14 CLINICAL STUDIES

14.1 Growth Failure due to Inadequate Secretion of Endogenous Growth Hormone

The efficacy and safety of NORDITROPIN was assessed in a multicenter, prospective randomized, open label, dose response study with three doses (0.025, 0.05 and 0.1 mg/kg/day). A total of 111 pediatric patients with GH deficiency were randomized to each dose; 37(0.025 mg/kg/day):38(0.05 mg/kg/day):36(0.1 mg/kg/day). Patients met the following entry criteria: chronological age ≥ 3 years with a skeletal age < 10 years if male and < 8 years if female; pubertal stage = stage 1; previously untreated GH deficiency; peak plasma hormone concentration < 7 ng/ml or < 10 ng/ml (depending on assay used) in two tests.

The results are displayed in Table 4. The adjusted mean increases in HSDS over the 2-year period were 0.81, 1.57 and 1.73 in the 0.025, 0.05 and 0.1 mg/kg/day dose groups, respectively. There was no significant difference in ΔHSDS between the 0.05 and 0.1 mg/kg/day treatment groups. Height velocity (HV, cm/year) and HVSDS increased considerably after initiation of treatment, with the greatest response observed during the first year of treatment.

Table 4 – Efficacy of NORDITROPIN in Pediatric GH Deficiency

	NORDITROPIN
	0.025 mg/kg/day			0.05 mg/kg/day			0.1 mg/kg/day
	N	Mean	SD	N	Mean	SD	N	Mean	SD
Change in Standing Height (cm)
Baseline to Month 12	37	9.5	2.1	37	13.2*	2.6	34	13.7*	2.7
Baseline to Month 24	34	17.6	3.4	37	22.2*	4.7	33	23.7*	4.0
Change in Sitting Height (cm)
Baseline to Month 12	32	5.4	2.4	36	6.5*	1.6	32	7.4**	1.5
Baseline to Month 24	29	9.3	2.5	35	10.8**	2.6	31	12.2**	2.0
Change in Bone Age (yr)
Baseline to Month 12	37	1.3	0.9	38	1.7	0.8	34	1.6	0.8
Month 12 to Month 24	37	0.6	2.5	38	1.4	2.7	34	1.6*	0.8

: *Significant (p <0.05) change from baseline compared to the 0.025 mg/kg/group

**Significant (p <0.05) change from baseline compared to both other groups

14.2 Short Stature Associated with Noonan Syndrome

A prospective, open label, randomized, parallel group study with 21 pediatric patients was conducted for 2 years to evaluate the efficacy and safety of NORDITROPIN. Additional 6 children were not randomized, but did follow the protocol. Inclusion criteria included bone age determination showing no significant acceleration, prepubertal status, height SDS <-2, and HV SDS <1 during the 12 months pre-treatment. Exclusion criteria were previous or ongoing treatment with growth hormone, anabolic steroids or corticosteroids, congenital heart disease or other serious disease perceived to possibly have major impact on growth, FPG >6.7 mmol/L (>120 mg/dL), or growth hormone deficiency (peak GH levels <10 ng/mL). The twenty-four, 12 female and 12 male, patients 3 – 14 years of age received either 0.033 mg/kg/day or 0.066 mg/kg/day of NORDITROPIN subcutaneously which was adjusted based on growth response after the first 2 years.

After the initial two-year study, NORDITROPIN treatment continued until final height. Retrospective final height was collected from 18 patients in the study and the 6 who had followed the protocol without randomization. Historical reference materials of height velocity and adult height analyses of Noonan patients served as the controls.

Patients obtained a final height (FH) gain from baseline of 1.5 and 1.6 SDS estimated according to the national and the Noonan reference, respectively. A height gain of 1.5 SDS (national) corresponds to a mean height gain of 9.9 cm in boys and 9.1 cm in girls at 18 years of age, while a height gain of 1.6 SDS (Noonan) corresponds to a mean height gain of 11.5 cm in boys and 11.0 cm in girls at 18 years of age.

A comparison of HV between the two treatment groups during the first two years of treatment for the randomized subjects was 10.1 and 7.6 cm/year with 0.066 mg/kg/day versus 8.55 and 6.7 cm/year with 0.033 mg/kg/day, for Year 1 and Year 2, respectively.

