E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Growth Hormone Deficiency |
|
E.1.1.1 | Medical condition in easily understood language |
lack of Growth Hormone in the body |
|
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 | 14.0 |
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 | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the safety, tolerability and Pharmacokinetics/
Pharmacodynamics (PK/PD) profile of three doses of MOD-4023 on a
weekly regime and one dose on an EOW regime administered for a
period of 4 weeks in Growth Hormone Deficient Adult (GHDA)
patients who previously were on a stable r-hGH treatment. |
|
E.2.2 | Secondary objectives of the trial |
1. To select the optimal dose and dosing regimen of MOD-4023
for the subsequent phase III study on the basis of safety and
PK/PD profile after 4 and 16 weeks of treatment.
2. To assess the long term safety and tolerability of MOD-4023
after 16 weeks dose administration.
3. To develop a population PK and PK/PD relationship model
that may be utilized in later studies to predict PK
concentrations for the PK/PD modeling and to simulate and
explore various dosing regimen scenarios for further
Prolor-Biotech studies.
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Genders Eligible for Study: Both
Ages Eligible for Study: Males - 23 to 60 years, Females – 23 to 50
years.
1. GHDA subjects as defined in the Consensus guidelines for the
diagnosis and treatment of adults with GH deficiency II
(2007).
2. Patients using hormonal replacement therapy(s) for
deficiencies of other hypothalamo-pituitary axes must be on an
optimized and stable treatment regimen (hormone levels within
normal ranges on screening) for at least three months prior to
screening:
a. Temporary adjustment of glucocorticoid replacement
therapy, as appropriate, is acceptable.
b. Peripheral thyroid hormones (FT4, FT3) within the
normal range.
3. Fertile females must agree to use appropriate contraceptive
methods
4. Female patients must have a negative serum pregnancy test at
inclusion.
5. GH replacement therapy for more than 6 months with
registered GH product.
6. The IGF-I level at screening within -2 to +2 SDS of the age
and sex normal ranges according to the central laboratory
measurements.1
7. Body Mass Index (BMI, kg/m2) of 19.0 to 35.0 kg/m2, both
inclusive
8. Confirmed to be negative for anti r-hGH antibodies at the time
of screening.
9. Willing and able to provide written informed consent prior to
performing any study procedures. |
|
E.4 | Principal exclusion criteria |
Females who are pregnant or breast-feeding
2. Evidence of growth of pituitary adenoma or other intracranial
tumor within the last 12 months (confirmed by computer
tomography (CT) or magnetic resonance imaging (MRI) scan
(with contrast) within 3 months prior to study entry or at
screening).
3. History of malignancy other than i) cranial irradiation (for
cranial tumor or leukemia) causing GHD or ii) fully treated
basal cell carcinoma
4. Signs of intracranial hypertension at screening
5. Heart insufficiency, NYHA class greater than 2
6. History of impaired glucose tolerance, insulin resistance or
overt diabetes mellitus defined according to the American
Diabetes Association (ADA) Criteria
7. Impaired liver function defined as elevation of liver enzymes >2
x upper limit of normal
8. Impaired kidney function defined as increased serum creatinine
levels >1.5 x upper limit of normal
9. Active acromegaly in the last 18 months and less than 6 months
of active r-hGH replacement therapy
10. Active Carpal tunnel syndrome
11. Prader-Willi syndrome
12. Active Cushing's syndrome within the last 12 months
13. Systemic corticosteroids other than in replacement doses within
the 3 months before study entry (temporary adjustment of
glucocorticoids, as appropriate, is acceptable)
14. Anabolic steroids other than gonadal steroid replacement
therapy within 2 months before study entry
15. History of non-compliance with medications, uncooperativeness
or drug abuse
16. Blood donation or any major blood loss >500 mL within the
past 90 days prior to study entry
17. Patients who, based on the investigator’s judgment, have a
clinically significant or unstable medical or surgical condition
that may preclude safe and complete study participation.
Conditions may include cardiovascular, peripheral vascular,
pulmonary, hepatic, renal, or neurological disease, as
determined by medical history, physical examination,
laboratory tests or ECG
18. Patients who participated in any investigational medicinal
product (IMP) study within the last 2 months
19. History of positive serology to HBC, HBV and HIV |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint will be the mean time interval of IGF-I
levels that lay within ±1.5 SDS after the last dose administration during
stage I expressed in hours.
|
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints:
1. Change of IGF-I levels over time in stage I and stage II expressed in
absolute and SDS values
2. Change of IGF-PB3 over time in stage I and stage II expressed in
absolute and SDS values
3. Number of patients achieving normalization of IGF-1 during dose
titration in stage II
Safety assessments will consist of monitoring and recording:
1. Adverse events throughout the study
2. Immunogenicity of MOD 4023 (development of neutralizing
antibodies)
3. Changes in vital signs and physical examination
4. Change in body weight
5. Fundoscopy for the occurrence of increased intracranial
pressure
6. Change in the parameters of glucose metabolism:
a. Fasting insulin level
b. Fasting glucose levels
c. HbA1c levels
7. Status of other hormonal axes:
a. Thyroid hormones (free T4 and TSH)
b. Cortisol levels
8. Laboratory parameters, including serum chemistry profile,
liver enzymes, hematology, lipoproteins and urinalysis
9. Local tolerability (Injection site reaction)
10. Relationship of IGF-I and IGFBP3 changes
PK/PD endpoints:Blood samples for analysis of serum concentrations will be collected
prior to dosing with the investigational product and at additional time
points after dosing. All serum samples from subjects who received
MOD-4023 will be analyzed for parent drug using a validated bio
analytical method. Pharmacokinetic parameters will be calculated
using standard methods. Analyses of dose proportionality and other
pertinent comparisons of pharmacokinetic parameters across or
between dosage levels will be performed, using appropriate statistical
methods.
The pharmacodynamics of MOD-4023 will be assessed by examining
blood levels of insulin-like growth factor-1 (IGF-I) and insulin-like
growth factor binding protein 3 (IGFBP-3). Analyses of dose
proportionality and other pertinent comparisons of pharmacodynamics
parameters across or between dosage levels will be performed, using
appropriate statistical methods. In Period II, exploratory analyses of
the clinical endpoints will also be performed.
A population PK and PK/PD modeling will be performed. The final
PK model will be used to predict PK concentrations for the PK/PD
modeling and to simulate and explore various dosing regimen
scenarios to support the design of future clinical studies with MOD-
4023. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
at the end of Stage I and Stage II |
|
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 | No |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
|
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.8.3 |
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 | 17 |
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 | Information not present in EudraCT |
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 |
Czech Republic |
Hungary |
Israel |
Serbia |
Slovakia |
Slovenia |
|
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
|
last visit of the last subject |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 0 |