1
Bo Feldt-Rasmussen, MD, DMSc
Chief of Division of Nephrology, Ass professor
Rigshospitalet, University of Copenhagen
21. Berliner DialyseSeminar
Growth Hormone Treatment during
Hemodialysis
2
Significant unmet medical need
• Annual mortality rate in ESRD patients
exceeds 20%
• Average patient has 14 hospitalisation days
per year (not including haemodialysis time)
• Increased mortality and morbidity is related to
catabolism, inflammation and malnutrition
• No treatment currently available to reverse or
improve protein-energy malnutrition state of
dialysis patients
– Major unmet medical need exists
3
Predictor for survival in ESRD
4
Serum Albumin Change (g/dL per quarter)
<-0.3 -0.2 to -0.3
-0.1 to -0.2
+0.1 to -0.1
+0.1 to +0.2
+0.2 to +0.3
>+0.3
All-C
au
se
D
ea
th
H
az
ard
R
atio
0.5
0.6
0.7
0.8
0.9
2
3
1.0
UnadjustedCase-mixMICS
Un
ch
an
ged
Drop in serum albumin Increased serum albumin
Drop in Albumin
↑Death
Rise in Albumin
↑Survival
Stable
Albumin
58,058 HD patients: 2001-2003, DaVita Kalantar-Zadeh et al, NDT 2005
Average Serum Albumin Change (g/dL) in 6 months
AL
L-C
AU
SE
D
ea
th
H
aza
rd
R
atio
5
Rationale for use of anabolic hormones
(rhGH) in dialysis patients
• Advanced uremia as a wasting illness with reduced
physical functioning and quality of life
• Uremic wasting is multi-factorial requiring a
multi-faceted approach
• Potential for combined use with other nutritional
interventions
6
Effects of GH treatment
• Study results suggest:
– Improved nutritional status
– Improved quality of life
– energy level
– appetite
– Reduced incidence of other health problems by
reduction of body fat mass and increasing muscle
mass
• GH was also shown to reduce protein catabolism or
breakdown
Garibotto et al. JCI. 1997.
Iglesias et al. Am J Kidney Dis. 1998.
Ikizler et al. Kidney Intl. 1994.
Johannsson et al. Am J Kidney Dis. 1999.
Phase 2:
study design and results
8
Hypothesis
• Growth hormone therapy for dialysis
treated adults with chronic renal failure will
improve markers of nutrition and mortality
Proof of concept and dose finding study
9
NN1606-1442:
Trial design
Recruitment
Screening
hGH low dose treatment
hGH medium dose treatment
hGH high dose treatment
Placebo
Max. 3 weeks 6 months
20μg/kg/d
35 μg/kg/d
50 μg/kg/d
10
NN606-1442:
Key inclusion criteria
• Serum albumin (median of 3) ≤ 38 g/L
– Later changed to ≤40 g/L due to recruitment
challenges
• Male or female, age 18 to 75 years in chronic
haemodialysis
• Stable and adequate haemodialysis treatment
three months prior to enrolment as defined by
Kt/V > 1.2 and/or haemodialysis performed 4
hours 3 times weekly
11
NN606-1442:
Key exclusion criteria
• Diabetes
• Peritoneal dialysis
• PTH ≥ 500 pmol/L (central laboratory)
• Blood Pressure (pre-dialysis) > 180/110
• Patients suffering from
– Active vasculitis
– Heart failure, NYHA class III-IV
– Severe hepatic disease (including Hepatitis B and C)
– Severe chronic systemic infections
NOTE: Exclusion criteria listed above are not exhaustive
12
NN1606-1442:
Patient demographics
1.5±0.31.4±0.21.5±0.31.4±0.3Dialysis quality, Kt/V
(mean ±SD)
24 ±424 ±524 ±624 ±4BMI, kg/m
2
(mean ±SD)
45±6226±2542±3248±55Time in dialysis, months
(mean ±SD)
59±1461±1260±1558±14Age, yrs
(mean±SD)
32/6838/6253/4738/62Gender (%)
34373434Number of patients
PlacebohGH highhGH mediumhGH lowVariable
Phase 2 Results
Efficacy
14
NN1606-1442:
Efficacy assessments
• Primary endpoints
– Lean body mass and serum albumin
• Secondary endpoints
– Nutritional status (pre-albumin and transferrin)
– CV- riskfactors (cholesterol, Homocystein)
– QoL and ADL
– Hand-grip strength
