1 cozaar™ (losartan) in type 2 diabetes and nephropathy michael c. elia, phd director, regulatory...
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COZAAR™ (losartan) inType 2 Diabetes and Nephropathy
Michael C. Elia, PhD
Director, Regulatory AffairsMerck Research Laboratories
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Reduction of Endpoints in NIDDM with the AII Antagonist Losartan
RENAAL
A multicenter, international, double-blind, randomized, placebo-controlled study designed to evaluate the long-term renal protective effects of losartan in patients with type 2 diabetes and nephropathy
Prior to initiating RENAAL: – No conclusive, long-term renal outcomes data in patients
with type 2 diabetes and nephropathy
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RENAAL
Primary endpoint - time to event analysis of the composite of:– Doubling of serum creatinine, – End-stage renal disease (defined as the need for chronic
dialysis or transplantation), or– Death
Key results– Losartan delays progression of renal disease
• ESRD and death status known for all patients– Safety and tolerability consistent with current labeling– Renal protective benefit of losartan exceeds that attributable
to reduction in blood pressure alone
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COZAAR™ (losartan): Proposed New Indication
Renal Protection in Type 2 Diabetic Patients with Proteinuria
COZAAR is indicated to delay the progression of renal disease as measured by a reduction in the combined incidence of doubling of serum creatinine, end-stage renal disease (need for dialysis or renal transplantation) or death.
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Evidentiary Standard for ApprovalsBased Primarily on a Single Study
In Jan-02, FDA Cardio-Renal Advisory Committee discussed the evidence needed to support a new claim for renal protection in patients with type 2 diabetes and proteinuria
Useful to review the evidentiary standard needed to support a new claim
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Use of a Single Study to Support a New Claim Points to Consider for COZAAR
Large multicenter study
Treatment benefit on multiple endpoints involving different events
Consistency among pre-defined subgroups
Supportive data from separate (smaller) clinical and preclinical studies
FDA Guidance - Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products (1998)
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COZAAR™ (losartan): Proposed New Indication
Renal Protection in Type 2 Diabetic Patients with Proteinuria
COZAAR is indicated to delay the progression of renal disease as measured by a reduction in the combined incidence of doubling of serum creatinine, end-stage renal disease (need for dialysis or renal transplantation) or death.
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COZAAR™ (losartan) inType 2 Diabetes and Nephropathy
Agenda for Merck Presentation
Dr. S. Shahinfar,Senior DirectorCV Clinical Research
Background and Rationale
RENAAL Demographicsand Efficacy Results
RENAAL Safety Results
Review of the Evidenceand Conclusions
Dr. W. Keane, Vice PresidentClinical Development
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Merck Consultants
Clinical Consultants
– Barry Brenner, MD - Chair, Steering Committee (P.I.)
Professor of Medicine, Harvard Medical SchoolDirector Emeritus, Renal Division, Brigham and Women’s Hospital, Boston
– Steven Haffner, MD - Chair, Adjudication Committee
Professor of Medicine, University of Texas Health Science Center, San Antonio
– Carl Erik Mogensen, MD - Chair, DSMC
Professor of Medicine, Aarhus Kommunehospital, Aarhus, Denmark
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Merck Consultants
Clinical Consultants (cont’d)
– Peter Kowey, MD - Member, DSMCProfessor of Medicine, Jefferson Medical CollegeChief, Division of Cardiovascular DiseasesMain Line Hospitals, Philadelphia
– Marvin Konstam, MDProfessor of Medicine & Radiology, Chief of CardiologyTufts-New England Medical Center, Boston
Statistical Consultant
– Scott Zeger, PhDProfessor and Chair, Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University
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Losartan in Type 2 Diabetes and Nephropathy
Shahnaz Shahinfar, MD
Senior Director, Cardiovascular Clinical ResearchMerck Research Laboratories
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Losartan in Type 2 Diabetes and NephropathyAgenda
Background and Rationale
RENAAL Demographics and Efficacy Results
RENAAL Safety Results
Review of Evidence and Conclusions
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End-Stage Renal Disease: An Unmet Medical Need
Type 2 diabetes is the most common type of diabetes
Up to 40% of Type 2 diabetic patients develop nephropathy
