PFIZER INC. PROTOCOL TITLE: Metabolic effects of growth hormone (Genotonorm ) in girls with Turner syndrome.

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 / Genotonorm / Somatropin PROTOCOL NO.: PROTOCOL TITLE: Metabolic effects of growth hormone (Genotonorm ) in girls with Turner syndrome. Study Centres: 22 centres in France. Study Initiation Date and Completion Dates: 02 January 1996 to 08 October 2003 Phase of Development: Phase 3B Study Objectives: The main objective of the study was to study the effects of growth hormone (GH) on bone mineral density (BMD) by the study of the modification in BMD after 12 and 24 months of treatment with Genotonorm. BMD was adjusted for bone age (BA). Secondary objectives were: to compare BMD modifications following 2 different GH doses; to evaluate the effects of Genotonorm on body composition; to evaluate the effects of 2 different doses of Genotonorm administered for 2 years on height change: 1.5 IU/kg/week compared to 1.0 IU/kg/week; to evaluate the effects of Genotonorm on lipid metabolism; and to evaluate the safety of Genotonorm. METHODS Study Design: This was a randomized, open, parallel-group, multicenter study comparing the effects of 2 different doses of Somatropin (Genotonorm) on BMD, body composition and growth rate in children with Turner syndrome. Girls aged 4 or more and with a Turner syndrome confirmed by a karyotype were randomized in 2 groups: Group A: received 1.0 IU/kg/week (0.33 mg/kg/week) Group B: received 1.5 IU/kg/week (0.50 mg/kg/week) The weekly dose was divided in 7 subcutaneous injections, 1 per day, and treatment duration was 24 months. Ten visits were planned including a pre-inclusion visit (V1), a inclusion/baseline visit (V2) and 8 follow-up visits taking place at every 3 months (M3 to M24) Page 1

2 Number of Subjects (Planned and Analysed): A total of 100 subjects were planned to be included in the study. In total, 68 subjects were screened and out of them 65 subjects were randomised. Diagnosis and Main Criteria for Inclusion: Enrolment of girls aged 4 years or more, with Turner s syndrome. BA had to be 11 years at inclusion and height for chronological age (CA) 1.5 Standard Deviation (SD) according to SEMPE standards or height for CA < -1 SD associated with a growth rate for CA < -1 SD (France Hypophyse criteria). Growth rate during the 6 months preceding inclusion had to be known and GH stimulation test had been performed. Study Treatment: Genotonorm KabiVial 16 IU or Genotonorm 36 IU or Genotonorm 16 IU were used in the study. Genotonorm 36 IU and Genotonorm 16 IU were used with the Genotonorm Pen 36 and Genotonorm Pen 16 GH delivery devices, respectively. Injections were administered subcutaneously in the thigh in the evening, before going to sleep. The injection site had to be changed daily to help prevent lipoatrophy. During the first 3 months of treatment, GH doses were calculated according to the weight measured at the baseline visit. Then, doses could be changed according to the weight measured at each follow-up visit. Group A: received 1.0 IU/kg/week (0.33 mg/kg/week) Group B: received 1.5 IU/kg/week (0.50 mg/kg/week) The weekly dose was divided in 7 subcutaneous injections. The duration of the study treatment was 24 months. Efficacy Evaluations: Primary Efficacy Endpoint: The evolution of BMD in standard deviation score (SDS) (corrected for BA) was the main criterion of efficacy and Dual Energy X-ray Absorptiometry (DEXA) at the lumbar spinal and on the total body studies was the main efficacy criterion to monitor the evolution of BMD and body composition before and after 12 and 24 months. The data was expressed in BMD-SDS. DEXA was performed at baseline, M12 and M24. It was decided to use the evolution of BMD of total body (BMD TB ) in SDS as estimated by the core lab after 24 months as main criterion of efficacy. Evolution data after 12 months and estimated by the core lab were secondary efficacy criteria. Secondary Efficacy Endpoints: - Measured height in cm and in SDS according to chronological age (CA) - Growth velocity (GV) was a main criterion in the follow-up of children with short stature such as Turner syndrome. This is why it was decided to add 2 criteria in the secondary efficacy criteria: GV in cm/year and in SDS according to CA and sex: GV (SDS/CA/Sex). Page 2

