A Research Study to Compare Somapacitan Once a Week With Norditropin® Once a Day in Children Who Need Help to Grow

Study Overview
=================
Brief Summary
-----------------
The study compares two medicines for treatment of children born small and who stay small, or with Turner Syndrome, Noonan Syndrome, or idiopathic short stature. The purpose of the study is to see how well treatment with somapacitan works compared to treatment with Norditropin®. Somapacitan is a new medicine, and Norditropin® is a medicine doctors can already prescribe in some countries. The study will last for about 3 years. The participants will either get somapacitan once a week for 3 years or Norditropin® once a day for 1 year followed by somapacitan once a week for 2 years. Which treatment the participants get is decided by chance.

Official Title
-----------------
A Study Comparing the Effect and Safety of Once Weekly Dosing of Somapacitan With Daily Norditropin® as Well as Evaluating Long-term Safety of Somapacitan in a Basket Study Design in Children With Short Stature Either Born Small for Gestational Age or With Turner Syndrome, Noonan Syndrome, or Idiopathic Short Stature

Conditions
-----------------
SGA, Turner Syndrome, Noonan Syndrome, ISS

Intervention / Treatment
-----------------
* Drug: Somapacitan
* Drug: Norditropin®


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: Informed consent of parent or legally acceptable representative of participant and child assent, as age appropriate must be obtained before any study-related activities. Study-related activities are any procedures that are carried out as part of the study, including activities to determine suitability for the study. No prior exposure to growth promoting therapy, including but not limited to growth hormone, IGF-I and ghrelin analogues. Applicable to children with SGA: Born small for gestational age (birth length below -2 SDS OR birth weight below -2 SDS OR both) (according to national standards). Prepubertal children: Boys: Age above or equal to 2 years and 26 weeks and below 11.0 years at screening. Testis volume below 4 mL Girls: Age above or equal to 2 years and 26 weeks and below 10.0 years at screening. Tanner stage 1 for breast development: No palpable glandular breast tissue) Impaired height defined as at least 2.5 standard deviations below the mean height for chronological age and sex at screening according to the standards of Centers for Disease Control and Prevention. Impaired height velocity defined as annualized height velocity below the 50th percentile for chronological age and sex according to the standards of Prader calculated over a time span of minimum 6 months and maximum 18 months prior to screening. Body Mass Index below the 95th percentile according to Centers for Disease Control and Prevention, Body Mass Index-for-age growth charts. Applicable to girls with TS: Confirmed diagnosis of TS by 30-cell (or more) lymphocyte chromosomal analysis.* Prepubertal girls: Age above or equal to 2 years and 26 weeks and below 10.0 years at screening. Tanner stage 1 for breast development: No palpable glandular breast tissue) Impaired height defined as at least 2.0 standard deviations below the mean height for chronological age and sex at screening according to the standards of Centers for Disease Control and Prevention. Historical height measured 6-18 months prior to screening. Thyroid hormone replacement therapy should be adequate and stable for at least 90 days prior to randomization, if applicable. Applicable to children with NS: Clinical diagnosis of NS according to van der Burgt score list Prepubertal children: Boys: Age above or equal to 2 years and 26 weeks and below 11.0 years at screening. Testis volume below 4 mL Girls: Age above or equal to 2 years and 26 weeks and below 10.0 years at screening. Tanner stage 1 for breast development: No palpable glandular breast tissue) Impaired height defined as at least 2.0 standard deviations below the mean height for chronological age and sex at screening according to the standards of Centers for Disease Control and Prevention. Historical height measured 6-18 months prior to screening. Thyroid hormone replacement therapy should be adequate and stable for at least 90 days prior to randomization, if applicable. Applicable to children with ISS: Prepubertal children: Boys: Age above or equal to 2 years and 26 weeks and below 11.0 years at screening. Testis volume below 4 mL Girls: Age above or equal to 2 years and 26 weeks and below 10.0 years at screening. Tanner stage 1 for breast development: No palpable glandular breast tissue) Bone age: Boys: Bone age below or equal to 12 years. Bone age not delayed or advanced more than 2 years compared to chronological age. Girls: Bone age below or equal to 11 years. Bone age not delayed or advanced more than 2 years compared to chronological age. Impaired height defined as at