl or ge16 to lt20 mgdl respectively)
After 1 year of treatment 82 of the patients in all febuxostat groups achieved sUA levels below 60 mgdl compared with 39 of the patients in both allopurinol groups In groups with moderate renal impairment the primary endpoint was achieved by 44 receiving febuxostat 80mg 45 receiving 120mg and 60 receiving 240mg compared with 0 in the allopurinol and placebo groups
However clinical endpoints were not statistically significant
The number of patients with moderate renal impairment was small
Febuxostat Comparative Extension Long-Term
study (EXCEL) 2009
160 week extension study for patients completing FACT and APEX
The studyrsquos aim was to determine long-term efficacy in sUA
lowering clinical benefits and safety of febuxostat or allopurinol
1086 patients were enrolled to receive fixed daily doses of
febuxostat 80mg or 120 mg or allopurinol 300 mg
After the first month of treatment nearly 80 of patients receiving
either febuxostat dose achieved sUA less than 6 mgdl compared
with only 46 of subjects on allopurinol There was no difference in
gout flare incidence and tophi reduction between the groups
Overall adverse events did not show significant differences among
groups
Febuxostat Open Label of Urate-Lowering
Efficacy and Safety (FOCUS) 2009
The FOCUS trial was a 5-year extension study that
assessed reduction and maintenance of sUA levels below
60 mgdl as the primary efficacy endpoint A total of
116 patients were initially enrolled to receive a dose of
80mg febuxostat with dose adjustment to either 40 or
120mg between weeks 4 and 24 93 maintained a sUA
level below 60 mgdl at 5 years
Objectives of CONFIRMS trial
The three-fold objectives of this Phase 3 double-blind RCT study were
1) To compare the UL efficacy of febuxostat at a dose of 40 mg with that of allopurinol at doses most commonly utilized in clinical practice
2) To evaluate UL efficacies of 80 mg and 40 mg daily doses of febuxostat compared with that of allopurinol in subjects with mild or moderate renal impairment
3) To gain prospective uniformly reviewed information regarding the safety of these agents particularly their comparative CV safety
Materials and methods
Subjects aged 18 to 85 years with a diagnosis of gout fulfilling American Rheumatology Association preliminary criteria and sUA ge 80 mgdL were eligible for enrollment
Subjects were enrolled at 324 sites in the United States
IRB approval was obtained and all the subjects provided written informed consent
At least 35 of subjects enrolled were to have mild or moderate renal impairment defined as baseline estimated creatinine clearance (eCLcr) of 60 to 89 mlminutes or 30 to 59 mlminutes
Subjects successfully completing either of the previously
reported long-term open-label febuxostat or
febuxostatallopurinol extension studies were also eligible for
enrollment
Exclusion criteria secondary hyperuricemia (for example
due to myeloproliferative disorder) xanthinuria severe renal
impairment (eCLcr lt30 mlminutes) alanine
aminotransferase and aspartate aminotransferase values gt15
times the upper limit of normal consumption of more than 14
alcoholic drinks per week or a history of alcoholism or drug
abuse within five years or a medical condition that in the
investigators opinion would interfere with treatment safety
or adherence to the protocol
Baseline characteristics of randomized subjects
Baseline characteristics of randomized subjects (cont)
Baseline characteristics of randomized subjects (cont)
2269 Subjects were randomized 111 on Day 1 to
receive daily febuxostat 40 mg febuxostat 80 mg or
allopurinol Among subjects randomized to allopurinol
those with normal renal function or mild renal
impairment received 300 mg daily and those with
moderate renal impairment received 200 mg
Throughout the subsequent six-month treatment period for all subjects prophylaxis for gout flares was given either as colchicine 06 mg daily or naproxen 250 mg twice daily All subjects receiving naproxen prophylaxis also received lansoprazole 15 mg daily
Choice of prophylaxis regimen was made by the investigator and subject taking into account prior drug tolerance and prophylaxis experience
In addition subjects with eCLcr lt50 mlminute were not to receive naproxen
Gout flares were regarded as expected gout manifestations rather than as AEs
The primary efficacy endpoint was the proportion of
subjects in each treatment group with sUA lt60 mgdL
at the final visit
Secondary efficacy variables included
1) The proportion of subjects with mild or moderate
renal impairment and final sUA lt60 mgdL
2) The proportion of subjects with sUA lt60 mgdL lt50
mgdL and lt40 mgdL at each visit
Efficacy analysisResults
Primary efficacy endpoint
1) The proportions of subjects achieving a final visit sUA lt60
mgdL were 452 671 and 421 in the febuxostat 40 mg
febuxostat 80 mg and allopurinol groups respectively
2) UL by febuxostat 40 mg was non-inferior to that by
allopurinol but the difference in the response rates between
the two groups (31 95 CI -19 to 81) was not significant
3) However the greater UL response rate with febuxostat 80 mg
compared with either febuxostat 40 mg (219) or allopurinol
(249) was significant (P lt 0001)
Secondary efficacy endpoints
Among subjects with any (mild or moderate) renal
impairment the UL response rate in the febuxostat 80
mg group (716 360503) significantly exceeded those
observed in the febuxostat 40 mg (497 238479) and
allopurinol (423 212501) groups (P le 0001 for each
comparison)
In addition among the total group of subjects with
renal impairment the UL response rate in the
febuxostat 40 mg group was significantly higher than
that in the allopurinol 300200 mg group (P = 0021)
At any sUA endpoint (lt60 mgdL lt50 mgdL or lt40 mgdL) and at any scheduled visit a significantly higher proportion of subjects receiving febuxostat 80 mg achieved the target endpoint than subjects receiving febuxostat 40 mg or allopurinol (P lt 0001)
Greater proportion of subjects in the febuxostat 40 mg group than the allopurinol group achieved sUAlt60 mgdL (at Month 2 visit P = 0031) and lt50 mgdL (at two- and six month visits P le 005) but significant differences were not seen at other visits including the final visit
Effect of baseline characteristic on treatment response
Adverse events
Adverse events
CONCLUSIONS
Results of the CONFIRMS trial establish equivalent UL efficacy for febuxostat 40 mg daily and allopurinol 300200 mg daily
At all levels of renal function studied UL efficacy of febuxostat 80 mg daily was superior to that of febuxostat 40 mg or allopurinol 300200 mg and was comparably safe
In subjects with mildly or moderately impaired renal function however febuxostat 40 mg daily was significantly more effective in lowering sUA than allopurinol
At the doses studied safety of febuxostat and allopurinol including CV safety was comparable
Febuxostat at 40 mg or 80 mg daily offers a well-tolerated UL alternative to allopurinol particularly for patients with mild or moderate renal impairment
Study limitations
The study does not address the efficacy of febuxostat compared with allopurinol in reducing clinically meaningful acute flares of gout
No mention is made of long-term cost-effectiveness of therapy
Additionally this study does not address the efficacy of febuxostat compared with allopurinol dosing that is more aggressive (ie gt 300 mg daily)
Allopurinol dosing was not titrated
The study population was not similar to the general population (majority of patients were white males)
Possible funding bias
Uloric Related Current Clinical
Trials
References
Dalbeth N Gracey E Pool B et al Identification of dairy fractions with anti-inflammatory properties in models of acute gout Ann
Rheum Dis 2010 69766ndash769
Choi HK Willett W Curhan G Coffee consumption and risk of incident gout in men a prospective study Arthritis Rheum 2007 562049ndash
2055
Hak AE Curhan GC Grodstein F Choi HK Menopause postmenopausal hormone use and risk of incident gout Ann Rheum Dis 2010
691305ndash1309
Becker MA Schumacher HR Wortmann RL et al (December 2005) Febuxostat compared with allopurinol in patients with hyperuricemia
and gout N Engl J Med 353 (23) 2450ndash61
Sarawate CA Patel PA Schumacher HR Yang W Brewer KK Bakst AW Serum urate levels and gout flares analysis from managed care
data J Clin Rheumatol 2006 1261-65
Schumacher HR Jr Becker MA Lloyd E MacDonald PA Lademacher C Febuxostat in the treatment of gout 5-yr findings of the FOCUS
efficacy and safety study Rheumatology (Oxford) 2009 48188-194
14 Becker MA Schumacher HR MacDonald PA Lloyd E Lademacher C Clinical efficacy and safety of successful long-term urate
lowering with febuxostat or allopurinol in subjects with gout J Rheumatol 2009 361273-1278
2012 ACR guidelines for management of gout
Uptodate
Medcape
Statistical Power
Power
The probability that the study will support the research hypothesis if it is true
1 Sample size (n)
2 Effect Size (d)
3 Significance Level (α)
4 Power (β)
As effect size increases power increases
As sample size increases power increases
As significance level increases power increases
Resources
httpwwwncbinlmnihgovpmcarticlesPMC3409926
httpswwwsealedenvelopecompowerbinary-superiority
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
Allopurinol Hypersensitivity
Syndrome
2 of all allopurinol users develop cutaneous rash
Frequency of hypersensitivity 1 in 260
DRESS syndrome
Drug Reaction Eosinophilia Systemic Symptoms
20 mortality rate
Life threatening toxicity vasculitis rash eosinophilia hepatitis progressive renal failure
Treatment early recognition withdrawal of drug supportive care Steroids N-acetyl-cysteine dialysis prn
29
Markel A IMAJ 2005
Terkeltaub RA in Primer on the Rheumatic Disease 13th ed 2008
The urate lowering efficacy and safety
of febuxostat in the treatment of the
hyperuricemia of gout
The CONFIRMS trial
Becker MA Schumacher HR Espinoza LR et al The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemia of gout the CONFIRMS trial Arthritis Res
Ther 201012(2)R63
Many long and short-term clinical trials have
proved the efficacy of Febuxostat in the treatment
of gout and lowering uric acid levels In these
studies Febuxostat was found to be superior to
allopurinol in reducing the serum uric acid levels
Some notable landmark clinical trials are FACT
APEX EXCEL FOCUS and CONFIRMS
Febuxostat versus Allopurinol Controlled Trial
(FACT) 2005
52 week randomized double-blind multicenter clinical trial that compared the safety and efficacy of febuxostat with allopurinol
760 patients with gout and a sUA gt80 mgdl were randomly assigned to receive either febuxostat 80 or 120mg or allopurinol 300mg once daily for 52 weeks
The primary endpoint was the proportion of patients to achieve a sUA concentration below 60 mgdl at the last three monthly measurements
The primary endpoint was achieved in 53 of patients receiving 80 mg febuxostat 62 of patients receiving 120mg and 21 of those receiving allopurinol (p lt0001 for each febuxostat group compared with allopurinol)
There was no statistical significance in the change in tophi size and number or the incidence of gout flare between the groups
Allopurinol Placebo controlled Efficacy study
of febuxostat (APEX) 2008
28 week randomized double-blind study of 1072 patients comparing the safety and efficacy of febuxostat allopurinol and placebo
Patients were randomized to a once daily fixed dose of placebo febuxostat 80mg120mg or 240 mg or allopurinol 300mg or 100mg depending on their baseline serum creatinine (le15 mgdl or ge16 to lt20 mgdl respectively)
After 1 year of treatment 82 of the patients in all febuxostat groups achieved sUA levels below 60 mgdl compared with 39 of the patients in both allopurinol groups In groups with moderate renal impairment the primary endpoint was achieved by 44 receiving febuxostat 80mg 45 receiving 120mg and 60 receiving 240mg compared with 0 in the allopurinol and placebo groups
However clinical endpoints were not statistically significant
The number of patients with moderate renal impairment was small
Febuxostat Comparative Extension Long-Term
study (EXCEL) 2009
160 week extension study for patients completing FACT and APEX
The studyrsquos aim was to determine long-term efficacy in sUA
lowering clinical benefits and safety of febuxostat or allopurinol
1086 patients were enrolled to receive fixed daily doses of
febuxostat 80mg or 120 mg or allopurinol 300 mg
After the first month of treatment nearly 80 of patients receiving
either febuxostat dose achieved sUA less than 6 mgdl compared
with only 46 of subjects on allopurinol There was no difference in
gout flare incidence and tophi reduction between the groups
Overall adverse events did not show significant differences among
groups
Febuxostat Open Label of Urate-Lowering
Efficacy and Safety (FOCUS) 2009
The FOCUS trial was a 5-year extension study that
assessed reduction and maintenance of sUA levels below
60 mgdl as the primary efficacy endpoint A total of
116 patients were initially enrolled to receive a dose of
80mg febuxostat with dose adjustment to either 40 or
120mg between weeks 4 and 24 93 maintained a sUA
level below 60 mgdl at 5 years
Objectives of CONFIRMS trial
The three-fold objectives of this Phase 3 double-blind RCT study were
1) To compare the UL efficacy of febuxostat at a dose of 40 mg with that of allopurinol at doses most commonly utilized in clinical practice
2) To evaluate UL efficacies of 80 mg and 40 mg daily doses of febuxostat compared with that of allopurinol in subjects with mild or moderate renal impairment
3) To gain prospective uniformly reviewed information regarding the safety of these agents particularly their comparative CV safety
Materials and methods
Subjects aged 18 to 85 years with a diagnosis of gout fulfilling American Rheumatology Association preliminary criteria and sUA ge 80 mgdL were eligible for enrollment
Subjects were enrolled at 324 sites in the United States
IRB approval was obtained and all the subjects provided written informed consent
At least 35 of subjects enrolled were to have mild or moderate renal impairment defined as baseline estimated creatinine clearance (eCLcr) of 60 to 89 mlminutes or 30 to 59 mlminutes
Subjects successfully completing either of the previously
reported long-term open-label febuxostat or
febuxostatallopurinol extension studies were also eligible for
enrollment
Exclusion criteria secondary hyperuricemia (for example
due to myeloproliferative disorder) xanthinuria severe renal
impairment (eCLcr lt30 mlminutes) alanine
aminotransferase and aspartate aminotransferase values gt15
times the upper limit of normal consumption of more than 14
alcoholic drinks per week or a history of alcoholism or drug
abuse within five years or a medical condition that in the
investigators opinion would interfere with treatment safety
or adherence to the protocol
Baseline characteristics of randomized subjects
Baseline characteristics of randomized subjects (cont)
Baseline characteristics of randomized subjects (cont)
2269 Subjects were randomized 111 on Day 1 to
receive daily febuxostat 40 mg febuxostat 80 mg or
allopurinol Among subjects randomized to allopurinol
those with normal renal function or mild renal
impairment received 300 mg daily and those with
moderate renal impairment received 200 mg
Throughout the subsequent six-month treatment period for all subjects prophylaxis for gout flares was given either as colchicine 06 mg daily or naproxen 250 mg twice daily All subjects receiving naproxen prophylaxis also received lansoprazole 15 mg daily
Choice of prophylaxis regimen was made by the investigator and subject taking into account prior drug tolerance and prophylaxis experience
In addition subjects with eCLcr lt50 mlminute were not to receive naproxen
Gout flares were regarded as expected gout manifestations rather than as AEs
The primary efficacy endpoint was the proportion of
subjects in each treatment group with sUA lt60 mgdL
at the final visit
Secondary efficacy variables included
1) The proportion of subjects with mild or moderate
renal impairment and final sUA lt60 mgdL
2) The proportion of subjects with sUA lt60 mgdL lt50
mgdL and lt40 mgdL at each visit
Efficacy analysisResults
Primary efficacy endpoint
1) The proportions of subjects achieving a final visit sUA lt60
mgdL were 452 671 and 421 in the febuxostat 40 mg
febuxostat 80 mg and allopurinol groups respectively
2) UL by febuxostat 40 mg was non-inferior to that by
allopurinol but the difference in the response rates between
the two groups (31 95 CI -19 to 81) was not significant
3) However the greater UL response rate with febuxostat 80 mg
compared with either febuxostat 40 mg (219) or allopurinol
(249) was significant (P lt 0001)
Secondary efficacy endpoints
Among subjects with any (mild or moderate) renal
impairment the UL response rate in the febuxostat 80
mg group (716 360503) significantly exceeded those
observed in the febuxostat 40 mg (497 238479) and
allopurinol (423 212501) groups (P le 0001 for each
comparison)
In addition among the total group of subjects with
renal impairment the UL response rate in the
febuxostat 40 mg group was significantly higher than
that in the allopurinol 300200 mg group (P = 0021)
At any sUA endpoint (lt60 mgdL lt50 mgdL or lt40 mgdL) and at any scheduled visit a significantly higher proportion of subjects receiving febuxostat 80 mg achieved the target endpoint than subjects receiving febuxostat 40 mg or allopurinol (P lt 0001)
Greater proportion of subjects in the febuxostat 40 mg group than the allopurinol group achieved sUAlt60 mgdL (at Month 2 visit P = 0031) and lt50 mgdL (at two- and six month visits P le 005) but significant differences were not seen at other visits including the final visit
Effect of baseline characteristic on treatment response
Adverse events
Adverse events
CONCLUSIONS
Results of the CONFIRMS trial establish equivalent UL efficacy for febuxostat 40 mg daily and allopurinol 300200 mg daily
At all levels of renal function studied UL efficacy of febuxostat 80 mg daily was superior to that of febuxostat 40 mg or allopurinol 300200 mg and was comparably safe
In subjects with mildly or moderately impaired renal function however febuxostat 40 mg daily was significantly more effective in lowering sUA than allopurinol
At the doses studied safety of febuxostat and allopurinol including CV safety was comparable
Febuxostat at 40 mg or 80 mg daily offers a well-tolerated UL alternative to allopurinol particularly for patients with mild or moderate renal impairment
Study limitations
The study does not address the efficacy of febuxostat compared with allopurinol in reducing clinically meaningful acute flares of gout
No mention is made of long-term cost-effectiveness of therapy
Additionally this study does not address the efficacy of febuxostat compared with allopurinol dosing that is more aggressive (ie gt 300 mg daily)
Allopurinol dosing was not titrated
The study population was not similar to the general population (majority of patients were white males)
Possible funding bias
Uloric Related Current Clinical
Trials
References
Dalbeth N Gracey E Pool B et al Identification of dairy fractions with anti-inflammatory properties in models of acute gout Ann
Rheum Dis 2010 69766ndash769
Choi HK Willett W Curhan G Coffee consumption and risk of incident gout in men a prospective study Arthritis Rheum 2007 562049ndash
2055
Hak AE Curhan GC Grodstein F Choi HK Menopause postmenopausal hormone use and risk of incident gout Ann Rheum Dis 2010
691305ndash1309
Becker MA Schumacher HR Wortmann RL et al (December 2005) Febuxostat compared with allopurinol in patients with hyperuricemia
and gout N Engl J Med 353 (23) 2450ndash61
Sarawate CA Patel PA Schumacher HR Yang W Brewer KK Bakst AW Serum urate levels and gout flares analysis from managed care
data J Clin Rheumatol 2006 1261-65
Schumacher HR Jr Becker MA Lloyd E MacDonald PA Lademacher C Febuxostat in the treatment of gout 5-yr findings of the FOCUS
efficacy and safety study Rheumatology (Oxford) 2009 48188-194
14 Becker MA Schumacher HR MacDonald PA Lloyd E Lademacher C Clinical efficacy and safety of successful long-term urate
lowering with febuxostat or allopurinol in subjects with gout J Rheumatol 2009 361273-1278
2012 ACR guidelines for management of gout
Uptodate
Medcape
Statistical Power
Power
The probability that the study will support the research hypothesis if it is true
1 Sample size (n)
2 Effect Size (d)
3 Significance Level (α)
4 Power (β)
As effect size increases power increases
As sample size increases power increases
As significance level increases power increases
Resources
httpwwwncbinlmnihgovpmcarticlesPMC3409926
httpswwwsealedenvelopecompowerbinary-superiority
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
The urate lowering efficacy and safety
of febuxostat in the treatment of the
hyperuricemia of gout
The CONFIRMS trial
