| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Growth hormone deficiency in pre-pubertal children |
|
| E.1.1.1 | Medical condition in easily understood language |
| Treatment of children with growth failure due to growth hormone deficiency |
|
| 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 | 10056438 |
| E.1.2 | Term | Growth hormone deficiency |
| E.1.2 | System Organ Class | 10014698 - Endocrine disorders |
|
| 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 demonstrate that weekly MOD-4023 administration is non-inferior to daily Genotropin administration |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the safety and tolerability of weekly MOD-4023 administration;
To evaluate the effect of weekly MOD-4023 and daily Genotropin administration on quality of life (QoL), as measured by the QoLISSY (Quality of Life in Short Stature Youth) at specific number of countries. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Pre-pubertal children aged ≥3 years, and not yet 11 years for girls (10 years and 364 days) or not yet 12 years (11 years and 364 days) for boys, (on the date of ICF signature), with either isolated GHD, or GH insufficiency as part of multiple pituitary hormone deficiency.
2. Confirmed diagnosis of GHD by 2 different GH provocation tests defined as a peak plasma GH level of ≤10 ng/mL, determined by local or central laboratory using a validated assaya. Global study MM may accept prior local laboratory results; subject to pre-approval and if the tests were conducted as recommended in the protocol Appendix B.
3. BA is not older than CA and should be < 10 for girls and < 11 for boys.
4. Without prior exposure to any recombinant hGH (r-hGH) therapy (naïve patients).
5. Impaired HV defined as:
• Annualized HV below the 25th percentile for CA (HV < -0.7 SDS) and gender according to the OPKO HV (Tanner, Prader and Hermanussen) calculator, provided.
• The interval between 2 Ht measurements should be at least 6 months, but should not exceed 18 months prior to inclusion.
6. Baseline IGF-1 level of at least 1 standard deviation (SD) below the mean IGF-1 level standardized for age and sex (IGF-1 SDS ≤-1)a according to the central laboratory reference values. A single re-test will be allowed (subject to discussion with global study MM) if all other criteria are met.
7. Normal calculated glomerular filtration rate (GFR) based on updated “bedside” Schwartz formula for pediatric patients (calculation is recommended below):
• Creatine Clearance Rate (CrCL) (mL/min/1.73 m2) =0.413 * Ht / serum
creatine (Scr)
- Ht in cm
- Scr in mg/dL
8. Children with multiple hormonal deficiencies must be on stable replacement therapies (no change in dose) for other hypothalamo-pituitary organ axes for at least 3 months prior to ICF signing.
9. Normal 46XX karyotype for girls.
10. Willing and able to provide written informed consent of the parent or legal guardian of the patient and written assent from pediatric patients (where applicable based on age and country regulation). |
|
| E.4 | Principal exclusion criteria |
1. Children with prior history of leukemia, lymphoma, sarcoma or any other forms of cancer.
2. History of radiation therapy or chemotherapy.
3. Malnourished children defined as BMI < -2 SDS for age and sex.
4. Children with psychosocial dwarfism.
5. Children born small for gestational age (SGA – birth weight and/or birth length <-2 SDS for gestational age).
6. Presence of anti-hGH Ab at screening.
7. Any clinically significant (CS) abnormality likely to affect growth or the ability to evaluate growth, such as, but not limited to, chronic diseases like renal insufficiency, spinal cord irradiation, etc.
8. Types 1 and 2 diabetic patients who, in the opinion of the investigator, are not receiving standard of care treatment, or are non-compliant with their prescribed treatment or who are in poor metabolic control.(Criteria for controlled diabetes are defined in Appendix F
9. Chromosomal abnormalities including Turner’s syndrome, Laron syndrome, Noonan syndrome, Prader-Willi syndrome, Russell-Silver syndrome, SHOX mutations/deletions and skeletal dysplasias.
10. Concomitant administration of other treatments that may have an effect on growth such as anabolic steroids, or sex steroids, with the exception of Attention-Deficit/Hyperactivity Disorder (ADHD) drugs or hormone replacement therapies (thyroxin, hydrocortisone, desmopressin [DDAVP®])
11. Children requiring glucocorticoid therapy (e.g. for asthma) that are taking chronically a dose > 400 μg/day of inhaled budesonide or equivalent as provided in Appendix J.
12. Major medical conditions and/or presence of contraindication to r-hGH treatment.
13. More than 1 closed epiphyses
14. Known or suspected Human Immunodeficiency Virus (HIV)-positive patient, or patient with advanced diseases such as Acquired Immunodeficiency Syndrome (AIDS) or tuberculosis.
15. Drug, substance, or alcohol abuse.
16. Known hypersensitivity to the components of study medication.
17. Other causes of short stature such as celiac disease, uncontrolled primary hypothyroidism and rickets.
18. The patient and/or the parent/legal guardian are likely to be non-compliant in respect to study conduct.
19. Participation in any other study of an investigational agent within 30 days prior to ICF signature (including administration of investigational agent).
20. Study enrollment requirements have been met or the study has been closed by the Sponsor prior to the completion of screening process. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Annual Height Velocity (HV) in cm/year |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Baseline and after 12 months of treatment |
|
| E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints (Auxology/Clinical):
• Annualized height velocity after 6 months of treatment
• Change in height SDS at 6 and 12 months, compared to baseline
• Change in bone maturation (BM) at the end of 12 months, compared to Screening bone age (calculated as BA/CA)
Secondary endpoints (Biochemical):
• Absolute IGF-I levels on day 4(-1) after MOD-4023 dosing across study visits
• IGF-I SDS on day 4(-1) after MOD-4023 dosing across study visits
•IGFBP-3 levels and IGFBP-3 SDS on day 4(-1) after MOD-4023 dosing across study visits
Additional Endpoints
•QoL endpoint measured by the QoLISSY core questionnaire at baseline and month 12 or early termination in specific countries per Appendix L.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| 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 | No |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 68 |
| 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 |
| Argentina |
| Australia |
| Belarus |
| Brazil |
| Bulgaria |
| Canada |
| Chile |
| Colombia |
| France |
| Georgia |
| Germany |
| Greece |
| India |
| Israel |
| Italy |
| Mexico |
| Netherlands |
| New Zealand |
| Poland |
| Romania |
| Russian Federation |
| Serbia |
| Spain |
| Taiwan |
| Turkey |
| Ukraine |
| United Kingdom |
| United States |
| Vietnam |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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