14.3 Short Stature Associated with Turner Syndrome

Two randomized, parallel group, open label, multicenter studies were conducted in the Netherlands to evaluate the efficacy and safety of NORDITROPIN. Patients were treated to final height in both studies [height velocity (HV) < 2 cm/year]. Changes in height were expressed as standard deviation scores (SDS) utilizing reference data for untreated Turner syndrome patients as well as the national Dutch population.

In Study 1, 68 euthyroid Caucasian patients stratified based on age and baseline height SDS were randomized in a 1:1:1 ratio to three different NORDITROPIN treatment regimens: 0.045 mg/kg/day (Dose A) for the entire study; 0.045 mg/kg/day for the first year and 0.067 mg/kg/day thereafter (Dose B); or 0.045 mg/kg/day for the first year, 0.067 for the second year, and 0.089 mg/kg/day thereafter (Dose C). At baseline, mean age was 6.5 years, mean height SDS (National standard) was -2.7, and mean HV during the previous year was 6.5 cm/year. Patients also received estrogen therapy after age 12 and following four years of NORDITROPIN treatment if they did not have spontaneous puberty.

Patients were treated for a mean of 8.4 years. As seen in Table 5, overall mean final height was 161 cm in the 46 children who attained final height. Seventy percent of these children reached a final height within the normal range (height SDS > -2 using the National standard). A greater percentage of children in the two escalated dose groups reached normal final height. The mean changes from baseline to final height in height SDS after treatment with Dose B and Dose C were significantly greater than the mean changes observed after treatment with Dose A (utilizing both the National and Turner standards). The mean changes from baseline to final height in height SDS (Turner standard) in Table 5 correspond to mean height gains of 9.4, 14.1 and 14.4 cm after treatment with Doses A, B and C, respectively. The mean changes from baseline to final height in height SDS (National standard) in Table 5 correspond to mean height gains of 4.5, 9.1 and 9.4 cm after treatment with Doses A, B and C, respectively. In each treatment group, peak HV was observed during treatment Year 1, and then gradually decreased each year; during Year 4, HV was less than the pre-treatment HV. However, between Year 2 and Year 6, a greater HV was observed in the two dose escalation groups compared to the 0.045 mg/kg/day group.

Table 5 – Final Height-Related Results After Treatment of Patients with Turner Syndrome with NORDITROPIN in a Randomized, Dose Escalating Study

	Dose A 0.045 mg/kg/day (n = 19)	Dose B up to 0.067 mg/kg/day (n = 15)	Dose C up to 0.089 mg/kg/day (n = 12)	Total (n = 46)
Baseline height (cm)1	105 (12)	108 (12.7)	107 (11.7)	106 (11.9)
Final height (cm)1	157 (6.7)	163 (6.0)	163 (4.9)	161 (6.5)
Number (%) of patients reaching normal height (height SDS >-2 using National standard)	10 (53%)	12 (80%)	10 (83%)	32 (70%)
Height SDS (Turner standard)2
Final [95% CI]	1.7 [1.4, 2.0]	2.5 [2.1, 2.8]3	2.5 [2.1, 2.9]4	NA
Change from baseline [95% CI]	1.5 [1.2, 1.8]	2.2 [1.9, 2.5]3	2.2 [1.9, 2.6]4	NA
Height SDS (National standard)2
Final [95% CI]	-1.9 [-2.2, -1.6]	-1.2 [-1.5, -0.9]4	-1.2 [-1.6, -0.8]5	NA
Change from baseline [95% CI]	0.7 [0.4, 1.0]	1.4 [1.1, 1.7]4	1.4 [1.1, 1.8]5	NA

Values are expressed as mean (SD) unless otherwise indicated. SDS: Standard deviation score.

1Unadjusted (raw) means; 2Adjusted (least squares) means based on an ANCOVA model including terms for treatment,

duration of treatment, age at baseline, bone age at baseline, height SDS at baseline, age at onset of puberty and mid-parental target height SDS;

3p=0.005 vs. Dose A; 4p=0.006 vs. Dose A; 5p=0.008 vs. Dose A

In Study 2, 19 euthyroid Caucasian patients (with bone age ≤13.9 years) were randomized to treatment with 0.067 mg/kg/day of NORDITROPIN as a single subcutaneous dose in the evening, or divided into two doses (1/3 morning and 2/3 evening). All subjects were treated with concomitant ethinyl estradiol. Overall, at baseline, mean age was 13.6 years, mean height SDS (National standard) was -3.5 and mean HV during the previous year was 4.3 cm/year. Patients were treated for a mean of 3.6 years. In that there were no significant differences between the two treatment groups for any linear growth variables, the data from all patients were pooled. Overall mean final height was 155 cm in the 17 children who attained final height. Height SDS changed significantly from -3.5 at baseline to -2.4 at final height (National standard), and from 0.7 to 1.3 at final height (Turner standard).