least 2.5 standard deviations below the mean height for chronological age and sex at screening according to the standards of Centers for Disease Control and Prevention. Historical height measured 6-18 months prior to screening. One normal GH secretion (GH peak above 7 ng/mL) during GH stimulation test performed within 18 months prior to screening or if such a test is not available for children with ISS, a test should be performed as part of the screening assessments and the result must be available prior to randomization. If a 30-cell count is not available for patients with TS, a test should be done, and results must be available prior to randomization. Exclusion criteria: Known or suspected hypersensitivity to study intervention(s) or related products. Previous randomization into same sub-study in this study. Receipt of any investigational medicinal product within 3 months before screening or participation in another clinical study at the time of randomization. Children with suspected or confirmed growth hormone deficiency according to local practice. laboratory of fasting plasma glucose above or equal to 126 mg/dL (7.0 mmol/L) or HbA1c above or equal to 6.5%. Current inflammatory diseases requiring systemic corticosteroid treatment for longer than 2 consecutive weeks within the last 3 months prior to screening. Children requiring inhaled glucocorticoid therapy at a dose greater than 400 µg/day of inhaled budesonide or equivalent (i.e., 250 µg/day for fluticasone propionate) for longer than 4 consecutive weeks within the last 12 months prior to screening. Concomitant administration of other treatments that may have an effect on growth, e.g., but not limited to methylphenidate for treatment of attention deficit hyperactivity disorder (ADHD). Diagnosis of attention deficit hyperactivity disorder (ADHD). History or known presence of any malignancy, intracranial tumour, or intracranial cyst. History or known presence of active Hepatitis B or Hepatitis C (exceptions to this exclusion criterion is the presence of antibodies due to vaccination against Hepatitis B). Any disorder, which in the investigator's opinion, might jeopardize participant's safety or compliance with the protocol. The participant or the parent/legally acceptable representative is likely to be non-compliant in respect to study conduct, as judged by the investigator. Current treatment with sex hormones or aromatase inhibitors. Any known or suspected clinically significant abnormality likely to affect growth or the ability to evaluate growth with standing height measurements, such as, but not limited to: Known family history of skeletal dysplasia. Significant spinal abnormalities including but not limited to scoliosis, kyphosis and spina bifida variants. Any other disorder/condition that can cause short stature such as, but not limited to, psychosocial deprivation, nutritional disorders, chronic systemic illness and chronic renal disease. Applicable to children with SGA: TS (including mosaicism). NS. Hormonal deficiencies. Children who are small due to malnutrition defined as -2 standard deviations according to standards. 0¬-5 years: weight for height on World Health Organization Multicentre Growth Reference Study 2006. Above 5 years: World Health Organization 2007 Body Mass Index. Known chromosomal aneuploidy or significant gene mutations causing medical 'syndromes' with short stature, including but not limited to Laron syndrome, Prader-Willi syndrome, Russell-Silver Syndrome, skeletal dysplasias, abnormal SHOX gene analysis or absence of GH receptors. Applicable to children with TS: NS. Mosaicism below 10%. TS with Y-chromosome mosaicism where gonadectomy has not been performed. NYHA class II or above or requiring medication for any heart condition. Coeliac disease where participant is not stable on gluten free diet for the previous 12 months prior to screening. Applicable to children with NS: TS (including mosaicism). Noonan-related disorders: Noonan syndrome with multiple lentigines (formerly called 'LEOPARD' syndrome), Noonan syndrome with loose anagen hair, cardiofaciocutaneous syndrome (CFC), Costello syndrome, neurofibromatosis type 1 (NF1) and Legius syndrome. Molecular genetic panel testing results must be available prior to randomisation to exclude these. Coeliac disease where participant is not stable on gluten free diet for the previous 12 months prior to screening. Applicable to children with ISS: TS (including mosaicism). NS. Hormonal deficiencies. Born small for gestational age (defined as birth length below -2 SDS OR birth weight below -2 SDS OR both) (according to national standards). Known chromosomal aneuploidy or significant gene mutations causing medical 'syndromes' with short stature, including but not limited to Laron syndrome, Prader-Willi syndrome, Russell-Silver Syndrome, skeletal dysplasias, abnormal SHOX gene analysis or absence of GH receptors.

