21. berliner dialyseseminar growth hormone treatment ... · 1 bo feldt-rasmussen, md, dmsc chief of...

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:






– CV-risk factors (cholesterol, homocystein)

– QoL and ADL



– 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:



Overall test:

p=0.0377

Laboratory efficacy - Estimated HDL level over time, ITT analysis set



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


Placebo

20

Homocysteine:

Significant decrease in pooled GH


Laboratory efficacy - Estimated homocystein level over time, ITT analysis set



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


Placebo

21

KDQoL role-physical:



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)


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:






– CV-risk factors (cholesterol, homocysteine)

– QoL and ADL



– 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)


* 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


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


Laboratory safety - IGF-I SDS per visit, ITT analysis set


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

[email protected]

Phase 2 study:

Design and results - metabolic

and cardiovascular implications

mailto:[email protected]

21. berliner dialyseseminar growth hormone treatment ... · 1 bo feldt-rasmussen, md, dmsc chief of...

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