Incidence of end-stage renal disease (ESRD) is increasing worldwide
Diabetic nephropathy is the leading cause of ESRD in the US– ESRD is an irreversible condition requiring dialysis as life
support– Up to 40% of patients die within 2 years after initiating
dialysis
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Diabetic Nephropathy
Diabetic nephropathy is primarily a glomerular disease
Progression of renal disease is multifactorial– Hemodynamic– Non-hemodynamic
Angiotensin II is hypothesized to play an important role in the progression of nephropathy
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Efferent ArterioleConstriction
Glomerulus
Increased Albuminuria
Afferent Arteriolar DilatationIncreasedGlomerularPressure
Angiotensin II
Theoretical Hemodynamic Role of Angiotensin II in Diabetic Glomerular Injury
Blood Flow
Blood Flow
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Theoretical Non-Hemodynamic Role of Angiotensin II in Diabetic Glomerular Injury
Glomerulosclerosis
Angiotensin II
Increased filtering membrane permeability
Inflammation and fibrosis
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Preclinical Renal Data: Blockade of Angiotensin II System
In experimental diabetic models, blockade of angiotensin II reduced glomerulosclerosis and proteinuria
In experimental models of non-diabetic renal disease, blockade of angiotensin II, but not other antihypertensive therapy, reduced glomerulosclerosis and proteinuria
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Clinical Renal Outcomes Data: Renin-Angiotensin System Blockade
in Diabetic Nephropathy
Type 1 Diabetes - Captopril Collaborative Study (1993), N=409
– ESRD/death reduced (RR: 50%; 95% CI:18,70)
Type 2 Diabetes - No conclusive evidence of a benefit on ESRD
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Factors that Differentiate Type 2 from Type 1 Diabetic Patients
Age
Obesity
Insulin resistance
Advanced atherosclerosis
Long standing hypertension
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Current Clinical Approaches to Delay Progression to ESRD in Type 2 Diabetes
Metabolic control
Blood pressure control
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In patients with type 2 diabetes and nephropathy, does angiotensin II blockade
with losartan offer renal protection?
Primary Study Question in RENAAL
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Reduction of Endpoints in NIDDM with the AII Antagonist Losartan
RENAAL
A multicenter, multinational, double-blind,
randomized, placebo-controlled study to evaluate the
renal protective effects of losartan in patients with
type 2 diabetes and nephropathy
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23250 centers from 28 countries worldwide
Merck Coordinating and Data Management Center
Data and Safety Monitoring Committee
(Unblinded)
Chairman:Carl Erik Mogensen, MD
Professor of Medicine,Aarhus Kommunehospital,
Denmark
Steering Committee (Blinded)
Chairman: Barry M. Brenner, MD
Professor of Medicine,Harvard Medical School
Director Emeritus, Renal Division
Brigham & Women’s Hospital, Boston
Endpoint AdjudicationCommittee
(Blinded)
Chairman: Steven M. Haffner, MD
Professor of MedicineUniversity of Texas Health
Science Center
RENAAL: Study Organization
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RENAAL: Primary Hypothesis
In type 2 diabetic patients with nephropathy, losartan compared to placebo will increase the time to the first event of the composite endpoint of:
– Doubling of serum creatinine (sCr)
– ESRD (need for chronic dialysis or transplantation)
– Death (all cause mortality)
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Time
Death from any cause may occur at any time
ESRD or Death
100% Loss ofRenal Function
Doublingof sCr
~50% Loss ofRenal Function
NormalRenal Function
Progression of Renal Diseasein Type 2 Diabetes
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RENAAL: Secondary Hypotheses
In type 2 diabetic patients with nephropathy, losartan compared to placebo will:
– Renal• Reduce the rate of progression of renal disease, as
measured by the slope of 1/sCr• Reduce proteinuria during the course of the study
– Cardiovascular• Increase the time to the first event of the composite
endpoint of cardiovascular morbidity/mortality (cardiovascular death, MI, stroke, first hospitalization for heart failure, first hospitalization for unstable angina, peripheral and coronary revascularization)
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Type 2 diabetes
Age 31-70 years
Proteinuria defined as:urine albumin/creatinine (UA/Cr) >300 mg/g or >500 mg protein/24hours
Serum creatinine:1.3-3.01 mg/dL
Known non-diabetic renal disease, e.g., renal artery stenosis
HbA1C >12%
History of:
MI or CABG (within 1 month)
Stroke or PTCA (within 6 months)
TIA (within 1 year)