Becker MA Schumacher HR Espinoza LR et al The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemia of gout the CONFIRMS trial Arthritis Res
Ther 201012(2)R63
Many long and short-term clinical trials have
proved the efficacy of Febuxostat in the treatment
of gout and lowering uric acid levels In these
studies Febuxostat was found to be superior to
allopurinol in reducing the serum uric acid levels
Some notable landmark clinical trials are FACT
APEX EXCEL FOCUS and CONFIRMS
Febuxostat versus Allopurinol Controlled Trial
(FACT) 2005
52 week randomized double-blind multicenter clinical trial that compared the safety and efficacy of febuxostat with allopurinol
760 patients with gout and a sUA gt80 mgdl were randomly assigned to receive either febuxostat 80 or 120mg or allopurinol 300mg once daily for 52 weeks
The primary endpoint was the proportion of patients to achieve a sUA concentration below 60 mgdl at the last three monthly measurements
The primary endpoint was achieved in 53 of patients receiving 80 mg febuxostat 62 of patients receiving 120mg and 21 of those receiving allopurinol (p lt0001 for each febuxostat group compared with allopurinol)
There was no statistical significance in the change in tophi size and number or the incidence of gout flare between the groups
Allopurinol Placebo controlled Efficacy study
of febuxostat (APEX) 2008
28 week randomized double-blind study of 1072 patients comparing the safety and efficacy of febuxostat allopurinol and placebo
Patients were randomized to a once daily fixed dose of placebo febuxostat 80mg120mg or 240 mg or allopurinol 300mg or 100mg depending on their baseline serum creatinine (le15 mgdl or ge16 to lt20 mgdl respectively)
After 1 year of treatment 82 of the patients in all febuxostat groups achieved sUA levels below 60 mgdl compared with 39 of the patients in both allopurinol groups In groups with moderate renal impairment the primary endpoint was achieved by 44 receiving febuxostat 80mg 45 receiving 120mg and 60 receiving 240mg compared with 0 in the allopurinol and placebo groups
However clinical endpoints were not statistically significant
The number of patients with moderate renal impairment was small
Febuxostat Comparative Extension Long-Term
study (EXCEL) 2009
160 week extension study for patients completing FACT and APEX
The studyrsquos aim was to determine long-term efficacy in sUA
lowering clinical benefits and safety of febuxostat or allopurinol
1086 patients were enrolled to receive fixed daily doses of
febuxostat 80mg or 120 mg or allopurinol 300 mg
After the first month of treatment nearly 80 of patients receiving
either febuxostat dose achieved sUA less than 6 mgdl compared
with only 46 of subjects on allopurinol There was no difference in
gout flare incidence and tophi reduction between the groups
Overall adverse events did not show significant differences among
groups
Febuxostat Open Label of Urate-Lowering
Efficacy and Safety (FOCUS) 2009
The FOCUS trial was a 5-year extension study that
assessed reduction and maintenance of sUA levels below
60 mgdl as the primary efficacy endpoint A total of
116 patients were initially enrolled to receive a dose of
80mg febuxostat with dose adjustment to either 40 or
120mg between weeks 4 and 24 93 maintained a sUA
level below 60 mgdl at 5 years
Objectives of CONFIRMS trial
The three-fold objectives of this Phase 3 double-blind RCT study were
1) To compare the UL efficacy of febuxostat at a dose of 40 mg with that of allopurinol at doses most commonly utilized in clinical practice
2) To evaluate UL efficacies of 80 mg and 40 mg daily doses of febuxostat compared with that of allopurinol in subjects with mild or moderate renal impairment
3) To gain prospective uniformly reviewed information regarding the safety of these agents particularly their comparative CV safety
Materials and methods
Subjects aged 18 to 85 years with a diagnosis of gout fulfilling American Rheumatology Association preliminary criteria and sUA ge 80 mgdL were eligible for enrollment
Subjects were enrolled at 324 sites in the United States
IRB approval was obtained and all the subjects provided written informed consent
At least 35 of subjects enrolled were to have mild or moderate renal impairment defined as baseline estimated creatinine clearance (eCLcr) of 60 to 89 mlminutes or 30 to 59 mlminutes
Subjects successfully completing either of the previously
reported long-term open-label febuxostat or
febuxostatallopurinol extension studies were also eligible for
enrollment
Exclusion criteria secondary hyperuricemia (for example
due to myeloproliferative disorder) xanthinuria severe renal
impairment (eCLcr lt30 mlminutes) alanine
aminotransferase and aspartate aminotransferase values gt15
times the upper limit of normal consumption of more than 14
alcoholic drinks per week or a history of alcoholism or drug
abuse within five years or a medical condition that in the
investigators opinion would interfere with treatment safety
or adherence to the protocol
Baseline characteristics of randomized subjects
Baseline characteristics of randomized subjects (cont)
Baseline characteristics of randomized subjects (cont)
2269 Subjects were randomized 111 on Day 1 to
receive daily febuxostat 40 mg febuxostat 80 mg or
allopurinol Among subjects randomized to allopurinol
those with normal renal function or mild renal
impairment received 300 mg daily and those with
moderate renal impairment received 200 mg
Throughout the subsequent six-month treatment period for all subjects prophylaxis for gout flares was given either as colchicine 06 mg daily or naproxen 250 mg twice daily All subjects receiving naproxen prophylaxis also received lansoprazole 15 mg daily
Choice of prophylaxis regimen was made by the investigator and subject taking into account prior drug tolerance and prophylaxis experience
In addition subjects with eCLcr lt50 mlminute were not to receive naproxen
Gout flares were regarded as expected gout manifestations rather than as AEs
The primary efficacy endpoint was the proportion of
subjects in each treatment group with sUA lt60 mgdL
at the final visit
Secondary efficacy variables included
1) The proportion of subjects with mild or moderate
renal impairment and final sUA lt60 mgdL
2) The proportion of subjects with sUA lt60 mgdL lt50
mgdL and lt40 mgdL at each visit
Efficacy analysisResults
Primary efficacy endpoint
1) The proportions of subjects achieving a final visit sUA lt60
mgdL were 452 671 and 421 in the febuxostat 40 mg
febuxostat 80 mg and allopurinol groups respectively
2) UL by febuxostat 40 mg was non-inferior to that by
allopurinol but the difference in the response rates between
the two groups (31 95 CI -19 to 81) was not significant
3) However the greater UL response rate with febuxostat 80 mg
compared with either febuxostat 40 mg (219) or allopurinol
(249) was significant (P lt 0001)
Secondary efficacy endpoints
Among subjects with any (mild or moderate) renal
impairment the UL response rate in the febuxostat 80
mg group (716 360503) significantly exceeded those
observed in the febuxostat 40 mg (497 238479) and
allopurinol (423 212501) groups (P le 0001 for each
comparison)
In addition among the total group of subjects with
renal impairment the UL response rate in the
febuxostat 40 mg group was significantly higher than
that in the allopurinol 300200 mg group (P = 0021)
At any sUA endpoint (lt60 mgdL lt50 mgdL or lt40 mgdL) and at any scheduled visit a significantly higher proportion of subjects receiving febuxostat 80 mg achieved the target endpoint than subjects receiving febuxostat 40 mg or allopurinol (P lt 0001)
Greater proportion of subjects in the febuxostat 40 mg group than the allopurinol group achieved sUAlt60 mgdL (at Month 2 visit P = 0031) and lt50 mgdL (at two- and six month visits P le 005) but significant differences were not seen at other visits including the final visit
Effect of baseline characteristic on treatment response
Adverse events
Adverse events
CONCLUSIONS
Results of the CONFIRMS trial establish equivalent UL efficacy for febuxostat 40 mg daily and allopurinol 300200 mg daily
At all levels of renal function studied UL efficacy of febuxostat 80 mg daily was superior to that of febuxostat 40 mg or allopurinol 300200 mg and was comparably safe
In subjects with mildly or moderately impaired renal function however febuxostat 40 mg daily was significantly more effective in lowering sUA than allopurinol
At the doses studied safety of febuxostat and allopurinol including CV safety was comparable
Febuxostat at 40 mg or 80 mg daily offers a well-tolerated UL alternative to allopurinol particularly for patients with mild or moderate renal impairment
Study limitations
The study does not address the efficacy of febuxostat compared with allopurinol in reducing clinically meaningful acute flares of gout
No mention is made of long-term cost-effectiveness of therapy
Additionally this study does not address the efficacy of febuxostat compared with allopurinol dosing that is more aggressive (ie gt 300 mg daily)
Allopurinol dosing was not titrated
The study population was not similar to the general population (majority of patients were white males)
Possible funding bias
Uloric Related Current Clinical
Trials
References
Dalbeth N Gracey E Pool B et al Identification of dairy fractions with anti-inflammatory properties in models of acute gout Ann
Rheum Dis 2010 69766ndash769
Choi HK Willett W Curhan G Coffee consumption and risk of incident gout in men a prospective study Arthritis Rheum 2007 562049ndash
2055
Hak AE Curhan GC Grodstein F Choi HK Menopause postmenopausal hormone use and risk of incident gout Ann Rheum Dis 2010
691305ndash1309
Becker MA Schumacher HR Wortmann RL et al (December 2005) Febuxostat compared with allopurinol in patients with hyperuricemia
and gout N Engl J Med 353 (23) 2450ndash61
Sarawate CA Patel PA Schumacher HR Yang W Brewer KK Bakst AW Serum urate levels and gout flares analysis from managed care
data J Clin Rheumatol 2006 1261-65
Schumacher HR Jr Becker MA Lloyd E MacDonald PA Lademacher C Febuxostat in the treatment of gout 5-yr findings of the FOCUS
efficacy and safety study Rheumatology (Oxford) 2009 48188-194
14 Becker MA Schumacher HR MacDonald PA Lloyd E Lademacher C Clinical efficacy and safety of successful long-term urate
lowering with febuxostat or allopurinol in subjects with gout J Rheumatol 2009 361273-1278
2012 ACR guidelines for management of gout
Uptodate
Medcape
Statistical Power
Power
The probability that the study will support the research hypothesis if it is true
1 Sample size (n)
2 Effect Size (d)
3 Significance Level (α)
4 Power (β)
As effect size increases power increases
As sample size increases power increases
As significance level increases power increases
Resources
httpwwwncbinlmnihgovpmcarticlesPMC3409926
httpswwwsealedenvelopecompowerbinary-superiority
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
Many long and short-term clinical trials have
proved the efficacy of Febuxostat in the treatment
of gout and lowering uric acid levels In these
studies Febuxostat was found to be superior to
allopurinol in reducing the serum uric acid levels
Some notable landmark clinical trials are FACT
APEX EXCEL FOCUS and CONFIRMS
Febuxostat versus Allopurinol Controlled Trial
(FACT) 2005
52 week randomized double-blind multicenter clinical trial that compared the safety and efficacy of febuxostat with allopurinol
760 patients with gout and a sUA gt80 mgdl were randomly assigned to receive either febuxostat 80 or 120mg or allopurinol 300mg once daily for 52 weeks
The primary endpoint was the proportion of patients to achieve a sUA concentration below 60 mgdl at the last three monthly measurements
The primary endpoint was achieved in 53 of patients receiving 80 mg febuxostat 62 of patients receiving 120mg and 21 of those receiving allopurinol (p lt0001 for each febuxostat group compared with allopurinol)
There was no statistical significance in the change in tophi size and number or the incidence of gout flare between the groups
Allopurinol Placebo controlled Efficacy study
of febuxostat (APEX) 2008
28 week randomized double-blind study of 1072 patients comparing the safety and efficacy of febuxostat allopurinol and placebo
Patients were randomized to a once daily fixed dose of placebo febuxostat 80mg120mg or 240 mg or allopurinol 300mg or 100mg depending on their baseline serum creatinine (le15 mgdl or ge16 to lt20 mgdl respectively)
After 1 year of treatment 82 of the patients in all febuxostat groups achieved sUA levels below 60 mgdl compared with 39 of the patients in both allopurinol groups In groups with moderate renal impairment the primary endpoint was achieved by 44 receiving febuxostat 80mg 45 receiving 120mg and 60 receiving 240mg compared with 0 in the allopurinol and placebo groups
However clinical endpoints were not statistically significant
The number of patients with moderate renal impairment was small
Febuxostat Comparative Extension Long-Term
study (EXCEL) 2009
160 week extension study for patients completing FACT and APEX
The studyrsquos aim was to determine long-term efficacy in sUA
lowering clinical benefits and safety of febuxostat or allopurinol
1086 patients were enrolled to receive fixed daily doses of
febuxostat 80mg or 120 mg or allopurinol 300 mg
After the first month of treatment nearly 80 of patients receiving
either febuxostat dose achieved sUA less than 6 mgdl compared
with only 46 of subjects on allopurinol There was no difference in
gout flare incidence and tophi reduction between the groups
Overall adverse events did not show significant differences among
groups
Febuxostat Open Label of Urate-Lowering
Efficacy and Safety (FOCUS) 2009
The FOCUS trial was a 5-year extension study that
assessed reduction and maintenance of sUA levels below
60 mgdl as the primary efficacy endpoint A total of
116 patients were initially enrolled to receive a dose of
80mg febuxostat with dose adjustment to either 40 or
120mg between weeks 4 and 24 93 maintained a sUA
level below 60 mgdl at 5 years
Objectives of CONFIRMS trial
The three-fold objectives of this Phase 3 double-blind RCT study were
1) To compare the UL efficacy of febuxostat at a dose of 40 mg with that of allopurinol at doses most commonly utilized in clinical practice
2) To evaluate UL efficacies of 80 mg and 40 mg daily doses of febuxostat compared with that of allopurinol in subjects with mild or moderate renal impairment
3) To gain prospective uniformly reviewed information regarding the safety of these agents particularly their comparative CV safety
Materials and methods
Subjects aged 18 to 85 years with a diagnosis of gout fulfilling American Rheumatology Association preliminary criteria and sUA ge 80 mgdL were eligible for enrollment
Subjects were enrolled at 324 sites in the United States
IRB approval was obtained and all the subjects provided written informed consent
At least 35 of subjects enrolled were to have mild or moderate renal impairment defined as baseline estimated creatinine clearance (eCLcr) of 60 to 89 mlminutes or 30 to 59 mlminutes
Subjects successfully completing either of the previously
reported long-term open-label febuxostat or
febuxostatallopurinol extension studies were also eligible for
enrollment
Exclusion criteria secondary hyperuricemia (for example
due to myeloproliferative disorder) xanthinuria severe renal
impairment (eCLcr lt30 mlminutes) alanine
aminotransferase and aspartate aminotransferase values gt15
times the upper limit of normal consumption of more than 14
alcoholic drinks per week or a history of alcoholism or drug
abuse within five years or a medical condition that in the
investigators opinion would interfere with treatment safety
or adherence to the protocol
Baseline characteristics of randomized subjects
Baseline characteristics of randomized subjects (cont)
Baseline characteristics of randomized subjects (cont)
2269 Subjects were randomized 111 on Day 1 to
receive daily febuxostat 40 mg febuxostat 80 mg or
allopurinol Among subjects randomized to allopurinol
those with normal renal function or mild renal
impairment received 300 mg daily and those with
moderate renal impairment received 200 mg
Throughout the subsequent six-month treatment period for all subjects prophylaxis for gout flares was given either as colchicine 06 mg daily or naproxen 250 mg twice daily All subjects receiving naproxen prophylaxis also received lansoprazole 15 mg daily
Choice of prophylaxis regimen was made by the investigator and subject taking into account prior drug tolerance and prophylaxis experience
In addition subjects with eCLcr lt50 mlminute were not to receive naproxen
Gout flares were regarded as expected gout manifestations rather than as AEs
The primary efficacy endpoint was the proportion of
subjects in each treatment group with sUA lt60 mgdL
at the final visit
Secondary efficacy variables included
1) The proportion of subjects with mild or moderate
renal impairment and final sUA lt60 mgdL
2) The proportion of subjects with sUA lt60 mgdL lt50
mgdL and lt40 mgdL at each visit
Efficacy analysisResults
Primary efficacy endpoint
1) The proportions of subjects achieving a final visit sUA lt60
mgdL were 452 671 and 421 in the febuxostat 40 mg
febuxostat 80 mg and allopurinol groups respectively
2) UL by febuxostat 40 mg was non-inferior to that by
allopurinol but the difference in the response rates between
the two groups (31 95 CI -19 to 81) was not significant
3) However the greater UL response rate with febuxostat 80 mg
compared with either febuxostat 40 mg (219) or allopurinol
(249) was significant (P lt 0001)
Secondary efficacy endpoints
Among subjects with any (mild or moderate) renal
impairment the UL response rate in the febuxostat 80
mg group (716 360503) significantly exceeded those
observed in the febuxostat 40 mg (497 238479) and
allopurinol (423 212501) groups (P le 0001 for each
comparison)
In addition among the total group of subjects with
renal impairment the UL response rate in the
febuxostat 40 mg group was significantly higher than
that in the allopurinol 300200 mg group (P = 0021)
At any sUA endpoint (lt60 mgdL lt50 mgdL or lt40 mgdL) and at any scheduled visit a significantly higher proportion of subjects receiving febuxostat 80 mg achieved the target endpoint than subjects receiving febuxostat 40 mg or allopurinol (P lt 0001)
Greater proportion of subjects in the febuxostat 40 mg group than the allopurinol group achieved sUAlt60 mgdL (at Month 2 visit P = 0031) and lt50 mgdL (at two- and six month visits P le 005) but significant differences were not seen at other visits including the final visit
Effect of baseline characteristic on treatment response
Adverse events
Adverse events
CONCLUSIONS
Results of the CONFIRMS trial establish equivalent UL efficacy for febuxostat 40 mg daily and allopurinol 300200 mg daily
At all levels of renal function studied UL efficacy of febuxostat 80 mg daily was superior to that of febuxostat 40 mg or allopurinol 300200 mg and was comparably safe
In subjects with mildly or moderately impaired renal function however febuxostat 40 mg daily was significantly more effective in lowering sUA than allopurinol
At the doses studied safety of febuxostat and allopurinol including CV safety was comparable
Febuxostat at 40 mg or 80 mg daily offers a well-tolerated UL alternative to allopurinol particularly for patients with mild or moderate renal impairment
Study limitations
The study does not address the efficacy of febuxostat compared with allopurinol in reducing clinically meaningful acute flares of gout
No mention is made of long-term cost-effectiveness of therapy
Additionally this study does not address the efficacy of febuxostat compared with allopurinol dosing that is more aggressive (ie gt 300 mg daily)
Allopurinol dosing was not titrated
The study population was not similar to the general population (majority of patients were white males)
Possible funding bias
Uloric Related Current Clinical
Trials
References
Dalbeth N Gracey E Pool B et al Identification of dairy fractions with anti-inflammatory properties in models of acute gout Ann
Rheum Dis 2010 69766ndash769
Choi HK Willett W Curhan G Coffee consumption and risk of incident gout in men a prospective study Arthritis Rheum 2007 562049ndash
2055
Hak AE Curhan GC Grodstein F Choi HK Menopause postmenopausal hormone use and risk of incident gout Ann Rheum Dis 2010
691305ndash1309
Becker MA Schumacher HR Wortmann RL et al (December 2005) Febuxostat compared with allopurinol in patients with hyperuricemia
and gout N Engl J Med 353 (23) 2450ndash61
Sarawate CA Patel PA Schumacher HR Yang W Brewer KK Bakst AW Serum urate levels and gout flares analysis from managed care
data J Clin Rheumatol 2006 1261-65
Schumacher HR Jr Becker MA Lloyd E MacDonald PA Lademacher C Febuxostat in the treatment of gout 5-yr findings of the FOCUS
efficacy and safety study Rheumatology (Oxford) 2009 48188-194
