| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Short stature born small for gestational age
Turner syndrome
Noonan syndrome
Idiopathic short stature |
|
| E.1.1.1 | Medical condition in easily understood language |
Short stature born small for gestational age
Turner syndrome
Noonan syndrome
Idiopathic short stature |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Hormonal diseases [C19] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10045181 |
| E.1.2 | Term | Turner's syndrome |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10029748 |
| E.1.2 | Term | Noonan syndrome |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10066333 |
| E.1.2 | Term | Idiopathic short stature |
| E.1.2 | System Organ Class | 100000004859 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10041093 |
| E.1.2 | Term | Small for gestational age |
| E.1.2 | System Organ Class | 100000004868 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To confirm non-inferiority of once-weekly somapacitan compared with once-daily
Norditropin® in terms of longitudinal growth measured by height velocity at week 52 in
children with each of the four indications: SGA, TS, NS or ISS. |
|
| E.2.2 | Secondary objectives of the trial |
1.To evaluate once-weekly somapacitan compared with once-daily Norditropin® in terms of other aspects of longitudinal growth in children with each of the four indications: SGA, TS, NS or ISS.
2. To evaluate safety of once-weekly somapacitan compared with once-daily Norditropin® in terms of safety parameters measured by glucose metabolism in children with each of the four indications: SGA, TS, NS or ISS.
3. To evaluate the steady state pharmacokinetics of once-weekly somapacitan in children with
each of the four indications: SGA, TS, NS or ISS.
4. To evaluate long-term safety of once-weekly somapacitan in terms of safety parameters measured by glucose metabolism in children with each of the four indications: SGA, TS, NS or ISS. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Four sub-studies are described in this protocol |
|
| E.3 | Principal inclusion criteria |
1. 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.
2. No prior exposure to growth promoting therapy, including but not limited to growth hormone, IGF-I and ghrelin analogues.
Applicable to children with SGA:
3. Born small for gestational age (birth length below -2 SDS OR birth weight below -2 SDS OR both) (according to national standards).
4. Prepubertal children:
a) Boys:
• Age above or equal to 2 years and 26 weeks and below 11.0 years at screening.
• Testis volume below 4 mL
b) 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.
5. 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.
6. Impaired height velocity defined as annualised 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.
7. 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:
8. Confirmed diagnosis of TS by 30-cell (or more) lymphocyte chromosomal analysis.*
9. 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.
10. 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.
11. Historical height measured 6–18 months prior to screening.
12. Thyroid hormone replacement therapy should be adequate and stable for at least 90 days prior to randomisation, if applicable.
Applicable to children with NS:
13. Clinical diagnosis of NS according to van der Burgt score list
14. Prepubertal children:
a) Boys:
• Age above or equal to 2 years and 26 weeks and below 11.0 years at screening.
• Testis volume below 4 mL
b) 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.
15. 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.
16. Historical height measured 6–18 months prior to screening.
17. Thyroid hormone replacement therapy should be adequate and stable for at least 90 days prior to randomisation, if applicable.
Applicable to children with ISS:
18. Prepubertal children:
a) Boys:
• Age above or equal to 2 years and 26 weeks and below 11.0 years at screening.
• Testis volume below 4 mL
b) 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.
19. Bone age:
a) Boys:
• Bone age below or equal to 12 years.
• Bone age not delayed or advanced more than 2 years compared to chronological age.
b) Girls:
• Bone age below or equal to 11 years.
• Bone age not delayed or advanced more than 2 years compared to chronological age.
20. 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.
21. Historical height measured 6–18 months prior to screening.
22. 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 randomisation.
*If a 30-cell count is not available for patients with TS, a test should be done, and results must be available prior to randomisation |
|
| E.4 | Principal exclusion criteria |
1. Known or suspected hypersensitivity to study intervention(s) or related products.
2. Previous randomisation into same sub-study in this study.
3. Receipt of any investigational medicinal product within 3 months before screening or participation in another clinical study at the time of randomisation.
4. Children with suspected or confirmed growth hormone deficiency according to local practice.
5. Children diagnosed with diabetes mellitus or screening values from the central laboratory of
a. fasting plasma glucose above or equal to 126 mg/dL (7.0 mmol/L) or
b. HbA1c above or equal to 6.5%.