Heart failure2
1 Lower limit 1.5 mg/dL in male patients >60 kg.2 Protocol amendment.
RENAAL: Key Inclusion/Exclusion Criteria
Inclusion CriteriaInclusion Criteria Exclusion Criteria
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RENAAL: Study Design (I)
Double-blind
Randomized
Placebo-controlled
Multicenter (250 sites in 28 countries)
Stratified for baseline proteinuria (UA/Cr <2000, 2000 mg/g)
Clinic visits every 3 months
Planned one year enrollment, 5 year maximum follow-up
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RENAAL: Study Design (II)
4 Wks
Losartan 100 mg
Losartan 100 mg + Titrate other antihypertensives
Goal: Titrate to achieve trough BP <140/90 mmHg
Losartan50 mg
Placebo
4 Wks6 Week Run-inPlanned 5 year maximum follow-up
Maintain other antihypertensives;
Discontinue ACEI or AIIA
Placebo
Baseline Stratificationand Randomization
Urine Protein Dipstick
Placebo + Titrate other antihypertensives
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Patient Follow-upRENAAL: Study Design (III)
Patients were to remain on study therapy, with clinic visits every three months, regardless of a non-fatal event, until study completion
For patients who discontinued study therapy: – Clinic visits for renal and CV endpoints were to be
conducted every three months – Telephone contact for ESRD and death information was
conducted if clinic visits were not feasible, therefore doubling of serum creatinine and CV morbidity were not collected
ESRD and death information was collected on all patients
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1Heart Outcomes Prevention Evaluation Study, NEJM 2000;342:145-53. 2Mann et al, Annals of Int Med, 2001;134:629-36.
RENAAL: Early Study Termination
On February 10, 2001, the Steering Committee, while blinded to the study results, voted unanimously to end RENAAL prior to its planned termination date of March 2002 because of concerns of continuing the placebo group without blockade of the renin-angiotensin system
This decision was based on increasing evidence that ACE inhibitors may be effective in reducing cardiovascular events in patients with cardiovascular risk factors1,2
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Agenda
Background and Rationale
RENAAL Demographics and Efficacy Results – Renal (Primary and Secondary)– Cardiovascular (Secondary)
RENAAL Safety Results
Review of Evidence and Conclusions
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1513 Randomized
2380 Ineligible 3893 Screened
751 Losartan 762 Placebo
RENAAL: Patient Disposition
407 Completed onstudy drug
142 D/C study drug after a
primary event
202 D/C study drug prior to
a primary event
359 Completed onstudy drug
162 D/C study drug after a
primary event
241 D/C study drug prior to
a primary event
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N
Age (yrs)
Male (%)
SBP/DBP (mmHg)
BMI (kg/m2)
751
60
62
152/82
30
762
60
65
153/82
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Losartan Placebo
RENAAL: Baseline Demographics (I)
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Race Asian Black Caucasian Hispanic
Region Asia Europe Latin America North America
16174819
17201845
Losartan(n=751)
%
18145018
17191846
Placebo(n=762)
%
RENAAL: Baseline Demographics (II)
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Treatment for hypertension
Angina pectoris
Myocardial infarction
Stroke
Anemia
Amputation
Neuropathy
Retinopathy
Laser therapy/photocoagulation
Smoking (current)
RENAAL: Medical History at BaselineLosartan(n=751)
%
92
9
12
0
21
9
50
66
7
20
Placebo(n=762)
%
95
10
14
0.1
22
9
49
62
7
17
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Urine albumin/creatinine (mg/g)1
Serum creatinine (mg/dL)
Serum potassium (mEq/L)
Hemoglobin (g/dL)
Hemoglobin A1c (%)
Losartan(n=751)
Placebo(n=762)
1UA/Cr 1873 mg/g = approximately 3.4 grams per 24 hours (calculated). 1743 mg/g = approximately 3.2 grams per 24 hours (calculated).
