| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pediatric Growth Hormone Deficiency |
|
| E.1.1.1 | Medical condition in easily understood language |
| Lack of Growth Hormone in Children |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Hormonal diseases [C19] |
| MedDRA Classification |
| 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 compare the safety, efficacy and tolerability of three MOD-4023
doses to that of a commercially available standard daily recombinant human growth hormone (r-hGH) formulation, in pre-pubertal children with growth failure due to insufficient secretion of endogenous growth hormone. |
|
| E.2.2 | Secondary objectives of the trial |
1.To evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) profiles of 3 different doses of MOD-4023 in pre-pubertal growth hormone deficient (GHD) children.
2.To select the optimal dose of MOD-4023 for the subsequent phase III study on the basis of safety and efficacy. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 ≤10 ng/ml, determined by central laboratory using a validated assay. If the patient has already been tested locally and reserve samples that were taken at appropriate time-points are available, these will be reanalyzed by the central laboratory. Historical tests missing the -30 minutes time point will be accepted. If no reserve samples are kept (only for tests performed prior to site initiation), then the details of the locally performed tests will be reviewed by the Coordinating Investigator: if the results cannot be
accepted, the patient will undergo both stimulation tests during the screening period and the samples will be analyzed by the central laboratory. At least one of the two stimulation tests (and preferably both) will be analyzed by the central laboratory. If the patient requires sex hormone priming (due to the age), and both stimulation tests must be performed during the Screening (no historical samples kept, or test was without priming), it is recommended to perform stimulation tests in consecutive setting in one day, or in two consecutive days, to avoid priming the patient twice. Local historical tests without sex-steroid priming will not be accepted for patients that require sex steroid priming according to the protocol.
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.Impaired height and height velocity defined as:
a.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).
b.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, but should not exceed 18 months prior to inclusion.
6.BMI must be within ±2 SD of mean BMI for the chronological age and sex according to the 2000 CDC standards.
7.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;
8.Children with normal fundoscopy (ophthalmoscopy) at screening (without signs/symptoms of intracranial hypertension as assessed by fundoscopy);
9.Children with multiple hormonal deficiencies must be on stable replacement therapies for other hypothalamo-pituitary-organ axes for at least 3 months and 6 months for thyroid replacement therapy prior to the first study drug administration;
10.Normal 46 XX karyotype for girls
11. Written informed consent of the parent or legal guardian of the patient and assent of the patient for the Main study and for the OLE. |
|
| E.4 | Principal 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:
a.Serum albumin below the lower limit of normal (LLN) according to the reference ranges of central laboratory;
b.Serum iron below the lower limit of normal (LLN) according to the reference ranges of central laboratory;
c.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.Children with idiopathic short stature.
7.Presence of anti-hGH antibodies at screening.
8.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.
9.Patients with diabetes mellitus.
10.Patients with impaired fasting sugar (based on WHO; fasting blood sugar >110 mg/dl or 6.1 mmol/l) after repeated blood analysis.
11.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.
12.Closed epiphyses.
13.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))
14.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.
15.Major medical conditions and/or presence of contraindication to r-hGH treatment.
16.Known or suspected HIV-positive patient, or patient with advanced diseases such as AIDS or tuberculosis.
17.Drug, substance, or alcohol abuse.
18.Known hypersensitivity to the components of study medication.
19.Other causes of short stature such as coeliac disease, hypothyroidism and rickets.
20.The patient and/or the parent/legal guardian are likely to be non-compliant in respect to study conduct.
21.Participation in any other trial of an investigational agent within 30 days prior to Screening.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Annual Height Velocity in cm/year at 12 months (Baseline – Visit 1). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 12 months after the Screening |
|
| E.5.2 | Secondary end point(s) |
Auxology/Clinical:
Height velocity at 6 months (Baseline – Visit 1).
Delta height SDS at 6 and 12 months (compared to Visit 1/Baseline value).
Biochemical:
Absolute IGF-I levels on day 4 after MOD-4023 dosing.
IGF-I SDS on day 4 after MOD-4023 dosing.
Other exploratory endpoints Main study and OLE):
IGFBP-3 levels on day 3 or 4 after MOD-4023 dosing.
Bone maturation every 12 months of treatment throughout (Main and OLE).
OLE endpoints:
Annual Height Velocity in cm/year at each 12 months interval.
Delta height SDS every 12 months (compared to the previous value). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Clinical:
6 and 12 months after the Screening
Biochemical:
day 4 after MOD-4023 dosing
Other:
-day 4 after MOD-4023 dosing
-after 12 months of treatment
OLE:
-after 12 months of treatment |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | 4 |
| 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 | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 2 |
| 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 |
| Belarus |
| Greece |
| Hungary |
| Russian Federation |
| Ukraine |
| United States |
|
| 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
|
The Main study is expected to end when all required patients have been enrolled and the last patient has completed the Main study (first 12 months of treatment) and the query resolution has been completed and clinical study report (CSR) has been compiled.
The OLE is expected to end when marketing approval is received in countries where the study was conducted. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
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