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

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.

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.

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.

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 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.

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.

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.

Change from baseline (within 4 weeks prior to week 0) in HbA1c was evaluated after 104 weeks of treatment.

Change from baseline (within 4 weeks prior to week 0) in haematological parameter - erythrocytes. Missing values were imputed using the LOCF method.

Change from baseline (within 4 weeks prior to week 0) in haematological parameter - leukocytes and thrombocytes. Missing values were imputed using the LOCF method.

Change from baseline (within 4 weeks prior to week 0) in haematological parameter - haemoglobin. Missing values were imputed using the LOCF method.

Change from baseline (within 4 weeks prior to week 0) in haematological parameter - haematocrit. Missing values were imputed using the LOCF method.

Change from baseline (within 4 weeks prior to week 0) in haematological parameter - neutrophils. Missing values were imputed using the LOCF method.

Change from baseline (within 4 weeks prior to week 0) in haematological parameter - lymphocytes. Missing values were imputed using the LOCF method.

Change from baseline (within 4 weeks prior to week 0) in haematological parameter - monocytes. Missing values were imputed using the LOCF method.

Change from baseline (within 4 weeks prior to week 0) in haematological parameter - eosinophils. Missing values were imputed using the LOCF method.

Change from baseline (within 4 weeks prior to week 0) in haematological parameter - basophils. Missing values were imputed using the LOCF method.

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.

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.

Change from baseline (within 4 weeks prior to week 0) in biochemical parameter - total protein. Missing values were imputed using the LOCF method.

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.

Change from baseline (within 4 weeks prior to week 0) in biochemical parameter - creatinine. Missing values were imputed using the LOCF method.

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'.

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'.

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.

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.

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.

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.

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.

Pulse was measured after a 5-minute rest in sitting position. Change from baseline (week 0) in pulse.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Change from baseline (within 4 weeks prior to week 0) in HbA1c was evaluated after 208 weeks of treatment.

Change from baseline (within 4 weeks prior to week 0) in haematological parameter - erythrocytes. Missing values were imputed using the LOCF method.

Change from baseline (within 4 weeks prior to week 0) in haematological parameter - leukocytes and thrombocytes. Missing values were imputed using the LOCF method.

Change from baseline (within 4 weeks prior to week 0) in haematological parameter - haemoglobin. Missing values were imputed using the LOCF method.

Change from baseline (within 4 weeks prior to week 0) in haematological parameter - haematocrit. Missing values were imputed using the LOCF method.

Change from baseline (within 4 weeks prior to week 0) in haematological parameter - neutrophils. Missing values were imputed using the LOCF method.

Change from baseline (within 4 weeks prior to week 0) in haematological parameter - lymphocytes. Missing values were imputed using the LOCF method.

Change from baseline (within 4 weeks prior to week 0) in haematological parameter - monocytes. Missing values were imputed using the LOCF method.

Change from baseline (within 4 weeks prior to week 0) in haematological parameter - eosinophils. Missing values were imputed using the LOCF method.

Change from baseline (within 4 weeks prior to week 0) in haematological parameter - basophils. Missing values were imputed using the LOCF method.

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.

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.

Change from baseline (within 4 weeks prior to week 0) in biochemical parameter - total protein. Missing values were imputed using the LOCF method.

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.

Change from baseline (within 4 weeks prior to week 0) in biochemical parameters - creatinine. Missing values were imputed using the LOCF method.

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'.

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'.

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.

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.

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.

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.

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.

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.

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.

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.

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.