14 Becker MA Schumacher HR MacDonald PA Lloyd E Lademacher C Clinical efficacy and safety of successful long-term urate
lowering with febuxostat or allopurinol in subjects with gout J Rheumatol 2009 361273-1278
2012 ACR guidelines for management of gout
Uptodate
Medcape
Statistical Power
Power
The probability that the study will support the research hypothesis if it is true
1 Sample size (n)
2 Effect Size (d)
3 Significance Level (α)
4 Power (β)
As effect size increases power increases
As sample size increases power increases
As significance level increases power increases
Resources
httpwwwncbinlmnihgovpmcarticlesPMC3409926
httpswwwsealedenvelopecompowerbinary-superiority
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
Febuxostat versus Allopurinol Controlled Trial
(FACT) 2005
52 week randomized double-blind multicenter clinical trial that compared the safety and efficacy of febuxostat with allopurinol
760 patients with gout and a sUA gt80 mgdl were randomly assigned to receive either febuxostat 80 or 120mg or allopurinol 300mg once daily for 52 weeks
The primary endpoint was the proportion of patients to achieve a sUA concentration below 60 mgdl at the last three monthly measurements
The primary endpoint was achieved in 53 of patients receiving 80 mg febuxostat 62 of patients receiving 120mg and 21 of those receiving allopurinol (p lt0001 for each febuxostat group compared with allopurinol)
There was no statistical significance in the change in tophi size and number or the incidence of gout flare between the groups
Allopurinol Placebo controlled Efficacy study
of febuxostat (APEX) 2008
28 week randomized double-blind study of 1072 patients comparing the safety and efficacy of febuxostat allopurinol and placebo
Patients were randomized to a once daily fixed dose of placebo febuxostat 80mg120mg or 240 mg or allopurinol 300mg or 100mg depending on their baseline serum creatinine (le15 mgdl or ge16 to lt20 mgdl respectively)
After 1 year of treatment 82 of the patients in all febuxostat groups achieved sUA levels below 60 mgdl compared with 39 of the patients in both allopurinol groups In groups with moderate renal impairment the primary endpoint was achieved by 44 receiving febuxostat 80mg 45 receiving 120mg and 60 receiving 240mg compared with 0 in the allopurinol and placebo groups
However clinical endpoints were not statistically significant
The number of patients with moderate renal impairment was small
Febuxostat Comparative Extension Long-Term
study (EXCEL) 2009
160 week extension study for patients completing FACT and APEX
The studyrsquos aim was to determine long-term efficacy in sUA
lowering clinical benefits and safety of febuxostat or allopurinol
1086 patients were enrolled to receive fixed daily doses of
febuxostat 80mg or 120 mg or allopurinol 300 mg
After the first month of treatment nearly 80 of patients receiving
either febuxostat dose achieved sUA less than 6 mgdl compared
with only 46 of subjects on allopurinol There was no difference in
gout flare incidence and tophi reduction between the groups
Overall adverse events did not show significant differences among
groups
Febuxostat Open Label of Urate-Lowering
Efficacy and Safety (FOCUS) 2009
The FOCUS trial was a 5-year extension study that
assessed reduction and maintenance of sUA levels below
60 mgdl as the primary efficacy endpoint A total of
116 patients were initially enrolled to receive a dose of
80mg febuxostat with dose adjustment to either 40 or
120mg between weeks 4 and 24 93 maintained a sUA
level below 60 mgdl at 5 years
Objectives of CONFIRMS trial
The three-fold objectives of this Phase 3 double-blind RCT study were
1) To compare the UL efficacy of febuxostat at a dose of 40 mg with that of allopurinol at doses most commonly utilized in clinical practice
2) To evaluate UL efficacies of 80 mg and 40 mg daily doses of febuxostat compared with that of allopurinol in subjects with mild or moderate renal impairment
3) To gain prospective uniformly reviewed information regarding the safety of these agents particularly their comparative CV safety
Materials and methods
Subjects aged 18 to 85 years with a diagnosis of gout fulfilling American Rheumatology Association preliminary criteria and sUA ge 80 mgdL were eligible for enrollment
Subjects were enrolled at 324 sites in the United States
IRB approval was obtained and all the subjects provided written informed consent
At least 35 of subjects enrolled were to have mild or moderate renal impairment defined as baseline estimated creatinine clearance (eCLcr) of 60 to 89 mlminutes or 30 to 59 mlminutes
Subjects successfully completing either of the previously
reported long-term open-label febuxostat or
febuxostatallopurinol extension studies were also eligible for
enrollment
Exclusion criteria secondary hyperuricemia (for example
due to myeloproliferative disorder) xanthinuria severe renal
impairment (eCLcr lt30 mlminutes) alanine
aminotransferase and aspartate aminotransferase values gt15
times the upper limit of normal consumption of more than 14
alcoholic drinks per week or a history of alcoholism or drug
abuse within five years or a medical condition that in the
investigators opinion would interfere with treatment safety
or adherence to the protocol
Baseline characteristics of randomized subjects
Baseline characteristics of randomized subjects (cont)
Baseline characteristics of randomized subjects (cont)
2269 Subjects were randomized 111 on Day 1 to
receive daily febuxostat 40 mg febuxostat 80 mg or
allopurinol Among subjects randomized to allopurinol
those with normal renal function or mild renal
impairment received 300 mg daily and those with
moderate renal impairment received 200 mg
Throughout the subsequent six-month treatment period for all subjects prophylaxis for gout flares was given either as colchicine 06 mg daily or naproxen 250 mg twice daily All subjects receiving naproxen prophylaxis also received lansoprazole 15 mg daily
Choice of prophylaxis regimen was made by the investigator and subject taking into account prior drug tolerance and prophylaxis experience
In addition subjects with eCLcr lt50 mlminute were not to receive naproxen
Gout flares were regarded as expected gout manifestations rather than as AEs
The primary efficacy endpoint was the proportion of
subjects in each treatment group with sUA lt60 mgdL
at the final visit
Secondary efficacy variables included
1) The proportion of subjects with mild or moderate
renal impairment and final sUA lt60 mgdL
2) The proportion of subjects with sUA lt60 mgdL lt50
mgdL and lt40 mgdL at each visit
Efficacy analysisResults
Primary efficacy endpoint
1) The proportions of subjects achieving a final visit sUA lt60
mgdL were 452 671 and 421 in the febuxostat 40 mg
febuxostat 80 mg and allopurinol groups respectively
2) UL by febuxostat 40 mg was non-inferior to that by
allopurinol but the difference in the response rates between
the two groups (31 95 CI -19 to 81) was not significant
3) However the greater UL response rate with febuxostat 80 mg
compared with either febuxostat 40 mg (219) or allopurinol
(249) was significant (P lt 0001)
Secondary efficacy endpoints
Among subjects with any (mild or moderate) renal
impairment the UL response rate in the febuxostat 80
mg group (716 360503) significantly exceeded those
observed in the febuxostat 40 mg (497 238479) and
allopurinol (423 212501) groups (P le 0001 for each
comparison)
In addition among the total group of subjects with
renal impairment the UL response rate in the
febuxostat 40 mg group was significantly higher than
that in the allopurinol 300200 mg group (P = 0021)
At any sUA endpoint (lt60 mgdL lt50 mgdL or lt40 mgdL) and at any scheduled visit a significantly higher proportion of subjects receiving febuxostat 80 mg achieved the target endpoint than subjects receiving febuxostat 40 mg or allopurinol (P lt 0001)
Greater proportion of subjects in the febuxostat 40 mg group than the allopurinol group achieved sUAlt60 mgdL (at Month 2 visit P = 0031) and lt50 mgdL (at two- and six month visits P le 005) but significant differences were not seen at other visits including the final visit
Effect of baseline characteristic on treatment response
Adverse events
Adverse events
CONCLUSIONS
Results of the CONFIRMS trial establish equivalent UL efficacy for febuxostat 40 mg daily and allopurinol 300200 mg daily
At all levels of renal function studied UL efficacy of febuxostat 80 mg daily was superior to that of febuxostat 40 mg or allopurinol 300200 mg and was comparably safe
In subjects with mildly or moderately impaired renal function however febuxostat 40 mg daily was significantly more effective in lowering sUA than allopurinol
At the doses studied safety of febuxostat and allopurinol including CV safety was comparable
Febuxostat at 40 mg or 80 mg daily offers a well-tolerated UL alternative to allopurinol particularly for patients with mild or moderate renal impairment
Study limitations
The study does not address the efficacy of febuxostat compared with allopurinol in reducing clinically meaningful acute flares of gout
No mention is made of long-term cost-effectiveness of therapy
Additionally this study does not address the efficacy of febuxostat compared with allopurinol dosing that is more aggressive (ie gt 300 mg daily)
Allopurinol dosing was not titrated
The study population was not similar to the general population (majority of patients were white males)
Possible funding bias
Uloric Related Current Clinical
Trials
References
Dalbeth N Gracey E Pool B et al Identification of dairy fractions with anti-inflammatory properties in models of acute gout Ann
Rheum Dis 2010 69766ndash769
Choi HK Willett W Curhan G Coffee consumption and risk of incident gout in men a prospective study Arthritis Rheum 2007 562049ndash
2055
Hak AE Curhan GC Grodstein F Choi HK Menopause postmenopausal hormone use and risk of incident gout Ann Rheum Dis 2010
691305ndash1309
Becker MA Schumacher HR Wortmann RL et al (December 2005) Febuxostat compared with allopurinol in patients with hyperuricemia
and gout N Engl J Med 353 (23) 2450ndash61
Sarawate CA Patel PA Schumacher HR Yang W Brewer KK Bakst AW Serum urate levels and gout flares analysis from managed care
data J Clin Rheumatol 2006 1261-65
Schumacher HR Jr Becker MA Lloyd E MacDonald PA Lademacher C Febuxostat in the treatment of gout 5-yr findings of the FOCUS
efficacy and safety study Rheumatology (Oxford) 2009 48188-194
14 Becker MA Schumacher HR MacDonald PA Lloyd E Lademacher C Clinical efficacy and safety of successful long-term urate
lowering with febuxostat or allopurinol in subjects with gout J Rheumatol 2009 361273-1278
2012 ACR guidelines for management of gout
Uptodate
Medcape
Statistical Power
Power
The probability that the study will support the research hypothesis if it is true
1 Sample size (n)
2 Effect Size (d)
3 Significance Level (α)
4 Power (β)
As effect size increases power increases
As sample size increases power increases
As significance level increases power increases
Resources
httpwwwncbinlmnihgovpmcarticlesPMC3409926
httpswwwsealedenvelopecompowerbinary-superiority
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
Allopurinol Placebo controlled Efficacy study
of febuxostat (APEX) 2008
28 week randomized double-blind study of 1072 patients comparing the safety and efficacy of febuxostat allopurinol and placebo
Patients were randomized to a once daily fixed dose of placebo febuxostat 80mg120mg or 240 mg or allopurinol 300mg or 100mg depending on their baseline serum creatinine (le15 mgdl or ge16 to lt20 mgdl respectively)
After 1 year of treatment 82 of the patients in all febuxostat groups achieved sUA levels below 60 mgdl compared with 39 of the patients in both allopurinol groups In groups with moderate renal impairment the primary endpoint was achieved by 44 receiving febuxostat 80mg 45 receiving 120mg and 60 receiving 240mg compared with 0 in the allopurinol and placebo groups
However clinical endpoints were not statistically significant
The number of patients with moderate renal impairment was small
Febuxostat Comparative Extension Long-Term
study (EXCEL) 2009
160 week extension study for patients completing FACT and APEX
The studyrsquos aim was to determine long-term efficacy in sUA
lowering clinical benefits and safety of febuxostat or allopurinol
1086 patients were enrolled to receive fixed daily doses of
febuxostat 80mg or 120 mg or allopurinol 300 mg
After the first month of treatment nearly 80 of patients receiving
either febuxostat dose achieved sUA less than 6 mgdl compared
with only 46 of subjects on allopurinol There was no difference in
gout flare incidence and tophi reduction between the groups
Overall adverse events did not show significant differences among
groups
Febuxostat Open Label of Urate-Lowering
Efficacy and Safety (FOCUS) 2009
The FOCUS trial was a 5-year extension study that
assessed reduction and maintenance of sUA levels below
60 mgdl as the primary efficacy endpoint A total of
116 patients were initially enrolled to receive a dose of
80mg febuxostat with dose adjustment to either 40 or
120mg between weeks 4 and 24 93 maintained a sUA
level below 60 mgdl at 5 years
Objectives of CONFIRMS trial
The three-fold objectives of this Phase 3 double-blind RCT study were
1) To compare the UL efficacy of febuxostat at a dose of 40 mg with that of allopurinol at doses most commonly utilized in clinical practice
2) To evaluate UL efficacies of 80 mg and 40 mg daily doses of febuxostat compared with that of allopurinol in subjects with mild or moderate renal impairment
3) To gain prospective uniformly reviewed information regarding the safety of these agents particularly their comparative CV safety
Materials and methods
Subjects aged 18 to 85 years with a diagnosis of gout fulfilling American Rheumatology Association preliminary criteria and sUA ge 80 mgdL were eligible for enrollment
Subjects were enrolled at 324 sites in the United States
IRB approval was obtained and all the subjects provided written informed consent
At least 35 of subjects enrolled were to have mild or moderate renal impairment defined as baseline estimated creatinine clearance (eCLcr) of 60 to 89 mlminutes or 30 to 59 mlminutes
Subjects successfully completing either of the previously
reported long-term open-label febuxostat or
febuxostatallopurinol extension studies were also eligible for
enrollment
Exclusion criteria secondary hyperuricemia (for example
due to myeloproliferative disorder) xanthinuria severe renal
impairment (eCLcr lt30 mlminutes) alanine
aminotransferase and aspartate aminotransferase values gt15
times the upper limit of normal consumption of more than 14
alcoholic drinks per week or a history of alcoholism or drug
abuse within five years or a medical condition that in the
investigators opinion would interfere with treatment safety
or adherence to the protocol
Baseline characteristics of randomized subjects
Baseline characteristics of randomized subjects (cont)
Baseline characteristics of randomized subjects (cont)
2269 Subjects were randomized 111 on Day 1 to
receive daily febuxostat 40 mg febuxostat 80 mg or
allopurinol Among subjects randomized to allopurinol
those with normal renal function or mild renal
impairment received 300 mg daily and those with
moderate renal impairment received 200 mg
Throughout the subsequent six-month treatment period for all subjects prophylaxis for gout flares was given either as colchicine 06 mg daily or naproxen 250 mg twice daily All subjects receiving naproxen prophylaxis also received lansoprazole 15 mg daily
Choice of prophylaxis regimen was made by the investigator and subject taking into account prior drug tolerance and prophylaxis experience
In addition subjects with eCLcr lt50 mlminute were not to receive naproxen
Gout flares were regarded as expected gout manifestations rather than as AEs
The primary efficacy endpoint was the proportion of
subjects in each treatment group with sUA lt60 mgdL
at the final visit
Secondary efficacy variables included
1) The proportion of subjects with mild or moderate
renal impairment and final sUA lt60 mgdL
2) The proportion of subjects with sUA lt60 mgdL lt50
mgdL and lt40 mgdL at each visit
Efficacy analysisResults
Primary efficacy endpoint
1) The proportions of subjects achieving a final visit sUA lt60
mgdL were 452 671 and 421 in the febuxostat 40 mg
febuxostat 80 mg and allopurinol groups respectively
2) UL by febuxostat 40 mg was non-inferior to that by
allopurinol but the difference in the response rates between
the two groups (31 95 CI -19 to 81) was not significant
3) However the greater UL response rate with febuxostat 80 mg
compared with either febuxostat 40 mg (219) or allopurinol
(249) was significant (P lt 0001)
Secondary efficacy endpoints
Among subjects with any (mild or moderate) renal
impairment the UL response rate in the febuxostat 80
mg group (716 360503) significantly exceeded those
observed in the febuxostat 40 mg (497 238479) and
allopurinol (423 212501) groups (P le 0001 for each
comparison)
In addition among the total group of subjects with
renal impairment the UL response rate in the
febuxostat 40 mg group was significantly higher than
that in the allopurinol 300200 mg group (P = 0021)
At any sUA endpoint (lt60 mgdL lt50 mgdL or lt40 mgdL) and at any scheduled visit a significantly higher proportion of subjects receiving febuxostat 80 mg achieved the target endpoint than subjects receiving febuxostat 40 mg or allopurinol (P lt 0001)
Greater proportion of subjects in the febuxostat 40 mg group than the allopurinol group achieved sUAlt60 mgdL (at Month 2 visit P = 0031) and lt50 mgdL (at two- and six month visits P le 005) but significant differences were not seen at other visits including the final visit
Effect of baseline characteristic on treatment response
Adverse events
Adverse events
CONCLUSIONS
Results of the CONFIRMS trial establish equivalent UL efficacy for febuxostat 40 mg daily and allopurinol 300200 mg daily
At all levels of renal function studied UL efficacy of febuxostat 80 mg daily was superior to that of febuxostat 40 mg or allopurinol 300200 mg and was comparably safe
In subjects with mildly or moderately impaired renal function however febuxostat 40 mg daily was significantly more effective in lowering sUA than allopurinol
At the doses studied safety of febuxostat and allopurinol including CV safety was comparable
Febuxostat at 40 mg or 80 mg daily offers a well-tolerated UL alternative to allopurinol particularly for patients with mild or moderate renal impairment
Study limitations
The study does not address the efficacy of febuxostat compared with allopurinol in reducing clinically meaningful acute flares of gout
No mention is made of long-term cost-effectiveness of therapy
Additionally this study does not address the efficacy of febuxostat compared with allopurinol dosing that is more aggressive (ie gt 300 mg daily)
Allopurinol dosing was not titrated
The study population was not similar to the general population (majority of patients were white males)
Possible funding bias
Uloric Related Current Clinical
Trials
References
Dalbeth N Gracey E Pool B et al Identification of dairy fractions with anti-inflammatory properties in models of acute gout Ann
Rheum Dis 2010 69766ndash769
Choi HK Willett W Curhan G Coffee consumption and risk of incident gout in men a prospective study Arthritis Rheum 2007 562049ndash
2055
Hak AE Curhan GC Grodstein F Choi HK Menopause postmenopausal hormone use and risk of incident gout Ann Rheum Dis 2010
691305ndash1309
Becker MA Schumacher HR Wortmann RL et al (December 2005) Febuxostat compared with allopurinol in patients with hyperuricemia
and gout N Engl J Med 353 (23) 2450ndash61
Sarawate CA Patel PA Schumacher HR Yang W Brewer KK Bakst AW Serum urate levels and gout flares analysis from managed care
data J Clin Rheumatol 2006 1261-65
Schumacher HR Jr Becker MA Lloyd E MacDonald PA Lademacher C Febuxostat in the treatment of gout 5-yr findings of the FOCUS
efficacy and safety study Rheumatology (Oxford) 2009 48188-194
14 Becker MA Schumacher HR MacDonald PA Lloyd E Lademacher C Clinical efficacy and safety of successful long-term urate
lowering with febuxostat or allopurinol in subjects with gout J Rheumatol 2009 361273-1278
2012 ACR guidelines for management of gout
Uptodate
Medcape
Statistical Power
Power
The probability that the study will support the research hypothesis if it is true
1 Sample size (n)
2 Effect Size (d)
3 Significance Level (α)
4 Power (β)
As effect size increases power increases
As sample size increases power increases
As significance level increases power increases
Resources
httpwwwncbinlmnihgovpmcarticlesPMC3409926
httpswwwsealedenvelopecompowerbinary-superiority
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
Febuxostat Comparative Extension Long-Term
study (EXCEL) 2009
160 week extension study for patients completing FACT and APEX
