PFIZER INC. PROTOCOL TITLE: Growth hormone therapy in short children after renal transplantation for chronic renal failure in Germany.

Transcription

1 PFIZER INC. These results are supplied for informational purposes only. Prescribing decisions should be made based on the approved package insert. For publications based on this study, see associated bibliography. PROPRIETARY DRUG NAME /GENERIC DRUG NAME: Genotropin / Somatropin PROTOCOL NO.: PROTOCOL TITLE: Growth hormone therapy in short children after renal transplantation for chronic renal failure in Germany. Study Centre: One study centre in Germany. Study Initiation Date and Completion Date: 01 September 1994 to 02 July 1999 Phase of Development: Phase 3b Study Objectives: Primary: To study the effect of treatment with recombinant human growth hormone (rhgh) on change in height standard deviation score (SDS) in children after renal transplantation for chronic renal insufficiency (CRI). Secondary: To study the safety of the treatment, and the pharmacokinetic (PK) profile after 3 months of Genotropin. METHODS Study Design: This was a 1-arm, uncontrolled open-labelled prospective multicentre study to evaluate efficacy of Genotropin in short children after renal transplantation for CRI. Subjects fulfilling inclusion criteria were treated with Genotropin in a dosage of 1.0 IU/kg body weight/week as a daily subcutaneous (s.c.) injection. The duration of treatment was 1 year with visits at every 3 months. Treatment could be continued for 1 additional year. Number of Subjects (Planned and Analysed): Fifty subjects were planned to be enrolled in this study. A total of 29 subjects were enrolled, 28 subjects were treated with Genotropin and were valid for safety analysis. Of them, 27 subjects were valid for intent-to-treat (ITT) analysis and 23 subjects were valid for per protocol (PP) analysis. Diagnosis and Main Criteria for Inclusion: Short children after renal transplantation for chronic renal failure (CRF) with clinically stable kidney graft function (no acute rejection crisis within the last 6 months). The height had to be below -2 standard deviation (SD) and/or height velocity must be below 25th percentile, and the chronological age had to be >3 years. Page 1

2 Study Treatment: Genotropin was to be administered as a daily s.c. injection, 7 days a week, in a dosage of 1.0 IU/kg body weight/week. The study duration was at least 1 year and could be continued for 1 additional year. Sterile lyophilised powder of recombinant somatropin was used. All children with a daily dose of 3 or more units used Genotropin 36 IU. Children with a known hypersensitivity to the preservative m-cresol used the preparation without m-cresol (4 IU/mL). The 3 preparations used were Genotropin 4 IU, Genotropin 16 IU and Genotropin 36 IU. Efficacy Evaluations: Primary efficacy variable was the change in the height standard deviation score (SDS), calculated as the growth rate before treatment compared to the growth rate under therapy. Further efficacy variables were bone age / chronological age quotient, subjects height, height velocity, and the laboratory markers insulin-like growth factor-i (IGF-I) and insulinlike growth factor binding protein-3 (IGFBP-3). The height and weight of the subject were measured at baseline and at each 3 monthly study visits. IGF-I was measured before start and during the study period every 3 months during the first treatment year and every 6 months thereafter. Safety Evaluations: Safety variables were adverse events (AEs), documented at each visit after baseline. Further safety variables were occurrence of rejection crises, estimated glomerular filtration rate (GFR), serum (S)-creatinine, routine haematology and blood biochemistry. All laboratory parameters were performed at each 3 monthly study visit. As a consequence of immunosuppressive treatment with corticosteroids, a development of diabetes mellitus (corticoid diabetes) was possible. As safety measurement, the blood-glycated haemoglobin (B-HbA 1c ) value was determined at each visit. In case of pathologic B-HbA 1c values, the development of diabetes mellitus had to be excluded. Growth hormone treatment had to be withdrawn when the development of diabetes mellitus was confirmed. Drug Concentration Measurement: Initially it was planned to determine a 12-hour pharmacokinetic (PK) profile in a maximum of 10 pre-pubertal or pubertal children, but later on the PK parameters were not calculated as no data concerning the PK profile was available. Page 2

