E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Growth hormone deficiency in pre-pubertal children |
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E.1.1.1 | Medical condition in easily understood language |
Treatment of children with growth failure due to growth hormone deficiency |
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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 |
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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 |
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E.2.2 | Secondary objectives of the trial |
To evaluate the safety and tolerability of weekly MOD-4023 administration.
To demonstrate LT safety and efficacy of MOD-4023 in an OLE |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Pre-pubertal children aged ≥3 yrs old 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 deficiencies.
2. Confirmed diagnosis of GHD by two different GH provocation tests defined as a peak plasma GH level of ≤10 ng/ml, determined by local (if done prior to signing the ICF) or central laboratory using a validated assay. Prior local laboratory results will be accepted subject to pre-approval by Sponsor Global Medical Monitor and if the tests were conducted according to one of the protocols in Appendix B.
3. Bone age (BA) is not older than chronological age and should be less than 10 for females and less than 11 for males.
4. Without prior exposure to any r-hGH therapy.
5. Impaired height and height velocity defined as:
- Annualized height velocity (HV) below the 25th percentile for CA (HV < -0.7 SDS) and gender according to OPKO HV (Tanner, Prader and Hermanussen) calculator provided.
- The interval between two height measurements should be at least 6 months, but should not exceed 18 months prior to inclusion.
6. Baseline IGF-I level of at least 1 SD below the mean IGF-I level standardized for age and sex (IGF-I SDS ≤ -1) according to the central laboratory reference values. A single re-test will be allowed (subject to discussion with medical monitor) if all other criteria are met.
7. Normal calculated GFR based on updated “bedside” Schwartz formula for pediatric patients (recommended calculation is provided below):
CrCL (mL/min/1.73 m2) =0.413 * Ht / Scr
Ht: height in cm;
Scr: serum creatinine 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 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).
Inclusion into the LT-OLE:
11. Completion of the main study (12 months of treatment) with adequate compliance.
12. 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).
13. Agreement to refrain from sexual activity during the LT-OLE i.e. observe complete sexual abstinence as the only acceptable contraceptive measure during the LT-OLE (for pubertal and post-pubertal patients). |
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E.4 | Principal exclusion criteria |
1. Children with prior history of leukemia, lymphoma, sarcoma or any other form 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 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. T2 and T1 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 of the protocol.
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 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 greater than 400 μg/day of inhaled budesonide or equivalent as described in Appendix J of the protocol.
12. Major medical conditions and/or presence of contraindication to r-hGH treatment
13. More than 1 closed epiphyses
14. Known or suspected HIV-positive patient, or patient with advanced diseases such as 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
Exclusion during the LT-OLE:
21. Concomitant administration of other treatments that may have an effect on growth such as anabolic steroids, or sex steroids (other than for hormonal replacement), with the exception of ADHD drugs or hormone replacement therapies (thyroxin, hydrocortisone, testosterone, estrogen/progesterone, desmopressin [DDAVP®])
22. Change in medical condition during the treatment period (such as, but not limited to, development of a serious inter-current critical illness, a severe adverse drug reaction, etc.)
23. Positive pregnancy test. 24. Unresolved drug related (MOD-4023 or Genotropin®) SAE from the treatment period as per MM judgement |
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E.5 End points |
E.5.1 | Primary end point(s) |
Annual (HV) in cm/year after 12 months of treatment. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Baseline and after 12 months of treatment |
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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 Baseline BA (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
LT-OLE Endpoints:
Safety Endpoints
• Incidence of AEs and SAEs;
• Incidence of anti-MOD-4023 Ab formation (including characterization of the Ab and neutralizing properties);
• Local injection site reaction assessment;
• Parameters of glucose metabolism: blood fasting glucose, fasting insulin level, HbA1c;
• Thyroid (endocrinology) status;
• Lipid profile;
• All other safety hematology, biochemical parameters and urinalysis;
• Physical examination;
• Fundoscopy results - if performed (normal/abnormal);
• Vital signs;
• ECG.
Auxology/Clinical Endpoints
• Annual HV in cm/year at each 12-month interval.
• Change in height SDS every 12 months (compared to the previous values).
• Change in bone maturation (BM) every 12 months, (compared to Week 52 BA (calculated as BA/CA) at completion of LT-OLE year 1 and to previous values from LT-OLE year 2 onwards).
Biochemical Endpoints
• IGF-1 and IGF-1 SDS levels 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. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | 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 | 2 |
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 |
Bulgaria |
Canada |
Colombia |
France |
Georgia |
Greece |
India |
Israel |
Mexico |
New Zealand |
Poland |
Romania |
Russian Federation |
Spain |
Taiwan |
Turkey |
Ukraine |
United Kingdom |
United States |
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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
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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 | 1 |
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 |