Safety and Efficacy Phase 3 Study of Long-acting hGH (MOD-4023) in Growth Hormone Deficient Children

This will be an open-label, randomized, multicenter, efficacy and safety study of weekly MOD-4023 compared to daily Genotropin therapy in pre-pubertal children with growth hormone deficiency.

The study will consist of a 12 month, open-label, randomized, active controlled, parallel group study comparing the efficacy and safety of weekly MOD-4023 to daily growth hormone (GH), Genotropin. After 12 months, subjects will have the option to enter the long term open-label extension.

Eligibility Criteria:
Main Study Inclusion Criteria:

1. Pre-pubertal children aged ≥3 years , and not yet 11 years for girls or not yet 12 years for boys with either isolated GHD, or GH insufficiency as part of multiple pituitary hormone deficiency.
2. Confirmed diagnosis of GHD by two different GH provocation tests defined as a peak plasma GH level of ≤10 ng/mL.
3. Bone age (BA) is not older than chronological age and should be less than 10 for girls and less than 11 for boys.
4. Without prior exposure to any r-hGH therapy (naïve patients).
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 sponsor calculator
   * The interval between 2 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-1 level standardized for age and sex (IGF-1 SDS ≤-1)
7. Normal calculated GFR per updated bedside Schwartz formula for pediatric patients
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 and written assent from patient

    LT-OLE Inclusion Criteria:
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 and written assent from patient
13. Agree to refrain from sexual activity

Main Study 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 antibodies at screening
7. Any clinically significant 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.
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)
11. Children requiring glucocorticoid therapy (e.g. for asthma) that are taking chronically a dose greater than 400 μg/d of inhaled budesonide or equivalent
12. Major medical conditions and/or presence of contraindication to r-hGH treatment.
13. More than one 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. Likely non-compliance in respect to study conduct
19. Participation in any other trial of an investigational agent within 30 days prior to consent
20. Study enrollment has been met or study is closed by sponsor prior to completion of screening process.

    LT-OLE Exclusion Criteria:
21. 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 HRT (thyroxin, hydrocortisone, desmopressin)
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 (Genotropin or MOD-4023) SAE from the treatment period as per medical monitor judgement.