3 - DEXA parameters. Only DEXA data obtained from central reading were used for analysis of the following: a) BMD TB in SDS at 12 months. b) BMD at lumbar spine (L1-L4;BMD LS ) expressed as g/cm2 and corrected for BA (SD) as estimated by the core lab. c) Total body BMD (BMD TB ) expressed as g/cm². d) Total Bone Mineral Content (BMC TB ) in g. e) Fat Mass (FM) in g, in %total body weight and in SDS according to CA for height and sex. f) Lean Mass (LM) in g, in % total body weight and in SDS according to CA for height and sex. g) Δ 24 months 12 months and Δ12 months-baseline for: FM in g; LM in g; BMC TB in g; BMD TB in g/cm²; and BMD TB in SDS h) Relative change as well as percentage change from baseline to 24 months for: BMI in kg; FM in g; LM in g; BMC TB in g; BMD TB in g/cm²; BMD TB in SDS; BMD LS in g/cm²; and BMD LS in SDS - Biological parameters listed in the protocol: Bone metabolism: calcemia (mmol/l), phosphatemia (mmol/l), calciuria (mmol/24h), phosphaturia (mmol/24h), 25-OH vitamin D3 (ng/ml), PTH (pg/ml), alkaline phosphatases, osteocalcin (ng/ml), urinary pyridoline (nmol/mmol creatininuria), and gamma-glutamyl transferase (GGT, IU/L). Safety Evaluations: The safety was evaluated by assessing adverse events (AEs) including serious adverse events (SAE) and laboratory evaluations. Laboratory safety measurements are presented in Table 1. Yearly laboratory parameters, at baseline, or otherwise specified and at 12 and 24 months were measured. For other parameters, delta from baseline and 12 months and delta from baseline and 24 months was also measured. Number of children with decrease in GH dose associated with plasma insulin-like growth factor-1 (IGF-1) level > 2 SD at 3 months and 12 months was measured. Frequency and percentage of children with HbA1c > upper normal level (UNL) of the laboratory was also measured. Page 3

4 Table 1 Laboratory Safety Assessment Haematology B-haemoglobin B-red blood cells B-hematocrit B-erythrocytes B-thrombocytes B-leucocytes B-neutrophils B-basophils B-lymphocytes B-eosinophiles B-monocytes HbA 1 C B-platelets Thyroid function (pre-inclusion) T4 /ft4 Fasting IGF-1 IGF-1 SDS ΔIGF-1 ΔIGFBP-3 Abbreviations: B = blood; HbA 1 C = glycated haemoglobin alpha 1; T 4 = thyroxin; ft4 = free thyroxin; IGF-1 = Insulin-like Growth Factor-1, IGFBP-3 = Insulin-like growth factor-binding protein 3, SDS = standard deviation score Statistical Methods: The evolution of BMD in SDS (corrected for BA) was the main criterion of efficacy. The null hypothesis for the primary efficacy endpoint was that there was no difference in BMD TB adjusted for BA after 24 months of treatment between the 2 treatment groups. The alternative hypothesis was that there was a difference. Baseline values were used as covariates for all parameters. Since parameters expressed in SDS corresponded to parameters standardized for CA or for BA, no covariance analysis was performed using age or sex as covariates. All statistical tests were 2-sided tests using a significance level of α = All analyses were tested against no change, i.e. a value of 0. Statistical tests were performed only to compare efficacy data at 12 months and 24 months. For continuous data, descriptive statistics included n, number of missing data, mean, standard deviation, range and median. When summarising changes from baseline or percentage changes, 95% confidence intervals around the mean were provided. A covariance analysis was used to compare the 2 treatment groups for all parameters to be analyzed, adjusting for value at baseline (fixed effect) for the corresponding dependent variable. For DEXA parameters, a mixed model was used with the engine model as random effect and baseline value as fixed effect. For categorical data, descriptive statistics included counts, percentages and number of missing values. Chi-square or if validity criteria for chi-square were not fulfilled, Fischer s exact test was used to compare categorical data. Safety data were summarized with respect to premature discontinuation, AEs and other safety data as needed and were presented in accordance with Pfizer s Worldwide Safety Standards. Covariance analysis (including baseline value as covariate) was used to compare the HbA1c (%), IGF-1 (SDS) and ΔIGFBP-3 (ng/ml): delta from baseline between the 2 treatment groups, after 12 and 24 months. Proportions of children with decrease in GH dose Page 4

