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GENOTROPIN® (somatropin) Clinical Studies

14 CLINICAL STUDIES

14.1 Adult Growth Hormone Deficiency (GHD)

GENOTROPIN lyophilized powder was compared with placebo in six randomized clinical trials involving a total of 172 adult GHD patients. These trials included a 6-month double-blind treatment period, during which 85 patients received GENOTROPIN and 87 patients received placebo, followed by an open-label treatment period in which participating patients received GENOTROPIN for up to a total of 24 months. GENOTROPIN was administered as a daily SC injection at a dose of 0.04 mg/kg/week for the first month of treatment and 0.08 mg/kg/week for subsequent months.

Beneficial changes in body composition were observed at the end of the 6-month treatment period for the patients receiving GENOTROPIN as compared with the placebo patients. Lean body mass, total body water, and lean/fat ratio increased while total body fat mass and waist circumference decreased. These effects on body composition were maintained when treatment was continued beyond 6 months. Bone mineral density declined after 6 months of treatment but returned to baseline values after 12 months of treatment.

14.2 Prader-Willi Syndrome (PWS)

The safety and efficacy of GENOTROPIN in the treatment of pediatric patients with Prader-Willi syndrome (PWS) were evaluated in two randomized, open-label, controlled clinical trials. Patients received either GENOTROPIN or no treatment for the first year of the studies, while all patients received GENOTROPIN during the second year. GENOTROPIN was administered as a daily SC injection, and the dose was calculated for each patient every 3 months. In Study 1, the treatment group received GENOTROPIN at a dose of 0.24 mg/kg/week during the entire study. During the second year, the control group received GENOTROPIN at a dose of 0.48 mg/kg/week. In Study 2, the treatment group received GENOTROPIN at a dose of 0.36 mg/kg/week during the entire study. During the second year, the control group received GENOTROPIN at a dose of 0.36 mg/kg/week.

Patients who received GENOTROPIN showed significant increases in linear growth during the first year of study, compared with patients who received no treatment (see Table 3). Linear growth continued to increase in the second year, when both groups received treatment with GENOTROPIN.

Table 3 Efficacy of GENOTROPIN in Pediatric Patients with Prader-Willi Syndrome (Mean ± SD)
Study 1 Study 2
GENOTROPIN Untreated Control
n=12
GENOTROPIN Untreated Control
n=9
(0.24 mg/kg/week)
n=15
(0.36 mg/kg/week)
n=7
*
p ≤ 0.001
p ≤ 0.002 (when comparing SDS change at 12 months)
Linear growth (cm)
  Baseline height
112.7 ± 14.9 109.5 ± 12.0 120.3 ± 17.5 120.5 ± 11.2
  Growth from months 0 to 12 11.6* ± 2.3 5.0 ± 1.2 10.7* ± 2.3 4.3 ± 1.5
Height Standard Deviation Score (SDS) for age
  Baseline SDS
-1.6 ± 1.3 -1.8 ± 1.5 -2.6 ± 1.7 -2.1 ± 1.4
  SDS at 12 months -0.5 ± 1.3 -1.9 ± 1.4 -1.4 ± 1.5 -2.2 ± 1.4

Changes in body composition were also observed in the patients receiving GENOTROPIN (see Table 4). These changes included a decrease in the amount of fat mass, and increases in the amount of lean body mass and the ratio of lean-to-fat tissue, while changes in body weight were similar to those seen in patients who received no treatment. Treatment with GENOTROPIN did not accelerate bone age, compared with patients who received no treatment.

