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

• Sponsor: Novo Nordisk A/S (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01927861
• Collaborator: (none)
• Enrollment: 51
• Locations: 27
• Arms: 2
• Actual Duration (Months): 58.7
• Patients Per Site: 1.9
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Genetic Disorder; Noonan Syndrome	Drug: somatropin	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 51 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: Aug 19, 2013
• Actual Primary Completion Date: Jul 12, 2018
• Actual Study Completion Date: Jul 12, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 0.033 mg/kg/day	Drug: somatropin; 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.
Experimental: 0.066 mg/kg/day	Drug: somatropin; 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.

Outcome Measures

Primary Outcome Measures

1. Change in Height SDS (Japanese National Reference Data) [Baseline, week 104]

   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.

Secondary Outcome Measures

1. Height Velocity SDS [Baseline to week 52]

   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.

2. Height Velocity SDS [Week 52 to week 104]

   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.

3. Height Velocity [Baseline to week 52]

   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.

4. Height Velocity [Week 52 to week 104]

   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.

5. Incidence of Treatment Emergent Adverse Events [During 104 weeks of treatment]

   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.

6. Change in IGF-I (Insulin-like Growth Factor-I) [Baseline, week 104]

   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.

7. Change in HbA1c (Glycosylated Haemoglobin) [Baseline, week 104]

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

8. Change in Clinical Laboratory Tests (Haematology: Erythrocytes) [Baseline, week 104]

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

9. Change in Clinical Laboratory Tests (Haematology: Leukocytes and Thrombocytes) [Baseline, week 104]

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

10. Change in Clinical Laboratory Tests (Haematology: Haemoglobin) [Baseline, week 104]

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

11. Change in Clinical Laboratory Tests (Haematology: Haematocrit) [Baseline, week 104]

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

12. Change in Clinical Laboratory Tests (Haematology: Neutrophils) [Baseline, week 104]

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

13. Change in Clinical Laboratory Tests (Haematology: Lymphocytes) [Baseline, week 104]

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

14. Change in Clinical Laboratory Tests (Haematology: Monocytes) [Baseline, week 104]

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

15. Change in Clinical Laboratory Tests (Haematology: Eosinophils) [Baseline, week 104]

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

16. Change in Clinical Laboratory Tests (Haematology: Basophils) [Baseline, week 104]

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

17. Change in Clinical Laboratory Tests (Lipids: Total Cholesterol, LDL Cholesterol and HDL Cholesterol) [Baseline, week 104]

    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.

18. Change in Clinical Laboratory Tests (Biochemistry: AST, ALT, r-GTP and Alkaline Phosphatase) [Baseline, week 104]

    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.

19. Change in Clinical Laboratory Tests (Biochemistry: Total Protein) [Baseline, week 104]

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

20. Change in Clinical Laboratory Tests (Biochemistry: Blood Urea Nitrogen, Sodium, Potassium, Chloride, Total Calcium and Phosphorus) [Baseline, week 104]

    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.

21. Change in Clinical Laboratory Tests (Biochemistry: Creatinine) [Baseline, Week 104]

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

22. Change in Glucose Tolerance (AUC of Glucose) Based on the OGTT [Baseline, week 104]

    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'.

23. Change in Glucose Tolerance (AUC of Insulin) Based on the OGTT [Baseline, week 104]

    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'.

24. Change in Bone Age [Baseline, week 104]

    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.

25. Change in Bone Age/Chronological Age [Baseline, week 104]

    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.

26. Yearly Change in Bone Age/Change in Chronological Age [Baseline, week 52]

    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.

27. Yearly Change in Bone Age/Change in Chronological Age [Week 52, week 104]

    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.

28. Change in Vital Signs (Diastolic Blood Pressure and Systolic Blood Pressure) [Baseline, week 104]

    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.

29. Change in Vital Signs (Pulse) [Baseline, week 104]

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

30. Change in Urinalysis (Protein, Glucose and Occult Blood) [Baseline, week 104]

    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.

31. Change in Blood Coagulation Test (Prothrombin Time and APTT) [Baseline, week 104]

    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.

32. Change in ECG [Baseline, week 104]

    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.

33. Change in Height SDS (Japanese National Reference Data) [Baseline, week 208]

    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.

34. Change in Height SDS (Noonan Syndrome Reference Data in Japanese) [Baseline, week 208]

    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.

35. Height Velocity [Week 104 to week 156]

    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.

36. Height Velocity [Week 156 to week 208]

    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.

37. Height Velocity SDS [Week 104 to week 156]

    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.

38. Height Velocity SDS [Week 156 to week 208]

    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.

39. Incidence of Treatment Emergent AEs [Week 0 to week 234 (208 weeks treatment period + 26 weeks extended treatment period) + 7 days (follow-up period)]

    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.

40. Change in IGF-I [Baseline, week 208]

    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.

41. Change in HbA1c [Baseline, week 208]

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

42. Change in Clinical Laboratory Tests (Haematology: Erythrocytes) [Baseline, week 208]

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

43. Change in Clinical Laboratory Tests (Haematology: Leukocytes and Thrombocytes) [Baseline, Week 208]

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

44. Change in Clinical Laboratory Tests (Haematology: Haemoglobin) [Baseline, week 208]

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

45. Change in Clinical Laboratory Tests (Haematology: Haematocrit) [Baseline, week 208]

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

46. Change in Clinical Laboratory Tests (Haematology: Neutrophils) [Baseline, week 208]

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

47. Change in Clinical Laboratory Tests (Haematology: Lymphocytes) [Baseline, week 208]

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

48. Change in Clinical Laboratory Tests (Haematology: Monocytes) [Baseline, week 208]

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

49. Change in Clinical Laboratory Tests (Haematology: Eosinophils) [Baseline, week 208]

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

50. Change in Clinical Laboratory Tests (Haematology: Basophils) [Baseline, week 208]

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

51. Change in Clinical Laboratory Tests (Lipids: Total Cholesterol, LDL Cholesterol and HDL Cholesterol) [Baseline, week 208]

    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.

52. Change in Clinical Laboratory Tests (Biochemistry: AST, ALT, r-GTP and Alkaline Phosphatase) [Baseline, week 208]

    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.

53. Change in Clinical Laboratory Tests (Biochemistry: Total Protein) [Baseline, week 208]

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

54. Change in Clinical Laboratory Tests (Biochemistry: Blood Urea Nitrogen, Sodium, Potassium, Chloride, Total Calcium and Phosphorus) [Baseline, week 208]

    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.