5 associated with plasma IGF-1 level > 2 SD at 3 months and 12 months were also compared between the 2 groups. RESULTS Subject Disposition and Demography: In total, 68 subjects were screened and out of them 65 subjects were randomised (32 and 33 subjects were allocated to Group A and Group B, respectively). Five and 4 subjects were excluded from Group A and Group B respectively, as no BMD results at baseline and at start of the treatment were available. This resulted in 27 subjects in Group A and 29 subjects in Group B. (which comprised the full analysis set (FAS, N=56). One subject each in Group A and Group B was excluded from the per protocol (PP) analyses as they had taken oestrogen treatment, which was considered to be a major protocol deviation. Hence, in the PP set, the total number of subjects was 54. In the FAS population (N=56), about 89% of the subjects were Caucasian. Other ethnic origins were black for 3 subjects (1 in Group A and 2 in Group B), oriental (1 in Group A) or from the Magreb (1 in each group). Data at birth were comparable between the 2 groups of treatment for birth weight, gestational age and birth length in cm. Mean birth length expressed in SDS/CA was shorter in Group B, compared to Group A (-1.84 vs ). More than half of the subjects in both groups had a history of prior medical problems. Most of these were related to infections (34%, mostly ear infection), ear and labyrinth disorders (8%, mostly otorrhoea) and surgical procedures (11%). Baseline characteristics of all subjects are presented in Table 2 below. Page 5

6 Table 2 Baseline characteristics of subjects at inclusion Group A GH 0.33mg/kg/week N = 27 Group B GH 0.50 mg/kg/week N = 29 Total N = 56 Chronological age (years) n mean (SD) 9.89 (2.94) 9.11 (2.21) 9.48 (2.59) median (min;max) (4.69; 16.02) 8.81 (4.28; 13.84) 9.18 (4.28; 16.02) Bone age (years) n mean (SD) 8.37 (2.42) 7.74 (2.16) 8.04 (2.29) median (min;max) 8.83 (3.25; 12.00) 7.83 (2.75; 11.50) 8.00 (2.75; 12.00) Standing height (cm) n mean (SD) (13.34) (11.45) (12.51) median (min;max) (95.30; ) (89.00; ) (89.00; ) Height (SDS/CA) n mean (SD) (0.62) (0.74) (0.69) median (min;max) (-3.90; -1.50) (-5.00; -1.30) (-5.00; -1.30) Weight (kg) n mean (SD) (9.33) (7.85) (8.69) median (min;max) (13.30; 47.20) (12.00; 40.80) (12.00; 47.20) BMI (kg/m²) n mean (SD) (2.94) (3.46) (3.21) median (min;max) (14.43; 25.51) (13.91; 29.65) (13.91; 29.65) BMI (SDS/CA) n mean (SD) 1.04 (1.36) 1.00 (2.06) 1.02 (1.74) median (min;max) 0.83 (-1.20; 4.18) 0.40 (-1.30; 8.86) 0.74 (-1.30; 8.86) Abbreviations: BMI = body mass index; CA = chronological age; GH = growth hormone, kg = kilogram; max = maximum; m = meter; min = minimum; mg = milligram N = number of subjects; n = number of subjects with data; SD = standard deviation; SDS = standard deviation score Efficacy Results: The main criterion of efficacy was the change in BMD on the whole body expressed as SDS adjusted for BA (BMD TB in SDS/BA) at 24 months. It appeared that this expression of BMD TB could only be applied when DEXA measures had been performed with a Dexa Lunar model. Only 10 subjects could be analyzed for this parameter: 6 in Group A and 4 in Group B. Results are summarised in Table 3 below. Page 6

