Investigating the Long-term Efficacy and Safety of Two Doses of NN-220 (Somatropin) in Short Stature Due to Noonan Syndrome

Study Overview
=================
Brief Summary
-----------------
This trial is conducted in Asia. The aim of the trial is to investigate the long-term efficacy and safety of two doses of NN-220 (somatropin) in short stature due to Noonan syndrome.

Official Title
-----------------
A 52-week, Multi-centre, Randomised, Double-blind, Parallel-group, no Treatment Controlled (Open-label) Trial Investigating the Efficacy and Safety of Two Doses of NN-220 in Short Stature With Noonan Syndrome

Conditions
-----------------
Noonan Syndrome, Genetic Disorder

Intervention / Treatment
-----------------
* Drug: somatropin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Japanese children with Noonan syndrome clinically diagnosed in one of the following ways: 1. Clinically diagnosed by at least two medical experts using van der Burgt score list, 2. Clinically diagnosed by one medical expert using van der Burgt score list and diagnosed by result of genetic testing for Noonan syndrome, 3. Clinically diagnosed by one medical expert using van der Burgt score list and diagnosed by the same medical expert based on the results of centralised evaluation of facial change using van der Burgt score list Height SDS (standard deviation score): -2 SDS or below (according to the Japanese reference data) Age: boys 3 to below 11 years, girls 3 to below 10 years Height records must be available within the period between 40 and 64 weeks prior to Visit 1 (screening) Prepubertal children (definition for girls breast and pubes of Tanner stage is I, and none of menses, and for boys testicular volume below 4 mL, and pubes and penis of Tanner stage is I) Exclusion Criteria: Children with known or suspected hypersensitivity against human growth hormone (hGH) or related products (including any components of the trial products) Children with diabetic type diagnosed with the Japanese Diabetes Society Classification Children with history or presence of active malignancy Children who have received GH (growth hormone) treatment Children who have received systemic administration of the following medications within two years prior to Visit 1 (screening): Thyroid hormone (except replacement therapy), antithyroid hormone, androgen, oestrogen, progesterone, anabolic steroid, adrenocortical steroid treatment period for at least 13 weeks), derivative of gonadotropin releasing hormone and somatomedin C (IGF-I)

Ages Eligible for Study
-----------------
Minimum Age: 3 Years
Maximum Age: 10 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 0.033 mg/kg/day<br> | Drug: somatropin<br>* Administered subcutaneously (s.c., under the skin) in a daily regimen for at least 104 weeks. Subject will be offered to continue treatment for another 104 weeks.<br>|
| Experimental: 0.066 mg/kg/day<br> | Drug: somatropin<br>* Administered subcutaneously (s.c., under the skin) in a daily regimen for at least 104 weeks. Subject will be offered to continue treatment for another 104 weeks.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Height SDS (Japanese National Reference Data) | Height SDS was calculated using the formula: SDS = (height - mean)/SD, where height was the height variable measured, mean and SD of height by sex and age for the reference population. The scores were centered around zero. Positive SDS indicated greater height and negative SDS indicated lesser height than the mean of the reference population. The change from baseline (week 0) in the height SDS after 104 weeks of treatment was analysed using an analysis of covariance (ANCOVA) model with treatment as a fixed effect and baseline height SDS as a covariate. Positive value in change from baseline indicated that SDS was better than baseline SDS. Missing values were imputed using the last observation carried forward (LOCF) method. | Baseline, week 104 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Height Velocity SDS | Height velocity is change in height per year. The height velocity was calculated as the difference between current height (week 52) and height at baseline (week 0) divided by time between those measurement time points and multiplied by 365 days. Height velocity SDS was calculated using the formula: SDS = (height velocity - mean)/SD, where height velocity was the height velocity variable measured, mean and SD of height velocity by sex and age for the reference population. The scores were centered around zero. Positive SDS indicated greater height velocity and negative SDS indicated lesser height velocity than the mean of the reference population. | Baseline to week 52 | 