55. Change in Clinical Laboratory Tests (Biochemistry: Creatinine) [Baseline, week 208]

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

56. Change in Glucose Tolerance (AUC of Glucose) Based on the OGTT [Baseline, week 208]

    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'.

57. Change in Glucose Tolerance (AUC of Insulin) Based on the OGTT [Baseline, week 208]

    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'.

58. Change in Bone Age [Baseline, week 208]

    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.

59. Change in Bone Age/Chronological Age [Baseline, week 208]

    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.

60. Yearly Change in Bone Age/Change in Chronological Age [Week 104, week 156]

    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.

61. Yearly Change in Bone Age/Change in Chronological Age [Week 156, week 208]

    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.

62. Change in Vital Signs (Diastolic Blood Pressure and Systolic Blood Pressure) [Baseline, week 208]

    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.

63. Change in Vital Signs (Pulse) [Baseline, week 208]

    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.

64. Change in Urinalysis (Protein, Glucose and Occult Blood) [Baseline, week 208]

    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.

65. Change in Blood Coagulation Test (Prothrombin Time and APTT) [Baseline, week 208]

    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.

66. Change in ECG [Baseline, week 208]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 3 Years to 10 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novo Nordisk Investigational Site	Asahikawa, Hokkaido		Japan	078-8510
2	Novo Nordisk Investigational Site	Fukuoka		Japan	812-8582
3	Novo Nordisk Investigational Site	Fukuoka		Japan	830-0011
4	Novo Nordisk Investigational Site	Iruma-gun, Saitama		Japan	350 0495
5	Novo Nordisk Investigational Site	Kanagawa		Japan	216-8511
6	Novo Nordisk Investigational Site	Kanagawa		Japan	232-8555
7	Novo Nordisk Investigational Site	Kyoto		Japan	602-8566
8	Novo Nordisk Investigational Site	Maebashi-shi, Gunma		Japan	371-8511
9	Novo Nordisk Investigational Site	Miyazaki		Japan	889-1692
10	Novo Nordisk Investigational Site	Nagoya, Aichi		Japan	467-8602
11	Novo Nordisk Investigational Site	Niigata-shi, Niigata		Japan	951 8520
12	Novo Nordisk Investigational Site	Oita		Japan	879-5593
13	Novo Nordisk Investigational Site	Osaka		Japan	534-0021
14	Novo Nordisk Investigational Site	Osaka		Japan	594-1101
15	Novo Nordisk Investigational Site	Saitama-city, Saitama		Japan	336-8522
16	Novo Nordisk Investigational Site	Saitama-shi, Saitama		Japan	330-8777
17	Novo Nordisk Investigational Site	Sapporo, Hokkaido		Japan	065-8611
18	Novo Nordisk Investigational Site	Sendai-shi, Miyagi		Japan	980 8574
19	Novo Nordisk Investigational Site	Shizuoka		Japan	431-3192
20	Novo Nordisk Investigational Site	Tochigi		Japan	329-0498
21	Novo Nordisk Investigational Site	Tokyo		Japan	113-8519
22	Novo Nordisk Investigational Site	Tokyo		Japan	113-8655
23	Novo Nordisk Investigational Site	Tokyo		Japan	157 8535
24	Novo Nordisk Investigational Site	Tokyo		Japan	160-8582
25	Novo Nordisk Investigational Site	Tokyo		Japan	162-8666
26	Novo Nordisk Investigational Site	Tokyo		Japan	183-8561
27	Novo Nordisk Investigational Site	Zentsuji, Kagawa		Japan	765-8507

Sponsors and Collaborators

• Novo Nordisk A/S

Investigators

• Study Director: Global Clinical Registry (GCR, 1452), Novo Nordisk A/S

Study Documents (Full-Text)

• Study Protocol - Nov 26, 2018
• Statistical Analysis Plan - Oct 28, 2016

More Information

Additional Information:

• Clinical Trials at Novo Nordisk

Publications

None provided.

• Responsible Party: Novo Nordisk A/S
• ClinicalTrials.gov Identifier: NCT01927861
• Other Study ID Numbers: GHLIQUID-4020; U1111-1131-5892; JapicCTI-132336
• First Posted: Aug 23, 2013
• Last Update Posted: Aug 10, 2020
• Last Verified: Jul 1, 2020

• Additional relevant MeSH terms: Dwarfism; Noonan Syndrome; Genetic Diseases, Inborn; Syndrome

Study Results

Participant Flow

Recruitment Details	The trial was conducted at 26 sites in Japan.
Pre-assignment Detail	Participants were assigned to treatment for 104 weeks in the pivotal phase and for further 104 weeks in the extension phase and were offered to continue treatment in the extended treatment phase for 26 weeks.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received subcutaneous (s.c.) injection of NN-220, 0.033 milligrams per kilogram per day (mg/kg/day) once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Period Title: Pivotal Phase (104 Weeks)
STARTED	25	26
COMPLETED	25	26
NOT COMPLETED	0	0
Period Title: Pivotal Phase (104 Weeks)
STARTED	25	26
COMPLETED	25	23
NOT COMPLETED	0	3
Period Title: Pivotal Phase (104 Weeks)
STARTED	15	14
COMPLETED	15	14
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day	Total
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Total of all reporting groups
Overall Participants	25	26	51
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	6.57 (2.42)	6.06 (2.25)	6.31 (2.32)
Sex: Female, Male (Count of Participants)
Female	11 44%	8 30.8%	19 37.3%
Male	14 56%	18 69.2%	32 62.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	25 100%	26 100%	51 100%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	0 0%	0 0%	0 0%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Height standard deviation score (SDS) (Japanese national reference data) (Standard deviation score) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Standard deviation score]	-3.24 (0.76)	-3.25 (0.71)	-3.24 (0.73)

Outcome Measures

1. Primary Outcome

Title	Change in Height SDS (Japanese National Reference Data)
Description	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.
Time Frame	Baseline, week 104

Outcome Measure Data

Analysis Population Description

FAS.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Least Squares Mean (Standard Error) [Standard deviation score]	0.84 (0.09)	1.47 (0.09)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NN-220 0.033 mg/kg/Day, NN-220 0.066 mg/kg/Day
	Comments	The change from baseline (week 0) in the height SDS after 104 weeks of treatment was analysed using an ANCOVA model with treatment as a fixed effect and baseline height SDS as a covariate.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	0.63
	Confidence Interval	(2-Sided) 95%; 0.38 to 0.88
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Height Velocity SDS
Description	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.
Time Frame	Baseline to week 52