1873
1.9
4.6
12.5
8.5
1743
1.9
4.6
12.5
8.4
RENAAL: Selected Mean Baseline Laboratory Values
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RENAAL: Primary Hypothesis
Losartan compared to placebo will increase the time to the first event of the composite endpoint of:
– Doubling of serum creatinine (DsCr)
– ESRD (need for chronic dialysis or transplantation)
– Death (all cause mortality)
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RENAAL: Analysis of Primary Composite Endpoint
A
B
C
D
E
Patient
Endpoint Captured
–
–
DsCr ESRD
–
–
–
Death
–
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RENAAL: Analysis of Primary Composite Endpoint
A
B
C
D
E
Patient
Endpoint Captured
–
–
DsCr ESRD
–
–
–
Death
–
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41Los147 AC PrimComp DsCr Stripped Mar. 26, 2002
Doubling of Serum Creatinine/ESRD/Death RENAAL: Primary Composite Endpoint
0 12 24 36 48Months
0
20
40
60%
Pat
ient
s w
ith a
n E
vent
p=0.022Risk Reduction: 16.1% (2.3, 27.9)
PboLos 751 692 583 330 51
762 689 554 296 37
PlaceboLosartan
n at Risk
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RENAAL: Analysis of Irreversible Clinical Endpoints (Pre-specified)
Irreversible clinical endpoints– ESRD, death, composite of ESRD or death
Key principles:– Patient counted as having endpoint in all
relevant analyses– Patient counted only once in any analysis
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RENAAL: Analysis of Irreversible Clinical Endpoints (Pre-specified)
ESRD: Time to ESRD, regardless of whether doubling of serum creatinine occurred first
Death: Time to death regardless of whether doubling of serum creatinine or ESRD occurred first
ESRD or death: Time to first event of ESRD or death, regardless of whether doubling of serum creatinine occurred first
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RENAAL: Analysis of IrreversibleClinical Endpoints (Pre-specified)
A
B
C
D
E
Patient
Endpoint Captured
–
–
DsCr ESRD
–
–
–
Death
–
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RENAAL: Analysis of IrreversibleClinical Endpoints (Pre-specified)
A
B
C
D
E
Patient
Endpoint Captured
–
–
DsCr ESRD
–
–
–
Death
–
ClinicalEndpoint Analysis
ESRD
X
X
–
–
–
Death
X
X
X
X
–
ESRD/Death
X
X
X
X
–
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ESRD strippedjan02 Mar. 26, 2002
ESRD RENAAL: Irreversible Clinical Endpoints (I)
0 12 24 36 48Months
0
20
40
60%
Pat
ient
s w
ith a
n E
vent
762 715 610 348 434343434343751 714 625 375 686868686868
PboLos
p=0.002Risk Reduction: 28.6% (11.5, 42.4)
n at Risk
PlaceboLosartan
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47Los147 AC Death1 stripped Mar. 26, 2002
RENAAL: Irreversible Clinical Endpoints (II)
0 12 24 36 48Months
0
20
40
60
% P
atie
nts
with
an
Eve
nt
p=0.884Risk Reduction: -1.7% (-26.9, 18.6)
751 730 680 430 84762 732 690 439 65Pbo
Los
n at Risk
PlaceboLosartan
All Cause Mortality
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48
PlaceboLosartan
Hard stripped Jan02 Mar. 26, 2002
ESRD or Death RENAAL: Irreversible Clinical Endpoints (III)
PboLos
0 12 24 36 48Months
0
20
40
60%
Pat
ient
s w
ith a
n E
vent
p=0.009Risk Reduction: 19.9% (5.3, 32.3)