Table 4 Effect of GENOTROPIN on Body Composition in Pediatric Patients with Prader-Willi Syndrome (Mean ± SD)
GENOTROPIN Untreated Control
n=10
n=14
*
p < 0.005
n=15 for the group receiving GENOTROPIN; n=12 for the Control group
n.s.
Fat mass (kg)
  Baseline 12.3 ± 6.8 9.4 ± 4.9
  Change from months 0 to 12 -0.9* ± 2.2 2.3 ± 2.4
Lean body mass (kg)
  Baseline 15.6 ± 5.7 14.3 ± 4.0
  Change from months 0 to 12 4.7* ± 1.9 0.7 ± 2.4
Lean body mass/Fat mass
  Baseline 1.4 ± 0.4 1.8 ± 0.8
  Change from months 0 to 12 1.0* ± 1.4 -0.1 ± 0.6
Body weight (kg)
  Baseline 27.2 ± 12.0 23.2 ± 7.0
  Change from months 0 to 12 3.7 ± 2.0 3.5 ± 1.9

14.3 SGA

Pediatric Patients Born Small for Gestational Age (SGA) Who Fail to Manifest Catch-up Growth by Age 2

The safety and efficacy of GENOTROPIN in the treatment of children born small for gestational age (SGA) were evaluated in 4 randomized, open-label, controlled clinical trials. Patients (age range of 2 to 8 years) were observed for 12 months before being randomized to receive either GENOTROPIN (two doses per study, most often 0.24 and 0.48 mg/kg/week) as a daily SC injection or no treatment for the first 24 months of the studies. After 24 months in the studies, all patients received GENOTROPIN.

Patients who received any dose of GENOTROPIN showed significant increases in growth during the first 24 months of study, compared with patients who received no treatment (see Table 5). Children receiving 0.48 mg/kg/week demonstrated a significant improvement in height standard deviation score (SDS) compared with children treated with 0.24 mg/kg/week. Both of these doses resulted in a slower but constant increase in growth between months 24 to 72 (data not shown).

Table 5 Efficacy of GENOTROPIN in Children Born Small for Gestational Age (Mean ± SD)
GENOTROPIN GENOTROPIN Untreated Control
n=40
(0.24 mg/kg/week)
n=76
(0.48 mg/kg/week)
n=93
*
p = 0.0001 vs Untreated Control group
p = 0.0001 vs group treated with GENOTROPIN 0.24 mg/kg/week
Height Standard Deviation Score (SDS)
Baseline SDS -3.2 ± 0.8 -3.4 ± 1.0 -3.1 ± 0.9
SDS at 24 months -2.0 ± 0.8 -1.7 ± 1.0 -2.9 ± 0.9
Change in SDS from baseline to month 24 1.2* ± 0.5 1.7* ± 0.6 0.1 ± 0.3

14.4 Turner Syndrome

Two randomized, open-label, clinical trials were conducted that evaluated the efficacy and safety of GENOTROPIN in Turner syndrome patients with short stature. Turner syndrome patients were treated with GENOTROPIN alone or GENOTROPIN plus adjunctive hormonal therapy (ethinylestradiol or oxandrolone). A total of 38 patients were treated with GENOTROPIN alone in the two studies. In Study 055, 22 patients were treated for 12 months, and in Study 092, 16 patients were treated for 12 months. Patients received GENOTROPIN at a dose between 0.13 to 0.33 mg/kg/week.

SDS for height velocity and height are expressed using either the Tanner (Study 055) or Sempé (Study 092) standards for age-matched normal children as well as the Ranke standard (both studies) for age-matched, untreated Turner syndrome patients. As seen in Table 6, height velocity SDS and height SDS values were smaller at baseline and after treatment with GENOTROPIN when the normative standards were utilized as opposed to the Turner syndrome standard.

Both studies demonstrated statistically significant increases from baseline in all of the linear growth variables (i.e., mean height velocity, height velocity SDS, and height SDS) after treatment with GENOTROPIN (see Table 6). The linear growth response was greater in Study 055 wherein patients were treated with a larger dose of GENOTROPIN.