– Inflammation (CRP and IL-6)
– Morbidity
– Mortality
15
Primary Efficacy:
Lean Body Mass and Serum Albumin
B
Treatment groups
Ch
an
ge
in se
rum
-alb
um
in (g
/L)
-3
-2
-1
0
1
2
3
4placebo20 µg/kg/day35 µg/kg/day50 µg/kg/day
errorbars = 95% CI
A
Treatment groups
Ch
an
ge
in le
an
bo
dy m
ass (kg
)
-2
-1
0
1
2
3
4
5
Placebo
Placebo
B: Strong trend in serum albumin
A: LBM improves significantly
during GH treatment
hGH low
hGH low
hGH
medium
hGH
medium
hGH high
hGH high
16
Fat mass:
change from baseline
-10
-8
-6
-4
-2
0
2
4
6
20 35 50 placebo
GH (µg/kg/day)
Ch
an
ge
fro
m b
ase
lin
e
in
fa
t m
ass (kg
)
Data are mean±SD
17
NN1606-1442:
Efficacy assessments
• Primary endpoints
– Lean body mass and serum albumin
• Secondary endpoints
– Nutritional status (pre-albumin and transferrin)
– CV-risk factors (cholesterol, homocystein)
– QoL and ADL
– Hand-grip strength
– Inflammation (CRP and IL-6)
– Morbidity
– Mortality
18
Serum transferrin:
Significant increase in pooled GH
treated groups compared to placebo
Laboratory efficacy - Estimated transferrin level over time, ITT analysis set
Estimated mean and corresponding 95% confidence intervals
Treatment group Placebo Pooled GH
Mean
lev
el (g
/L
)
1.42
1.44
1.46
1.48
1.50
1.52
1.54
1.56
1.58
1.60
1.62
1.64
1.66
1.68
1.70
1.72
1.74
1.76
1.78
1.80
1.82
Weeks
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Estimated mean ± 95% Confidence limits
GH
Overall test:
p=0.0014
Placebo
19
Serum HDL Cholesterol:
Significant increase in pooled GH
treated groups compared to placebo
Overall test:
p=0.0377
Laboratory efficacy - Estimated HDL level over time, ITT analysis set
Estimated mean and corresponding 95% confidence intervals
Treatment group Placebo Pooled GH
Mean
lev
el (m
mo
l/L
)
1.00
1.01
1.02
1.03
1.04
1.05
1.06
1.07
1.08
1.09
1.10
1.11
1.12
1.13
1.14
1.15
1.16
1.17
1.18
1.19
1.20
1.21
1.22
1.23
Weeks
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
GH
Estimated mean ± 95% Confidence limits
Placebo
20
Homocysteine:
Significant decrease in pooled GH
treated groups compared to placebo
Laboratory efficacy - Estimated homocystein level over time, ITT analysis set
Estimated mean and corresponding 95% confidence intervals
Treatment group Placebo Pooled GH
Mean
lev
el (u
mo
l/L
)
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
Weeks
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
GH
Overall test:
p=0.0294
Estimated mean ± 95% Confidence limits
Placebo
21
KDQoL role-physical:
Significant increase in pooled GH
treated groups compared to placebo
KDQoL - Change in Role--physical, ITT analysis set);
hgh-1442/current - 27APR2006 - analysis_QoL/qol_plot_RH_ITT.cgm
Mean
d
ifferen
ce (sco
re)
-20.0
-10.0
0.00
10.00
20.00
30.00
Treatment group
Norditropin (n=57) Placebo (n=25)
Overall test:
p=0.0421
Pooled GH
(n=57)
Placebo (n=25)
Estimated mean ± 95% Confidence limits
Overall test:
p=0.0421
22
Non-significant results
The following markers showed no significant
change in pooled GH treated groups
compared to placebo:
• Serum pre-albumin
• Serum CRP
• Serum IL-6
• Serum TNF-
23
NN1606-1442:
Efficacy assessments
• Primary endpoints
– Lean body mass and serum albumin
• Secondary endpoints
– Nutritional status (pre-albumin and transferrin)
– CV-risk factors (cholesterol, homocysteine)
– QoL and ADL
– Hand-grip strength
– Inflammation (CRP and IL-6)
– Morbidity
– Mortality
24
No differences in morbidity and
mortality between groups
15 (11%) *3 (8%)3 (9%)2 (6%)4 (12%)Deaths (N (%))
246666
Other HC visits (N)
461411129Hosp. visits (N)
126402
Hospitalised (N)
(overnight)
236584
Hospitalised (N)