Outcome Measure Data

Analysis Population Description

FAS.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Mean (Standard Deviation) [Standard deviation score]	2.80 (1.13)	5.01 (1.92)

3. Secondary Outcome

Title	Height Velocity SDS
Description	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.
Time Frame	Week 52 to week 104

Outcome Measure Data

Analysis Population Description

FAS.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Mean (Standard Deviation) [Standard deviation score]	0.58 (1.59)	2.65 (1.76)

4. Secondary Outcome

Title	Height Velocity
Description	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.
Time Frame	Baseline to week 52

Outcome Measure Data

Analysis Population Description

FAS.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Mean (Standard Deviation) [Centimeters per year (cm/year)]	7.88 (0.87)	9.90 (1.49)

5. Secondary Outcome

Title	Height Velocity
Description	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.
Time Frame	Week 52 to week 104

Outcome Measure Data

Analysis Population Description

FAS.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Mean (Standard Deviation) [cm/year]	6.20 (0.95)	7.99 (1.20)

6. Secondary Outcome

Title	Incidence of Treatment Emergent Adverse Events
Description	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.
Time Frame	During 104 weeks of treatment

Outcome Measure Data

Analysis Population Description

Safety analysis set (SAS) which included all participants who received at least one dose of trial product (NN-220, 0.033 mg/kg/day or NN-220, 0.066 mg/kg/day).

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Number [Events]	265	306

7. Secondary Outcome

Title	Change in IGF-I (Insulin-like Growth Factor-I)
Description	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.
Time Frame	Baseline, week 104

Outcome Measure Data

Analysis Population Description

SAS.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Mean (Standard Deviation) [Nanograms per milliliter (ng/mL)]	90.4 (65.5)	159.1 (88.0)

8. Secondary Outcome

Title	Change in HbA1c (Glycosylated Haemoglobin)
Description	Change from baseline (within 4 weeks prior to week 0) in HbA1c was evaluated after 104 weeks of treatment.
Time Frame	Baseline, week 104

Outcome Measure Data

Analysis Population Description

SAS.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Mean (Standard Deviation) [Percentage of HbA1c]	0.14 (0.18)	0.13 (0.20)

9. Secondary Outcome

Title	Change in Clinical Laboratory Tests (Haematology: Erythrocytes)
Description	Change from baseline (within 4 weeks prior to week 0) in haematological parameter - erythrocytes. Missing values were imputed using the LOCF method.
Time Frame	Baseline, week 104

Outcome Measure Data

Analysis Population Description

SAS.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Mean (Standard Deviation) [10^12 cells per liter (10^12 cells/L)]	0.106 (0.300)	0.165 (0.234)

10. Secondary Outcome

Title	Change in Clinical Laboratory Tests (Haematology: Leukocytes and Thrombocytes)
Description	Change from baseline (within 4 weeks prior to week 0) in haematological parameter - leukocytes and thrombocytes. Missing values were imputed using the LOCF method.
Time Frame	Baseline, week 104

Outcome Measure Data

Analysis Population Description

SAS. Number analyzed = participants with available data.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Leukocytes	-0.69 (2.28)	-1.01 (1.77)
Thrombocytes	-6.9 (60.2)	-29.0 (63.2)

11. Secondary Outcome

Title	Change in Clinical Laboratory Tests (Haematology: Haemoglobin)
Description	Change from baseline (within 4 weeks prior to week 0) in haematological parameter - haemoglobin. Missing values were imputed using the LOCF method.
Time Frame	Baseline, week 104

Outcome Measure Data

Analysis Population Description

SAS.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Mean (Standard Deviation) [Millimoles per liter (mmol/L)]	0.26 (0.46)	0.32 (0.55)

12. Secondary Outcome

Title	Change in Clinical Laboratory Tests (Haematology: Haematocrit)
Description	Change from baseline (within 4 weeks prior to week 0) in haematological parameter - haematocrit. Missing values were imputed using the LOCF method.
Time Frame	Baseline, week 104

Outcome Measure Data

Analysis Population Description

SAS.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Mean (Standard Deviation) [Percentage of red blood cells]	0.85 (2.11)	0.94 (1.93)

13. Secondary Outcome

Title	Change in Clinical Laboratory Tests (Haematology: Neutrophils)
Description	Change from baseline (within 4 weeks prior to week 0) in haematological parameter - neutrophils. Missing values were imputed using the LOCF method.
Time Frame	Baseline, week 104

Outcome Measure Data

Analysis Population Description

SAS.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Mean (Standard Deviation) [Percentage of neutrophils]	-4.28 (11.44)	4.50 (9.01)

14. Secondary Outcome

Title	Change in Clinical Laboratory Tests (Haematology: Lymphocytes)
Description	Change from baseline (within 4 weeks prior to week 0) in haematological parameter - lymphocytes. Missing values were imputed using the LOCF method.
Time Frame	Baseline, week 104

Outcome Measure Data

Analysis Population Description

SAS.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Mean (Standard Deviation) [Percentage of lymphocytes]	2.80 (9.07)	-4.73 (8.73)

15. Secondary Outcome

Title	Change in Clinical Laboratory Tests (Haematology: Monocytes)
Description	Change from baseline (within 4 weeks prior to week 0) in haematological parameter - monocytes. Missing values were imputed using the LOCF method.
Time Frame	Baseline, week 104

Outcome Measure Data

Analysis Population Description

SAS.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Mean (Standard Deviation) [Percentage of monocytes]	0.38 (1.41)	0.39 (1.35)

16. Secondary Outcome

Title	Change in Clinical Laboratory Tests (Haematology: Eosinophils)
Description	Change from baseline (within 4 weeks prior to week 0) in haematological parameter - eosinophils. Missing values were imputed using the LOCF method.
Time Frame	Baseline, week 104

Outcome Measure Data

Analysis Population Description

SAS.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Mean (Standard Deviation) [Percentage of eosinophils]	0.99 (2.95)	-0.05 (1.33)

17. Secondary Outcome

Title	Change in Clinical Laboratory Tests (Haematology: Basophils)
Description	Change from baseline (within 4 weeks prior to week 0) in haematological parameter - basophils. Missing values were imputed using the LOCF method.
Time Frame	Baseline, week 104

Outcome Measure Data

Analysis Population Description

SAS.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Mean (Standard Deviation) [Percentage of basophils]	0.10 (0.36)	-0.07 (0.27)