The studyrsquos aim was to determine long-term efficacy in sUA
lowering clinical benefits and safety of febuxostat or allopurinol
1086 patients were enrolled to receive fixed daily doses of
febuxostat 80mg or 120 mg or allopurinol 300 mg
After the first month of treatment nearly 80 of patients receiving
either febuxostat dose achieved sUA less than 6 mgdl compared
with only 46 of subjects on allopurinol There was no difference in
gout flare incidence and tophi reduction between the groups
Overall adverse events did not show significant differences among
groups
Febuxostat Open Label of Urate-Lowering
Efficacy and Safety (FOCUS) 2009
The FOCUS trial was a 5-year extension study that
assessed reduction and maintenance of sUA levels below
60 mgdl as the primary efficacy endpoint A total of
116 patients were initially enrolled to receive a dose of
80mg febuxostat with dose adjustment to either 40 or
120mg between weeks 4 and 24 93 maintained a sUA
level below 60 mgdl at 5 years
Objectives of CONFIRMS trial
The three-fold objectives of this Phase 3 double-blind RCT study were
1) To compare the UL efficacy of febuxostat at a dose of 40 mg with that of allopurinol at doses most commonly utilized in clinical practice
2) To evaluate UL efficacies of 80 mg and 40 mg daily doses of febuxostat compared with that of allopurinol in subjects with mild or moderate renal impairment
3) To gain prospective uniformly reviewed information regarding the safety of these agents particularly their comparative CV safety
Materials and methods
Subjects aged 18 to 85 years with a diagnosis of gout fulfilling American Rheumatology Association preliminary criteria and sUA ge 80 mgdL were eligible for enrollment
Subjects were enrolled at 324 sites in the United States
IRB approval was obtained and all the subjects provided written informed consent
At least 35 of subjects enrolled were to have mild or moderate renal impairment defined as baseline estimated creatinine clearance (eCLcr) of 60 to 89 mlminutes or 30 to 59 mlminutes
Subjects successfully completing either of the previously
reported long-term open-label febuxostat or
febuxostatallopurinol extension studies were also eligible for
enrollment
Exclusion criteria secondary hyperuricemia (for example
due to myeloproliferative disorder) xanthinuria severe renal
impairment (eCLcr lt30 mlminutes) alanine
aminotransferase and aspartate aminotransferase values gt15
times the upper limit of normal consumption of more than 14
alcoholic drinks per week or a history of alcoholism or drug
abuse within five years or a medical condition that in the
investigators opinion would interfere with treatment safety
or adherence to the protocol
Baseline characteristics of randomized subjects
Baseline characteristics of randomized subjects (cont)
Baseline characteristics of randomized subjects (cont)
2269 Subjects were randomized 111 on Day 1 to
receive daily febuxostat 40 mg febuxostat 80 mg or
allopurinol Among subjects randomized to allopurinol
those with normal renal function or mild renal
impairment received 300 mg daily and those with
moderate renal impairment received 200 mg
Throughout the subsequent six-month treatment period for all subjects prophylaxis for gout flares was given either as colchicine 06 mg daily or naproxen 250 mg twice daily All subjects receiving naproxen prophylaxis also received lansoprazole 15 mg daily
Choice of prophylaxis regimen was made by the investigator and subject taking into account prior drug tolerance and prophylaxis experience
In addition subjects with eCLcr lt50 mlminute were not to receive naproxen
Gout flares were regarded as expected gout manifestations rather than as AEs
The primary efficacy endpoint was the proportion of
subjects in each treatment group with sUA lt60 mgdL
at the final visit
Secondary efficacy variables included
1) The proportion of subjects with mild or moderate
renal impairment and final sUA lt60 mgdL
2) The proportion of subjects with sUA lt60 mgdL lt50
mgdL and lt40 mgdL at each visit
Efficacy analysisResults
Primary efficacy endpoint
1) The proportions of subjects achieving a final visit sUA lt60
mgdL were 452 671 and 421 in the febuxostat 40 mg
febuxostat 80 mg and allopurinol groups respectively
2) UL by febuxostat 40 mg was non-inferior to that by
allopurinol but the difference in the response rates between
the two groups (31 95 CI -19 to 81) was not significant
3) However the greater UL response rate with febuxostat 80 mg
compared with either febuxostat 40 mg (219) or allopurinol
(249) was significant (P lt 0001)
Secondary efficacy endpoints
Among subjects with any (mild or moderate) renal
impairment the UL response rate in the febuxostat 80
mg group (716 360503) significantly exceeded those
observed in the febuxostat 40 mg (497 238479) and
allopurinol (423 212501) groups (P le 0001 for each
comparison)
In addition among the total group of subjects with
renal impairment the UL response rate in the
febuxostat 40 mg group was significantly higher than
that in the allopurinol 300200 mg group (P = 0021)
At any sUA endpoint (lt60 mgdL lt50 mgdL or lt40 mgdL) and at any scheduled visit a significantly higher proportion of subjects receiving febuxostat 80 mg achieved the target endpoint than subjects receiving febuxostat 40 mg or allopurinol (P lt 0001)
Greater proportion of subjects in the febuxostat 40 mg group than the allopurinol group achieved sUAlt60 mgdL (at Month 2 visit P = 0031) and lt50 mgdL (at two- and six month visits P le 005) but significant differences were not seen at other visits including the final visit
Effect of baseline characteristic on treatment response
Adverse events
Adverse events
CONCLUSIONS
Results of the CONFIRMS trial establish equivalent UL efficacy for febuxostat 40 mg daily and allopurinol 300200 mg daily
At all levels of renal function studied UL efficacy of febuxostat 80 mg daily was superior to that of febuxostat 40 mg or allopurinol 300200 mg and was comparably safe
In subjects with mildly or moderately impaired renal function however febuxostat 40 mg daily was significantly more effective in lowering sUA than allopurinol
At the doses studied safety of febuxostat and allopurinol including CV safety was comparable
Febuxostat at 40 mg or 80 mg daily offers a well-tolerated UL alternative to allopurinol particularly for patients with mild or moderate renal impairment
Study limitations
The study does not address the efficacy of febuxostat compared with allopurinol in reducing clinically meaningful acute flares of gout
No mention is made of long-term cost-effectiveness of therapy
Additionally this study does not address the efficacy of febuxostat compared with allopurinol dosing that is more aggressive (ie gt 300 mg daily)
Allopurinol dosing was not titrated
The study population was not similar to the general population (majority of patients were white males)
Possible funding bias
Uloric Related Current Clinical
Trials
References
Dalbeth N Gracey E Pool B et al Identification of dairy fractions with anti-inflammatory properties in models of acute gout Ann
Rheum Dis 2010 69766ndash769
Choi HK Willett W Curhan G Coffee consumption and risk of incident gout in men a prospective study Arthritis Rheum 2007 562049ndash
2055
Hak AE Curhan GC Grodstein F Choi HK Menopause postmenopausal hormone use and risk of incident gout Ann Rheum Dis 2010
691305ndash1309
Becker MA Schumacher HR Wortmann RL et al (December 2005) Febuxostat compared with allopurinol in patients with hyperuricemia
and gout N Engl J Med 353 (23) 2450ndash61
Sarawate CA Patel PA Schumacher HR Yang W Brewer KK Bakst AW Serum urate levels and gout flares analysis from managed care
data J Clin Rheumatol 2006 1261-65
Schumacher HR Jr Becker MA Lloyd E MacDonald PA Lademacher C Febuxostat in the treatment of gout 5-yr findings of the FOCUS
efficacy and safety study Rheumatology (Oxford) 2009 48188-194
14 Becker MA Schumacher HR MacDonald PA Lloyd E Lademacher C Clinical efficacy and safety of successful long-term urate
lowering with febuxostat or allopurinol in subjects with gout J Rheumatol 2009 361273-1278
2012 ACR guidelines for management of gout
Uptodate
Medcape
Statistical Power
Power
The probability that the study will support the research hypothesis if it is true
1 Sample size (n)
2 Effect Size (d)
3 Significance Level (α)
4 Power (β)
As effect size increases power increases
As sample size increases power increases
As significance level increases power increases
Resources
httpwwwncbinlmnihgovpmcarticlesPMC3409926
httpswwwsealedenvelopecompowerbinary-superiority
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
Febuxostat Open Label of Urate-Lowering
Efficacy and Safety (FOCUS) 2009
The FOCUS trial was a 5-year extension study that
assessed reduction and maintenance of sUA levels below
60 mgdl as the primary efficacy endpoint A total of
116 patients were initially enrolled to receive a dose of
80mg febuxostat with dose adjustment to either 40 or
120mg between weeks 4 and 24 93 maintained a sUA
level below 60 mgdl at 5 years
Objectives of CONFIRMS trial
The three-fold objectives of this Phase 3 double-blind RCT study were
1) To compare the UL efficacy of febuxostat at a dose of 40 mg with that of allopurinol at doses most commonly utilized in clinical practice
2) To evaluate UL efficacies of 80 mg and 40 mg daily doses of febuxostat compared with that of allopurinol in subjects with mild or moderate renal impairment
3) To gain prospective uniformly reviewed information regarding the safety of these agents particularly their comparative CV safety
Materials and methods
Subjects aged 18 to 85 years with a diagnosis of gout fulfilling American Rheumatology Association preliminary criteria and sUA ge 80 mgdL were eligible for enrollment
Subjects were enrolled at 324 sites in the United States
IRB approval was obtained and all the subjects provided written informed consent
At least 35 of subjects enrolled were to have mild or moderate renal impairment defined as baseline estimated creatinine clearance (eCLcr) of 60 to 89 mlminutes or 30 to 59 mlminutes
Subjects successfully completing either of the previously
reported long-term open-label febuxostat or
febuxostatallopurinol extension studies were also eligible for
enrollment
Exclusion criteria secondary hyperuricemia (for example
due to myeloproliferative disorder) xanthinuria severe renal
impairment (eCLcr lt30 mlminutes) alanine
aminotransferase and aspartate aminotransferase values gt15
times the upper limit of normal consumption of more than 14
alcoholic drinks per week or a history of alcoholism or drug
abuse within five years or a medical condition that in the
investigators opinion would interfere with treatment safety
or adherence to the protocol
Baseline characteristics of randomized subjects
Baseline characteristics of randomized subjects (cont)
Baseline characteristics of randomized subjects (cont)
2269 Subjects were randomized 111 on Day 1 to
receive daily febuxostat 40 mg febuxostat 80 mg or
allopurinol Among subjects randomized to allopurinol
those with normal renal function or mild renal
impairment received 300 mg daily and those with
moderate renal impairment received 200 mg
Throughout the subsequent six-month treatment period for all subjects prophylaxis for gout flares was given either as colchicine 06 mg daily or naproxen 250 mg twice daily All subjects receiving naproxen prophylaxis also received lansoprazole 15 mg daily
Choice of prophylaxis regimen was made by the investigator and subject taking into account prior drug tolerance and prophylaxis experience
In addition subjects with eCLcr lt50 mlminute were not to receive naproxen
Gout flares were regarded as expected gout manifestations rather than as AEs
The primary efficacy endpoint was the proportion of
subjects in each treatment group with sUA lt60 mgdL
at the final visit
Secondary efficacy variables included
1) The proportion of subjects with mild or moderate
renal impairment and final sUA lt60 mgdL
2) The proportion of subjects with sUA lt60 mgdL lt50
mgdL and lt40 mgdL at each visit
Efficacy analysisResults
Primary efficacy endpoint
1) The proportions of subjects achieving a final visit sUA lt60
mgdL were 452 671 and 421 in the febuxostat 40 mg
febuxostat 80 mg and allopurinol groups respectively
2) UL by febuxostat 40 mg was non-inferior to that by
allopurinol but the difference in the response rates between
the two groups (31 95 CI -19 to 81) was not significant
3) However the greater UL response rate with febuxostat 80 mg
compared with either febuxostat 40 mg (219) or allopurinol
(249) was significant (P lt 0001)
Secondary efficacy endpoints
Among subjects with any (mild or moderate) renal
impairment the UL response rate in the febuxostat 80
mg group (716 360503) significantly exceeded those
observed in the febuxostat 40 mg (497 238479) and
allopurinol (423 212501) groups (P le 0001 for each
comparison)
In addition among the total group of subjects with
renal impairment the UL response rate in the
febuxostat 40 mg group was significantly higher than
that in the allopurinol 300200 mg group (P = 0021)
At any sUA endpoint (lt60 mgdL lt50 mgdL or lt40 mgdL) and at any scheduled visit a significantly higher proportion of subjects receiving febuxostat 80 mg achieved the target endpoint than subjects receiving febuxostat 40 mg or allopurinol (P lt 0001)
Greater proportion of subjects in the febuxostat 40 mg group than the allopurinol group achieved sUAlt60 mgdL (at Month 2 visit P = 0031) and lt50 mgdL (at two- and six month visits P le 005) but significant differences were not seen at other visits including the final visit
Effect of baseline characteristic on treatment response
Adverse events
Adverse events
CONCLUSIONS
Results of the CONFIRMS trial establish equivalent UL efficacy for febuxostat 40 mg daily and allopurinol 300200 mg daily
At all levels of renal function studied UL efficacy of febuxostat 80 mg daily was superior to that of febuxostat 40 mg or allopurinol 300200 mg and was comparably safe
In subjects with mildly or moderately impaired renal function however febuxostat 40 mg daily was significantly more effective in lowering sUA than allopurinol
At the doses studied safety of febuxostat and allopurinol including CV safety was comparable
Febuxostat at 40 mg or 80 mg daily offers a well-tolerated UL alternative to allopurinol particularly for patients with mild or moderate renal impairment
Study limitations
The study does not address the efficacy of febuxostat compared with allopurinol in reducing clinically meaningful acute flares of gout
No mention is made of long-term cost-effectiveness of therapy
Additionally this study does not address the efficacy of febuxostat compared with allopurinol dosing that is more aggressive (ie gt 300 mg daily)
Allopurinol dosing was not titrated
The study population was not similar to the general population (majority of patients were white males)
Possible funding bias
Uloric Related Current Clinical
Trials
References
Dalbeth N Gracey E Pool B et al Identification of dairy fractions with anti-inflammatory properties in models of acute gout Ann
Rheum Dis 2010 69766ndash769
Choi HK Willett W Curhan G Coffee consumption and risk of incident gout in men a prospective study Arthritis Rheum 2007 562049ndash
2055
Hak AE Curhan GC Grodstein F Choi HK Menopause postmenopausal hormone use and risk of incident gout Ann Rheum Dis 2010
691305ndash1309
Becker MA Schumacher HR Wortmann RL et al (December 2005) Febuxostat compared with allopurinol in patients with hyperuricemia
and gout N Engl J Med 353 (23) 2450ndash61
Sarawate CA Patel PA Schumacher HR Yang W Brewer KK Bakst AW Serum urate levels and gout flares analysis from managed care
data J Clin Rheumatol 2006 1261-65
Schumacher HR Jr Becker MA Lloyd E MacDonald PA Lademacher C Febuxostat in the treatment of gout 5-yr findings of the FOCUS
efficacy and safety study Rheumatology (Oxford) 2009 48188-194
14 Becker MA Schumacher HR MacDonald PA Lloyd E Lademacher C Clinical efficacy and safety of successful long-term urate
lowering with febuxostat or allopurinol in subjects with gout J Rheumatol 2009 361273-1278
2012 ACR guidelines for management of gout
Uptodate
Medcape
Statistical Power
Power
The probability that the study will support the research hypothesis if it is true
1 Sample size (n)
2 Effect Size (d)
3 Significance Level (α)
4 Power (β)
As effect size increases power increases
As sample size increases power increases
As significance level increases power increases
Resources
httpwwwncbinlmnihgovpmcarticlesPMC3409926
httpswwwsealedenvelopecompowerbinary-superiority
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
Objectives of CONFIRMS trial
The three-fold objectives of this Phase 3 double-blind RCT study were
1) To compare the UL efficacy of febuxostat at a dose of 40 mg with that of allopurinol at doses most commonly utilized in clinical practice
2) To evaluate UL efficacies of 80 mg and 40 mg daily doses of febuxostat compared with that of allopurinol in subjects with mild or moderate renal impairment
3) To gain prospective uniformly reviewed information regarding the safety of these agents particularly their comparative CV safety
Materials and methods
Subjects aged 18 to 85 years with a diagnosis of gout fulfilling American Rheumatology Association preliminary criteria and sUA ge 80 mgdL were eligible for enrollment
Subjects were enrolled at 324 sites in the United States
IRB approval was obtained and all the subjects provided written informed consent
At least 35 of subjects enrolled were to have mild or moderate renal impairment defined as baseline estimated creatinine clearance (eCLcr) of 60 to 89 mlminutes or 30 to 59 mlminutes
Subjects successfully completing either of the previously
reported long-term open-label febuxostat or
febuxostatallopurinol extension studies were also eligible for
enrollment
Exclusion criteria secondary hyperuricemia (for example
due to myeloproliferative disorder) xanthinuria severe renal
impairment (eCLcr lt30 mlminutes) alanine
aminotransferase and aspartate aminotransferase values gt15
times the upper limit of normal consumption of more than 14
alcoholic drinks per week or a history of alcoholism or drug
abuse within five years or a medical condition that in the
investigators opinion would interfere with treatment safety
or adherence to the protocol
Baseline characteristics of randomized subjects
Baseline characteristics of randomized subjects (cont)
Baseline characteristics of randomized subjects (cont)
2269 Subjects were randomized 111 on Day 1 to
receive daily febuxostat 40 mg febuxostat 80 mg or
allopurinol Among subjects randomized to allopurinol
those with normal renal function or mild renal
impairment received 300 mg daily and those with
moderate renal impairment received 200 mg
Throughout the subsequent six-month treatment period for all subjects prophylaxis for gout flares was given either as colchicine 06 mg daily or naproxen 250 mg twice daily All subjects receiving naproxen prophylaxis also received lansoprazole 15 mg daily
Choice of prophylaxis regimen was made by the investigator and subject taking into account prior drug tolerance and prophylaxis experience
In addition subjects with eCLcr lt50 mlminute were not to receive naproxen
Gout flares were regarded as expected gout manifestations rather than as AEs
The primary efficacy endpoint was the proportion of
subjects in each treatment group with sUA lt60 mgdL
at the final visit
Secondary efficacy variables included
1) The proportion of subjects with mild or moderate
renal impairment and final sUA lt60 mgdL
2) The proportion of subjects with sUA lt60 mgdL lt50
mgdL and lt40 mgdL at each visit
Efficacy analysisResults
Primary efficacy endpoint
1) The proportions of subjects achieving a final visit sUA lt60
mgdL were 452 671 and 421 in the febuxostat 40 mg
febuxostat 80 mg and allopurinol groups respectively
2) UL by febuxostat 40 mg was non-inferior to that by
allopurinol but the difference in the response rates between
the two groups (31 95 CI -19 to 81) was not significant
3) However the greater UL response rate with febuxostat 80 mg
compared with either febuxostat 40 mg (219) or allopurinol
(249) was significant (P lt 0001)
Secondary efficacy endpoints
Among subjects with any (mild or moderate) renal
impairment the UL response rate in the febuxostat 80
mg group (716 360503) significantly exceeded those
observed in the febuxostat 40 mg (497 238479) and
allopurinol (423 212501) groups (P le 0001 for each
comparison)
In addition among the total group of subjects with
renal impairment the UL response rate in the
febuxostat 40 mg group was significantly higher than
that in the allopurinol 300200 mg group (P = 0021)
At any sUA endpoint (lt60 mgdL lt50 mgdL or lt40 mgdL) and at any scheduled visit a significantly higher proportion of subjects receiving febuxostat 80 mg achieved the target endpoint than subjects receiving febuxostat 40 mg or allopurinol (P lt 0001)