751 714 625 375 686868686868762 715 610 348 434343434343
n at Risk
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49
DsCr/ESRD/Death
ESRD
Death
ESRD or death
+50 0 -50
Percent Risk Reduction (95% CI)
Favors Losartan Favors Placebo
RENAAL: Summary of Primary Compositeand Clinical Endpoints
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50
RENAAL: Imbalance in Baseline Risk
Patients were stratified for baseline level of proteinuria, <2000 and 2000 mg/g UA/Cr
– Equal numbers of patients were randomized to losartan and placebo within the low and high strata
However, within the high stratum of 2000 mg/g, an imbalance in the distribution of patients was observed
– There were more losartan patients in the highest level of proteinuria that led to the imbalance in risk
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51
0
10
20
30
40
50
60
70
% o
f Pa
tien
ts
LosartanPlacebo
501 511
250 251
<2000 mg/g 2000 mg/g
Baseline Proteinuria (UA/Cr, mg/g)
RENAAL: Distribution of Baseline Proteinuria by Stratum
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52
RENAAL: Distribution of Baseline Proteinuria within Strata
<1000 1000-1999
2000-2999
3000-3999
4000
Baseline Proteinuria (UA/Cr, mg/g)
0
10
20
30
40
50
% o
f P
atie
nts
326
175
9761
92
330
181
11565 71
LosartanPlacebo
<2000 mg/g Stratum 2000 mg/g Stratum
p = 0.012
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53
0
5
10
15
Haz
ard
Rat
io
300 2000 4000 6000
1
Baseline Proteinuria (UA/Cr, mg/g)
Pooled Analysis
RENAAL: Risk for Primary Composite Endpoint Rises with Increasing Baseline Proteinuria
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54Baseline Proteinuria (UA/Cr, mg/g)
Haz
ard
Rat
io
300 2000 4000 60000
5
10
15
1
RENAAL: Risk for Primary Composite Endpoint Rises with Increasing Baseline Proteinuria
Pooled Analysis
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55
PlaceboLosartan
Los147 AC Prim-uacr adjE stripped Apr. 4, 2002
0 12 24 36 48Month
0
20
40
60%
Pat
ient
s w
ith a
n E
vent
751 692 583 330 51762 689 554 296 37
n at RiskPboLos
Risk Reduction: 22.2% (9.4, 33.2)p=0.001
RENAAL: Primary Composite Endpoint Adjusted by Baseline Proteinuria (post hoc)
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56
+50 0 -50
Percent Risk Reduction (95% CI)
Favors Losartan Favors Placebo
RENAAL: Endpoints Adjusted for Baseline Proteinuria as a Continuous Covariate (post hoc)
ESRD or death
Death
ESRD
DsCr/ESRD/Death Pre-specified
Adjusted
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57
RENAAL: Pre-defined Sensitivity Analyses
HbA1c
Mean arterial pressure (MAP)
Baseline subgroups
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58
RENAAL: Blood Pressure Control
Study therapy– Titrate losartan or placebo from 50 to 100 mg at Month 1
if BP >140/90 mmHg– Increase other open-label antihypertensives if BP >140/90
mmHg at Month 2 or at any subsequent clinic visit (ACEI and AIIA excluded)
Clinic visits– Additional visits performed to adjust study therapy and open-
label antihypertensives if BP >140/90 mmHg
Goal: Trough <140/90 mmHg
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59
RENAAL: Concurrent Antihypertensive Medications
LosartanPlacebo
0
20
40
60
80
100
% o