18. Secondary Outcome

Title	Change in Clinical Laboratory Tests (Lipids: Total Cholesterol, LDL Cholesterol and HDL Cholesterol)
Description	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.
Time Frame	Baseline, week 104

Outcome Measure Data

Analysis Population Description

SAS.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Total cholesterol	0.073 (0.655)	-0.110 (0.371)
LDL cholesterol	0.040 (0.521)	-0.120 (0.323)
HDL cholesterol	-0.020 (0.212)	-0.034 (0.210)

19. Secondary Outcome

Title	Change in Clinical Laboratory Tests (Biochemistry: AST, ALT, r-GTP and Alkaline Phosphatase)
Description	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.
Time Frame	Baseline, week 104

Outcome Measure Data

Analysis Population Description

SAS. Number analyzed = participants with available data.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
AST	-3.6 (2.9)	-6.0 (4.3)
ALT	-1.04 (3.10)	-1.73 (4.20)
r-GTP	0.4 (1.6)	-3.7 (19.4)
Alkaline phosphatase	73.8 (76.3)	124.3 (124.0)

20. Secondary Outcome

Title	Change in Clinical Laboratory Tests (Biochemistry: Total Protein)
Description	Change from baseline (within 4 weeks prior to week 0) in biochemical parameter - total protein. Missing values were imputed using the LOCF method.
Time Frame	Baseline, week 104

Outcome Measure Data

Analysis Population Description

SAS. Number analyzed = participants with available data.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Mean (Standard Deviation) [Grams per deciliter (g/dL)]	0.02 (0.38)	-0.05 (0.27)

21. Secondary Outcome

Title	Change in Clinical Laboratory Tests (Biochemistry: Blood Urea Nitrogen, Sodium, Potassium, Chloride, Total Calcium and Phosphorus)
Description	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.
Time Frame	Baseline, week 104

Outcome Measure Data

Analysis Population Description

SAS. Number analyzed = participants with available data.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Blood urea nitrogen	-0.17 (0.38)	-0.21 (0.44)
Sodium	-0.3 (2.4)	-0.2 (2.6)
Potassium	-0.03 (0.32)	-0.15 (0.41)
Chloride	-0.8 (2.3)	-1.3 (1.9)
Total calcium	0.00 (0.08)	0.01 (0.07)
Phosphorus	0.124 (0.125)	0.129 (0.141)

22. Secondary Outcome

Title	Change in Clinical Laboratory Tests (Biochemistry: Creatinine)
Description	Change from baseline (within 4 weeks prior to week 0) in biochemical parameter - creatinine. Missing values were imputed using the LOCF method.
Time Frame	Baseline, Week 104

Outcome Measure Data

Analysis Population Description

SAS.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Mean (Standard Deviation) [Micromoles per liter (umol/L)]	1.8 (3.5)	2.5 (3.4)

23. Secondary Outcome

Title	Change in Glucose Tolerance (AUC of Glucose) Based on the OGTT
Description	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'.
Time Frame	Baseline, week 104

Outcome Measure Data

Analysis Population Description

SAS.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Geometric Mean (Geometric Coefficient of Variation) [Ratio of AUC]	0.98 (12.19)	1.04 (17.75)

24. Secondary Outcome

Title	Change in Glucose Tolerance (AUC of Insulin) Based on the OGTT
Description	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'.
Time Frame	Baseline, week 104

Outcome Measure Data

Analysis Population Description

SAS. Number analyzed = participants with available data.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Geometric Mean (Geometric Coefficient of Variation) [Ratio of AUC]	1.25 (45.08)	1.72 (85.78)

25. Secondary Outcome

Title	Change in Bone Age
Description	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.
Time Frame	Baseline, week 104

Outcome Measure Data

Analysis Population Description

SAS.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Mean (Standard Deviation) [Years]	2.07 (0.80)	2.63 (0.94)

26. Secondary Outcome

Title	Change in Bone Age/Chronological Age
Description	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.
Time Frame	Baseline, week 104

Outcome Measure Data

Analysis Population Description

SAS.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Mean (Standard Deviation) [Ratio (bone age/chronological age)]	0.047 (0.127)	0.133 (0.127)

27. Secondary Outcome

Title	Yearly Change in Bone Age/Change in Chronological Age
Description	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.
Time Frame	Baseline, week 52

Outcome Measure Data

Analysis Population Description

SAS.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Mean (Standard Deviation) [Ratio (bone age/chronological age)]	0.93 (0.66)	1.28 (0.70)

28. Secondary Outcome

Title	Yearly Change in Bone Age/Change in Chronological Age
Description	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.
Time Frame	Week 52, week 104

Outcome Measure Data

Analysis Population Description

SAS.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Mean (Standard Deviation) [Ratio (bone age/chronological age)]	1.15 (0.57)	1.38 (0.91)

29. Secondary Outcome

Title	Change in Vital Signs (Diastolic Blood Pressure and Systolic Blood Pressure)
Description	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.
Time Frame	Baseline, week 104

Outcome Measure Data

Analysis Population Description

SAS. Number analyzed = participants with available data.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Diastolic blood pressure	2.3 (13.2)	6.3 (15.8)
Systolic blood pressure	5.5 (11.9)	4.1 (12.1)

30. Secondary Outcome

Title	Change in Vital Signs (Pulse)
Description	Pulse was measured after a 5-minute rest in sitting position. Change from baseline (week 0) in pulse.
Time Frame	Baseline, week 104

Outcome Measure Data

Analysis Population Description

SAS. Number analyzed = participants with available data.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Mean (Standard Deviation) [Beats per minute (beats/min)]	-9.5 (15.7)	1.8 (21.9)

31. Secondary Outcome

Title	Change in Urinalysis (Protein, Glucose and Occult Blood)
Description	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.
Time Frame	Baseline, week 104