14.4 Short Stature in Pediatric Patients Born Small for Gestational Age (SGA) with No Catch-up Growth by Age 2-4 Years

A multi-center, randomized, double-blind, two-arm study to final height (Study 1) and a 2-year, multi-center, randomized, double-blind, parallel-group study (Study 2) were conducted to assess the efficacy and safety of NORDITROPIN. Changes in height and height velocity were compared to a national reference population in both studies.

Study 1 included 53, 38 male, 15 female, non-GHD, Dutch prepubertal pediatric patients 3-11 years of age with short stature born SGA with no catch-up growth. Catch-up growth was defined as obtaining a height of ≥ 3rd percentile within the first 2 years of life or at a later stage. Inclusion criteria included: birth length < 3rd percentile for gestational age, and height velocity (cm/year) for chronological age < 50th percentile. Exclusion criteria included chromosomal abnormalities, signs of a syndrome (except for Silver-Russell syndrome), serious/chronic co-morbid disease, malignancy, and previous rhGH therapy. NORDITROPIN was administered subcutaneously daily at bedtime at a dose of approximately 0.033 (Dose A) or 0.067 mg/kg/day (Dose B) for the entire treatment period. Final height was defined as a height velocity below 2 cm/year. Treatment with NORDITROPIN was continued to final height for up to 13 years. Mean duration of treatment was 9.5 years (boys) and 7.9 years (girls).

38 out of 53 children (72%) reached final height. Sixty-three percent (24 out of 38) of the children who reached final height were within the normal range of their healthy peers (Dutch national reference). For both doses combined, actual mean final height was 171 (SD 6.1) cm in boys and 159 (SD 4.3) cm in girls.

As seen in Table 6, for boys and girls combined, both mean final height SDS, and increase in height SDS from baseline to final height, were significantly greater after treatment with Dose B (0.067 mg/kg/day). A similar dose response was observed for the increase in height SDS from baseline to Year 2 (Table 6).

Overall mean height velocity at baseline was 5.4 cm/y (SD 1.2; n=29). Height velocity was greatest during the first year of NORDITROPIN treatment and was significantly greater after treatment with Dose B (mean 11.1 cm/y [SD 1.9; n=19]) compared with Dose A (mean 9.7 cm/y [SD 1.3; n=10]).

Table 6 – Study 1: Results for Final Height SDS and Change from Baseline to Final Height in Height SDS Using National Standard After Long-Term Treatment of SGA Children with NORDITROPIN

	Raw Mean ± SD (N)
	Dose A 0.033 mg/kg/day	Dose B 0.067 mg/kg/day	Total
Baseline Height SDS	-3.2 ± 0.7 (26)	-3.2 ± 0.7 (27)	-3.2 ± 0.7 (53)
Adjusted least-squares mean ± standard error (N), Treatment Difference [95% confidence intervals]
Height SDS: Change from Baseline at Year 22	1.4 ± 0.1 (26)	1.8 ± 0.1 (26)	Treatment Diff = 0.4 [0.2, 0.7]3
Height SDS: Change from Baseline at Final Height1	1.4 ± 0.2 (19)	1.8 ± 0.2 (19)	Treatment Diff = 0.5 [0.0, 0.9]3
Final Height SDS1	-1.8 ± 0.2 (19)	-1.3 ± 0.2 (19)	Treatment Diff = 0.5 [0.0, 0.9]3
Final Height SDS > -2	13/19 (68%)	11/19 (58%)	24/38 (63%)

SDS: Standard deviation score.

1Adjusted (least-squares) means based on an ANCOVA model including terms for treatment, gender, age at baseline, bone age at baseline, height SDS at baseline, duration of treatment, peak GH after stimulation and baseline IGF-1.

2 Adjusted (least-squares) means based on an ANCOVA model including terms for treatment, gender, age at baseline, height SDS at baseline, and pubertal status.