Greater proportion of subjects in the febuxostat 40 mg group than the allopurinol group achieved sUAlt60 mgdL (at Month 2 visit P = 0031) and lt50 mgdL (at two- and six month visits P le 005) but significant differences were not seen at other visits including the final visit
Effect of baseline characteristic on treatment response
Adverse events
Adverse events
CONCLUSIONS
Results of the CONFIRMS trial establish equivalent UL efficacy for febuxostat 40 mg daily and allopurinol 300200 mg daily
At all levels of renal function studied UL efficacy of febuxostat 80 mg daily was superior to that of febuxostat 40 mg or allopurinol 300200 mg and was comparably safe
In subjects with mildly or moderately impaired renal function however febuxostat 40 mg daily was significantly more effective in lowering sUA than allopurinol
At the doses studied safety of febuxostat and allopurinol including CV safety was comparable
Febuxostat at 40 mg or 80 mg daily offers a well-tolerated UL alternative to allopurinol particularly for patients with mild or moderate renal impairment
Study limitations
The study does not address the efficacy of febuxostat compared with allopurinol in reducing clinically meaningful acute flares of gout
No mention is made of long-term cost-effectiveness of therapy
Additionally this study does not address the efficacy of febuxostat compared with allopurinol dosing that is more aggressive (ie gt 300 mg daily)
Allopurinol dosing was not titrated
The study population was not similar to the general population (majority of patients were white males)
Possible funding bias
Uloric Related Current Clinical
Trials
References
Dalbeth N Gracey E Pool B et al Identification of dairy fractions with anti-inflammatory properties in models of acute gout Ann
Rheum Dis 2010 69766ndash769
Choi HK Willett W Curhan G Coffee consumption and risk of incident gout in men a prospective study Arthritis Rheum 2007 562049ndash
2055
Hak AE Curhan GC Grodstein F Choi HK Menopause postmenopausal hormone use and risk of incident gout Ann Rheum Dis 2010
691305ndash1309
Becker MA Schumacher HR Wortmann RL et al (December 2005) Febuxostat compared with allopurinol in patients with hyperuricemia
and gout N Engl J Med 353 (23) 2450ndash61
Sarawate CA Patel PA Schumacher HR Yang W Brewer KK Bakst AW Serum urate levels and gout flares analysis from managed care
data J Clin Rheumatol 2006 1261-65
Schumacher HR Jr Becker MA Lloyd E MacDonald PA Lademacher C Febuxostat in the treatment of gout 5-yr findings of the FOCUS
efficacy and safety study Rheumatology (Oxford) 2009 48188-194
14 Becker MA Schumacher HR MacDonald PA Lloyd E Lademacher C Clinical efficacy and safety of successful long-term urate
lowering with febuxostat or allopurinol in subjects with gout J Rheumatol 2009 361273-1278
2012 ACR guidelines for management of gout
Uptodate
Medcape
Statistical Power
Power
The probability that the study will support the research hypothesis if it is true
1 Sample size (n)
2 Effect Size (d)
3 Significance Level (α)
4 Power (β)
As effect size increases power increases
As sample size increases power increases
As significance level increases power increases
Resources
httpwwwncbinlmnihgovpmcarticlesPMC3409926
httpswwwsealedenvelopecompowerbinary-superiority
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
Materials and methods
Subjects aged 18 to 85 years with a diagnosis of gout fulfilling American Rheumatology Association preliminary criteria and sUA ge 80 mgdL were eligible for enrollment
Subjects were enrolled at 324 sites in the United States
IRB approval was obtained and all the subjects provided written informed consent
At least 35 of subjects enrolled were to have mild or moderate renal impairment defined as baseline estimated creatinine clearance (eCLcr) of 60 to 89 mlminutes or 30 to 59 mlminutes
Subjects successfully completing either of the previously
reported long-term open-label febuxostat or
febuxostatallopurinol extension studies were also eligible for
enrollment
Exclusion criteria secondary hyperuricemia (for example
due to myeloproliferative disorder) xanthinuria severe renal
impairment (eCLcr lt30 mlminutes) alanine
aminotransferase and aspartate aminotransferase values gt15
times the upper limit of normal consumption of more than 14
alcoholic drinks per week or a history of alcoholism or drug
abuse within five years or a medical condition that in the
investigators opinion would interfere with treatment safety
or adherence to the protocol
Baseline characteristics of randomized subjects
Baseline characteristics of randomized subjects (cont)
Baseline characteristics of randomized subjects (cont)
2269 Subjects were randomized 111 on Day 1 to
receive daily febuxostat 40 mg febuxostat 80 mg or
allopurinol Among subjects randomized to allopurinol
those with normal renal function or mild renal
impairment received 300 mg daily and those with
moderate renal impairment received 200 mg
Throughout the subsequent six-month treatment period for all subjects prophylaxis for gout flares was given either as colchicine 06 mg daily or naproxen 250 mg twice daily All subjects receiving naproxen prophylaxis also received lansoprazole 15 mg daily
Choice of prophylaxis regimen was made by the investigator and subject taking into account prior drug tolerance and prophylaxis experience
In addition subjects with eCLcr lt50 mlminute were not to receive naproxen
Gout flares were regarded as expected gout manifestations rather than as AEs
The primary efficacy endpoint was the proportion of
subjects in each treatment group with sUA lt60 mgdL
at the final visit
Secondary efficacy variables included
1) The proportion of subjects with mild or moderate
renal impairment and final sUA lt60 mgdL
2) The proportion of subjects with sUA lt60 mgdL lt50
mgdL and lt40 mgdL at each visit
Efficacy analysisResults
Primary efficacy endpoint
1) The proportions of subjects achieving a final visit sUA lt60
mgdL were 452 671 and 421 in the febuxostat 40 mg
febuxostat 80 mg and allopurinol groups respectively
2) UL by febuxostat 40 mg was non-inferior to that by
allopurinol but the difference in the response rates between
the two groups (31 95 CI -19 to 81) was not significant
3) However the greater UL response rate with febuxostat 80 mg
compared with either febuxostat 40 mg (219) or allopurinol
(249) was significant (P lt 0001)
Secondary efficacy endpoints
Among subjects with any (mild or moderate) renal
impairment the UL response rate in the febuxostat 80
mg group (716 360503) significantly exceeded those
observed in the febuxostat 40 mg (497 238479) and
allopurinol (423 212501) groups (P le 0001 for each
comparison)
In addition among the total group of subjects with
renal impairment the UL response rate in the
febuxostat 40 mg group was significantly higher than
that in the allopurinol 300200 mg group (P = 0021)
At any sUA endpoint (lt60 mgdL lt50 mgdL or lt40 mgdL) and at any scheduled visit a significantly higher proportion of subjects receiving febuxostat 80 mg achieved the target endpoint than subjects receiving febuxostat 40 mg or allopurinol (P lt 0001)
Greater proportion of subjects in the febuxostat 40 mg group than the allopurinol group achieved sUAlt60 mgdL (at Month 2 visit P = 0031) and lt50 mgdL (at two- and six month visits P le 005) but significant differences were not seen at other visits including the final visit
Effect of baseline characteristic on treatment response
Adverse events
Adverse events
CONCLUSIONS
Results of the CONFIRMS trial establish equivalent UL efficacy for febuxostat 40 mg daily and allopurinol 300200 mg daily
At all levels of renal function studied UL efficacy of febuxostat 80 mg daily was superior to that of febuxostat 40 mg or allopurinol 300200 mg and was comparably safe
In subjects with mildly or moderately impaired renal function however febuxostat 40 mg daily was significantly more effective in lowering sUA than allopurinol
At the doses studied safety of febuxostat and allopurinol including CV safety was comparable
Febuxostat at 40 mg or 80 mg daily offers a well-tolerated UL alternative to allopurinol particularly for patients with mild or moderate renal impairment
Study limitations
The study does not address the efficacy of febuxostat compared with allopurinol in reducing clinically meaningful acute flares of gout
No mention is made of long-term cost-effectiveness of therapy
Additionally this study does not address the efficacy of febuxostat compared with allopurinol dosing that is more aggressive (ie gt 300 mg daily)
Allopurinol dosing was not titrated
The study population was not similar to the general population (majority of patients were white males)
Possible funding bias
Uloric Related Current Clinical
Trials
References
Dalbeth N Gracey E Pool B et al Identification of dairy fractions with anti-inflammatory properties in models of acute gout Ann
Rheum Dis 2010 69766ndash769
Choi HK Willett W Curhan G Coffee consumption and risk of incident gout in men a prospective study Arthritis Rheum 2007 562049ndash
2055
Hak AE Curhan GC Grodstein F Choi HK Menopause postmenopausal hormone use and risk of incident gout Ann Rheum Dis 2010
691305ndash1309
Becker MA Schumacher HR Wortmann RL et al (December 2005) Febuxostat compared with allopurinol in patients with hyperuricemia
and gout N Engl J Med 353 (23) 2450ndash61
Sarawate CA Patel PA Schumacher HR Yang W Brewer KK Bakst AW Serum urate levels and gout flares analysis from managed care
data J Clin Rheumatol 2006 1261-65
Schumacher HR Jr Becker MA Lloyd E MacDonald PA Lademacher C Febuxostat in the treatment of gout 5-yr findings of the FOCUS
efficacy and safety study Rheumatology (Oxford) 2009 48188-194
14 Becker MA Schumacher HR MacDonald PA Lloyd E Lademacher C Clinical efficacy and safety of successful long-term urate
lowering with febuxostat or allopurinol in subjects with gout J Rheumatol 2009 361273-1278
2012 ACR guidelines for management of gout
Uptodate
Medcape
Statistical Power
Power
The probability that the study will support the research hypothesis if it is true
1 Sample size (n)
2 Effect Size (d)
3 Significance Level (α)
4 Power (β)
As effect size increases power increases
As sample size increases power increases
As significance level increases power increases
Resources
httpwwwncbinlmnihgovpmcarticlesPMC3409926
httpswwwsealedenvelopecompowerbinary-superiority
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
Subjects successfully completing either of the previously
reported long-term open-label febuxostat or
febuxostatallopurinol extension studies were also eligible for
enrollment
Exclusion criteria secondary hyperuricemia (for example
due to myeloproliferative disorder) xanthinuria severe renal
impairment (eCLcr lt30 mlminutes) alanine
aminotransferase and aspartate aminotransferase values gt15
times the upper limit of normal consumption of more than 14
alcoholic drinks per week or a history of alcoholism or drug
abuse within five years or a medical condition that in the
investigators opinion would interfere with treatment safety
or adherence to the protocol
Baseline characteristics of randomized subjects
Baseline characteristics of randomized subjects (cont)
Baseline characteristics of randomized subjects (cont)
2269 Subjects were randomized 111 on Day 1 to
receive daily febuxostat 40 mg febuxostat 80 mg or
allopurinol Among subjects randomized to allopurinol
those with normal renal function or mild renal
impairment received 300 mg daily and those with
moderate renal impairment received 200 mg
Throughout the subsequent six-month treatment period for all subjects prophylaxis for gout flares was given either as colchicine 06 mg daily or naproxen 250 mg twice daily All subjects receiving naproxen prophylaxis also received lansoprazole 15 mg daily
Choice of prophylaxis regimen was made by the investigator and subject taking into account prior drug tolerance and prophylaxis experience
In addition subjects with eCLcr lt50 mlminute were not to receive naproxen
Gout flares were regarded as expected gout manifestations rather than as AEs
The primary efficacy endpoint was the proportion of
subjects in each treatment group with sUA lt60 mgdL
at the final visit
Secondary efficacy variables included
1) The proportion of subjects with mild or moderate
renal impairment and final sUA lt60 mgdL
2) The proportion of subjects with sUA lt60 mgdL lt50
mgdL and lt40 mgdL at each visit
Efficacy analysisResults
Primary efficacy endpoint
1) The proportions of subjects achieving a final visit sUA lt60
mgdL were 452 671 and 421 in the febuxostat 40 mg
febuxostat 80 mg and allopurinol groups respectively
2) UL by febuxostat 40 mg was non-inferior to that by
allopurinol but the difference in the response rates between
the two groups (31 95 CI -19 to 81) was not significant
3) However the greater UL response rate with febuxostat 80 mg
compared with either febuxostat 40 mg (219) or allopurinol
(249) was significant (P lt 0001)
Secondary efficacy endpoints
Among subjects with any (mild or moderate) renal
impairment the UL response rate in the febuxostat 80
mg group (716 360503) significantly exceeded those
observed in the febuxostat 40 mg (497 238479) and
allopurinol (423 212501) groups (P le 0001 for each
comparison)
In addition among the total group of subjects with
renal impairment the UL response rate in the
febuxostat 40 mg group was significantly higher than
that in the allopurinol 300200 mg group (P = 0021)
At any sUA endpoint (lt60 mgdL lt50 mgdL or lt40 mgdL) and at any scheduled visit a significantly higher proportion of subjects receiving febuxostat 80 mg achieved the target endpoint than subjects receiving febuxostat 40 mg or allopurinol (P lt 0001)
Greater proportion of subjects in the febuxostat 40 mg group than the allopurinol group achieved sUAlt60 mgdL (at Month 2 visit P = 0031) and lt50 mgdL (at two- and six month visits P le 005) but significant differences were not seen at other visits including the final visit
Effect of baseline characteristic on treatment response
Adverse events
Adverse events
CONCLUSIONS
Results of the CONFIRMS trial establish equivalent UL efficacy for febuxostat 40 mg daily and allopurinol 300200 mg daily
At all levels of renal function studied UL efficacy of febuxostat 80 mg daily was superior to that of febuxostat 40 mg or allopurinol 300200 mg and was comparably safe
In subjects with mildly or moderately impaired renal function however febuxostat 40 mg daily was significantly more effective in lowering sUA than allopurinol
At the doses studied safety of febuxostat and allopurinol including CV safety was comparable
Febuxostat at 40 mg or 80 mg daily offers a well-tolerated UL alternative to allopurinol particularly for patients with mild or moderate renal impairment
Study limitations
The study does not address the efficacy of febuxostat compared with allopurinol in reducing clinically meaningful acute flares of gout
No mention is made of long-term cost-effectiveness of therapy
Additionally this study does not address the efficacy of febuxostat compared with allopurinol dosing that is more aggressive (ie gt 300 mg daily)
Allopurinol dosing was not titrated
The study population was not similar to the general population (majority of patients were white males)
Possible funding bias
Uloric Related Current Clinical
Trials
References
Dalbeth N Gracey E Pool B et al Identification of dairy fractions with anti-inflammatory properties in models of acute gout Ann
Rheum Dis 2010 69766ndash769
Choi HK Willett W Curhan G Coffee consumption and risk of incident gout in men a prospective study Arthritis Rheum 2007 562049ndash
2055
Hak AE Curhan GC Grodstein F Choi HK Menopause postmenopausal hormone use and risk of incident gout Ann Rheum Dis 2010
691305ndash1309
Becker MA Schumacher HR Wortmann RL et al (December 2005) Febuxostat compared with allopurinol in patients with hyperuricemia
and gout N Engl J Med 353 (23) 2450ndash61
Sarawate CA Patel PA Schumacher HR Yang W Brewer KK Bakst AW Serum urate levels and gout flares analysis from managed care
data J Clin Rheumatol 2006 1261-65
Schumacher HR Jr Becker MA Lloyd E MacDonald PA Lademacher C Febuxostat in the treatment of gout 5-yr findings of the FOCUS
efficacy and safety study Rheumatology (Oxford) 2009 48188-194
14 Becker MA Schumacher HR MacDonald PA Lloyd E Lademacher C Clinical efficacy and safety of successful long-term urate
lowering with febuxostat or allopurinol in subjects with gout J Rheumatol 2009 361273-1278
2012 ACR guidelines for management of gout
Uptodate
Medcape
Statistical Power
Power
The probability that the study will support the research hypothesis if it is true
1 Sample size (n)
2 Effect Size (d)
3 Significance Level (α)
4 Power (β)
As effect size increases power increases
As sample size increases power increases
As significance level increases power increases
Resources
httpwwwncbinlmnihgovpmcarticlesPMC3409926
httpswwwsealedenvelopecompowerbinary-superiority
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
Baseline characteristics of randomized subjects
Baseline characteristics of randomized subjects (cont)
Baseline characteristics of randomized subjects (cont)
2269 Subjects were randomized 111 on Day 1 to
receive daily febuxostat 40 mg febuxostat 80 mg or
allopurinol Among subjects randomized to allopurinol
those with normal renal function or mild renal
impairment received 300 mg daily and those with
moderate renal impairment received 200 mg
Throughout the subsequent six-month treatment period for all subjects prophylaxis for gout flares was given either as colchicine 06 mg daily or naproxen 250 mg twice daily All subjects receiving naproxen prophylaxis also received lansoprazole 15 mg daily
Choice of prophylaxis regimen was made by the investigator and subject taking into account prior drug tolerance and prophylaxis experience
In addition subjects with eCLcr lt50 mlminute were not to receive naproxen
Gout flares were regarded as expected gout manifestations rather than as AEs
The primary efficacy endpoint was the proportion of
subjects in each treatment group with sUA lt60 mgdL
at the final visit
Secondary efficacy variables included
1) The proportion of subjects with mild or moderate
renal impairment and final sUA lt60 mgdL
2) The proportion of subjects with sUA lt60 mgdL lt50
mgdL and lt40 mgdL at each visit
Efficacy analysisResults
Primary efficacy endpoint
1) The proportions of subjects achieving a final visit sUA lt60
mgdL were 452 671 and 421 in the febuxostat 40 mg
febuxostat 80 mg and allopurinol groups respectively
2) UL by febuxostat 40 mg was non-inferior to that by
allopurinol but the difference in the response rates between
the two groups (31 95 CI -19 to 81) was not significant
3) However the greater UL response rate with febuxostat 80 mg
compared with either febuxostat 40 mg (219) or allopurinol
(249) was significant (P lt 0001)
Secondary efficacy endpoints
Among subjects with any (mild or moderate) renal
impairment the UL response rate in the febuxostat 80
mg group (716 360503) significantly exceeded those
observed in the febuxostat 40 mg (497 238479) and
allopurinol (423 212501) groups (P le 0001 for each
comparison)
In addition among the total group of subjects with
renal impairment the UL response rate in the
febuxostat 40 mg group was significantly higher than
that in the allopurinol 300200 mg group (P = 0021)
At any sUA endpoint (lt60 mgdL lt50 mgdL or lt40 mgdL) and at any scheduled visit a significantly higher proportion of subjects receiving febuxostat 80 mg achieved the target endpoint than subjects receiving febuxostat 40 mg or allopurinol (P lt 0001)
Greater proportion of subjects in the febuxostat 40 mg group than the allopurinol group achieved sUAlt60 mgdL (at Month 2 visit P = 0031) and lt50 mgdL (at two- and six month visits P le 005) but significant differences were not seen at other visits including the final visit
Effect of baseline characteristic on treatment response
Adverse events
Adverse events
CONCLUSIONS
Results of the CONFIRMS trial establish equivalent UL efficacy for febuxostat 40 mg daily and allopurinol 300200 mg daily
At all levels of renal function studied UL efficacy of febuxostat 80 mg daily was superior to that of febuxostat 40 mg or allopurinol 300200 mg and was comparably safe
In subjects with mildly or moderately impaired renal function however febuxostat 40 mg daily was significantly more effective in lowering sUA than allopurinol
At the doses studied safety of febuxostat and allopurinol including CV safety was comparable
Febuxostat at 40 mg or 80 mg daily offers a well-tolerated UL alternative to allopurinol particularly for patients with mild or moderate renal impairment
Study limitations
The study does not address the efficacy of febuxostat compared with allopurinol in reducing clinically meaningful acute flares of gout
No mention is made of long-term cost-effectiveness of therapy