| Height Velocity SDS | Height velocity is change in height per year. The height velocity was calculated as the difference between current height (week 104) and height at week 52 divided by time between those measurement time points and multiplied by 365 days. Height velocity SDS was calculated using the formula: SDS = (height velocity - mean)/SD, where height velocity was the height velocity variable measured, mean and SD of height velocity by sex and age for the reference population. The scores were centered around zero. Positive SDS indicated greater height velocity and negative SDS indicated lesser height velocity than the mean of the reference population. | Week 52 to week 104 | 
| Height Velocity | Height velocity is change in height per year. The height velocity was calculated as the difference between current height (week 52) and height at baseline (week 0) divided by time between those measurement time points and multiplied by 365 days. | Baseline to week 52 | 
| Height Velocity | Height velocity is change in height per year. The height velocity was calculated as the difference between current height (week 104) and height at week 52 divided by time between those measurement time points and multiplied by 365 days. | Week 52 to week 104 | 
| Incidence of Treatment Emergent Adverse Events | A treatment emergent adverse event (TEAE; for the pivotal phase) was defined as an event that had onset date on or after the date of visit 2 (week 0; start of treatment) and no later than the date of visit 12 (104 weeks; end of pivotal phase). For withdrawal participants (if any), an adverse event with onset date no later than 7 days after the last day of NN-220 treatment was included. | During 104 weeks of treatment | 
| Change in IGF-I (Insulin-like Growth Factor-I) | Change from baseline (within 4 weeks prior to week 0) in IGF-I was evaluated after 104 weeks of treatment. Missing values were imputed using the LOCF method. | Baseline, week 104 | 
| Change in HbA1c (Glycosylated Haemoglobin) | Change from baseline (within 4 weeks prior to week 0) in HbA1c was evaluated after 104 weeks of treatment. | Baseline, week 104 | 
| Change in Clinical Laboratory Tests (Haematology: Erythrocytes) | Change from baseline (within 4 weeks prior to week 0) in haematological parameter - erythrocytes. Missing values were imputed using the LOCF method. | Baseline, week 104 | 
| Change in Clinical Laboratory Tests (Haematology: Leukocytes and Thrombocytes) | Change from baseline (within 4 weeks prior to week 0) in haematological parameter - leukocytes and thrombocytes. Missing values were imputed using the LOCF method. | Baseline, week 104 | 
| Change in Clinical Laboratory Tests (Haematology: Haemoglobin) | Change from baseline (within 4 weeks prior to week 0) in haematological parameter - haemoglobin. Missing values were imputed using the LOCF method. | Baseline, week 104 | 
| Change in Clinical Laboratory Tests (Haematology: Haematocrit) | Change from baseline (within 4 weeks prior to week 0) in haematological parameter - haematocrit. Missing values were imputed using the LOCF method. | Baseline, week 104 | 
| Change in Clinical Laboratory Tests (Haematology: Neutrophils) | Change from baseline (within 4 weeks prior to week 0) in haematological parameter - neutrophils. Missing values were imputed using the LOCF method. | Baseline, week 104 | 
| Change in Clinical Laboratory Tests (Haematology: Lymphocytes) | Change from baseline (within 4 weeks prior to week 0) in haematological parameter - lymphocytes. Missing values were imputed using the LOCF method. | Baseline, week 104 | 
| Change in Clinical Laboratory Tests (Haematology: Monocytes) | Change from baseline (within 4 weeks prior to week 0) in haematological parameter - monocytes. Missing values were imputed using the LOCF method. | Baseline, week 104 | 