7 Table 3 BMD TB in SDS/BA: Values at Baseline, M12, M24, Change and Relative Change BMD TB in SDS/BA Baseline M12 Group A GH 0.33mg/kg/week N = 27 Group B GH 0.50 mg/kg/week N = 29 Total N = 56 n mean (SD) (0.57) (0.38) (0.52) median (min;max) (-1.20; 0.50) (-1.25; -0.40) (-1.25; 0.50) n mean (SD) (0.45) (1.32) (1.17) median (min;max) (-1.40; -0.21) (-3.80; -0.63) (-3.80; -0.21) M24 n mean (SD) (0.57) (0.67) (0.72) median (min;max) (-0.48; 0.53) (-1.60; -0.26) (-1.60; 0.53) Delta between baseline and M12 n mean (SD) (0.64) (1.19) (0.95) median (min;max) (-1.34; 0.23) (-2.67; -0.11) (-2.67; 0.23) Delta between M12 and M24 n mean (SD) 0.67 (0.44) 0.85 (1.18) 0.78 (0.87) median (min;max) 0.67 (0.35; 0.98) 0.37 (-0.02; 2.20) 0.37 (-0.02; 2.20) % change between baseline and M12 n mean (SD) (127.62) (96.27) (110.59) median (min;max) ( ; 52.61) ( ; ) ( ; 52.61) % change between M12 and M24 n mean (SD) (19.69) (34.70) (28.20) median (min;max) (42.39; 70.24) (-1.67; 58.95) (-1.67; 70.24) % change between baseline and M24 n mean (SD) (190.55) (38.58) 3.90 (123.50) median (min;max) ( ; ) (-41.18; 35.00) ( ; ) Abbreviations: BA = bone age; BMD TB = Bone Mineral Density of total body; GH = growth hormone; kg = kilogram; m = meter; max = maximum; min = minimum; mg = milligram; M12 = visit at 12 months; M24 = visit at 24 months; N = number of subjects; n = number of subjects with data; SD = standard deviation; SDS = standard deviation score Considering the small number of subjects and the great inter-individual variability, it was difficult to draw conclusions from these results. Mean BMD TB expressed in SDS/BA was (±0.52) for 10 subjects at baseline and (±0.72) for 6 subjects after 24 months of treatment. The percent change between baseline and M24 could be measured on only 3 subjects in each group and was extremely variable from 1 subject to another. Page 7

8 Mean measured height increased from (±13.65) cm at baseline to (±12.38) cm at M24 for subjects receiving 0.33 mg GH/kg/week and from (±11.50) cm to (±11.33) cm for subjects receiving 0.50 mg GH/kg/week. The difference between the 2 groups of treatment was significant at M24 (p= 0.013), showing a greater height increase with higher dose of GH. A marked inter-individual variability was still present. When height was analyzed in terms of SDS/CA, the difference between the 2 doses of treatment was significant after 12 months and after 24 months of treatment (p=0.025 and p=0.017, respectively). Mean values went from (±0.70) at baseline to (±0.98) at M24 for Group A and from (±0.75) to (±0.85) for Group B. Growth velocity increased from a mean 3.80 (±1.17) cm/year at baseline to 8.62 (±1.84) cm/year at M12 and 6.80 (±1.77) cm/year at M24. There was no statistically significant difference between the 2 doses of GH in growth velocity after 12 months of treatment but growth velocity was significantly better with the higher dose after 24 months of treatment (p=0.043). This difference between the 2 doses disappeared when growth velocity was analyzed in terms of SDS/CA. Mean growth velocity for all subjects progressed from (±1.95) SDS at baseline to 2.04 (±4.55) SDS at M24. BMI values were very variable. There was a mean percent change after 24 months of treatment of 5.8% (±7.3%). BMD LS increased from 0.61 (±0.14) g/cm² at baseline to 0.68 (±0.11) g/cm² at M24 for Group A and from 0.58 (±0.08) g/cm² to 0.68(±0.09) g/cm² for Group B. Percent change between baseline and M24 was variable from 1 subject to another and no significant difference was shown between the 2 treatment doses. Like the main criterion, results on BMD LS expressed in SDS/CA could be analyzed only on a small number of subjects and could not lead to conclusions on the effect of GH doses. Mean BMD measured in g/cm² on the whole body slightly increased from baseline to M24 in the 2 treatment groups: from 0.81 (±0.08) g/cm² to 0.85 (±0.07) g/cm² for Group A and from 0.74 (±0.08) g/cm² to 0.78 (±0.08) g/cm² for Group B. Mean percent change from baseline to M24 was 6.3% (±5.86) for all subjects but variability between individuals was important ranging from -3.5% to 30.7%. Mean BMC TB increased from 821g at baseline to 1081g after 24 months of treatment. There was no significant difference in the relative change between baseline and M24 between the 2 treatment groups. There was a decrease in mean FM between baseline and M12 (-6.5 (±24.6) % change) and an increase between M12 and M24 (35.2 (±30.8) % change). Like the other parameters previously described, inter-individual variability was important. Still, when FM was expressed in % total body weight, mean FM decreased from 26.0% (±10.3) at baseline to 22.1% (±10.1%) at M24. A decrease in FM as % total body weight was observed in the 2 groups. LM increased between baseline and M24 with a mean percent change of 46.5% (±14.7). In % total body weight LM represented 69.5% (±9.6) at baseline and 74.6% (±8.5) at M24. Page 8