Additionally this study does not address the efficacy of febuxostat compared with allopurinol dosing that is more aggressive (ie gt 300 mg daily)
Allopurinol dosing was not titrated
The study population was not similar to the general population (majority of patients were white males)
Possible funding bias
Uloric Related Current Clinical
Trials
References
Dalbeth N Gracey E Pool B et al Identification of dairy fractions with anti-inflammatory properties in models of acute gout Ann
Rheum Dis 2010 69766ndash769
Choi HK Willett W Curhan G Coffee consumption and risk of incident gout in men a prospective study Arthritis Rheum 2007 562049ndash
2055
Hak AE Curhan GC Grodstein F Choi HK Menopause postmenopausal hormone use and risk of incident gout Ann Rheum Dis 2010
691305ndash1309
Becker MA Schumacher HR Wortmann RL et al (December 2005) Febuxostat compared with allopurinol in patients with hyperuricemia
and gout N Engl J Med 353 (23) 2450ndash61
Sarawate CA Patel PA Schumacher HR Yang W Brewer KK Bakst AW Serum urate levels and gout flares analysis from managed care
data J Clin Rheumatol 2006 1261-65
Schumacher HR Jr Becker MA Lloyd E MacDonald PA Lademacher C Febuxostat in the treatment of gout 5-yr findings of the FOCUS
efficacy and safety study Rheumatology (Oxford) 2009 48188-194
14 Becker MA Schumacher HR MacDonald PA Lloyd E Lademacher C Clinical efficacy and safety of successful long-term urate
lowering with febuxostat or allopurinol in subjects with gout J Rheumatol 2009 361273-1278
2012 ACR guidelines for management of gout
Uptodate
Medcape
Statistical Power
Power
The probability that the study will support the research hypothesis if it is true
1 Sample size (n)
2 Effect Size (d)
3 Significance Level (α)
4 Power (β)
As effect size increases power increases
As sample size increases power increases
As significance level increases power increases
Resources
httpwwwncbinlmnihgovpmcarticlesPMC3409926
httpswwwsealedenvelopecompowerbinary-superiority
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
Baseline characteristics of randomized subjects (cont)
Baseline characteristics of randomized subjects (cont)
2269 Subjects were randomized 111 on Day 1 to
receive daily febuxostat 40 mg febuxostat 80 mg or
allopurinol Among subjects randomized to allopurinol
those with normal renal function or mild renal
impairment received 300 mg daily and those with
moderate renal impairment received 200 mg
Throughout the subsequent six-month treatment period for all subjects prophylaxis for gout flares was given either as colchicine 06 mg daily or naproxen 250 mg twice daily All subjects receiving naproxen prophylaxis also received lansoprazole 15 mg daily
Choice of prophylaxis regimen was made by the investigator and subject taking into account prior drug tolerance and prophylaxis experience
In addition subjects with eCLcr lt50 mlminute were not to receive naproxen
Gout flares were regarded as expected gout manifestations rather than as AEs
The primary efficacy endpoint was the proportion of
subjects in each treatment group with sUA lt60 mgdL
at the final visit
Secondary efficacy variables included
1) The proportion of subjects with mild or moderate
renal impairment and final sUA lt60 mgdL
2) The proportion of subjects with sUA lt60 mgdL lt50
mgdL and lt40 mgdL at each visit
Efficacy analysisResults
Primary efficacy endpoint
1) The proportions of subjects achieving a final visit sUA lt60
mgdL were 452 671 and 421 in the febuxostat 40 mg
febuxostat 80 mg and allopurinol groups respectively
2) UL by febuxostat 40 mg was non-inferior to that by
allopurinol but the difference in the response rates between
the two groups (31 95 CI -19 to 81) was not significant
3) However the greater UL response rate with febuxostat 80 mg
compared with either febuxostat 40 mg (219) or allopurinol
(249) was significant (P lt 0001)
Secondary efficacy endpoints
Among subjects with any (mild or moderate) renal
impairment the UL response rate in the febuxostat 80
mg group (716 360503) significantly exceeded those
observed in the febuxostat 40 mg (497 238479) and
allopurinol (423 212501) groups (P le 0001 for each
comparison)
In addition among the total group of subjects with
renal impairment the UL response rate in the
febuxostat 40 mg group was significantly higher than
that in the allopurinol 300200 mg group (P = 0021)
At any sUA endpoint (lt60 mgdL lt50 mgdL or lt40 mgdL) and at any scheduled visit a significantly higher proportion of subjects receiving febuxostat 80 mg achieved the target endpoint than subjects receiving febuxostat 40 mg or allopurinol (P lt 0001)
Greater proportion of subjects in the febuxostat 40 mg group than the allopurinol group achieved sUAlt60 mgdL (at Month 2 visit P = 0031) and lt50 mgdL (at two- and six month visits P le 005) but significant differences were not seen at other visits including the final visit
Effect of baseline characteristic on treatment response
Adverse events
Adverse events
CONCLUSIONS
Results of the CONFIRMS trial establish equivalent UL efficacy for febuxostat 40 mg daily and allopurinol 300200 mg daily
At all levels of renal function studied UL efficacy of febuxostat 80 mg daily was superior to that of febuxostat 40 mg or allopurinol 300200 mg and was comparably safe
In subjects with mildly or moderately impaired renal function however febuxostat 40 mg daily was significantly more effective in lowering sUA than allopurinol
At the doses studied safety of febuxostat and allopurinol including CV safety was comparable
Febuxostat at 40 mg or 80 mg daily offers a well-tolerated UL alternative to allopurinol particularly for patients with mild or moderate renal impairment
Study limitations
The study does not address the efficacy of febuxostat compared with allopurinol in reducing clinically meaningful acute flares of gout
No mention is made of long-term cost-effectiveness of therapy
Additionally this study does not address the efficacy of febuxostat compared with allopurinol dosing that is more aggressive (ie gt 300 mg daily)
Allopurinol dosing was not titrated
The study population was not similar to the general population (majority of patients were white males)
Possible funding bias
Uloric Related Current Clinical
Trials
References
Dalbeth N Gracey E Pool B et al Identification of dairy fractions with anti-inflammatory properties in models of acute gout Ann
Rheum Dis 2010 69766ndash769
Choi HK Willett W Curhan G Coffee consumption and risk of incident gout in men a prospective study Arthritis Rheum 2007 562049ndash
2055
Hak AE Curhan GC Grodstein F Choi HK Menopause postmenopausal hormone use and risk of incident gout Ann Rheum Dis 2010
691305ndash1309
Becker MA Schumacher HR Wortmann RL et al (December 2005) Febuxostat compared with allopurinol in patients with hyperuricemia
and gout N Engl J Med 353 (23) 2450ndash61
Sarawate CA Patel PA Schumacher HR Yang W Brewer KK Bakst AW Serum urate levels and gout flares analysis from managed care
data J Clin Rheumatol 2006 1261-65
Schumacher HR Jr Becker MA Lloyd E MacDonald PA Lademacher C Febuxostat in the treatment of gout 5-yr findings of the FOCUS
efficacy and safety study Rheumatology (Oxford) 2009 48188-194
14 Becker MA Schumacher HR MacDonald PA Lloyd E Lademacher C Clinical efficacy and safety of successful long-term urate
lowering with febuxostat or allopurinol in subjects with gout J Rheumatol 2009 361273-1278
2012 ACR guidelines for management of gout
Uptodate
Medcape
Statistical Power
Power
The probability that the study will support the research hypothesis if it is true
1 Sample size (n)
2 Effect Size (d)
3 Significance Level (α)
4 Power (β)
As effect size increases power increases
As sample size increases power increases
As significance level increases power increases
Resources
httpwwwncbinlmnihgovpmcarticlesPMC3409926
httpswwwsealedenvelopecompowerbinary-superiority
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
Baseline characteristics of randomized subjects (cont)
2269 Subjects were randomized 111 on Day 1 to
receive daily febuxostat 40 mg febuxostat 80 mg or
allopurinol Among subjects randomized to allopurinol
those with normal renal function or mild renal
impairment received 300 mg daily and those with
moderate renal impairment received 200 mg
Throughout the subsequent six-month treatment period for all subjects prophylaxis for gout flares was given either as colchicine 06 mg daily or naproxen 250 mg twice daily All subjects receiving naproxen prophylaxis also received lansoprazole 15 mg daily
Choice of prophylaxis regimen was made by the investigator and subject taking into account prior drug tolerance and prophylaxis experience
In addition subjects with eCLcr lt50 mlminute were not to receive naproxen
Gout flares were regarded as expected gout manifestations rather than as AEs
The primary efficacy endpoint was the proportion of
subjects in each treatment group with sUA lt60 mgdL
at the final visit
Secondary efficacy variables included
1) The proportion of subjects with mild or moderate
renal impairment and final sUA lt60 mgdL
2) The proportion of subjects with sUA lt60 mgdL lt50
mgdL and lt40 mgdL at each visit
Efficacy analysisResults
Primary efficacy endpoint
1) The proportions of subjects achieving a final visit sUA lt60
mgdL were 452 671 and 421 in the febuxostat 40 mg
febuxostat 80 mg and allopurinol groups respectively
2) UL by febuxostat 40 mg was non-inferior to that by
allopurinol but the difference in the response rates between
the two groups (31 95 CI -19 to 81) was not significant
3) However the greater UL response rate with febuxostat 80 mg
compared with either febuxostat 40 mg (219) or allopurinol
(249) was significant (P lt 0001)
Secondary efficacy endpoints
Among subjects with any (mild or moderate) renal
impairment the UL response rate in the febuxostat 80
mg group (716 360503) significantly exceeded those
observed in the febuxostat 40 mg (497 238479) and
allopurinol (423 212501) groups (P le 0001 for each
comparison)
In addition among the total group of subjects with
renal impairment the UL response rate in the
febuxostat 40 mg group was significantly higher than
that in the allopurinol 300200 mg group (P = 0021)
At any sUA endpoint (lt60 mgdL lt50 mgdL or lt40 mgdL) and at any scheduled visit a significantly higher proportion of subjects receiving febuxostat 80 mg achieved the target endpoint than subjects receiving febuxostat 40 mg or allopurinol (P lt 0001)
Greater proportion of subjects in the febuxostat 40 mg group than the allopurinol group achieved sUAlt60 mgdL (at Month 2 visit P = 0031) and lt50 mgdL (at two- and six month visits P le 005) but significant differences were not seen at other visits including the final visit
Effect of baseline characteristic on treatment response
Adverse events
Adverse events
CONCLUSIONS
Results of the CONFIRMS trial establish equivalent UL efficacy for febuxostat 40 mg daily and allopurinol 300200 mg daily
At all levels of renal function studied UL efficacy of febuxostat 80 mg daily was superior to that of febuxostat 40 mg or allopurinol 300200 mg and was comparably safe
In subjects with mildly or moderately impaired renal function however febuxostat 40 mg daily was significantly more effective in lowering sUA than allopurinol
At the doses studied safety of febuxostat and allopurinol including CV safety was comparable
Febuxostat at 40 mg or 80 mg daily offers a well-tolerated UL alternative to allopurinol particularly for patients with mild or moderate renal impairment
Study limitations
The study does not address the efficacy of febuxostat compared with allopurinol in reducing clinically meaningful acute flares of gout
No mention is made of long-term cost-effectiveness of therapy
Additionally this study does not address the efficacy of febuxostat compared with allopurinol dosing that is more aggressive (ie gt 300 mg daily)
Allopurinol dosing was not titrated
The study population was not similar to the general population (majority of patients were white males)
Possible funding bias
Uloric Related Current Clinical
Trials
References
Dalbeth N Gracey E Pool B et al Identification of dairy fractions with anti-inflammatory properties in models of acute gout Ann
Rheum Dis 2010 69766ndash769
Choi HK Willett W Curhan G Coffee consumption and risk of incident gout in men a prospective study Arthritis Rheum 2007 562049ndash
2055
Hak AE Curhan GC Grodstein F Choi HK Menopause postmenopausal hormone use and risk of incident gout Ann Rheum Dis 2010
691305ndash1309
Becker MA Schumacher HR Wortmann RL et al (December 2005) Febuxostat compared with allopurinol in patients with hyperuricemia
and gout N Engl J Med 353 (23) 2450ndash61
Sarawate CA Patel PA Schumacher HR Yang W Brewer KK Bakst AW Serum urate levels and gout flares analysis from managed care
data J Clin Rheumatol 2006 1261-65
Schumacher HR Jr Becker MA Lloyd E MacDonald PA Lademacher C Febuxostat in the treatment of gout 5-yr findings of the FOCUS
efficacy and safety study Rheumatology (Oxford) 2009 48188-194
14 Becker MA Schumacher HR MacDonald PA Lloyd E Lademacher C Clinical efficacy and safety of successful long-term urate
lowering with febuxostat or allopurinol in subjects with gout J Rheumatol 2009 361273-1278
2012 ACR guidelines for management of gout
Uptodate
Medcape
Statistical Power
Power
The probability that the study will support the research hypothesis if it is true
1 Sample size (n)
2 Effect Size (d)
3 Significance Level (α)
4 Power (β)
As effect size increases power increases
As sample size increases power increases
As significance level increases power increases
Resources
httpwwwncbinlmnihgovpmcarticlesPMC3409926
httpswwwsealedenvelopecompowerbinary-superiority
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
2269 Subjects were randomized 111 on Day 1 to
receive daily febuxostat 40 mg febuxostat 80 mg or
allopurinol Among subjects randomized to allopurinol
those with normal renal function or mild renal
impairment received 300 mg daily and those with
moderate renal impairment received 200 mg
Throughout the subsequent six-month treatment period for all subjects prophylaxis for gout flares was given either as colchicine 06 mg daily or naproxen 250 mg twice daily All subjects receiving naproxen prophylaxis also received lansoprazole 15 mg daily
Choice of prophylaxis regimen was made by the investigator and subject taking into account prior drug tolerance and prophylaxis experience
In addition subjects with eCLcr lt50 mlminute were not to receive naproxen
Gout flares were regarded as expected gout manifestations rather than as AEs
The primary efficacy endpoint was the proportion of
subjects in each treatment group with sUA lt60 mgdL
at the final visit
Secondary efficacy variables included
1) The proportion of subjects with mild or moderate
renal impairment and final sUA lt60 mgdL
2) The proportion of subjects with sUA lt60 mgdL lt50
mgdL and lt40 mgdL at each visit
Efficacy analysisResults
Primary efficacy endpoint
1) The proportions of subjects achieving a final visit sUA lt60
mgdL were 452 671 and 421 in the febuxostat 40 mg
febuxostat 80 mg and allopurinol groups respectively
2) UL by febuxostat 40 mg was non-inferior to that by
allopurinol but the difference in the response rates between
the two groups (31 95 CI -19 to 81) was not significant
3) However the greater UL response rate with febuxostat 80 mg
compared with either febuxostat 40 mg (219) or allopurinol
(249) was significant (P lt 0001)
Secondary efficacy endpoints
Among subjects with any (mild or moderate) renal
impairment the UL response rate in the febuxostat 80
mg group (716 360503) significantly exceeded those
observed in the febuxostat 40 mg (497 238479) and
allopurinol (423 212501) groups (P le 0001 for each
comparison)
In addition among the total group of subjects with
renal impairment the UL response rate in the
febuxostat 40 mg group was significantly higher than
that in the allopurinol 300200 mg group (P = 0021)
At any sUA endpoint (lt60 mgdL lt50 mgdL or lt40 mgdL) and at any scheduled visit a significantly higher proportion of subjects receiving febuxostat 80 mg achieved the target endpoint than subjects receiving febuxostat 40 mg or allopurinol (P lt 0001)
Greater proportion of subjects in the febuxostat 40 mg group than the allopurinol group achieved sUAlt60 mgdL (at Month 2 visit P = 0031) and lt50 mgdL (at two- and six month visits P le 005) but significant differences were not seen at other visits including the final visit
Effect of baseline characteristic on treatment response
Adverse events
Adverse events
CONCLUSIONS
Results of the CONFIRMS trial establish equivalent UL efficacy for febuxostat 40 mg daily and allopurinol 300200 mg daily
At all levels of renal function studied UL efficacy of febuxostat 80 mg daily was superior to that of febuxostat 40 mg or allopurinol 300200 mg and was comparably safe
In subjects with mildly or moderately impaired renal function however febuxostat 40 mg daily was significantly more effective in lowering sUA than allopurinol
At the doses studied safety of febuxostat and allopurinol including CV safety was comparable
Febuxostat at 40 mg or 80 mg daily offers a well-tolerated UL alternative to allopurinol particularly for patients with mild or moderate renal impairment
Study limitations
The study does not address the efficacy of febuxostat compared with allopurinol in reducing clinically meaningful acute flares of gout
No mention is made of long-term cost-effectiveness of therapy
Additionally this study does not address the efficacy of febuxostat compared with allopurinol dosing that is more aggressive (ie gt 300 mg daily)
Allopurinol dosing was not titrated
The study population was not similar to the general population (majority of patients were white males)
Possible funding bias
Uloric Related Current Clinical
Trials
References
Dalbeth N Gracey E Pool B et al Identification of dairy fractions with anti-inflammatory properties in models of acute gout Ann
Rheum Dis 2010 69766ndash769
Choi HK Willett W Curhan G Coffee consumption and risk of incident gout in men a prospective study Arthritis Rheum 2007 562049ndash
2055
Hak AE Curhan GC Grodstein F Choi HK Menopause postmenopausal hormone use and risk of incident gout Ann Rheum Dis 2010
691305ndash1309
Becker MA Schumacher HR Wortmann RL et al (December 2005) Febuxostat compared with allopurinol in patients with hyperuricemia
and gout N Engl J Med 353 (23) 2450ndash61
Sarawate CA Patel PA Schumacher HR Yang W Brewer KK Bakst AW Serum urate levels and gout flares analysis from managed care
data J Clin Rheumatol 2006 1261-65
Schumacher HR Jr Becker MA Lloyd E MacDonald PA Lademacher C Febuxostat in the treatment of gout 5-yr findings of the FOCUS
efficacy and safety study Rheumatology (Oxford) 2009 48188-194
14 Becker MA Schumacher HR MacDonald PA Lloyd E Lademacher C Clinical efficacy and safety of successful long-term urate
lowering with febuxostat or allopurinol in subjects with gout J Rheumatol 2009 361273-1278
2012 ACR guidelines for management of gout
Uptodate
Medcape
Statistical Power
Power
The probability that the study will support the research hypothesis if it is true
1 Sample size (n)
2 Effect Size (d)
3 Significance Level (α)
4 Power (β)
As effect size increases power increases
As sample size increases power increases
As significance level increases power increases
Resources
httpwwwncbinlmnihgovpmcarticlesPMC3409926
httpswwwsealedenvelopecompowerbinary-superiority
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
Throughout the subsequent six-month treatment period for all subjects prophylaxis for gout flares was given either as colchicine 06 mg daily or naproxen 250 mg twice daily All subjects receiving naproxen prophylaxis also received lansoprazole 15 mg daily
Choice of prophylaxis regimen was made by the investigator and subject taking into account prior drug tolerance and prophylaxis experience
In addition subjects with eCLcr lt50 mlminute were not to receive naproxen
Gout flares were regarded as expected gout manifestations rather than as AEs
The primary efficacy endpoint was the proportion of
subjects in each treatment group with sUA lt60 mgdL
at the final visit
Secondary efficacy variables included
1) The proportion of subjects with mild or moderate
renal impairment and final sUA lt60 mgdL
2) The proportion of subjects with sUA lt60 mgdL lt50
mgdL and lt40 mgdL at each visit
Efficacy analysisResults
Primary efficacy endpoint
1) The proportions of subjects achieving a final visit sUA lt60
mgdL were 452 671 and 421 in the febuxostat 40 mg
febuxostat 80 mg and allopurinol groups respectively
2) UL by febuxostat 40 mg was non-inferior to that by
allopurinol but the difference in the response rates between
the two groups (31 95 CI -19 to 81) was not significant
3) However the greater UL response rate with febuxostat 80 mg
compared with either febuxostat 40 mg (219) or allopurinol
(249) was significant (P lt 0001)
Secondary efficacy endpoints
Among subjects with any (mild or moderate) renal