| Change in Clinical Laboratory Tests (Haematology: Eosinophils) | Change from baseline (within 4 weeks prior to week 0) in haematological parameter - eosinophils. Missing values were imputed using the LOCF method. | Baseline, week 104 | 
| Change in Clinical Laboratory Tests (Haematology: Basophils) | Change from baseline (within 4 weeks prior to week 0) in haematological parameter - basophils. Missing values were imputed using the LOCF method. | Baseline, week 104 | 
| Change in Clinical Laboratory Tests (Lipids: Total Cholesterol, LDL Cholesterol and HDL Cholesterol) | Change from baseline (within 4 weeks prior to week 0) in lipids: total cholesterol, LDL (low-density lipoprotein) cholesterol and HDL (high-density lipoprotein) cholesterol. Missing values were imputed using the LOCF method. | Baseline, week 104 | 
| Change in Clinical Laboratory Tests (Biochemistry: AST, ALT, r-GTP and Alkaline Phosphatase) | Change from baseline (within 4 weeks prior to week 0) in biochemical parameters - aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (r-GTP) and alkaline phosphatase. Missing values were imputed using the LOCF method. | Baseline, week 104 | 
| Change in Clinical Laboratory Tests (Biochemistry: Total Protein) | Change from baseline (within 4 weeks prior to week 0) in biochemical parameter - total protein. Missing values were imputed using the LOCF method. | Baseline, week 104 | 
| Change in Clinical Laboratory Tests (Biochemistry: Blood Urea Nitrogen, Sodium, Potassium, Chloride, Total Calcium and Phosphorus) | Change from baseline (within 4 weeks prior to week 0) in biochemical parameters - blood urea nitrogen, sodium, potassium, chloride, total calcium and phosphorus. Missing values were imputed using the LOCF method. | Baseline, week 104 | 
| Change in Clinical Laboratory Tests (Biochemistry: Creatinine) | Change from baseline (within 4 weeks prior to week 0) in biochemical parameter - creatinine. Missing values were imputed using the LOCF method. | Baseline, Week 104 | 
| Change in Glucose Tolerance (AUC of Glucose) Based on the OGTT | AUC (area under the curve) of glucose was calculated by the trapezoidal method. Change from baseline (within 4 weeks prior to week 0) in glucose tolerance (AUC of glucose: 30, 60, 90 and 120 min after oral glucose load) at week 104 was evaluated based on the oral glucose tolerance test (OGTT). Change from baseline results are presented as 'ratio to baseline'. | Baseline, week 104 | 
| Change in Glucose Tolerance (AUC of Insulin) Based on the OGTT | AUC of insulin was calculated by the trapezoidal method. Change from baseline (within 4 weeks prior to week 0) in glucose tolerance (AUC of insulin: 30, 60, 90 and 120 min after oral glucose load) at week 104 was evaluated based on the OGTT. Change from baseline results are presented as 'ratio to baseline'. | Baseline, week 104 | 
| Change in Bone Age | X-ray picture of carpal bones of left hand was taken for bone age determination. Centralised evaluation of bone age was done by the radius, ulna and short bones (RUS) score method of Tanner-Whitehouse II (TW2). Change from baseline (week 0) in bone age. | Baseline, week 104 | 
| Change in Bone Age/Chronological Age | X-ray picture of carpal bones of left hand was taken for bone age determination. Centralised evaluation of bone age was done by the RUS score method of Tanner-Whitehouse II (TW2). Change from baseline (week 0) in bone age/chronological age. | Baseline, week 104 | 
| Yearly Change in Bone Age/Change in Chronological Age | X-ray picture of carpal bones of left hand was taken for bone age determination. Centralised evaluation of bone age was done by the RUS score method of Tanner-Whitehouse II (TW2). Yearly change from baseline (week 0) in bone age/change in chronological age was presented. | Baseline, week 52 | 
| Yearly Change in Bone Age/Change in Chronological Age | X-ray picture of carpal bones of left hand was taken for bone age determination. Centralised evaluation of bone age was done by the RUS score method of Tanner-Whitehouse II (TW2). Yearly change from week 52 in bone age/change in chronological age was presented. | Week 52, week 104 | 
| Change in Vital Signs (Diastolic Blood Pressure and Systolic Blood Pressure) | Systolic and diastolic blood pressure were measured after a 5-minute rest in sitting position. Change from baseline (week 0) in systolic blood pressure and diastolic blood pressure. | Baseline, week 104 | 