f Pat
ient
s
Diuretic CCB AlphaBlocker
BetaBlocker
85% 81%
42%36%
85% 83%
47%38%
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60
Los147 AC BP stacked 1 stripped Apr. 8, 2002
RENAAL: Comparable Blood Pressure (Trough) Control Between Treatment Groups
0 12 24 36 48Months
80
100
120
140
160B
lood
Pre
ssur
e (m
mH
g)
751 662 529 295 44762 641 491 247 30
Systolic
Diastolic
Pbo (n)Los (n)
PlaceboLosartan
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61
Baseline 12 24 36 >36Months
70
80
90
100
110
120
130M
AP
(m
mH
g)
LosartanPlacebo
Distribution at 5, 25, 50, 75, and 95 percentiles at each timepoint
Pbo 762 758 621 469 189Los 751 749 632 510 228
RENAAL: Mean Arterial Pressure
n
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62
+50 0 -50Favors
Losartan
Percent Risk Reduction (95% CI)
RENAAL: Endpoints Adjusted for Mean Arterial Blood Pressure
FavorsPlacebo
DsCr/ESRD/Death
ESRD
UnadjustedAdjusted
Death
ESRD/Death
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63
Percent Risk Reduction (95% CI)
Age
Gender
Race
BMI
Region
SiSBP
<65 years65 years
FemaleMale
AsianBlackWhiteHispanic
<30 kg/m2
30 kg/m2
AsiaLatin AmericaEuropeNorth America
<140 mmHg140 mmHg
Overall Primary Composite
+50 0 -50
Insulin
DihydropyridineCCB
Prev. ACEI/AIIA
Smoking
Duration of Hypertension
Yes
No
Yes
No
Yes
No
Yes
No
<10 yr
10 yr
Overall Primary Composite
+50 0 -50
Proteinuria
Ser. Creatinine
Ser. Albumin
Ser. Cholesterol
Ser. Uric Acid
Hemoglobin
HbA1c
<2000 mg/g2000 mg/g
<2 mg/dL2 mg/dL
<3.6 g/dL3.6 g/dL
<240 mg/dL240 mg/dL
<7 mg/dL7 mg/dL
<12 g/dL12 g/dL
<10%10%
Overall Primary Composite
+50 0 -50Favors Favors
Los PboFavors Favors
Los Pbo Favors Favors
Los Pbo
RENAAL: Baseline Subgroups
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64
Age
Gender
Race
BMI
Region
SiSBP
<65 years65 years
FemaleMale
AsianBlackWhiteHispanic
<30 kg/m2
30 kg/m2
AsiaLatin AmericaEuropeNorth America
<140 mmHg140 mmHg
Overall Primary Composite
+50 0 -50
Yes
No
Yes
No
Yes
No
Yes
No
<10 yr
10 yr
Overall Primary Composite
+50 0 -50
Proteinuria
Ser. Creatinine
Ser. Albumin
Ser. Cholesterol
Ser. Uric Acid
Hemoglobin
HbA1c
<2000 mg/g2000 mg/g
<2 mg/dL2 mg/dL
<3.6 g/dL3.6 g/dL
<240 mg/dL240 mg/dL
<7 mg/dL7 mg/dL
<12 g/dL12 g/dL
<10%10%
Overall Primary Composite
+50 0 -50Favors Favors
Los PboFavors Favors
Los Pbo Favors Favors
Los Pbo
RENAAL: Baseline Subgroups
Percent Risk Reduction (95% CI)
Insulin
DihydropyridineCCB
Prev. ACEI/AIIA
Smoking
Duration of Hypertension
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65
RENAAL: Secondary Hypotheses (Renal)
In type 2 diabetic patients with nephropathy, losartan compared to placebo will:
– Reduce the rate of progression of renal disease, as measured by the slope of 1/sCr
– Reduce proteinuria during the course of the study
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66
Median 1/sCr Slope
-.08
-.06
-.04
-.02
0
Med
ian
Cha
nge
in 1
/sC
r(d
L/m
g/yr
)
Losartan Placebo
18% Reductionp=0.01
RENAAL: Reduction in the Rate of Loss of Renal Function (On-treatment Approach)
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67
0 3 12 24 36 >36Months
Cha
nge
in M
ean
UA
/Cr
(%)1
-60
-40
-20
0
20
1Based on geometric mean (95% CI).