3 p<0.05

In study 2, 84 randomized, prepubertal, non-GHD, Japanese children (age 3-8) were treated for 2 years with 0.033 or 0.067 mg/kg/day of NORDITROPIN subcutaneously daily at bedtime or received no treatment for 1 year. Additional inclusion criteria included birth length or weight SDS ≤ -2 or < 10th percentile for gestational age, height SDS for chronological age ≤ -2, and height velocity SDS for chronological age < 0 within one year prior to Visit 1. Exclusion criteria included diabetes mellitus, history or presence of active malignancy, and serious co-morbid conditions.

As seen in Table 7, for boys and girls combined, there was a dose-dependent increase in height SDS at Year 1 and Year 2. The increase in height SDS from baseline to Year 2 (0.033 mg/kg/day, 0.8 vs. 0.067 mg/kg/day, 1.4) was significantly greater after treatment with 0.067 mg/kg/day. In addition, the increase in height SDS at Year 1 was significantly greater in both active treatment groups compared to the untreated control group.

Table 7 – Study 2: Results for Change from Baseline in Height SDS At Year 1 and Year 2 Using National Standard After Short-Term Treatment of SGA Children with NORDITROPIN

	Raw Mean ± SD (N)
	No Treatment	0.033 mg/kg/day	0.067 mg/kg/day
Height SDS: Baseline	-2.9 ± 0.5 (15)	-3.0 ± 0.6 (35)	-2.9 ± 0.7 (34)
Height SDS: Year 1	-2.8 ± 0.5 (15)	-2.4 ± 0.6 (33)	-2.0 ± 0.8 (34)
Height SDS: Year 2	NA	-2.2 ± 0.7 (33)	-1.4 ± 0.7 (32)
Adjusted least-squares mean ± standard error (N), Treatment Diff [95% confidence intervals]
Height SDS: Change from Baseline at Year 11	0.1 ± 0.1 (15)	0.6 ± 0.1 (33)	0.9 ± 0.1 (34)
Height SDS: Change from Baseline at Year 11	0.033 vs. No Treatment: Treatment Diff = 0.5, [0.3, 0.7]2 0.067 vs. No Treatment: Treatment Diff = 0.8, [0.6, 1.0]2 0.067 vs. 0.033: Treatment Diff = 0.3, [0.2, 0.5]2
Height SDS: Change from Baseline at Year 21	NA	0.8 ± 0.1 (33)	1.4 ± 0.1 (32)
Height SDS: Change from Baseline at Year 21	0.067 vs. 0.033: Treatment Diff = 0.6, [0.5, 0.8], p-value < 0.0001

SDS: Standard deviation score.

1Adjusted (least-squares) means based on an ANCOVA model including terms for treatment, gender, age at baseline, and height SDS at baseline. All children remained prepubertal during the study.

2 p< 0.0001

14.5 Idiopathic Short Stature (ISS)

The efficacy and safety of another somatropin product was evaluated in 105 patients who were retrospectively identified as having ISS in a randomized, open-label, clinical study. Patients were enrolled on the basis of short stature, stimulated GH secretion > 10 ng/mL, and prepubertal status. All patients were observed for height progression for 12 months and were subsequently randomized to this other somatropin product or observation only and followed to final height. Two doses of this other somatropin product 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 8. 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 8 – Final height SDS results for pre-pubertal patients with ISS*

		Another Somatropin Product
	Untreated (n=30)	0.033 mg/kg/day (n=30)	0.067 mg/kg/day (n=42)	0.033 vs Untreated (95% CI)	0.067 vs Untreated (95% CI)
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)**	+0.94 (0.63, 1.26)**
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)**	+0.90 (0.42, 1.39)**

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

**p<0.05

14.6 Growth Failure Due to Prader-Willi Syndrome (PWS)

The safety and efficacy of another somatropin product were evaluated in two randomized, open-label, controlled clinical studies. Patients received either this other somatropin product or no treatment for the first year of the studies, while all patients received this other somatropin product during the second year. This other somatropin product 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 this other somatropin product at a dose of 0.24 mg/kg/week during the entire study. During the second year, the control group received this other somatropin product at a dose of 0.48 mg/kg/week. In Study 2, the treatment group received this other somatropin product at a dose of 0.36 mg/kg/week during the entire study. During the second year, the control group received this other somatropin product at a dose of 0.36 mg/kg/week.