| Change in Vital Signs (Pulse) | Pulse was measured after a 5-minute rest in sitting position. Change from baseline (week 0) in pulse. | Baseline, week 104 | 
| Change in Urinalysis (Protein, Glucose and Occult Blood) | The urinalysis was the measurements of protein, glucose, and occult blood at baseline (within 4 weeks prior to week 0) and week 104 and categorised as negative, trace, 1+, 2+ and 3+. Missing values were imputed using the LOCF method. Number of participants in each category at baseline and week 104 are presented. | Baseline, week 104 | 
| Change in Blood Coagulation Test (Prothrombin Time and APTT) | Change from baseline (within 4 weeks prior to week 0) in blood coagulation test parameters: Prothrombin time and APTT (activated partial thromboplastin time). Missing values were imputed using the LOCF method. | Baseline, week 104 | 
| Change in ECG | The ECG was recorded after a 3-minute rest in supine position at baseline (within 4 weeks prior to week 0) and week 104 and categorised as normal, abnormal NCS (not clinically significant) or abnormal CS (clinically significant). Number of participants in each ECG category at baseline and week 104 are presented. Missing values were imputed using the LOCF method. | Baseline, week 104 | 
| Change in Height SDS (Japanese National Reference Data) | Height SDS was calculated using the formula: SDS = (height - mean)/SD, where height was the height variable measured, mean and SD of height by sex and age for the reference population. The scores were centered around zero. Positive SDS indicated greater height and negative SDS indicated lesser height than the mean of the reference population. The change from baseline (week 0) in the height SDS after 208 weeks of treatment was analysed. Positive value in change from baseline indicated that SDS was better than baseline SDS. Missing values were imputed using the LOCF method. | Baseline, week 208 | 
| Change in Height SDS (Noonan Syndrome Reference Data in Japanese) | Height SDS was calculated using the formula: Z=[(value/M)^L-1]/(S*L); where L, M and S are skewness (L), median (M) and coefficient of variation (S) of Japanese Noonan syndrome' height provided for each sex and age. For each participant, a standard deviation score Z (SDS) was calculated based on age and sex referring to the values L, M and S. The scores were centered around zero. Positive SDS indicated greater height and negative SDS indicated lesser height than the mean of the reference population. The change from baseline (week 0) in the height SDS after 208 weeks of treatment was analysed. Positive value in change from baseline indicated that SDS was better than baseline SDS. Missing values were imputed using the LOCF method. | Baseline, week 208 | 
| Height Velocity | Height velocity is change in height per year. The height velocity was calculated as the difference between current height (week 156) and height at week 104 divided by time between those measurement time points and multiplied by 365 days. Missing values were imputed using the LOCF method. | Week 104 to week 156 | 
| Height Velocity | Height velocity is change in height per year. The height velocity was calculated as the difference between current height (week 208) and height at week 156 divided by time between those measurement time points and multiplied by 365 days. Missing values were imputed using the LOCF method. | Week 156 to week 208 | 
| Height Velocity SDS | Height velocity is change in height per year. The height velocity was calculated as the difference between current height (week 156) and height at week 104 divided by time between those measurement time points and multiplied by 365 days. Height velocity SDS was calculated using the formula: SDS = (height velocity - mean)/SD, where height velocity was the height velocity variable measured, mean and SD of height velocity by sex and age for the reference population. The scores were centered around zero. Positive SDS indicated greater height velocity and negative SDS indicated lesser height velocity than the mean of the reference population. | Week 104 to week 156 | 