(+overnight)
13937343434ITT (n)
TotalhGH highhGH mediumhGH lowPlacebo
15 (11%) *3 (8%)3 (9%)2 (6%)4 (12%)Deaths (N (%))
461411129Hosp visits (N)
236584
Hospitalised (N)
(+overnight)
TotalhGH highhGH mediumhGH lowPlacebo
* 3 randomised patients died before receiving treatment
Phase 2 Results
Safety
26
NN1606-1442:
Safety assessments
• Adverse events
• Fasting plasma glucose
• HbA
1c
• IGF-I and IGFBP-3
• Physical examination
• ECG
• Routine haematology and blood chemistry
27
Adverse Events
• In total, 596 treatment emergent* adverse
events experienced by 92% of the trial
population
• Most common AEs were infections and
gastrointestinal disorders
• Approximately 13% of the AEs were rated as
possible or probable related to trial product
(n=75 events)
• Tendency towards increased number of possible
or probable AEs with increasing dose
* Treatment emergent adverse events are events occurring
in the period from first drug date to last drug + 7 days
28
AE frequency
• Distribution of events per treatment group
• Frequency of events per month
8(22)124(12)6Probable
10(27)219(27)176(18)117(21)8Possible
16(43)2215(44)2219(56)3914(41)25Serious
35(95)16531(91)12731(91)15731(91)147All
N(%)EN(%)EN(%)EN(%)E
hGH highhGH mediumhGH lowPlacebo
0.981.021.031.020.86
TotalhGH highhGH mediumhGH lowPlacebo
29
Fluid retention
• No difference between active treatment and placebo
observed for:
– Heamatocrit
– Post dialysis body weight
– Dialysis time
– Adverse events
• Overall, there was a total of 11 serious adverse
events due to fluid retention or pulmonary oedema
or possibly related to cardiac congestive failure
reported during this trial:
– Placebo 1
– hGH low 2
– hGH medium 2
– hGH high 6
Phase 2 Results
Metabolic
implications
31
Fasting plasma glucose
4
4.5
5
5.5
6
6.5
7
0 2 6 13 26
Fastin
g p
lasm
a glu
co
se
(m
mo
l/L)
Time (weeks)
20 µg/kg/day
35 µg/kg/day
50 µg/kg/day
placebo
Data are mean
32
Fasting plasma insulin
0
5
10
15
20
25
30
0 2 6 13 26
Fastin
g p
lasm
a glu
co
se
(m
mo
l/L)
Time (weeks)
20 µg/kg/day
35 µg/kg/day
50 µg/kg/day
placebo
Data are mean
33
IGF-I: Initial rapid increase appeared to
decrease over time in
medium and high dose groups
The decrease
observed in the
two high dose
groups appear
not to be
caused by poor
compliance or
drop-outs
Estimated mean ± 95% Confidence limits
Laboratory safety - IGF-I SDS per visit, ITT analysis set
Estimated mean and corresponding 95% confidence intervals
Treatment group Placebo hGH 20 ug/kg/day hGH 35 ug/kg/day hGH 50 ug/kg/day
Mean level (S
DS
)
-2.0
-1.0
0.0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
Weeks
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Treatment group Placebo hGH low
hGH medium
hGH high
Phase 2 Results
Cardiovascular
implications
35
Phase 2 conclusions
• Lean Body Mass (LBM) increased
significantly at all doses compared to
placebo
• A positive trend, approaching significance
(p=0.06), in serum albumin was observed
• Significant beneficial changes in other
biomarkers of mortality (homocysteine,
transferrin, HDL) as well as HRQoL were
observed
36
Phase 2 conclusions
• GH treatment was well tolerated and safe
• GH therapy was not associated with any
adverse structural changes in the heart
• From a risk/benefit perspective, the low dose
was considered most optimal dose for the
Phase 3 trial
• Based on correlation of albumin and LBM with
mortality and morbidity, GH treatment in chronic
dialysis patients will decrease mortality and
morbidity and increase HRQoL
37
Thank you for your attention
Phase 2 study:
Design and results - metabolic
and cardiovascular implications