Ages Eligible for Study
-----------------
Minimum Age: 2 Years
Maximum Age: 10 Years

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

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

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Somapacitan<br>Participants will receive Somapacitan for 156 weeks | Drug: Somapacitan<br>* Somapacitan will be administered subcutaneously (s.c.) once weekly using PDS290 pen-injector.<br>|
| Active Comparator: Norditropin®<br>Participants will receive Norditropin® for 52 weeks (main phase) and Somapacitan for 104 weeks (extension phase) | Drug: Norditropin®<br>* Norditropin® will be administered s.c. once daily using FlexPro® pen-injector.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Height velocity reported separately for small for gestational age (SGA), Turner syndrome (TS), Noonan syndrome (NS) and idiopathic short stature (ISS) | Measured in centimeter per year (cm/year) | From baseline (week 0) to visit 7 (week 52) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Height standard deviation scores (SDS) reported separately for SGA, TS, NS and ISS | Measured in score. Positive score indicates that the value is closer to or above the reference population compared to baseline. | From baseline (week 0) to visit 7 (week 52) | 
| Change in Height Velocity SDS reported separately for SGA, TS, NS and ISS | Measured in score. Positive score indicates that the value is closer to or above the reference population compared to baseline. | From baseline (week 0) to visit 7 (week 52) | 
| Change in bone age reported separately for SGA, TS and NS | Measured in ratio | From baseline (week 0) to visit 7 (week 52) | 
| Change in bone age for ISS | Measured in ratio | From screening (visit 1) to visit 7 (week 52) | 
| Change in insulin-like growth factor 1 (IGF-1) SDS reported separately for SGA, TS, NA and ISS | Measured in score. Positive score indicates that the value is closer to or above the reference population compared to baseline. | From baseline (week 0) to visit 7 (week 52). | 
| Change in insulin-like growth factor binding protein-3 (IGFBP-3) SDS reported separately for SGA, TS, NA and ISS | Measured in score. Positive score indicates that the value is closer to or above the reference population compared to baseline. | From baseline (week 0) to visit 7 (week 52). | 
| Change in fasting plasma glucose reported separately for SGA, TS, NS and ISS | Measured in millimoles per litre (mmol/L) | From screening (visit 1) to visit 7 (week 52) | 
| Change in homeostatic model assessment-B (HOMA-B) reported separately for SGA, TS, NS and ISS | Measured in percentage (%) | From screening (visit 1) to visit 7 (week 52) | 
| Change in homeostatic model assessment of insulin resistance (HOMAIR) reported separately for SGA, TS, NS and ISS | Measured in % | From screening (visit 1) to visit 7 (week 52) | 
| Change in glycated haemoglobin (HbA1c) reported separately for SGA, TS, NS and ISS | Measured in percentage of HbA1c | From screening (visit 1) to visit 7 (week 52) | 
| Weekly average somapacitan concentration (Cavg) based on population PK analysis | Measured in nanograms per milliliter (ng/mL) | From visit 3 (week 4) to visit 7 (week 52) | 
| Change in fasting plasma glucose reported separately for SGA, TS, NS and ISS | Measured in mmol/L | From screening (visit 1) to visit 15 (week 156) | 
| Change in homeostatic model assessment-B (HOMA-B) reported separately for SGA, TS, NS and ISS | Measured in % | From screening (visit 1) to visit 15 (week 156) | 
| Change in homeostatic model assessment of insulin resistance (HOMA-IR) reported separately for SGA, TS, NS and ISS | Measured in % | From screening (visit 1) to visit 15 (week 156) | 
| Change in glycated haemoglobin (HbA1c) reported separately for SGA, TS, NS and ISS | Measured in percentage of HbA1c | From screening (visit 1) to visit 15 (week 156) |