| Height Velocity SDS | Height velocity is change in height per year. The height velocity was calculated as the difference between current height (week 208) and height at week 156 divided by time between those measurement time points and multiplied by 365 days. Height velocity SDS was calculated using the formula: SDS = (height velocity - mean)/SD, where height velocity was the height velocity variable measured, mean and SD of height velocity by sex and age for the reference population. The scores were centered around zero. Positive SDS indicated greater height velocity and negative SDS indicated lesser height velocity than the mean of the reference population. | Week 156 to week 208 | 
| Incidence of Treatment Emergent AEs | A treatment emergent AE (TEAE) was defined as an event that had onset date on or after the date of visit 2 (week 0; start of treatment) and no later than 7 days after the last day of NN-220 treatment. | Week 0 to week 234 (208 weeks treatment period + 26 weeks extended treatment period) + 7 days (follow-up period) | 
| Change in IGF-I | Change from baseline (within 4 weeks prior to week 0) in IGF-I was evaluated after 208 weeks of treatment. Missing values were imputed using the LOCF method. | Baseline, week 208 | 
| Change in HbA1c | Change from baseline (within 4 weeks prior to week 0) in HbA1c was evaluated after 208 weeks of treatment. | Baseline, week 208 | 
| Change in Clinical Laboratory Tests (Haematology: Erythrocytes) | Change from baseline (within 4 weeks prior to week 0) in haematological parameter - erythrocytes. Missing values were imputed using the LOCF method. | Baseline, week 208 | 
| Change in Clinical Laboratory Tests (Haematology: Leukocytes and Thrombocytes) | Change from baseline (within 4 weeks prior to week 0) in haematological parameter - leukocytes and thrombocytes. Missing values were imputed using the LOCF method. | Baseline, Week 208 | 
| Change in Clinical Laboratory Tests (Haematology: Haemoglobin) | Change from baseline (within 4 weeks prior to week 0) in haematological parameter - haemoglobin. Missing values were imputed using the LOCF method. | Baseline, week 208 | 
| Change in Clinical Laboratory Tests (Haematology: Haematocrit) | Change from baseline (within 4 weeks prior to week 0) in haematological parameter - haematocrit. Missing values were imputed using the LOCF method. | Baseline, week 208 | 
| Change in Clinical Laboratory Tests (Haematology: Neutrophils) | Change from baseline (within 4 weeks prior to week 0) in haematological parameter - neutrophils. Missing values were imputed using the LOCF method. | Baseline, week 208 | 
| Change in Clinical Laboratory Tests (Haematology: Lymphocytes) | Change from baseline (within 4 weeks prior to week 0) in haematological parameter - lymphocytes. Missing values were imputed using the LOCF method. | Baseline, week 208 | 
| Change in Clinical Laboratory Tests (Haematology: Monocytes) | Change from baseline (within 4 weeks prior to week 0) in haematological parameter - monocytes. Missing values were imputed using the LOCF method. | Baseline, week 208 | 
| Change in Clinical Laboratory Tests (Haematology: Eosinophils) | Change from baseline (within 4 weeks prior to week 0) in haematological parameter - eosinophils. Missing values were imputed using the LOCF method. | Baseline, week 208 | 
| Change in Clinical Laboratory Tests (Haematology: Basophils) | Change from baseline (within 4 weeks prior to week 0) in haematological parameter - basophils. Missing values were imputed using the LOCF method. | Baseline, week 208 | 
| Change in Clinical Laboratory Tests (Lipids: Total Cholesterol, LDL Cholesterol and HDL Cholesterol) | Change from baseline (within 4 weeks prior to week 0) in lipids: total cholesterol, LDL cholesterol and HDL cholesterol. Missing values were imputed using the LOCF method. | Baseline, week 208 | 
| Change in Clinical Laboratory Tests (Biochemistry: AST, ALT, r-GTP and Alkaline Phosphatase) | Change from baseline (within 4 weeks prior to week 0) in biochemical parameters - AST, ALT, r-GTP and alkaline phosphatase. Missing values were imputed using the LOCF method. | Baseline, week 208 | 
| Change in Clinical Laboratory Tests (Biochemistry: Total Protein) | Change from baseline (within 4 weeks prior to week 0) in biochemical parameter - total protein. Missing values were imputed using the LOCF method. | Baseline, week 208 | 