9 Concerning the biological parameters of bone metabolism, no real difference was observed in the level of calcemia from baseline and M24 and between groups, and phosphatemia values were only slightly higher in the group receiving the higher dose of GH. Results for calciuria and phosphaturia were available for less than 60% of the subjects. Mean phosphaturia increased from baseline to M24 but range of values was large. Gamma GT median values were comparable between the 2 groups of treatment. There was a slight increase at M24 compared to baseline in each group. Safety Results: Numbers of AEs, SAEs, treatment related AEs, per treatment group and in total are presented in Table 4 below. Table 4 Summary of Adverse Events Group A GH 0.33 mg/kg/week N = 32 Group B GH 0.50 mg/kg/week N = 33 Total N = 65 Number of subjects with at least 1 AE Number of AEs Number of subjects with at least 1 SAE Number of SAEs Number of subjects with at least 1 AE possibly or probably related to treatment Number of AEs probably or possibly related to treatment Abbreviations: AE = Adverse event; GH = growth hormone; N = number of subjects; SAE = serious adverse event Most AEs were mild (73%) or moderate (25%), these results being comparable in the 2 groups. Two AEs in Group B were graded of severe intensity: 1 case of asthma was considered a SAE and not related to treatment and one case of headache was not serious and possibly related to treatment. Six AEs in Group A and nine AEs in Group B were considered as possibly or probably related to treatment. Headache was the most common treatmentrelated event (2 subjects in each group). The most frequent AEs reported during the study by system organ class were: infections and infestations (Group A, n=13; Group B, n=17), mostly ear infection and nasopharyngitis, followed by respiratory disorders (Group A, n=6; Group B, n=7), essentially sore throats and surgical and medical procedures (Group A, n=3 Group B, n=9). Most procedures concerned the ears. Page 9

10 There were no cases of death, diabetes or neoplasm reported during the study. Fifteen subjects presented with at least 1 SAE: 5 in Group A (0.33mg/kg/week) and 10 in Group B (0.50 mg GH/kg/week). Most SAEs were graded mild or moderate in intensity, 1 was not graded and only 1 was graded severe (asthma). Only 1 SAE (surgery for pterygium) was possibly related to the study treatment. For 1 SAE (osteoarthritis), relationship to the study treatment was not determined. None of the subjects discontinued treatment because of any AE. The number of subjects with deteriorations in laboratory measures was low. When considering descriptive statistics of haematology data at baseline, M12 and M24, there was little change in mean and median values for all these parameters between baseline and M24 and values were comparable between the 2 groups of treatment. ANCOVA analysis of HbA1c levels with the baseline value as covariate did not show a statistically significant difference between the 2 groups (p=0.74 for M12 values and p=0.43 for M24 values). Mean FT4 did not change significantly between baseline and M24. Fasting IGF-1 values were available for only 15 subjects at baseline and 14 subjects at M24 as other IGF-1 samples were lost due to a problem with cold-storage. ANCOVA analysis with the baseline value as covariate did not show a statistically significant difference between the 2 groups at M12 (p=0.24) or at M24 (p=0.062) at a 5% confidence level. At baseline, 3 subjects had a fasting IGF-1 value expressed in SDS of > 2SDS, including 1 with a IGF-1 value > 2.5 SDS. At M12, 12 subjects (5 in Group A and 7 in Group B) had IGF-1 values > 2 SDS and for 9 of them, these values were even > 2.5 SDS. At M24, 12 subjects, 6 in each treatment group, had an IGF-1 value > 2.5 SDS. Mean (±SD) BA was slightly lower in Group B at baseline (7.55 ±2.34 years compared to 8.25 ±2.38 years in Group A) and at M12 (8.76 ±2.13 years compared to 9.38 ±2.64 years in Group A). However, at M24, it was similar in the 2 groups of treatment (10.43 ±1.87 years for Group B and ±2.34 years for Group A). CONCLUSION: This study did not demonstrate an effect of growth hormone treatment on bone mineral density as the final number of subjects who were analyzed was too small. A slight increase was observed in average but there was a large inter-individual variability. This study confirmed the beneficial effect of GH treatment on growth velocity and height in young girls with Turner s syndrome. The higher dose of GH was more effective after 24 months of treatment. Change in body composition was also shown with a decrease in fat mass and an increase in lean mass. Overall, GH treatment at either dose was well tolerated. Page 10