Outcome Measure Data

Analysis Population Description

SAS.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Protein: Negative (Baseline)	23 92%	22 84.6%
Protein: Trace (Baseline)	2 8%	4 15.4%
Protein: 1+ (Baseline)	0 0%	0 0%
Protein: 2+ (Baseline)	0 0%	0 0%
Protein: 3+ (Baseline)	0 0%	0 0%
Protein: Negative (Week 104)	18 72%	16 61.5%
Protein: Trace (Week 104)	7 28%	8 30.8%
Protein: 1+ (Week 104)	0 0%	2 7.7%
Protein: 2+ (Week 104)	0 0%	0 0%
Protein: 3+ (Week 104)	0 0%	0 0%
Glucose: Negative (Baseline)	25 100%	26 100%
Glucose: Trace (Baseline)	0 0%	0 0%
Glucose: 1+ (Baseline)	0 0%	0 0%
Glucose: 2+ (Baseline)	0 0%	0 0%
Glucose: 3+ (Baseline)	0 0%	0 0%
Glucose: Negative (Week 104)	25 100%	26 100%
Glucose: Trace (Week 104)	0 0%	0 0%
Glucose: 1+ (Week 104)	0 0%	0 0%
Glucose: 2+ (Week 104)	0 0%	0 0%
Glucose: 3+ (Week 104)	0 0%	0 0%
Occult blood: Negative (Baseline)	24 96%	25 96.2%
Occult blood: Trace (Baseline)	1 4%	1 3.8%
Occult blood: 1+ (Baseline)	0 0%	0 0%
Occult blood: 2+ (Baseline)	0 0%	0 0%
Occult blood: 3+ (Baseline)	0 0%	0 0%
Occult blood: Negative (Week 104)	25 100%	20 76.9%
Occult blood: Trace (Week 104)	0 0%	5 19.2%
Occult blood: 1+ (Week 104)	0 0%	0 0%
Occult blood: 2+ (Week 104)	0 0%	1 3.8%
Occult blood: 3+ (Week 104)	0 0%	0 0%

32. Secondary Outcome

Title	Change in Blood Coagulation Test (Prothrombin Time and APTT)
Description	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.
Time Frame	Baseline, week 104

Outcome Measure Data

Analysis Population Description

SAS.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Prothrombin time	0.50	0.80
APTT	0.60	0.25

33. Secondary Outcome

Title	Change in ECG
Description	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.
Time Frame	Baseline, week 104

Outcome Measure Data

Analysis Population Description

SAS.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Normal (Baseline)	15 60%	14 53.8%
Abnormal NCS (Baseline)	10 40%	12 46.2%
Abnormal CS (Baseline)	0 0%	0 0%
Normal (Week 104)	16 64%	13 50%
Abnormal NCS (Week 104)	9 36%	13 50%
Abnormal CS (Week 104)	0 0%	0 0%

34. Secondary Outcome

Title	Change in Height SDS (Japanese National Reference Data)
Description	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.
Time Frame	Baseline, week 208

Outcome Measure Data

Analysis Population Description

FAS.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Mean (Standard Deviation) [Standard deviation score]	0.85 (0.60)	1.84 (0.70)

35. Secondary Outcome

Title	Change in Height SDS (Noonan Syndrome Reference Data in Japanese)
Description	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.
Time Frame	Baseline, week 208

Outcome Measure Data

Analysis Population Description

FAS.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Mean (Standard Deviation) [Standard deviation score]	0.96 (0.47)	1.92 (0.60)

36. Secondary Outcome

Title	Height Velocity
Description	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.
Time Frame	Week 104 to week 156

Outcome Measure Data

Analysis Population Description

FAS.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Mean (Standard Deviation) [cm/year]	5.77 (1.26)	7.01 (1.12)

37. Secondary Outcome

Title	Height Velocity
Description	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.
Time Frame	Week 156 to week 208

Outcome Measure Data

Analysis Population Description

FAS.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Mean (Standard Deviation) [cm/year]	5.64 (1.23)	6.11 (1.28)

38. Secondary Outcome

Title	Height Velocity SDS
Description	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.
Time Frame	Week 104 to week 156

Outcome Measure Data

Analysis Population Description

FAS.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Mean (Standard Deviation) [Standard deviation score]	-0.39 (1.61)	1.44 (1.25)

39. Secondary Outcome

Title	Height Velocity SDS
Description	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.
Time Frame	Week 156 to week 208

Outcome Measure Data

Analysis Population Description

FAS.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Mean (Standard Deviation) [Standard deviation score]	-0.73 (1.52)	0.92 (1.69)

40. Secondary Outcome

Title	Incidence of Treatment Emergent AEs
Description	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.
Time Frame	Week 0 to week 234 (208 weeks treatment period + 26 weeks extended treatment period) + 7 days (follow-up period)

Outcome Measure Data

Analysis Population Description

SAS.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Number [Events]	507	539

41. Secondary Outcome

Title	Change in IGF-I
Description	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.
Time Frame	Baseline, week 208

Outcome Measure Data

Analysis Population Description

SAS.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Mean (Standard Deviation) [ng/mL]	133.5 (97.6)	217.2 (91.1)

42. Secondary Outcome

Title	Change in HbA1c
Description	Change from baseline (within 4 weeks prior to week 0) in HbA1c was evaluated after 208 weeks of treatment.
Time Frame	Baseline, week 208

Outcome Measure Data

Analysis Population Description

SAS. Number analyzed = participants with available data.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Mean (Standard Deviation) [Percentage of HbA1c]	0.19 (0.13)	0.20 (0.21)

43. Secondary Outcome

Title	Change in Clinical Laboratory Tests (Haematology: Erythrocytes)
Description	Change from baseline (within 4 weeks prior to week 0) in haematological parameter - erythrocytes. Missing values were imputed using the LOCF method.
Time Frame	Baseline, week 208

Outcome Measure Data

Analysis Population Description

SAS.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Mean (Standard Deviation) [10^12 cells/L]	0.121 (0.328)	0.095 (0.204)

44. Secondary Outcome

Title	Change in Clinical Laboratory Tests (Haematology: Leukocytes and Thrombocytes)
Description	Change from baseline (within 4 weeks prior to week 0) in haematological parameter - leukocytes and thrombocytes. Missing values were imputed using the LOCF method.
Time Frame	Baseline, Week 208

Outcome Measure Data

Analysis Population Description

SAS. Number analyzed = participants with available data.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Leukocytes	-1.50 (2.22)	-1.50 (1.57)
Thrombocytes	-27.5 (55.5)	-56.6 (58.5)

45. Secondary Outcome

Title	Change in Clinical Laboratory Tests (Haematology: Haemoglobin)
Description	Change from baseline (within 4 weeks prior to week 0) in haematological parameter - haemoglobin. Missing values were imputed using the LOCF method.
Time Frame	Baseline, week 208

Outcome Measure Data

Analysis Population Description

SAS.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Mean (Standard Deviation) [mmol/L]	0.46 (0.58)	0.46 (0.35)