| Change in Clinical Laboratory Tests (Biochemistry: Blood Urea Nitrogen, Sodium, Potassium, Chloride, Total Calcium and Phosphorus) | Change from baseline (within 4 weeks prior to week 0) in biochemical parameters - blood urea nitrogen, sodium, potassium, chloride, total calcium and phosphorus. Missing values were imputed using the LOCF method. | Baseline, week 208 | 
| Change in Clinical Laboratory Tests (Biochemistry: Creatinine) | Change from baseline (within 4 weeks prior to week 0) in biochemical parameters - creatinine. Missing values were imputed using the LOCF method. | Baseline, week 208 | 
| Change in Glucose Tolerance (AUC of Glucose) Based on the OGTT | AUC of glucose was calculated by the trapezoidal method. Change from baseline (within 4 weeks prior to week 0) in glucose tolerance (AUC of glucose: 30, 60, 90 and 120 min after oral glucose load) at week 208 was evaluated based on the OGTT. Change from baseline results are presented as 'ratio to baseline'. | Baseline, week 208 | 
| Change in Glucose Tolerance (AUC of Insulin) Based on the OGTT | AUC of insulin was calculated by the trapezoidal method. Change from baseline (within 4 weeks prior to week 0) in glucose tolerance (AUC of insulin: 30, 60, 90 and 120 min after oral glucose load) at week 208 was evaluated based on the OGTT. Change from baseline results are presented as 'ratio to baseline'. | Baseline, week 208 | 
| Change in Bone Age | X-ray picture of carpal bones of left hand was taken for bone age determination. Centralised evaluation of bone age was done by the RUS score method of Tanner-Whitehouse II (TW2). Change from baseline (week 0) in bone age. | Baseline, week 208 | 
| Change in Bone Age/Chronological Age | X-ray picture of carpal bones of left hand was taken for bone age determination. Centralised evaluation of bone age was done by the RUS score method of Tanner-Whitehouse II (TW2). Change from baseline (week 0) in bone age/chronological age. | Baseline, week 208 | 
| Yearly Change in Bone Age/Change in Chronological Age | X-ray picture of carpal bones of left hand was taken for bone age determination. Centralised evaluation of bone age was done by the RUS score method of Tanner-Whitehouse II (TW2). Yearly change from week 104 in bone age/change in chronological age was presented. | Week 104, week 156 | 
| Yearly Change in Bone Age/Change in Chronological Age | X-ray picture of carpal bones of left hand was taken for bone age determination. Centralised evaluation of bone age was done by the RUS score method of Tanner-Whitehouse II (TW2). Yearly change from week 156 in bone age/change in chronological age was presented. | Week 156, week 208 | 
| Change in Vital Signs (Diastolic Blood Pressure and Systolic Blood Pressure) | Systolic and diastolic blood pressure were measured after a 5-minute rest in sitting position. Change from baseline (week 0) in systolic blood pressure and diastolic blood pressure. Missing values were imputed using the LOCF method. | Baseline, week 208 | 
| Change in Vital Signs (Pulse) | Pulse was measured after a 5-minute rest in sitting position. Change from baseline (week 0) in pulse. Missing values were imputed using the LOCF method. | Baseline, week 208 | 
| Change in Urinalysis (Protein, Glucose and Occult Blood) | The urinalysis was the measurements of protein, glucose, and occult blood at baseline (within 4 weeks prior to week 0) and week 208 and categorised as negative, trace, 1+, 2+ and 3+. Number of participants in each category at baseline and week 208 are presented. Missing values were imputed using the LOCF method. | Baseline, week 208 | 
| Change in Blood Coagulation Test (Prothrombin Time and APTT) | Change from baseline (within 4 weeks prior to week 0) in blood coagulation test parameters: prothrombin time and APTT. Missing values were imputed using the LOCF method. | Baseline, week 208 | 
| Change in ECG | The ECG was recorded after a 3-minute rest in supine position at baseline (within 4 weeks prior to week 0) and week 208 and categorised as normal, abnormal NCS or abnormal CS. Number of participants in each ECG category at baseline and week 208 are presented. Missing values were imputed using the LOCF method. | Baseline, week 208 |