3 Statistical Methods: The growth rate of the subjects was calculated over a yearly period. Growth rates were expressed as cm/year, change in standard deviation score based on chronological age (ΔSDS CA ) and change in standard deviation score based on bone age (ΔSDS BA ). The individual response was defined as the difference between growth rate on therapy minus growth rate before therapy. The growth response was correlated to clinical and biochemical parameters in order to identify relevant prognostic factors. Parametric and non-parametric statistical methods were used for testing, depending on the scale level of the data. The safety analysis included all subjects enrolled into the study and treated at least once with study medication. The ITT analysis included all subjects of the safety analysis from whom data of the primary efficacy variable were available, irrespective of any protocol deviations. The PP analysis included all subjects of the ITT analysis who had finished the study without protocol deviations and from whom evaluable data of the primary efficacy variable were available. RESULTS Subject Disposition and Demography: A total of 29 subjects were included in this study. Of these, 28 subjects were treated with Genotropin. The safety analysis included 28 subjects, as data for 1 subject was available only prior to study start. The ITT analysis included 27 subjects, as no efficacy data was available for 1 subject withdrawn from safety analysis. The PP analysis included 23 subjects, as 4 subjects from ITT analyses were excluded due to the reason reported as compliance below 85%, bone age >14 years, premature termination due to change in immunosuppressive therapy and premature termination due to AE in 1 subject each. A summary of baseline demographic characteristic of ITT and PP analysis is presented in Table 1 below. Table 1 Sex, n (%) Age (years) Weight (kg) Baseline Demographic Characteristic ITT Analysis (N = 27) PP Analysis (N = 23) Male 21 (78%) 17 (74%) Female 6 (22%) 6 (26%) Mean ± SD 12.6 ± ± 2.8 (range) ( ) ( ) Mean ± SD 34.7 ± ± 13.5 (range) ( ) ( ) The most common cause of renal insufficiency was malformation followed by hereditary nephropathy and glomerulonephritis. Page 3

4 Efficacy Results: The results of primary efficacy variable, change in the height standard deviation scores, are presented in Table 2 below. Table 2 Height Standard Deviation Score ITT Analysis PP Analysis N Mean ± SD p-value a N Mean ± SD p-value a SDS based on chronological age Study start ± ± After 12 months b ± ± Last examination c ± ± Difference: 12 months study start ± ± Difference: Last examination study start ± ± SDS based on bone age Study start ± ± After 12 months b ± ± Last examination c ± ± Difference: 12 months study start ± ± Difference: Last examination study start ± ± a measured by t-test b The values for subjects who discontinued prematurely (Month 9) was carried forward to the Month 12 examination. c Last examination was determined at Month 11 at the earliest, the value for subject number 1-8 was carried forward. Abbreviations: ITT = intent- to- treat; N = number of subjects; PP = per protocol; SD = standard deviation; SDS = standard deviation score. The SDS based on chronological age decreased during the first 12 months of treatment compared to study start in the ITT population (p = 0.19) and in the PP population (p = 0.27). Until last determination a further decrease compared to study start was observed in both the ITT (p = 0.01) and PP (p = 0.02) populations. Although after 12 months of treatment, the deviation of subjects bone age from healthy children showed nearly no change in both populations. Until last determination of bone age, the deviation was extended in the both populations (p = 0.02 in both populations). The quotient of bone age and chronological age according to Tanner/Whitehouse 2 RUS changed from 0.77 ± 0.14 (0.76 ± 0.15) [ITT population (PP population)] at the visit next to study start to 0.80 ± 0.13 in both populations at the last examination indicating a slight approximation of bone age to chronological age. In the mean, the subjects height increased by 6.5 ± 3.0 (6.6 ± 3.0) cm after 12 months of treatment and by 10.6 ± 7.9 (11.8 ± 7.8) cm until last examination. Concomitantly height velocity increased in the mean by 2.49 ± 2.51 cm/year in the ITT population (2.54 ± 2.55 cm/year in the PP population, p<0.01 for both populations) after 12 months of Page 4

5 treatment compared to study start. This difference was 1.00 ± 2.42 cm/year in the ITT population (p = 0.05) and 0.97 ± 2.47 cm/year in the PP population (p = 0.07) at the end of treatment, i.e. after a study duration of ± 54.9 weeks (112.9 ± 53.8 weeks). The blood levels of the laboratory markers IGF-I and IGFBP-3 increased during study as expected. It should be noted that for the examination of the factors IGF-I and IGFBP-3 only values from about half of the subjects were available. Safety Results: The total duration of the study (screening - final visit) was ± 54.9 weeks in the ITT population (112.9 ± 53.8 weeks in the PP population). The treatment continued until final visit with a mean duration of exposure to study medication of 93.8 ± 54.1(103.6 ± 52.4) weeks, ranging from 26.9 to (34.7 to 210.0) weeks. The mean dosage in the ITT population at study start was 4.1 ± 1.6 IU/day, ranging from 1.8 to 7.5 IU/day (PP population: 4.2 ± 1.7 IU/day, ranging from 1.8 to 7.5 IU/day). Until study end, the mean dosage changed to 5.1 ± 2.2 (5.0 ± 2.4) IU/day, ranging from 0.0 to 10.0 IU/day in both populations. Overall 99 AEs were observed in 20 subjects (71.4%) during the study. For 66 AEs the relationship was considered to be unlikely. For 26 and 4 AEs a possible and a probable relationship, respectively, was assessed. Most of the AEs were assessed to be of mild (39 events) or moderate (45 events) intensity, and 15 AEs were assessed to be of severe intensity. The subjects recovered from 67 AEs without residual effects. Nineteen AEs led to residual effects, and the subjects did not recover from 13 AEs. All AEs are listed by body system in Table 3. Page 5