46. Secondary Outcome

Title	Change in Clinical Laboratory Tests (Haematology: Haematocrit)
Description	Change from baseline (within 4 weeks prior to week 0) in haematological parameter - haematocrit. Missing values were imputed using the LOCF method.
Time Frame	Baseline, week 208

Outcome Measure Data

Analysis Population Description

SAS.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Mean (Standard Deviation) [Percentage of red blood cells]	1.24 (2.45)	1.26 (1.63)

47. Secondary Outcome

Title	Change in Clinical Laboratory Tests (Haematology: Neutrophils)
Description	Change from baseline (within 4 weeks prior to week 0) in haematological parameter - neutrophils. Missing values were imputed using the LOCF method.
Time Frame	Baseline, week 208

Outcome Measure Data

Analysis Population Description

SAS.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Mean (Standard Deviation) [Percentage of neutrophils]	-1.23 (10.80)	4.88 (9.41)

48. Secondary Outcome

Title	Change in Clinical Laboratory Tests (Haematology: Lymphocytes)
Description	Change from baseline (within 4 weeks prior to week 0) in haematological parameter - lymphocytes. Missing values were imputed using the LOCF method.
Time Frame	Baseline, week 208

Outcome Measure Data

Analysis Population Description

SAS.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Mean (Standard Deviation) [Percentage of lymphocytes]	-0.14 (8.88)	-5.70 (8.86)

49. Secondary Outcome

Title	Change in Clinical Laboratory Tests (Haematology: Monocytes)
Description	Change from baseline (within 4 weeks prior to week 0) in haematological parameter - monocytes. Missing values were imputed using the LOCF method.
Time Frame	Baseline, week 208

Outcome Measure Data

Analysis Population Description

SAS.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Mean (Standard Deviation) [Percentage of monocytes]	0.08 (1.21)	0.56 (1.18)

50. Secondary Outcome

Title	Change in Clinical Laboratory Tests (Haematology: Eosinophils)
Description	Change from baseline (within 4 weeks prior to week 0) in haematological parameter - eosinophils. Missing values were imputed using the LOCF method.
Time Frame	Baseline, week 208

Outcome Measure Data

Analysis Population Description

SAS.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Mean (Standard Deviation) [Percentage of eosinophils]	1.30 (3.57)	0.42 (1.44)

51. Secondary Outcome

Title	Change in Clinical Laboratory Tests (Haematology: Basophils)
Description	Change from baseline (within 4 weeks prior to week 0) in haematological parameter - basophils. Missing values were imputed using the LOCF method.
Time Frame	Baseline, week 208

Outcome Measure Data

Analysis Population Description

SAS.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Mean (Standard Deviation) [Percentage of basophils]	-0.01 (0.26)	-0.12 (0.26)

52. Secondary Outcome

Title	Change in Clinical Laboratory Tests (Lipids: Total Cholesterol, LDL Cholesterol and HDL Cholesterol)
Description	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.
Time Frame	Baseline, week 208

Outcome Measure Data

Analysis Population Description

SAS.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Total cholesterol	0.031 (0.639)	-0.110 (0.609)
LDL cholesterol	-0.005 (0.550)	-0.173 (0.523)
HDL cholesterol	0.036 (0.275)	0.056 (0.173)

53. Secondary Outcome

Title	Change in Clinical Laboratory Tests (Biochemistry: AST, ALT, r-GTP and Alkaline Phosphatase)
Description	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.
Time Frame	Baseline, week 208

Outcome Measure Data

Analysis Population Description

SAS. Number analyzed = participants with available data.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
AST	-5.4 (2.4)	-7.4 (5.2)
ALT	-1.28 (2.65)	-1.81 (4.42)
r-GTP	1.0 (1.6)	-3.5 (22.8)
Alkaline phosphatase	113.9 (126.4)	84.8 (140.9)

54. Secondary Outcome

Title	Change in Clinical Laboratory Tests (Biochemistry: Total Protein)
Description	Change from baseline (within 4 weeks prior to week 0) in biochemical parameter - total protein. Missing values were imputed using the LOCF method.
Time Frame	Baseline, week 208

Outcome Measure Data

Analysis Population Description

SAS. Number analyzed = participants with available data.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Mean (Standard Deviation) [g/dL]	0.02 (0.33)	0.05 (0.37)

55. Secondary Outcome

Title	Change in Clinical Laboratory Tests (Biochemistry: Blood Urea Nitrogen, Sodium, Potassium, Chloride, Total Calcium and Phosphorus)
Description	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.
Time Frame	Baseline, week 208

Outcome Measure Data

Analysis Population Description

SAS. Number analyzed = participants with available data.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Blood urea nitrogen	-0.10 (0.52)	-0.15 (0.53)
Sodium	0.9 (2.1)	1.4 (2.5)
Potassium	-0.13 (0.28)	-0.09 (0.38)
Chloride	-0.3 (2.2)	-0.2 (2.2)
Total calcium	-0.02 (0.07)	-0.00 (0.08)
Phosphorus	0.036 (0.111)	0.111 (0.103)

56. Secondary Outcome

Title	Change in Clinical Laboratory Tests (Biochemistry: Creatinine)
Description	Change from baseline (within 4 weeks prior to week 0) in biochemical parameters - creatinine. Missing values were imputed using the LOCF method.
Time Frame	Baseline, week 208

Outcome Measure Data

Analysis Population Description

SAS.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Mean (Standard Deviation) [umol/L]	5.5 (4.4)	6.7 (4.1)

57. Secondary Outcome

Title	Change in Glucose Tolerance (AUC of Glucose) Based on the OGTT
Description	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'.
Time Frame	Baseline, week 208

Outcome Measure Data

Analysis Population Description

SAS. Number analyzed = participants with available data.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Geometric Mean (Geometric Coefficient of Variation) [Ratio of AUC]	1.03 (12.34)	1.10 (14.55)

58. Secondary Outcome

Title	Change in Glucose Tolerance (AUC of Insulin) Based on the OGTT
Description	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'.
Time Frame	Baseline, week 208

Outcome Measure Data

Analysis Population Description

SAS. Number analyzed = participants with available data.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Geometric Mean (Geometric Coefficient of Variation) [Ratio of AUC]	1.52 (49.97)	2.38 (47.04)

59. Secondary Outcome

Title	Change in Bone Age
Description	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.
Time Frame	Baseline, week 208