Table 6 Growth Parameters (mean ± SD) after 12 Months of Treatment with GENOTROPIN in Pediatric Patients with Turner Syndrome in Two Open Label Studies
GENOTROPIN
0.33 mg/kg/week
Study 055^ n=22
GENOTROPIN
0.13–0.23 mg/kg/week
Study 092# n=16
SDS = Standard Deviation Score
Ranke standard based on age-matched, untreated Turner syndrome patients
Tanner^/Sempé# standards based on age-matched normal children
p<0.05, for all changes from baseline
Height Velocity (cm/yr)
  Baseline 4.1 ± 1.5 3.9 ± 1.0
  Month 12 7.8 ± 1.6 6.1 ± 0.9
  Change from baseline (95% CI) 3.7 (3.0, 4.3) 2.2 (1.5, 2.9)
Height Velocity SDS (Tanner^/Sempé# Standards) (n=20)
  Baseline -2.3 ± 1.4 -1.6 ± 0.6
  Month 12 2.2 ± 2.3 0.7 ± 1.3
  Change from baseline (95% CI) 4.6 (3.5, 5.6) 2.2 (1.4, 3.0)
Height Velocity SDS (Ranke Standard)
  Baseline -0.1 ± 1.2 -0.4 ± 0.6
  Month 12 4.2 ± 1.2 2.3 ± 1.2
  Change from baseline (95% CI) 4.3 (3.5, 5.0) 2.7 (1.8, 3.5)
Height SDS (Tanner^/Sempé# Standards)
  Baseline -3.1 ± 1.0 -3.2 ± 1.0
  Month 12 -2.7 ± 1.1 -2.9 ± 1.0
  Change from baseline (95% CI) 0.4 (0.3, 0.6) 0.3 (0.1, 0.4)
Height SDS (Ranke Standard)
  Baseline -0.2 ± 0.8 -0.3 ± 0.8
  Month 12 0.6 ± 0.9 0.1 ± 0.8
  Change from baseline (95% CI) 0.8 (0.7, 0.9) 0.5 (0.4, 0.5)

14.5 Idiopathic Short Stature

The long-term efficacy and safety of GENOTROPIN in patients with idiopathic short stature (ISS) were evaluated in one randomized, open-label, clinical trial that enrolled 177 children. Patients were enrolled on the basis of short stature, stimulated GH secretion > 10 ng/mL, and prepubertal status (criteria for idiopathic short stature were retrospectively applied and included 126 patients). All patients were observed for height progression for 12 months and were subsequently randomized to GENOTROPIN or observation only and followed to final height. Two GENOTROPIN doses were evaluated in this trial: 0.23 mg/kg/week (0.033 mg/kg/day) and 0.47 mg/kg/week (0.067 mg/kg/day). Baseline patient characteristics for the ISS patients who remained prepubertal at randomization (n= 105) were: mean (± SD): chronological age 11.4 (1.3) years, height SDS -2.4 (0.4), height velocity SDS -1.1 (0.8), and height velocity 4.4 (0.9) cm/yr, IGF-1 SDS -0.8 (1.4). Patients were treated for a median duration of 5.7 years. Results for final height SDS are displayed by treatment arm in Table 7. GENOTROPIN therapy improved final height in ISS children relative to untreated controls. The observed mean gain in final height was 9.8 cm for females and 5.0 cm for males for both doses combined compared to untreated control subjects. A height gain of 1 SDS was observed in 10 % of untreated subjects, 50% of subjects receiving 0.23 mg/kg/week and 69% of subjects receiving 0.47 mg/kg/week.

Table 7. Final height SDS results for pre-pubertal patients with ISS*
Untreated
(n=30)
GEN 0.033
(n=30)
GEN 0.067
(n=42)
GEN 0.033 vs. Untreated
(95% CI)
GEN 0.067 vs. Untreated
(95% CI)
**Least square means based on ANCOVA (final height SDS and final height SDS minus baseline predicted height SDS were adjusted for baseline height SDS)
*
Mean (SD) are observed values.
Baseline height SDS
Final height SDS minus baseline 0.41 (0.58) 0.95 (0.75) 1.36 (0.64) +0.53 (0.20, 0.87)
p=0.0022
+0.94 (0.63, 1.26)
p<0.0001
Baseline predicted ht
Final height SDS minus baseline predicted final height SDS 0.23 (0.66) 0.73 (0.63) 1.05 (0.83) +0.60 (0.09, 1.11)
p=0.0217
+0.90 (0.42, 1.39)
p=0.0004

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