The results are presented in Table 9. Linear growth continued to increase in the second year, when both groups received treatment with this other somatropin product.

Table 9 – Efficacy of Another Somatropin Product in Pediatric Patients with Prader-Willi Syndrome (Mean ± SD)
	Study 1		Study 2
	Another Somatropin Product (0.24 mg/kg/week) (n=15)	Untreated Control (n=12)	Another Somatropin Product (0.36 mg/kg/week) (n=7)	Untreated Control (n=9)
Linear growth (cm) Baseline height	112.7 ± 14.9	109.5 ± 12.0	120.3 ± 17.5	120.5 ± 11.2
Growth from 0 to 12 months	11.6* ± 2.3	5.0 ± 1.2	10.7* ± 2.3	4.3 ± 1.5
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

* p <0.05

14.7 Adults with Growth Hormone Deficiency (GHD)

A total of six randomized, double-blind, placebo-controlled studies were performed. Two representative studies, one in adult onset (AO) GHD patients and a second in childhood onset (CO) GHD patients, are described below.

Study 1

A single center, randomized, double-blind, placebo-controlled, parallel-group, six month clinical trial was conducted in 31 adults with AO GHD comparing the effects of NORDITROPIN (somatropin) injection and placebo on body composition. Patients in the active treatment arm were treated with NORDITROPIN 0.017 mg/kg/day (not to exceed 1.33 mg/day). The changes from baseline in lean body mass (LBM) and percent total body fat (TBF) were measured by total body potassium (TBP) after 6 months.

Treatment with NORDITROPIN produced a significant increase from baseline in LBM compared to placebo (Table 10).

Table 10 – Lean Body Mass (kg) by TBP

	NORDITROPIN (n=15)	Placebo (n=16)
Baseline (mean)	50.27	51.72
Change from baseline at 6 months (mean)	1.12	-0.63
Treatment difference (mean) 95% confidence interval p-value	1.74 (0.65, 2.83) p=0.0028*

*Least square mean based on an ANOVA model including treatment and sex as factors

Analysis of the treatment difference on the change from baseline in percent TBF revealed a significant decrease in the NORDITROPIN-treated group compared to the placebo group (Table 11).

Table 11 – Total Body Fat (%) by TBP

	NORDITROPIN (n=15)	Placebo (n=16)
Baseline (mean)	44.74	42.26
Change from baseline at 6 months (mean)	-2.83	1.92
Treatment difference (mean) 95% confidence interval p-value	-4.74 (-7.18, -2.30) p=0.0004*

*Least square mean based on an ANOVA model including treatment and sex as factors

NORDITROPIN also significantly increased serum osteocalcin (a marker of osteoblastic activity).

Study 2

A single center, randomized, double-blind, placebo-controlled, parallel-group, dose-finding, six month clinical trial was conducted in 49 men with CO GHD comparing the effects of NORDITROPIN and placebo on body composition. Patients were randomized to placebo or one of three active treatment groups (0.008, 0.016, and 0.024 mg/kg/day). Thirty three percent of the total dose to which each patient was randomized was administered during weeks 1-4, 67% during weeks 5-8, and 100% for the remainder of the study. The changes from baseline in LBM and percent TBF were measured by TBP after 6 months.

Treatment with NORDITROPIN produced a significant increase from baseline in LBM compared to placebo (pooled data) (Table 12).

Table 12 – Lean Body Mass (kg) by TBP

	NORDITROPIN (n=36)	Placebo (n=13)
Baseline (mean)	48.18	48.90
Change from baseline at 6 months (mean)	2.06	0.70
Treatment difference (mean) 95% confidence interval p-value	1.40 (0.39, 2.41) p=0.0079*

*Least square mean based on an ANOVA model including treatment as a factor

Analysis of the treatment difference on the change from baseline in percent TBF revealed a significant decrease in the NORDITROPIN-treated groups (pooled data) compared to the placebo group (Table 13).

Table 13 – Total Body Fat (%) by TBP

	NORDITROPIN (n=36)	Placebo (n=13)
Baseline (mean)	34.55	34.07
Change from baseline at 6 months (mean)	-6.00	-1.78
Treatment difference (mean) 95% confidence interval p-value	-4.24 (-7.11, -1.37) p=0.0048*

*Least square mean based on an ANOVA model including treatment as a factor