6. Current inflammatory diseases requiring systemic corticosteroid treatment for longer than 2 consecutive weeks within the last 3 months prior to screening.
7. 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.
8. 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).
9. Diagnosis of attention deficit hyperactivity disorder (ADHD).
10. History or known presence of malignancy including intracranial tumours.
11. 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).
12. Any disorder, which in the investigator’s opinion, might jeopardise participant’s safety or compliance with the protocol.
13. The participant or the parent/legally acceptable representative is likely to be non-compliant in respect to study conduct, as judged by the investigator.
14. Current treatment with sex hormones or aromatase inhibitors.
15. 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:
a. Known family history of skeletal dysplasia.
b. Significant spinal abnormalities including but not limited to scoliosis, kyphosis and spina bifida variants.
c. 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:
a. TS (including mosaicism).
b. NS.
c. Hormonal deficiencies.
d. Children who are small due to malnutrition defined as -2 standard deviations according to standards. 0¬–5 years: weight for height on World Health Organisation Multicentre Growth Reference Study 2006. Above 5 years: World Health Organisation 2007 Body Mass Index.
e. 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:
a. NS.
b. Mosaicism below 10%.
c. TS with Y-chromosome mosaicism where gonadectomy has not been performed.
d. NYHA class II or above or requiring medication for any heart condition.
e. Coeliac disease where participant is not stable on gluten free diet for the previous 12 months prior to screening.
Applicable to children with NS:
a. TS (including mosaicism).
b. 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 testing results must be available prior to randomisation to exclude these.
c. Coeliac disease where participant is not stable on gluten free diet for the previous 12 months prior to screening.
Applicable to children with ISS:
a. TS (including mosaicism).
b. NS.
c. Hormonal deficiencies.
d. Born small for gestational age (defined as birth length below -2 SDS OR birth weight below -2 SDS OR both) (according to national standards).
e. 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Height velocity reported for each indication separately. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From baseline (week 0) to visit 7 (week 52) |
|
| E.5.2 | Secondary end point(s) |
1.1 Change in Height SDS reported for each indication separately.
1.2 Change in Height Velocity SDS reported for each indication separately.
1.3 Change in bone age reported for each indication separately
1.4 Change in IGF-I SDS reported for each indication separately.
1.5 Change in IGFBP-3 SDS reported for each indication separately.
2.1 Change in fasting plasma glucose reported for each indication separately.
2.2 Change in homeostatic model assessment-B (HOMA-B) reported for each indication separately.
2.3 Change in homeostatic model assessment-IR (HOMAIR) reported for each indication separately.
2.4 Change in glycated haemoglobin (HbA1c) reported for each indication separately.
3.1 Weekly average somapacitan concentration (Cavg) based on population PK analysis.
4.1 Change in fasting plasma glucose reported for each indication separately.
4.2 Change in homeostatic model assessment-B (HOMA-B) reported for each indication separately.
4.3 Change in homeostatic model assessment-IR (HOMA-IR) reported for each indication
separately.
4.4 Change in glycated haemoglobin (HbA1c) reported for each indication separately. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.1 From baseline (week 0) to visit 7 (week 52).
1.2 From baseline (week 0) to visit 7 (week 52).
1.3 For SGA, TS and NS: From baseline (week 0) to visit 7 (week 52).
For ISS: From screening (visit 1) to visit 7 (week 52).
1.4 From baseline (week 0) to visit 7 (week 52).
1.5 From baseline (week 0) to visit 7 (week 52).
2.1 From screening (visit 1) to visit 7(week 52).
2.2 From screening (visit 1) to visit 7(week 52).
2.3 From screening (visit 1) to visit 7(week 52).
2.4 From screening (visit 1) to visit 7(week 52).
3.1 From visit 3 (week 4) to visit 7 (week 52).
4.1 From screening (visit 1) to visit 15 (week 156).
4.2 From screening (visit 1) to visit 15 (week 156).
4.3 From screening (visit 1) to visit 15 (week 156).
4.4 From screening (visit 1) to visit 15 (week 156). |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 61 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Brazil |
| Canada |
| China |
| India |
| Israel |
| Japan |
| Korea, Republic of |
| Malaysia |
| Mexico |
| Saudi Arabia |
| South Africa |
| Thailand |
| United States |
| European Union |
| Switzerland |
| Russian Federation |
| Serbia |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 15 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 15 |
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