impairment the UL response rate in the febuxostat 80
mg group (716 360503) significantly exceeded those
observed in the febuxostat 40 mg (497 238479) and
allopurinol (423 212501) groups (P le 0001 for each
comparison)
In addition among the total group of subjects with
renal impairment the UL response rate in the
febuxostat 40 mg group was significantly higher than
that in the allopurinol 300200 mg group (P = 0021)
At any sUA endpoint (lt60 mgdL lt50 mgdL or lt40 mgdL) and at any scheduled visit a significantly higher proportion of subjects receiving febuxostat 80 mg achieved the target endpoint than subjects receiving febuxostat 40 mg or allopurinol (P lt 0001)
Greater proportion of subjects in the febuxostat 40 mg group than the allopurinol group achieved sUAlt60 mgdL (at Month 2 visit P = 0031) and lt50 mgdL (at two- and six month visits P le 005) but significant differences were not seen at other visits including the final visit
Effect of baseline characteristic on treatment response
Adverse events
Adverse events
CONCLUSIONS
Results of the CONFIRMS trial establish equivalent UL efficacy for febuxostat 40 mg daily and allopurinol 300200 mg daily
At all levels of renal function studied UL efficacy of febuxostat 80 mg daily was superior to that of febuxostat 40 mg or allopurinol 300200 mg and was comparably safe
In subjects with mildly or moderately impaired renal function however febuxostat 40 mg daily was significantly more effective in lowering sUA than allopurinol
At the doses studied safety of febuxostat and allopurinol including CV safety was comparable
Febuxostat at 40 mg or 80 mg daily offers a well-tolerated UL alternative to allopurinol particularly for patients with mild or moderate renal impairment
Study limitations
The study does not address the efficacy of febuxostat compared with allopurinol in reducing clinically meaningful acute flares of gout
No mention is made of long-term cost-effectiveness of therapy
Additionally this study does not address the efficacy of febuxostat compared with allopurinol dosing that is more aggressive (ie gt 300 mg daily)
Allopurinol dosing was not titrated
The study population was not similar to the general population (majority of patients were white males)
Possible funding bias
Uloric Related Current Clinical
Trials
References
Dalbeth N Gracey E Pool B et al Identification of dairy fractions with anti-inflammatory properties in models of acute gout Ann
Rheum Dis 2010 69766ndash769
Choi HK Willett W Curhan G Coffee consumption and risk of incident gout in men a prospective study Arthritis Rheum 2007 562049ndash
2055
Hak AE Curhan GC Grodstein F Choi HK Menopause postmenopausal hormone use and risk of incident gout Ann Rheum Dis 2010
691305ndash1309
Becker MA Schumacher HR Wortmann RL et al (December 2005) Febuxostat compared with allopurinol in patients with hyperuricemia
and gout N Engl J Med 353 (23) 2450ndash61
Sarawate CA Patel PA Schumacher HR Yang W Brewer KK Bakst AW Serum urate levels and gout flares analysis from managed care
data J Clin Rheumatol 2006 1261-65
Schumacher HR Jr Becker MA Lloyd E MacDonald PA Lademacher C Febuxostat in the treatment of gout 5-yr findings of the FOCUS
efficacy and safety study Rheumatology (Oxford) 2009 48188-194
14 Becker MA Schumacher HR MacDonald PA Lloyd E Lademacher C Clinical efficacy and safety of successful long-term urate
lowering with febuxostat or allopurinol in subjects with gout J Rheumatol 2009 361273-1278
2012 ACR guidelines for management of gout
Uptodate
Medcape
Statistical Power
Power
The probability that the study will support the research hypothesis if it is true
1 Sample size (n)
2 Effect Size (d)
3 Significance Level (α)
4 Power (β)
As effect size increases power increases
As sample size increases power increases
As significance level increases power increases
Resources
httpwwwncbinlmnihgovpmcarticlesPMC3409926
httpswwwsealedenvelopecompowerbinary-superiority
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
The primary efficacy endpoint was the proportion of
subjects in each treatment group with sUA lt60 mgdL
at the final visit
Secondary efficacy variables included
1) The proportion of subjects with mild or moderate
renal impairment and final sUA lt60 mgdL
2) The proportion of subjects with sUA lt60 mgdL lt50
mgdL and lt40 mgdL at each visit
Efficacy analysisResults
Primary efficacy endpoint
1) The proportions of subjects achieving a final visit sUA lt60
mgdL were 452 671 and 421 in the febuxostat 40 mg
febuxostat 80 mg and allopurinol groups respectively
2) UL by febuxostat 40 mg was non-inferior to that by
allopurinol but the difference in the response rates between
the two groups (31 95 CI -19 to 81) was not significant
3) However the greater UL response rate with febuxostat 80 mg
compared with either febuxostat 40 mg (219) or allopurinol
(249) was significant (P lt 0001)
Secondary efficacy endpoints
Among subjects with any (mild or moderate) renal
impairment the UL response rate in the febuxostat 80
mg group (716 360503) significantly exceeded those
observed in the febuxostat 40 mg (497 238479) and
allopurinol (423 212501) groups (P le 0001 for each
comparison)
In addition among the total group of subjects with
renal impairment the UL response rate in the
febuxostat 40 mg group was significantly higher than
that in the allopurinol 300200 mg group (P = 0021)
At any sUA endpoint (lt60 mgdL lt50 mgdL or lt40 mgdL) and at any scheduled visit a significantly higher proportion of subjects receiving febuxostat 80 mg achieved the target endpoint than subjects receiving febuxostat 40 mg or allopurinol (P lt 0001)
Greater proportion of subjects in the febuxostat 40 mg group than the allopurinol group achieved sUAlt60 mgdL (at Month 2 visit P = 0031) and lt50 mgdL (at two- and six month visits P le 005) but significant differences were not seen at other visits including the final visit
Effect of baseline characteristic on treatment response
Adverse events
Adverse events
CONCLUSIONS
Results of the CONFIRMS trial establish equivalent UL efficacy for febuxostat 40 mg daily and allopurinol 300200 mg daily
At all levels of renal function studied UL efficacy of febuxostat 80 mg daily was superior to that of febuxostat 40 mg or allopurinol 300200 mg and was comparably safe
In subjects with mildly or moderately impaired renal function however febuxostat 40 mg daily was significantly more effective in lowering sUA than allopurinol
At the doses studied safety of febuxostat and allopurinol including CV safety was comparable
Febuxostat at 40 mg or 80 mg daily offers a well-tolerated UL alternative to allopurinol particularly for patients with mild or moderate renal impairment
Study limitations
The study does not address the efficacy of febuxostat compared with allopurinol in reducing clinically meaningful acute flares of gout
No mention is made of long-term cost-effectiveness of therapy
Additionally this study does not address the efficacy of febuxostat compared with allopurinol dosing that is more aggressive (ie gt 300 mg daily)
Allopurinol dosing was not titrated
The study population was not similar to the general population (majority of patients were white males)
Possible funding bias
Uloric Related Current Clinical
Trials
References
Dalbeth N Gracey E Pool B et al Identification of dairy fractions with anti-inflammatory properties in models of acute gout Ann
Rheum Dis 2010 69766ndash769
Choi HK Willett W Curhan G Coffee consumption and risk of incident gout in men a prospective study Arthritis Rheum 2007 562049ndash
2055
Hak AE Curhan GC Grodstein F Choi HK Menopause postmenopausal hormone use and risk of incident gout Ann Rheum Dis 2010
691305ndash1309
Becker MA Schumacher HR Wortmann RL et al (December 2005) Febuxostat compared with allopurinol in patients with hyperuricemia
and gout N Engl J Med 353 (23) 2450ndash61
Sarawate CA Patel PA Schumacher HR Yang W Brewer KK Bakst AW Serum urate levels and gout flares analysis from managed care
data J Clin Rheumatol 2006 1261-65
Schumacher HR Jr Becker MA Lloyd E MacDonald PA Lademacher C Febuxostat in the treatment of gout 5-yr findings of the FOCUS
efficacy and safety study Rheumatology (Oxford) 2009 48188-194
14 Becker MA Schumacher HR MacDonald PA Lloyd E Lademacher C Clinical efficacy and safety of successful long-term urate
lowering with febuxostat or allopurinol in subjects with gout J Rheumatol 2009 361273-1278
2012 ACR guidelines for management of gout
Uptodate
Medcape
Statistical Power
Power
The probability that the study will support the research hypothesis if it is true
1 Sample size (n)
2 Effect Size (d)
3 Significance Level (α)
4 Power (β)
As effect size increases power increases
As sample size increases power increases
As significance level increases power increases
Resources
httpwwwncbinlmnihgovpmcarticlesPMC3409926
httpswwwsealedenvelopecompowerbinary-superiority
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
Efficacy analysisResults
Primary efficacy endpoint
1) The proportions of subjects achieving a final visit sUA lt60
mgdL were 452 671 and 421 in the febuxostat 40 mg
febuxostat 80 mg and allopurinol groups respectively
2) UL by febuxostat 40 mg was non-inferior to that by
allopurinol but the difference in the response rates between
the two groups (31 95 CI -19 to 81) was not significant
3) However the greater UL response rate with febuxostat 80 mg
compared with either febuxostat 40 mg (219) or allopurinol
(249) was significant (P lt 0001)
Secondary efficacy endpoints
Among subjects with any (mild or moderate) renal
impairment the UL response rate in the febuxostat 80
mg group (716 360503) significantly exceeded those
observed in the febuxostat 40 mg (497 238479) and
allopurinol (423 212501) groups (P le 0001 for each
comparison)
In addition among the total group of subjects with
renal impairment the UL response rate in the
febuxostat 40 mg group was significantly higher than
that in the allopurinol 300200 mg group (P = 0021)
At any sUA endpoint (lt60 mgdL lt50 mgdL or lt40 mgdL) and at any scheduled visit a significantly higher proportion of subjects receiving febuxostat 80 mg achieved the target endpoint than subjects receiving febuxostat 40 mg or allopurinol (P lt 0001)
Greater proportion of subjects in the febuxostat 40 mg group than the allopurinol group achieved sUAlt60 mgdL (at Month 2 visit P = 0031) and lt50 mgdL (at two- and six month visits P le 005) but significant differences were not seen at other visits including the final visit
Effect of baseline characteristic on treatment response
Adverse events
Adverse events
CONCLUSIONS
Results of the CONFIRMS trial establish equivalent UL efficacy for febuxostat 40 mg daily and allopurinol 300200 mg daily
At all levels of renal function studied UL efficacy of febuxostat 80 mg daily was superior to that of febuxostat 40 mg or allopurinol 300200 mg and was comparably safe
In subjects with mildly or moderately impaired renal function however febuxostat 40 mg daily was significantly more effective in lowering sUA than allopurinol
At the doses studied safety of febuxostat and allopurinol including CV safety was comparable
Febuxostat at 40 mg or 80 mg daily offers a well-tolerated UL alternative to allopurinol particularly for patients with mild or moderate renal impairment
Study limitations
The study does not address the efficacy of febuxostat compared with allopurinol in reducing clinically meaningful acute flares of gout
No mention is made of long-term cost-effectiveness of therapy
Additionally this study does not address the efficacy of febuxostat compared with allopurinol dosing that is more aggressive (ie gt 300 mg daily)
Allopurinol dosing was not titrated
The study population was not similar to the general population (majority of patients were white males)
Possible funding bias
Uloric Related Current Clinical
Trials
References
Dalbeth N Gracey E Pool B et al Identification of dairy fractions with anti-inflammatory properties in models of acute gout Ann
Rheum Dis 2010 69766ndash769
Choi HK Willett W Curhan G Coffee consumption and risk of incident gout in men a prospective study Arthritis Rheum 2007 562049ndash
2055
Hak AE Curhan GC Grodstein F Choi HK Menopause postmenopausal hormone use and risk of incident gout Ann Rheum Dis 2010
691305ndash1309
Becker MA Schumacher HR Wortmann RL et al (December 2005) Febuxostat compared with allopurinol in patients with hyperuricemia
and gout N Engl J Med 353 (23) 2450ndash61
Sarawate CA Patel PA Schumacher HR Yang W Brewer KK Bakst AW Serum urate levels and gout flares analysis from managed care
data J Clin Rheumatol 2006 1261-65
Schumacher HR Jr Becker MA Lloyd E MacDonald PA Lademacher C Febuxostat in the treatment of gout 5-yr findings of the FOCUS
efficacy and safety study Rheumatology (Oxford) 2009 48188-194
14 Becker MA Schumacher HR MacDonald PA Lloyd E Lademacher C Clinical efficacy and safety of successful long-term urate
lowering with febuxostat or allopurinol in subjects with gout J Rheumatol 2009 361273-1278
2012 ACR guidelines for management of gout
Uptodate
Medcape
Statistical Power
Power
The probability that the study will support the research hypothesis if it is true
1 Sample size (n)
2 Effect Size (d)
3 Significance Level (α)
4 Power (β)
As effect size increases power increases
As sample size increases power increases
As significance level increases power increases
Resources
httpwwwncbinlmnihgovpmcarticlesPMC3409926
httpswwwsealedenvelopecompowerbinary-superiority
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
Secondary efficacy endpoints
Among subjects with any (mild or moderate) renal
impairment the UL response rate in the febuxostat 80
mg group (716 360503) significantly exceeded those
observed in the febuxostat 40 mg (497 238479) and
allopurinol (423 212501) groups (P le 0001 for each
comparison)
In addition among the total group of subjects with
renal impairment the UL response rate in the
febuxostat 40 mg group was significantly higher than
that in the allopurinol 300200 mg group (P = 0021)
At any sUA endpoint (lt60 mgdL lt50 mgdL or lt40 mgdL) and at any scheduled visit a significantly higher proportion of subjects receiving febuxostat 80 mg achieved the target endpoint than subjects receiving febuxostat 40 mg or allopurinol (P lt 0001)
Greater proportion of subjects in the febuxostat 40 mg group than the allopurinol group achieved sUAlt60 mgdL (at Month 2 visit P = 0031) and lt50 mgdL (at two- and six month visits P le 005) but significant differences were not seen at other visits including the final visit
Effect of baseline characteristic on treatment response
Adverse events
Adverse events
CONCLUSIONS
Results of the CONFIRMS trial establish equivalent UL efficacy for febuxostat 40 mg daily and allopurinol 300200 mg daily
At all levels of renal function studied UL efficacy of febuxostat 80 mg daily was superior to that of febuxostat 40 mg or allopurinol 300200 mg and was comparably safe
In subjects with mildly or moderately impaired renal function however febuxostat 40 mg daily was significantly more effective in lowering sUA than allopurinol
At the doses studied safety of febuxostat and allopurinol including CV safety was comparable
Febuxostat at 40 mg or 80 mg daily offers a well-tolerated UL alternative to allopurinol particularly for patients with mild or moderate renal impairment
Study limitations
The study does not address the efficacy of febuxostat compared with allopurinol in reducing clinically meaningful acute flares of gout
No mention is made of long-term cost-effectiveness of therapy
Additionally this study does not address the efficacy of febuxostat compared with allopurinol dosing that is more aggressive (ie gt 300 mg daily)
Allopurinol dosing was not titrated
The study population was not similar to the general population (majority of patients were white males)
Possible funding bias
Uloric Related Current Clinical
Trials
References
Dalbeth N Gracey E Pool B et al Identification of dairy fractions with anti-inflammatory properties in models of acute gout Ann
Rheum Dis 2010 69766ndash769
Choi HK Willett W Curhan G Coffee consumption and risk of incident gout in men a prospective study Arthritis Rheum 2007 562049ndash
2055
Hak AE Curhan GC Grodstein F Choi HK Menopause postmenopausal hormone use and risk of incident gout Ann Rheum Dis 2010
691305ndash1309
Becker MA Schumacher HR Wortmann RL et al (December 2005) Febuxostat compared with allopurinol in patients with hyperuricemia
and gout N Engl J Med 353 (23) 2450ndash61
Sarawate CA Patel PA Schumacher HR Yang W Brewer KK Bakst AW Serum urate levels and gout flares analysis from managed care
data J Clin Rheumatol 2006 1261-65
Schumacher HR Jr Becker MA Lloyd E MacDonald PA Lademacher C Febuxostat in the treatment of gout 5-yr findings of the FOCUS
efficacy and safety study Rheumatology (Oxford) 2009 48188-194
14 Becker MA Schumacher HR MacDonald PA Lloyd E Lademacher C Clinical efficacy and safety of successful long-term urate
lowering with febuxostat or allopurinol in subjects with gout J Rheumatol 2009 361273-1278
2012 ACR guidelines for management of gout
Uptodate
Medcape
Statistical Power
Power
The probability that the study will support the research hypothesis if it is true
1 Sample size (n)
2 Effect Size (d)
3 Significance Level (α)
4 Power (β)
As effect size increases power increases
As sample size increases power increases
As significance level increases power increases
Resources
httpwwwncbinlmnihgovpmcarticlesPMC3409926
httpswwwsealedenvelopecompowerbinary-superiority
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
At any sUA endpoint (lt60 mgdL lt50 mgdL or lt40 mgdL) and at any scheduled visit a significantly higher proportion of subjects receiving febuxostat 80 mg achieved the target endpoint than subjects receiving febuxostat 40 mg or allopurinol (P lt 0001)
Greater proportion of subjects in the febuxostat 40 mg group than the allopurinol group achieved sUAlt60 mgdL (at Month 2 visit P = 0031) and lt50 mgdL (at two- and six month visits P le 005) but significant differences were not seen at other visits including the final visit
Effect of baseline characteristic on treatment response
Adverse events
Adverse events
CONCLUSIONS
Results of the CONFIRMS trial establish equivalent UL efficacy for febuxostat 40 mg daily and allopurinol 300200 mg daily
At all levels of renal function studied UL efficacy of febuxostat 80 mg daily was superior to that of febuxostat 40 mg or allopurinol 300200 mg and was comparably safe
In subjects with mildly or moderately impaired renal function however febuxostat 40 mg daily was significantly more effective in lowering sUA than allopurinol
At the doses studied safety of febuxostat and allopurinol including CV safety was comparable
Febuxostat at 40 mg or 80 mg daily offers a well-tolerated UL alternative to allopurinol particularly for patients with mild or moderate renal impairment
Study limitations
The study does not address the efficacy of febuxostat compared with allopurinol in reducing clinically meaningful acute flares of gout
No mention is made of long-term cost-effectiveness of therapy
Additionally this study does not address the efficacy of febuxostat compared with allopurinol dosing that is more aggressive (ie gt 300 mg daily)
Allopurinol dosing was not titrated
The study population was not similar to the general population (majority of patients were white males)
Possible funding bias
Uloric Related Current Clinical
Trials
References
Dalbeth N Gracey E Pool B et al Identification of dairy fractions with anti-inflammatory properties in models of acute gout Ann
Rheum Dis 2010 69766ndash769
Choi HK Willett W Curhan G Coffee consumption and risk of incident gout in men a prospective study Arthritis Rheum 2007 562049ndash
2055
Hak AE Curhan GC Grodstein F Choi HK Menopause postmenopausal hormone use and risk of incident gout Ann Rheum Dis 2010
691305ndash1309
Becker MA Schumacher HR Wortmann RL et al (December 2005) Febuxostat compared with allopurinol in patients with hyperuricemia
and gout N Engl J Med 353 (23) 2450ndash61
Sarawate CA Patel PA Schumacher HR Yang W Brewer KK Bakst AW Serum urate levels and gout flares analysis from managed care
data J Clin Rheumatol 2006 1261-65
Schumacher HR Jr Becker MA Lloyd E MacDonald PA Lademacher C Febuxostat in the treatment of gout 5-yr findings of the FOCUS
efficacy and safety study Rheumatology (Oxford) 2009 48188-194
14 Becker MA Schumacher HR MacDonald PA Lloyd E Lademacher C Clinical efficacy and safety of successful long-term urate
lowering with febuxostat or allopurinol in subjects with gout J Rheumatol 2009 361273-1278
2012 ACR guidelines for management of gout
Uptodate
Medcape
Statistical Power
Power
The probability that the study will support the research hypothesis if it is true
1 Sample size (n)
2 Effect Size (d)
3 Significance Level (α)
4 Power (β)
As effect size increases power increases
As sample size increases power increases
As significance level increases power increases
