Safety and Efficacy Phase 2 Study of Long-acting hGH (MOD-4023) in Growth Hormone Deficient Children

Safety and Dose Finding Study of Different MOD-4023 Dose Levels Compared to Daily r-hGH Therapy in Pre-pubertal Growth Hormone Deficient Children

This is a phase II, open label, active-controlled, randomized safety and dose finding study of different MOD-4023 dose levels compared to daily r-hGH therapy in pre-pubertal growth hormone deficient children.

Inclusion Criteria:

1. Pre-pubertal child aged ≥ 3 yrs old and not above 10 years for girls or 11 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 ≤7 ng/ml, determined by central laboratory using a validated assay .

3. Bone age (BA) is not older than chronological age and should be no greater than 9 years for girls and 10 years for boys.

4. Without prior exposure to any r-hGH therapy.

5. Normal birth size, birth weight and length for gestational age

6. Impaired height and height velocity defined as:

   1. Height (HT) of at least 2.0 standard deviations (SD) below the mean height for chronological age (CA) and gender according to the standards from Prader et. al, 1989 , (HT SDS ≤ -2.0).
   2. Annualized height velocity (HV) below the 25th percentile for CA (HV <-0.7 SDS) and gender according to the standards of Prader et al (1989). The interval between two height measurements should be at least 6 months before inclusion.

7. BMI must be within ±2 SD of mean BMI for the chronological age and sex according to the 2000 CDC standards.

8. Baseline IGF-I level of at least 1 SD below the mean IGF-I level standardized for age and sex (IGF-I SDS ≤ -1.0) according to the central laboratory reference values;

9. 12. Written informed consent of the parent or legal guardian of the patient and assent of the patient (if the patient can read).

Exclusion Criteria:

1. Children with past or present intracranial tumor growth as confirmed by an MRI scan (with contrast).

2. History of radiation therapy or chemotherapy.

3. Malnourished children defined as:

   1. Serum albumin below the lower limit of normal (LLN) according to the reference ranges of central laboratory;
   2. Serum iron below the lower limit of normal (LLN) according to the reference ranges of central laboratory;
   3. BMI < -2 SD for age and sex;

4. Children with psychosocial dwarfism.

5. Children born small for gestational age (SGA - birth weight and/or birth length < -2 SD 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. Patients with diabetes mellitus.

9. Patients with impaired fasting sugar (based on WHO; fasting blood sugar >110 mg/dl or 6.1 mmol/l) after repeated blood analysis.

10. Chromosomal abnormalities and medical "syndromes" (Turner's syndrome, Laron syndrome, Noonan syndrome, Prader-Willi Syndrome, Russell-Silver Syndrome, SHOX mutations/deletions and skeletal dysplasias), with the exception of septo-optic dysplasia.

11. Closed epiphyses.

12. Concomitant administration of other treatments that may have an effect on growth such as anabolic steroids and methylphenidate for attention deficit hyperactivity disorder (ADHD), with the exception of hormone replacement therapies (thyroxine, hydrocortisone, desmopressin (DDAVP))

13. Children requiring glucocorticoid therapy (e.g. asthma) who are taking a dose of greater than 400 µg/d of inhaled budesonide or equivalents for longer than 1 month during a calendar year.

14. Major medical conditions and/or presence of contraindication to r-hGH treatment.

15. Known or suspected HIV-positive patient, or patient with advanced diseases such as AIDS or tuberculosis.

16. Drug, substance, or alcohol abuse.

17. Known hypersensitivity to the components of study medication.

18. Other causes of short stature such as coeliac disease, hypothyroidism and rickets.

19. The patient and/or the parent/legal guardian are likely to be non-compliant in respect to study conduct.

20. Participation in any other trial of an investigational agent within 30 days prior to Screening.