34% OverallReductionp<0.001
Losartan
751 661 558 432 163762 632 529 389 120Pbo (n)
Los (n)
Placebo
RENAAL: Losartan Reduces Proteinuria(On-treatment Approach)
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68
RENAAL: Efficacy Summary (Renal)
In type 2 diabetic patients with proteinuria, losartan:– Is renal protective by delaying the onset of the primary
composite endpoint of doubling of serum creatinine, ESRD (need for chronic dialysis or transplantation), or death
• Reduces the risk of ESRD by 28.6%
– Reduces the rate of decline in renal function as measured by the slope of 1/sCr
– Reduces proteinuria – Has a beneficial effect on the primary composite endpoint
and proteinuria beyond its beneficial effect on blood pressure
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69
Agenda
Background and Rationale
RENAAL Demographics and Efficacy Results – Renal (Primary and Secondary)– Cardiovascular (Secondary)
RENAAL Safety Results
Review of Evidence and Conclusions
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70
RENAAL: Secondary Hypotheses (Cardiovascular)
In type 2 diabetic patients with nephropathy, losartan compared to placebo will increase the time to the first event of the composite of cardiovascular morbidity/mortality:
– Cardiovascular death
– Myocardial infarction
– Stroke
– First hospitalization for heart failure
– First hospitalization for angina
– Revascularization (coronary and peripheral)
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71
RENAAL: Secondary Cardiovascular Composite Endpoint
0 12 24 36 48Months
0
20
40
60%
Pat
ient
s w
ith a
n E
vent
p=0.253Risk Reduction: 9.6% (-7.5, 24.0)
751 658 569 329 61762 646 551 328 48
n at RiskPboLos
PlaceboLosartan
Los147 AC SecCom stripped Mar. 26, 2002
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72
Favors Losartan Favors Placebo+50 0 -50
Percent Risk Reduction (95% CI)
RENAAL: Secondary Cardiovascular Composite Endpoint and Components
CV composite
CV death
Myocardial infarction
Stroke
Hosp. for heart failure
Hosp. for angina
Revascularization
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73
Los147 AC SecKM ITT stripped Mar. 26, 2002
PlaceboLosartan
0 12 24 36 48Months
0
20
40
60
% P
atie
nts
with
an
Eve
nt
p=0.003Risk Reduction: 21.2% (7.8, 32.6)
751 684 585 350 62762 685 565 314 39Pbo
Los
n at Risk
RENAAL: Composite of ESRD/MI/Stroke/Death (post hoc)
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74
RENAAL: Summary of Cardiovascular Data
There was no statistically significant difference in cardiovascular morbidity and mortality between losartan and placebo
The renal protective effects of losartan are not at the expense of increased risk of cardiovascular outcomes and support the overall benefits of therapy in this population
– Post hoc analysis of ESRD/MI/Stroke/Death demonstrated the beneficial effect of losartan in diabetic patients with proteinuria
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75
Agenda
Background and Rationale
RENAAL Demographics and Efficacy Results
RENAAL Safety Results
Review of Evidence and Conclusions
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76
RENAAL: Clinical Adverse Experience Summary
LosartanPlacebo
With Oneor More
AEs
WithSerious
AEs
WithDrug-
RelatedAEs
With SeriousDrug-Related
AEs
DeathDue to
AE
Discon.Due to
AE
95.3
17.2
64.0
3.2
19.0
9.1
95.7
13.9
63.9
2.6
24.0
9.2
0
20
40
60
80
100
% o
f P
atie
nts
![Page 77: 1 COZAAR™ (losartan) in Type 2 Diabetes and Nephropathy Michael C. Elia, PhD Director, Regulatory Affairs Merck Research Laboratories](https://reader035.vdocument.in/reader035/viewer/2022062516/56649dc05503460f94ab4ed0/html5/thumbnails/77.jpg)
77
RENAAL: Laboratory Adverse Experience Summary
0
20
40
60
80
100
49.5
0.8 02.7
42.4
1.1 02.1
% o
f P
atie
nts
14.87.5
0.4 2.6
LosartanPlacebo
With Oneor More
AEs
WithSerious
AEs
WithDrug-
RelatedAEs
With SeriousDrug-Related
AEs
DeathDue to
AE
Discon.Due to
AE
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78
RENAAL: Pre-specified Analysis of Adverse Experiences
Adverse Experience
Acute renal failure
Hyperkalemia
Hypokalemia
Anemia
Hyperglycemia
Hypoglycemia
Losartan(n=751)
%
1.7
24.2
2.5
14.1
13.0
14.9
Placebo(n=762)
%
1.6
12.3
4.7
10.8
15.0
11.8
Losartan vs. PlaceboHazard Ratio (95% CI)
1.01 (0.46, 2.21)
2.00 (1.56, 2.57)
0.50 (0.28, 0.86)
1.25 (0.94, 1.67)
0.82 (0.63, 1.08)
1.21 (0.92, 1.60)
p-Value
0.981
<0.001
0.013
0.126
0.156
0.174