Outcome Measure Data

Analysis Population Description

SAS. Number analyzed = participants with available data.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Mean (Standard Deviation) [Years]	3.89 (1.35)	4.68 (1.11)

60. Secondary Outcome

Title	Change in Bone Age/Chronological Age
Description	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.
Time Frame	Baseline, week 208

Outcome Measure Data

Analysis Population Description

SAS. Number analyzed = participants with available data.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Mean (Standard Deviation) [Ratio (bone age/chronological age)]	0.049 (0.159)	0.149 (0.151)

61. Secondary Outcome

Title	Yearly Change in Bone Age/Change in Chronological Age
Description	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.
Time Frame	Week 104, week 156

Outcome Measure Data

Analysis Population Description

SAS. Number analyzed = participants with available data.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Mean (Standard Deviation) [Ratio (bone age/chronological age)]	0.94 (0.70)	0.97 (0.56)

62. Secondary Outcome

Title	Yearly Change in Bone Age/Change in Chronological Age
Description	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.
Time Frame	Week 156, week 208

Outcome Measure Data

Analysis Population Description

SAS. Number analyzed = participants with available data.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Mean (Standard Deviation) [Ratio (bone age/chronological age)]	0.87 (0.55)	1.05 (0.51)

63. Secondary Outcome

Title	Change in Vital Signs (Diastolic Blood Pressure and Systolic Blood Pressure)
Description	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.
Time Frame	Baseline, week 208

Outcome Measure Data

Analysis Population Description

SAS. Number analyzed = participants with available data.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Diastolic blood pressure	5.8 (13.4)	3.5 (8.4)
Systolic blood pressure	6.8 (11.9)	5.8 (16.1)

64. Secondary Outcome

Title	Change in Vital Signs (Pulse)
Description	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.
Time Frame	Baseline, week 208

Outcome Measure Data

Analysis Population Description

SAS. Number analyzed = participants with available data.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Mean (Standard Deviation) [beats/min]	-15.3 (14.2)	-3.8 (16.5)

65. Secondary Outcome

Title	Change in Urinalysis (Protein, Glucose and Occult Blood)
Description	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.
Time Frame	Baseline, week 208

Outcome Measure Data

Analysis Population Description

SAS.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Protein: Negative (Baseline)	23 92%	22 84.6%
Protein: Trace (Baseline)	2 8%	4 15.4%
Protein: 1+ (Baseline)	0 0%	0 0%
Protein: 2+ (Baseline)	0 0%	0 0%
Protein: 3+ (Baseline)	0 0%	0 0%
Protein: Negative (Week 208)	17 68%	18 69.2%
Protein: Trace (Week 208)	8 32%	7 26.9%
Protein: 1+ (Week 208)	0 0%	0 0%
Protein: 2+ (Week 208)	0 0%	1 3.8%
Protein: 3+ (Week 208)	0 0%	0 0%
Glucose: Negative (Baseline)	25 100%	26 100%
Glucose: Trace (Baseline)	0 0%	0 0%
Glucose: 1+ (Baseline)	0 0%	0 0%
Glucose: 2+ (Baseline)	0 0%	0 0%
Glucose: 3+ (Baseline)	0 0%	0 0%
Glucose: Negative (Week 208)	25 100%	26 100%
Glucose: Trace (Week 208)	0 0%	0 0%
Glucose: 1+ (Week 208)	0 0%	0 0%
Glucose: 2+ (Week 208)	0 0%	0 0%
Glucose: 3+ (Week 208)	0 0%	0 0%
Occult blood: Negative (Baseline)	24 96%	25 96.2%
Occult blood: Trace (Baseline)	1 4%	1 3.8%
Occult blood: 1+ (Baseline)	0 0%	0 0%
Occult blood: 2+ (Baseline)	0 0%	0 0%
Occult blood: 3+ (Baseline)	0 0%	0 0%
Occult blood: Negative (Week 208)	24 96%	22 84.6%
Occult blood: Trace (Week 208)	1 4%	2 7.7%
Occult blood: 1+ (Week 208)	0 0%	1 3.8%
Occult blood: 2+ (Week 208)	0 0%	0 0%
Occult blood: 3+ (Week 208)	0 0%	1 3.8%

66. Secondary Outcome

Title	Change in Blood Coagulation Test (Prothrombin Time and APTT)
Description	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.
Time Frame	Baseline, week 208

Outcome Measure Data

Analysis Population Description

SAS.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Prothrombin time	0.70	1.20
APTT	0.70	0.80

67. Secondary Outcome

Title	Change in ECG
Description	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.
Time Frame	Baseline, week 208

Outcome Measure Data

Analysis Population Description

SAS.

Arm/Group Title	NN-220 0.033 mg/kg/Day	NN-220 0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).	Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
Measure Participants	25	26
Normal (Baseline)	15 60%	14 53.8%
Abnormal NCS (Baseline)	10 40%	12 46.2%
Abnormal CS (Baseline)	0 0%	0 0%
Normal (Week 208)	20 80%	16 61.5%
Abnormal NCS (Week 208)	5 20%	9 34.6%
Abnormal CS (Week 208)	0 0%	1 3.8%