Resources
httpwwwncbinlmnihgovpmcarticlesPMC3409926
httpswwwsealedenvelopecompowerbinary-superiority
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
Effect of baseline characteristic on treatment response
Adverse events
Adverse events
CONCLUSIONS
Results of the CONFIRMS trial establish equivalent UL efficacy for febuxostat 40 mg daily and allopurinol 300200 mg daily
At all levels of renal function studied UL efficacy of febuxostat 80 mg daily was superior to that of febuxostat 40 mg or allopurinol 300200 mg and was comparably safe
In subjects with mildly or moderately impaired renal function however febuxostat 40 mg daily was significantly more effective in lowering sUA than allopurinol
At the doses studied safety of febuxostat and allopurinol including CV safety was comparable
Febuxostat at 40 mg or 80 mg daily offers a well-tolerated UL alternative to allopurinol particularly for patients with mild or moderate renal impairment
Study limitations
The study does not address the efficacy of febuxostat compared with allopurinol in reducing clinically meaningful acute flares of gout
No mention is made of long-term cost-effectiveness of therapy
Additionally this study does not address the efficacy of febuxostat compared with allopurinol dosing that is more aggressive (ie gt 300 mg daily)
Allopurinol dosing was not titrated
The study population was not similar to the general population (majority of patients were white males)
Possible funding bias
Uloric Related Current Clinical
Trials
References
Dalbeth N Gracey E Pool B et al Identification of dairy fractions with anti-inflammatory properties in models of acute gout Ann
Rheum Dis 2010 69766ndash769
Choi HK Willett W Curhan G Coffee consumption and risk of incident gout in men a prospective study Arthritis Rheum 2007 562049ndash
2055
Hak AE Curhan GC Grodstein F Choi HK Menopause postmenopausal hormone use and risk of incident gout Ann Rheum Dis 2010
691305ndash1309
Becker MA Schumacher HR Wortmann RL et al (December 2005) Febuxostat compared with allopurinol in patients with hyperuricemia
and gout N Engl J Med 353 (23) 2450ndash61
Sarawate CA Patel PA Schumacher HR Yang W Brewer KK Bakst AW Serum urate levels and gout flares analysis from managed care
data J Clin Rheumatol 2006 1261-65
Schumacher HR Jr Becker MA Lloyd E MacDonald PA Lademacher C Febuxostat in the treatment of gout 5-yr findings of the FOCUS
efficacy and safety study Rheumatology (Oxford) 2009 48188-194
14 Becker MA Schumacher HR MacDonald PA Lloyd E Lademacher C Clinical efficacy and safety of successful long-term urate
lowering with febuxostat or allopurinol in subjects with gout J Rheumatol 2009 361273-1278
2012 ACR guidelines for management of gout
Uptodate
Medcape
Statistical Power
Power
The probability that the study will support the research hypothesis if it is true
1 Sample size (n)
2 Effect Size (d)
3 Significance Level (α)
4 Power (β)
As effect size increases power increases
As sample size increases power increases
As significance level increases power increases
Resources
httpwwwncbinlmnihgovpmcarticlesPMC3409926
httpswwwsealedenvelopecompowerbinary-superiority
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
Adverse events
Adverse events
CONCLUSIONS
Results of the CONFIRMS trial establish equivalent UL efficacy for febuxostat 40 mg daily and allopurinol 300200 mg daily
At all levels of renal function studied UL efficacy of febuxostat 80 mg daily was superior to that of febuxostat 40 mg or allopurinol 300200 mg and was comparably safe
In subjects with mildly or moderately impaired renal function however febuxostat 40 mg daily was significantly more effective in lowering sUA than allopurinol
At the doses studied safety of febuxostat and allopurinol including CV safety was comparable
Febuxostat at 40 mg or 80 mg daily offers a well-tolerated UL alternative to allopurinol particularly for patients with mild or moderate renal impairment
Study limitations
The study does not address the efficacy of febuxostat compared with allopurinol in reducing clinically meaningful acute flares of gout
No mention is made of long-term cost-effectiveness of therapy
Additionally this study does not address the efficacy of febuxostat compared with allopurinol dosing that is more aggressive (ie gt 300 mg daily)
Allopurinol dosing was not titrated
The study population was not similar to the general population (majority of patients were white males)
Possible funding bias
Uloric Related Current Clinical
Trials
References
Dalbeth N Gracey E Pool B et al Identification of dairy fractions with anti-inflammatory properties in models of acute gout Ann
Rheum Dis 2010 69766ndash769
Choi HK Willett W Curhan G Coffee consumption and risk of incident gout in men a prospective study Arthritis Rheum 2007 562049ndash
2055
Hak AE Curhan GC Grodstein F Choi HK Menopause postmenopausal hormone use and risk of incident gout Ann Rheum Dis 2010
691305ndash1309
Becker MA Schumacher HR Wortmann RL et al (December 2005) Febuxostat compared with allopurinol in patients with hyperuricemia
and gout N Engl J Med 353 (23) 2450ndash61
Sarawate CA Patel PA Schumacher HR Yang W Brewer KK Bakst AW Serum urate levels and gout flares analysis from managed care
data J Clin Rheumatol 2006 1261-65
Schumacher HR Jr Becker MA Lloyd E MacDonald PA Lademacher C Febuxostat in the treatment of gout 5-yr findings of the FOCUS
efficacy and safety study Rheumatology (Oxford) 2009 48188-194
14 Becker MA Schumacher HR MacDonald PA Lloyd E Lademacher C Clinical efficacy and safety of successful long-term urate
lowering with febuxostat or allopurinol in subjects with gout J Rheumatol 2009 361273-1278
2012 ACR guidelines for management of gout
Uptodate
Medcape
Statistical Power
Power
The probability that the study will support the research hypothesis if it is true
1 Sample size (n)
2 Effect Size (d)
3 Significance Level (α)
4 Power (β)
As effect size increases power increases
As sample size increases power increases
As significance level increases power increases
Resources
httpwwwncbinlmnihgovpmcarticlesPMC3409926
httpswwwsealedenvelopecompowerbinary-superiority
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
Adverse events
CONCLUSIONS
Results of the CONFIRMS trial establish equivalent UL efficacy for febuxostat 40 mg daily and allopurinol 300200 mg daily
At all levels of renal function studied UL efficacy of febuxostat 80 mg daily was superior to that of febuxostat 40 mg or allopurinol 300200 mg and was comparably safe
In subjects with mildly or moderately impaired renal function however febuxostat 40 mg daily was significantly more effective in lowering sUA than allopurinol
At the doses studied safety of febuxostat and allopurinol including CV safety was comparable
Febuxostat at 40 mg or 80 mg daily offers a well-tolerated UL alternative to allopurinol particularly for patients with mild or moderate renal impairment
Study limitations
The study does not address the efficacy of febuxostat compared with allopurinol in reducing clinically meaningful acute flares of gout
No mention is made of long-term cost-effectiveness of therapy
Additionally this study does not address the efficacy of febuxostat compared with allopurinol dosing that is more aggressive (ie gt 300 mg daily)
Allopurinol dosing was not titrated
The study population was not similar to the general population (majority of patients were white males)
Possible funding bias
Uloric Related Current Clinical
Trials
References
Dalbeth N Gracey E Pool B et al Identification of dairy fractions with anti-inflammatory properties in models of acute gout Ann
Rheum Dis 2010 69766ndash769
Choi HK Willett W Curhan G Coffee consumption and risk of incident gout in men a prospective study Arthritis Rheum 2007 562049ndash
2055
Hak AE Curhan GC Grodstein F Choi HK Menopause postmenopausal hormone use and risk of incident gout Ann Rheum Dis 2010
691305ndash1309
Becker MA Schumacher HR Wortmann RL et al (December 2005) Febuxostat compared with allopurinol in patients with hyperuricemia
and gout N Engl J Med 353 (23) 2450ndash61
Sarawate CA Patel PA Schumacher HR Yang W Brewer KK Bakst AW Serum urate levels and gout flares analysis from managed care
data J Clin Rheumatol 2006 1261-65
Schumacher HR Jr Becker MA Lloyd E MacDonald PA Lademacher C Febuxostat in the treatment of gout 5-yr findings of the FOCUS
efficacy and safety study Rheumatology (Oxford) 2009 48188-194
14 Becker MA Schumacher HR MacDonald PA Lloyd E Lademacher C Clinical efficacy and safety of successful long-term urate
lowering with febuxostat or allopurinol in subjects with gout J Rheumatol 2009 361273-1278
2012 ACR guidelines for management of gout
Uptodate
Medcape
Statistical Power
Power
The probability that the study will support the research hypothesis if it is true
1 Sample size (n)
2 Effect Size (d)
3 Significance Level (α)
4 Power (β)
As effect size increases power increases
As sample size increases power increases
As significance level increases power increases
Resources
httpwwwncbinlmnihgovpmcarticlesPMC3409926
httpswwwsealedenvelopecompowerbinary-superiority
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
CONCLUSIONS
Results of the CONFIRMS trial establish equivalent UL efficacy for febuxostat 40 mg daily and allopurinol 300200 mg daily
At all levels of renal function studied UL efficacy of febuxostat 80 mg daily was superior to that of febuxostat 40 mg or allopurinol 300200 mg and was comparably safe
In subjects with mildly or moderately impaired renal function however febuxostat 40 mg daily was significantly more effective in lowering sUA than allopurinol
At the doses studied safety of febuxostat and allopurinol including CV safety was comparable
Febuxostat at 40 mg or 80 mg daily offers a well-tolerated UL alternative to allopurinol particularly for patients with mild or moderate renal impairment
Study limitations
The study does not address the efficacy of febuxostat compared with allopurinol in reducing clinically meaningful acute flares of gout
No mention is made of long-term cost-effectiveness of therapy
Additionally this study does not address the efficacy of febuxostat compared with allopurinol dosing that is more aggressive (ie gt 300 mg daily)
Allopurinol dosing was not titrated
The study population was not similar to the general population (majority of patients were white males)
Possible funding bias
Uloric Related Current Clinical
Trials
References
Dalbeth N Gracey E Pool B et al Identification of dairy fractions with anti-inflammatory properties in models of acute gout Ann
Rheum Dis 2010 69766ndash769
Choi HK Willett W Curhan G Coffee consumption and risk of incident gout in men a prospective study Arthritis Rheum 2007 562049ndash
2055
Hak AE Curhan GC Grodstein F Choi HK Menopause postmenopausal hormone use and risk of incident gout Ann Rheum Dis 2010
691305ndash1309
Becker MA Schumacher HR Wortmann RL et al (December 2005) Febuxostat compared with allopurinol in patients with hyperuricemia
and gout N Engl J Med 353 (23) 2450ndash61
Sarawate CA Patel PA Schumacher HR Yang W Brewer KK Bakst AW Serum urate levels and gout flares analysis from managed care
data J Clin Rheumatol 2006 1261-65
Schumacher HR Jr Becker MA Lloyd E MacDonald PA Lademacher C Febuxostat in the treatment of gout 5-yr findings of the FOCUS
efficacy and safety study Rheumatology (Oxford) 2009 48188-194
14 Becker MA Schumacher HR MacDonald PA Lloyd E Lademacher C Clinical efficacy and safety of successful long-term urate
lowering with febuxostat or allopurinol in subjects with gout J Rheumatol 2009 361273-1278
2012 ACR guidelines for management of gout
Uptodate
Medcape
Statistical Power
Power
The probability that the study will support the research hypothesis if it is true
1 Sample size (n)
2 Effect Size (d)
3 Significance Level (α)
4 Power (β)
As effect size increases power increases
As sample size increases power increases
As significance level increases power increases
Resources
httpwwwncbinlmnihgovpmcarticlesPMC3409926
httpswwwsealedenvelopecompowerbinary-superiority
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
Study limitations
The study does not address the efficacy of febuxostat compared with allopurinol in reducing clinically meaningful acute flares of gout
No mention is made of long-term cost-effectiveness of therapy
Additionally this study does not address the efficacy of febuxostat compared with allopurinol dosing that is more aggressive (ie gt 300 mg daily)
Allopurinol dosing was not titrated
The study population was not similar to the general population (majority of patients were white males)
Possible funding bias
Uloric Related Current Clinical
Trials
References
Dalbeth N Gracey E Pool B et al Identification of dairy fractions with anti-inflammatory properties in models of acute gout Ann
Rheum Dis 2010 69766ndash769
Choi HK Willett W Curhan G Coffee consumption and risk of incident gout in men a prospective study Arthritis Rheum 2007 562049ndash
2055
Hak AE Curhan GC Grodstein F Choi HK Menopause postmenopausal hormone use and risk of incident gout Ann Rheum Dis 2010
691305ndash1309
Becker MA Schumacher HR Wortmann RL et al (December 2005) Febuxostat compared with allopurinol in patients with hyperuricemia
and gout N Engl J Med 353 (23) 2450ndash61
Sarawate CA Patel PA Schumacher HR Yang W Brewer KK Bakst AW Serum urate levels and gout flares analysis from managed care
data J Clin Rheumatol 2006 1261-65
Schumacher HR Jr Becker MA Lloyd E MacDonald PA Lademacher C Febuxostat in the treatment of gout 5-yr findings of the FOCUS
efficacy and safety study Rheumatology (Oxford) 2009 48188-194
14 Becker MA Schumacher HR MacDonald PA Lloyd E Lademacher C Clinical efficacy and safety of successful long-term urate
lowering with febuxostat or allopurinol in subjects with gout J Rheumatol 2009 361273-1278
2012 ACR guidelines for management of gout
Uptodate
Medcape
Statistical Power
Power
The probability that the study will support the research hypothesis if it is true
1 Sample size (n)
2 Effect Size (d)
3 Significance Level (α)
4 Power (β)
As effect size increases power increases
As sample size increases power increases
As significance level increases power increases
Resources
httpwwwncbinlmnihgovpmcarticlesPMC3409926
httpswwwsealedenvelopecompowerbinary-superiority
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
Uloric Related Current Clinical
Trials
References
Dalbeth N Gracey E Pool B et al Identification of dairy fractions with anti-inflammatory properties in models of acute gout Ann
Rheum Dis 2010 69766ndash769
Choi HK Willett W Curhan G Coffee consumption and risk of incident gout in men a prospective study Arthritis Rheum 2007 562049ndash
2055
Hak AE Curhan GC Grodstein F Choi HK Menopause postmenopausal hormone use and risk of incident gout Ann Rheum Dis 2010
691305ndash1309
Becker MA Schumacher HR Wortmann RL et al (December 2005) Febuxostat compared with allopurinol in patients with hyperuricemia
and gout N Engl J Med 353 (23) 2450ndash61
Sarawate CA Patel PA Schumacher HR Yang W Brewer KK Bakst AW Serum urate levels and gout flares analysis from managed care
data J Clin Rheumatol 2006 1261-65
Schumacher HR Jr Becker MA Lloyd E MacDonald PA Lademacher C Febuxostat in the treatment of gout 5-yr findings of the FOCUS
efficacy and safety study Rheumatology (Oxford) 2009 48188-194
14 Becker MA Schumacher HR MacDonald PA Lloyd E Lademacher C Clinical efficacy and safety of successful long-term urate
lowering with febuxostat or allopurinol in subjects with gout J Rheumatol 2009 361273-1278
2012 ACR guidelines for management of gout
Uptodate
Medcape
Statistical Power
Power
The probability that the study will support the research hypothesis if it is true
1 Sample size (n)
2 Effect Size (d)
3 Significance Level (α)
4 Power (β)
As effect size increases power increases
As sample size increases power increases
As significance level increases power increases
Resources
httpwwwncbinlmnihgovpmcarticlesPMC3409926
httpswwwsealedenvelopecompowerbinary-superiority
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
References
Dalbeth N Gracey E Pool B et al Identification of dairy fractions with anti-inflammatory properties in models of acute gout Ann
Rheum Dis 2010 69766ndash769
Choi HK Willett W Curhan G Coffee consumption and risk of incident gout in men a prospective study Arthritis Rheum 2007 562049ndash
2055
Hak AE Curhan GC Grodstein F Choi HK Menopause postmenopausal hormone use and risk of incident gout Ann Rheum Dis 2010
691305ndash1309
Becker MA Schumacher HR Wortmann RL et al (December 2005) Febuxostat compared with allopurinol in patients with hyperuricemia
and gout N Engl J Med 353 (23) 2450ndash61
Sarawate CA Patel PA Schumacher HR Yang W Brewer KK Bakst AW Serum urate levels and gout flares analysis from managed care
data J Clin Rheumatol 2006 1261-65
Schumacher HR Jr Becker MA Lloyd E MacDonald PA Lademacher C Febuxostat in the treatment of gout 5-yr findings of the FOCUS
efficacy and safety study Rheumatology (Oxford) 2009 48188-194
14 Becker MA Schumacher HR MacDonald PA Lloyd E Lademacher C Clinical efficacy and safety of successful long-term urate
lowering with febuxostat or allopurinol in subjects with gout J Rheumatol 2009 361273-1278
2012 ACR guidelines for management of gout
Uptodate
Medcape
Statistical Power
Power
The probability that the study will support the research hypothesis if it is true
1 Sample size (n)
2 Effect Size (d)
3 Significance Level (α)
4 Power (β)
As effect size increases power increases
As sample size increases power increases
As significance level increases power increases
Resources
httpwwwncbinlmnihgovpmcarticlesPMC3409926
httpswwwsealedenvelopecompowerbinary-superiority
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
Statistical Power
Power
The probability that the study will support the research hypothesis if it is true
1 Sample size (n)
2 Effect Size (d)
3 Significance Level (α)
4 Power (β)
As effect size increases power increases
As sample size increases power increases
As significance level increases power increases
Resources
httpwwwncbinlmnihgovpmcarticlesPMC3409926
httpswwwsealedenvelopecompowerbinary-superiority
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
Power
The probability that the study will support the research hypothesis if it is true
1 Sample size (n)
2 Effect Size (d)
3 Significance Level (α)
4 Power (β)
As effect size increases power increases
As sample size increases power increases
As significance level increases power increases
Resources
httpwwwncbinlmnihgovpmcarticlesPMC3409926
httpswwwsealedenvelopecompowerbinary-superiority
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
Resources
httpwwwncbinlmnihgovpmcarticlesPMC3409926
httpswwwsealedenvelopecompowerbinary-superiority
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES
The urate-lowering efficacy and safety of
febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
Regression statistical tool describing and assessing the relationship between two or more variables
Description based upon an assumed model of the relationship
Assessment indicates how well the model fits the data
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
ŷ = value of y predicted by the regression line formula y = a + bx
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
The equation used to fit the data can be of nearly any form not just a straight line
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
LimitationThe independent variable (x axis)
and the dependent variable (y axis) must both be continuous variables
Not able to analyze dichotomous or binary outcomes
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)
Outcome achieving or not achieving treatment goal (binary)
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome
Answer Logistic Regression
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)
p = probability of positive outcome1 - p = probability of negative outcome
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
Linear Regression vs Logistic Regression
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1
no tophi = 0)
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then
P = 067 = α + ẞ1x0 + ẞ2x2 + hellip
Repeat for every subgroup combination to solve for α and ẞs
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
Problem
For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
we have no way to ensure P is between 0 and 1 so convert to log formhellip
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk
- infin lt ln(P(1-P) lt + infin)
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)
By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level
Now we can repeat for every subgroup combination to solve for α and ẞs
Thus the value of each ẞ tells us how much each subgroup affects the
outcome ndash eg in all treatment groups having mild renal impairment
significantly ( p lt 0001) increases the likelihood of achieving the desired
serum uric acid level