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79
Baseline 12 24 36 >36Months
3
4
5
6
Ser
um P
otas
sium
(m
Eq/
L)
LosartanPlacebo
Distribution at 5, 25, 50, 75 and 95 percentile at each time point
RENAAL: Distribution of Serum Potassium Values at Each Time Point
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80
Potassium 3.5 mEq/L
Potassium 6.0 mEq/L
RENAAL: Serum Potassium at Any Time During the Study
32/751 (4.2)
73/751 (10.0)
Losartann/N (%)
43/762 (5.6)
40/762 (5.0)
Placebon/N (%)
Patients Who Had at Least One Measurement of 3.5 and/or 6.0 mEq/L
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81
RENAAL: Hyperkalemia
0
5
10
15
20
% o
f P
atie
nts
WithSerious AEs
Discon.Due to AE
DeathDue to AE
2.61.3
01.3 0.7 0
Adverse Experiences
LosartanPlacebo
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82
RENAAL: Summary of Safety
In type 2 diabetic patients with proteinuria:
– There were no unusual or unexpected adverse experiences beyond those already noted in the US prescribing information for losartan
– Losartan had a higher incidence of hyperkalemia and lower incidence of hypokalemia compared to placebo
– Losartan was generally well tolerated
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83
RENAAL:Review of Evidence and Conclusions
William F. Keane, MD
Vice President, Clinical DevelopmentMerck US Human Health
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84
RENAAL: Strength of the Evidence
Robust design features
Results are clinically important and statistically significant
Internal consistency across multiple endpoints and multiple subgroups
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85
RENAAL: Robust Study Design
Large multinational study conducted in 28 countries at 250 clinical sites
Diverse study population consistent with disease demographics
No patients lost to follow-up for ESRD and death
Renal and cardiovascular endpoints adjudicated
For the primary composite endpoint, no patients missing from ITT analysis
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86
RENAAL: Clinically Important and Statistically Significant Results
Primary composite endpoint:
– Doubling sCr/ESRD/death
Clinical endpoints:
– ESRD
– Death
– ESRD or death
RR (%)
16.1
28.6
-1.7
19.9
p-Value
0.022
0.002
0.884
0.009
Unadjusted
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RENAAL: Imbalance in Baseline Risk
Patients were stratified for baseline level of proteinuria, <2000 and 2000 mg/g UA/Cr
However, within the high stratum of 2000 mg/g, an imbalance in the distribution of patients was observed
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RENAAL: Clinically Important and Statistically Significant Results
Primary composite endpoint:
– Doubling sCr/ESRD/death
Clinical endpoints:
– ESRD
– Death
– ESRD or death
RR (%)
16.1
28.6
-1.7
19.9
p-Value
0.022
0.002
0.884
0.009
Unadjusted
RR (%)
22.2
36.7
1.3
25.7
p-Value
0.001
<0.001
0.907
<0.001
Adjusted forBaseline
Proteinuria
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RENAAL: Renal Protective Effects and Blood Pressure Control
Effective blood pressure control is critically important in treatment of type 2 diabetic patients with proteinuria
In RENAAL:– Blood pressure was aggressively treated and comparable
BP control was achieved in both treatment groups– Small differences in MAP were not sufficient to account for
the renal protective effects of losartan
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RENAAL: Clinically Important and Statistically Significant Results
Secondary renal endpoints
– Rate of progression of renal disease (1/sCr)
– Reduction in proteinuria
0.01
<0.001
p-Value
18%
34%
Reduction
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RENAAL: Secondary Cardiovascular Composite Endpoint and Components
+50 0 -50
Percent Risk
Favors Losartan Favors Placebo
0.003
Reduction (95% CI) p-Value
Composite of ESRD/MI/stroke/death (post hoc)
0.253CV composite0.453CV death0.079Myocardial infarction0.783Stroke0.006Hosp. for heart failure0.888Hosp. for angina0.337Revascularization
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Conclusions
As demonstrated in RENAAL, in patients with type 2 diabetes and proteinuria:
– The beneficial treatment effects of losartan across multiple renal endpoints provide robust, reliable and clinically relevant evidence for renal protection
– The safety profile of losartan in this population is consistent with the current US prescribing information for losartan