6 Table 3 Adverse Events, listed by Body System Safety Analysis Number of Events Number of Subjects (%) a Metabolic and nutritional disorders 18 7 (25.0) Resistance mechanism disorders 9 6 (21.4) Respiratory system disorders 8 6 (21.4) Gastro-intestinal system disorders 12 5 (17.9) Rejection crises 11 4 (14.3) Body as a whole general disorders 6 4 (14.3) Urinary system disorders 4 4 (14.3) Central & peripheral nervous system 3 3 (10.7) Endocrine disorders 3 2 (7.1) Red blood cell disorders 3 2 (7.1) White cell and RES disorders 3 2 (7.1) Skin and appendages disorders 2 2 (7.1) Musculoskeletal system disorders 1 1 (3.6) Vision disorders 1 1 (3.6) Hearing and vestibular disorders 1 1 (3.6) Psychiatric disorders 1 1 (3.6) General cardiovascular disorders 1 1 (3.6) Platelet, bleeding and clotting disorders 1 1 (3.6) Reproductive disorders (female) 1 1 (3.6) Foetal disorders 1 1 (3.6) Application site disorders 1 1 (3.6) Not codable 8 4 (14.3) Total (71.4) a multiple answers possible A total of 51 serious AEs (SAEs) were observed in 14 subjects. For 35 SAEs the relationship to study drug was considered to be unlikely, for 14 SAEs a possible relationship was assessed and for 2 SAEs relationship was considered to be probable. The SAEs were classified as mild (8 events), moderate (28 events) or severe (15 events). Subjects recovered without residual effects from 34 SAEs and with residual effects from 12 SAEs, for 5 SAEs the subjects did not recover. All SAEs are listed by body system in Table 4. Page 6

7 Table 4 Serious Adverse Events, listed by Body System Safety Analysis Number of Events Number of Subjects (%) a Rejection crises 10 4 (14.3) Urinary system disorders 4 4 (14.3) Metabolic and nutritional disorders 7 3 (10.7) Central & peripheral nervous system 3 3 (10.7) Gastro-intestinal system disorders 5 2 (7.1) Resistance mechanism disorders 3 2 (7.1) White cell and RES disorders 2 2 (7.1) Vision disorders 1 1 (3.6) Hearing and vestibular disorders 1 1 (3.6) Psychiatric disorders 1 1 (3.6) General cardiovascular disorders 1 1 (3.6) Respiratory system disorders 1 1 (3.6) Red blood cell disorders 1 1 (3.6) Platelet, bleeding and clotting disorders 1 1 (3.6) Reproductive disorders (female) 1 1 (3.6) Foetal disorders 1 1 (3.6) Skin and appendages disorders 1 1 (3.6) Body as a whole general disorders 1 1 (3.6) Not codable 7 4 (14.3) Total (50.0) a multiple answers possible A total of 13 AEs in 7 subjects led to subjects discontinuation of the intake of study medication, 10 of them were serious. Table 5 summarises the discontinuations due to AEs. Table 5 Discontinuations due to Adverse Events Safety Analysis Adverse Event Severity Seriousness Relationship Outcome Suspected graft rejection Mild Non-serious Possible Recovered Infection (respiratory) Mild Non-serious Possible Recovered Graft rejection crisis Moderate Serious Possible Recovered Acute rejection episode Severe Serious Possible Recovered Increase in S-creatinine a Severe Serious Possible Recovered Mild Non-serious Possible Recovered Pre-renal failure and bacterial Infection Severe Serious Unlikely Recovered Severe peripheral insulin resistance Moderate Serious Possible Recovered Papilledema Moderate Serious Probable Not recovered Dysfunction of the transplant Moderate Serious b Unlikely Not recovered Gastroenteritis Moderate Serious b Unlikely Not recovered Viral infection Severe Serious b Unlikely Recovered Benign intracranial hypertension Severe Serious b Probable Not recovered a 2 different events were reported b AEs documented only on the adverse events report form At study start, the values for HbA 1c were outside normal ranges in 7 subjects. However, the deviations were assessed to be due to the underlying disease. The values for blood glucose and HbA 1c changed only marginally during the study. Page 7

8 As a consequence of renal insufficiency, the GFR was outside normal range at study start and during the study in most subjects. GFR did not change markedly between baseline and last examination. The investigators reported that most abnormal laboratory values were a consequence of the underlying disease, and only a minor number of abnormal values were defined as clinically significant and not related to the inclusion diagnosis. Acute rejection episodes were documented for 4 subjects during study. CONCLUSION: Results of the primary and the secondary parameters indicated a positive treatment effect of the study drug. As the AEs could mainly be seen as a consequence of the underlying disease the treatment with Genotropin can be regarded as safe. Page 8