Adverse Events

Time Frame	Week 0 to week 234 (208 weeks treatment period + 26 weeks extended treatment period) + 7 days (follow-up period).
Adverse Event Reporting Description	All presented AEs are TEAEs. A TEAE (for the entire trial) 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 trial product administration. Results are based on the SAS, which included all participants receiving at least one dose of trial product.
Arm/Group Title	0.033 mg/kg/Day		0.066 mg/kg/Day
Arm/Group Description	Participants received s.c. injection of NN-220, 0.033 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).		Participants received s.c. injection of NN-220, 0.066 mg/kg/day once daily for 234 weeks (104 weeks of pivotal phase + 104 weeks of extension phase + 26 weeks extended treatment phase).
All Cause Mortality
	0.033 mg/kg/Day		0.066 mg/kg/Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/25 (0%)		0/26 (0%)
Serious Adverse Events
	0.033 mg/kg/Day		0.066 mg/kg/Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/25 (36%)		10/26 (38.5%)
Cardiac disorders
Atrial fibrillation	0/25 (0%)	0	1/26 (3.8%)	1
Congenital, familial and genetic disorders
Arnold-Chiari malformation	1/25 (4%)	1	0/26 (0%)	0
Craniosynostosis	1/25 (4%)	1	1/26 (3.8%)	1
Hamartoma	1/25 (4%)	1	0/26 (0%)	0
Phimosis	1/25 (4%)	1	0/26 (0%)	0
Ear and labyrinth disorders
Conductive deafness	0/25 (0%)	0	1/26 (3.8%)	1
Gastrointestinal disorders
Dental caries	2/25 (8%)	2	0/26 (0%)	0
Salivary gland calculus	1/25 (4%)	1	0/26 (0%)	0
Supernumerary teeth	0/25 (0%)	0	1/26 (3.8%)	1
Infections and infestations
Gastroenteritis	0/25 (0%)	0	1/26 (3.8%)	1
Pneumonia	1/25 (4%)	1	0/26 (0%)	0
Pneumonia mycoplasmal	1/25 (4%)	1	1/26 (3.8%)	1
Tonsillitis	0/25 (0%)	0	1/26 (3.8%)	1
Musculoskeletal and connective tissue disorders
Polymyositis	0/25 (0%)	0	1/26 (3.8%)	1
Nervous system disorders
Febrile convulsion	0/25 (0%)	0	1/26 (3.8%)	1
Psychiatric disorders
Head banging	1/25 (4%)	1	0/26 (0%)	0
Reproductive system and breast disorders
Testicular swelling	0/25 (0%)	0	1/26 (3.8%)	1
Respiratory, thoracic and mediastinal disorders
Velopharyngeal incompetence	0/25 (0%)	0	1/26 (3.8%)	1
Surgical and medical procedures
Pulmonary artery therapeutic procedure	0/25 (0%)	0	1/26 (3.8%)	1
Other (Not Including Serious) Adverse Events
	0.033 mg/kg/Day		0.066 mg/kg/Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	24/25 (96%)		26/26 (100%)
Eye disorders
Conjunctivitis allergic	6/25 (24%)	11	5/26 (19.2%)	5
Gastrointestinal disorders
Abdominal pain	2/25 (8%)	2	2/26 (7.7%)	10
Dental caries	4/25 (16%)	4	4/26 (15.4%)	11
Diarrhoea	7/25 (28%)	12	3/26 (11.5%)	4
Enteritis	2/25 (8%)	3	1/26 (3.8%)	1
Nausea	2/25 (8%)	2	1/26 (3.8%)	1
Stomatitis	0/25 (0%)	0	5/26 (19.2%)	6
Toothache	0/25 (0%)	0	2/26 (7.7%)	2
Vomiting	4/25 (16%)	9	3/26 (11.5%)	3
General disorders
Pyrexia	9/25 (36%)	24	9/26 (34.6%)	12
Immune system disorders
Seasonal allergy	2/25 (8%)	2	1/26 (3.8%)	1
Infections and infestations
Bronchitis	4/25 (16%)	5	7/26 (26.9%)	12
Bronchitis bacterial	0/25 (0%)	0	2/26 (7.7%)	2
Conjunctivitis	5/25 (20%)	6	6/26 (23.1%)	6
Gastroenteritis	8/25 (32%)	14	14/26 (53.8%)	33
Gingivitis	2/25 (8%)	2	1/26 (3.8%)	1
Hordeolum	1/25 (4%)	1	3/26 (11.5%)	5
Impetigo	2/25 (8%)	2	2/26 (7.7%)	2
Influenza	20/25 (80%)	34	18/26 (69.2%)	31
Molluscum contagiosum	3/25 (12%)	3	1/26 (3.8%)	1
Nasopharyngitis	19/25 (76%)	115	21/26 (80.8%)	121
Otitis media	7/25 (28%)	9	8/26 (30.8%)	9
Otitis media acute	4/25 (16%)	6	1/26 (3.8%)	1
Pharyngitis	2/25 (8%)	3	5/26 (19.2%)	6
Pharyngitis streptococcal	0/25 (0%)	0	2/26 (7.7%)	2
Rhinitis	1/25 (4%)	1	4/26 (15.4%)	7
Sinusitis	5/25 (20%)	14	2/26 (7.7%)	2
Streptococcal infection	2/25 (8%)	3	3/26 (11.5%)	4
Tinea pedis	0/25 (0%)	0	5/26 (19.2%)	9
Upper respiratory tract infection	8/25 (32%)	38	9/26 (34.6%)	43
Varicella	2/25 (8%)	2	5/26 (19.2%)	5
Injury, poisoning and procedural complications
Arthropod bite	2/25 (8%)	2	3/26 (11.5%)	8
Arthropod sting	0/25 (0%)	0	2/26 (7.7%)	3
Chillblains	2/25 (8%)	4	0/26 (0%)	0
Contusion	1/25 (4%)	1	2/26 (7.7%)	2
Skin abrasion	2/25 (8%)	2	0/26 (0%)	0
Thermal burn	2/25 (8%)	2	0/26 (0%)	0
Metabolism and nutrition disorders
Hyperinsulinaemia	0/25 (0%)	0	2/26 (7.7%)	2
Musculoskeletal and connective tissue disorders
Arthralgia	2/25 (8%)	2	2/26 (7.7%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin papilloma	2/25 (8%)	2	0/26 (0%)	0
Nervous system disorders
Headache	6/25 (24%)	10	2/26 (7.7%)	5
Psychiatric disorders
Attention deficit/hyperactivity disorder	2/25 (8%)	2	0/26 (0%)	0
Respiratory, thoracic and mediastinal disorders
Asthma	3/25 (12%)	4	2/26 (7.7%)	3
Cough	6/25 (24%)	8	3/26 (11.5%)	5
Epistaxis	3/25 (12%)	4	1/26 (3.8%)	1
Rhinitis allergic	4/25 (16%)	4	4/26 (15.4%)	4
Rhinorrhoea	2/25 (8%)	3	3/26 (11.5%)	3
Upper respiratory tract inflammation	7/25 (28%)	35	9/26 (34.6%)	30
Skin and subcutaneous tissue disorders
Dermatitis	0/25 (0%)	0	2/26 (7.7%)	2
Dry skin	1/25 (4%)	1	2/26 (7.7%)	2
Eczema	3/25 (12%)	4	8/26 (30.8%)	13
Hyperkeratosis	0/25 (0%)	0	2/26 (7.7%)	3
Miliaria	2/25 (8%)	2	5/26 (19.2%)	10
Rash	3/25 (12%)	3	0/26 (0%)	0
Urticaria	5/25 (20%)	8	2/26 (7.7%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

At the end of the trial, one or more scientific publications may be prepared collaboratively by the investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or communication for up to 60 days to protect intellectual property.