| 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 |
| Growth hormone deficiency (GHD) is a medical condition, caused by problems arising in the pituitary gland, in which the body does not produce enough growth hormone (GH). |
|
| 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 | 18.0 |
| 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 | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of this study is to compare the safety and tolerability of weekly TV-1106 with daily Genotropin. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary Objectives: The secondary objective of this study is to assess and compare weekly TV-1106 with daily Genotropin with regard to pharmacodynamic (IGF-I SDS) and exploratory efficacy variables and endpoints.
Exploratory Objectives: To assess and compare quality of life (QOL), injection experience satisfaction, and compliance of weekly TV-1106 with daily Genotropin. To explore potential correlation between genetic polymorphisms and response to TV-1106 (eg, pharmacokinetic, tolerability, and safety features) compared with Genotropin. To explore potential pharmacodynamic markers (as well as those in the secondary objective). |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Pharmacogenomic substudy:
Patients who have consented to participate in the voluntary PGx substudy will have blood samples collected at visit 2 (or subsequent visits). The samples will be stored for use in analysis for the assessment of possible associations between genetic polymorphisms and response to TV-1106 in terms of safety, pharmacokinetic and pharmacodynamic parameters. Evaluations will be based on results obtained from the patients as a phenotypic group. |
|
| E.3 | Principal inclusion criteria |
Patients may be included in the study if they meet all of the following criteria:
a. provision of written informed consent and agreement to comply with study requirements
b. males and females 18 years of age or over
c. body mass index (BMI) between 19 and 35 kg/m2 inclusive
d. diagnosis of adult GHD for at least 6 months, confirmed by medical record diagnostic testing specified by an accepted guidance (eg, Carroll 1998; Cook 2009; Ho 2007; Molitch 2011) in effect at the time of diagnosis or patients who have hypopituitarism from surgical resection
e. treated with a stable dose of daily rhGH for at least 3 months prior to screening
f. IGF-I SDS level between -0.5 and +1.5 at screening
g. stable, adequate doses of replacement hormones (adrenal, thyroid, estrogen, testosterone, vasopressin) for at least 3 months prior to screening as clinically judged by the investigator to be adequate patients who are not receiving glucocorticoid replacement therapy must have adequate adrenal function confirmed by adrenocorticotropic hormone (ACTH) stimulation test at screening
i. women of child-bearing potential must be willing to use a medically accepted method of contraception for the duration of the study and for 30 days after last study treatment. Acceptable methods of contraception include: double barrier method (condom or diaphragm with spermicide), intrauterine device (IUD), partner’s vasectomy, or steroidal contraceptive (oral, transdermal, implanted, injected). Patients who are gonadotropin deficient, surgically sterile, or at least 1 year post-menopausal are not required to use contraception. |
|
| E.4 | Principal exclusion criteria |
Patients will be excluded from participating in this study if they meet 1 or more of the following criteria:
a. patients with acute or chronic conditions or diseases that could confound results of the study or put the patient at undue risk as determined by the investigator
b. patients who have participated in another clinical trial with a new chemical/biological entity within 3 months of screening
c. patients with known active malignancy (excluding surgically removed basal cell carcinoma or carcinoma in situ of cervix)
d. patients with a previously treated pituitary tumor with evidence of tumor progression in the past year (evidence will be established by magnetic resonance imaging [MRI] or computerized tomography [CT] obtained within 3 months of screening or at screening. Patients will be excluded if they show any progression from a prior scan taken at least 12 months prior to the current scan).
e. patients with a new diagnosis of pituitary adenoma or other intracranial tumor within 12 months of screening
f. presence of Prader-Willi syndrome, Turner’s syndrome, untreated adrenal insufficiency, active acromegaly in the past 5 years, or active Cushing’s syndrome in the past year.
g. patients with known allergy or hypersensitivity to rhGH, human serum albumin (HSA), yeast-derived products, or any other component of the formulation
h. patients with previous signs or history of increased intracranial pressure (ICP) with rhGH treatment, or documented ICP or signs of ICP on fundoscopic examination at the time of screening (may be performed by investigator or referred to an ophthalmologist) (patients with previous history of ICP due to treated tumors that have resolved can be included in the study.)
i. patients with severe, clinically significant, persistent or recurring migraines, edema, or history or presence of carpal tunnel syndrome, or other nerve compression symptoms assessed as clinically important by the investigator
j. patients with untreated or poorly controlled stage 2 hypertension (systolic blood pressure [SBP] ≥150 mmHg and/or diastolic blood pressure [DBP] ≥90 mmHg).
k. patients with clinically significant abnormalities on the screening laboratory assessments, electrocardiogram (ECG), or physical examination that would confound the interpretation of the study or put the patient at undue risk of participation in the study as determined by the investigator
l. patients with type 1 diabetes mellitus or poorly controlled type 2 diabetes mellitus as indicated by a glycated hemoglobin (HbA1c) ≥8%
m. patients who use anabolic steroids or corticosteroids, except for physiological maintenance doses used as treatment for patients with hormone deficiencies (limited use of low dose glucocorticoid preparations is allowed [eg, topical preparations]; inhaled budesonide will be permitted at a dose not to exceed 400 μg/day for 3 days [total <1200 μg/month] or equivalent.)
n. patients using weight reducing agents or appetite suppressants
o. women who are pregnant or nursing, or planning pregnancy during the study period
p. patients with active or known history of substance abuse that in the investigator’s opinion would affect compliance with the study
q. patients with known tendency to have injection site lipoatrophy |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety Variables and Endpoints:
- adverse event reports throughout the study
- clinical laboratory test results
- vital sign measurements
- ECG findings and physical examination findings
- concomitant medication usage throughout the study
- changes in replacement hormones (thyroid-stimulating hormones [TSH], free T4, total T3)
- glucose homeostasis (HbA1c, fasting blood glucose, and insulin)
Tolerability Variables and Endpoints:
- proportion of patients who prematurely discontinue treatment
- proportion of patients who prematurely discontinue treatment due to adverse events
- time to premature treatment discontinuation
- time to premature treatment discontinuation due to adverse events
- proportions of patients with injection site reactions
- proportion of patients with occurrence of lipoatrophy |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Efficacy Variables and Endpoints:
- IGF-I SDS
- QOL: QOL in Adult Growth hormone-deficiency Assessment (QOL-AGHDA) and
EuroQol 5D (EQ5D-5L) questionnaires
- patient satisfaction/experience with injections
- adherence/compliance
- lipid profile |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| 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 | 73 |
| 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 |
| Austria |
| Brazil |
| Bulgaria |
| Canada |
| Chile |
| Croatia |
| Czech Republic |
| France |
| Georgia |
| Germany |
| Greece |
| Hungary |
| Israel |
| Italy |
| Lithuania |
| Mexico |
| Peru |
| Poland |
| Romania |
| Russian Federation |
| Serbia |
| Slovakia |
| Slovenia |
| Spain |
| Sweden |
| Turkey |
| Ukraine |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
LVLS
Patients who complete the study will be contacted via telephone call 2 weeks after the final dose of study drug (2 weeks after the end of the study) for safety follow up. |
|
| 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 | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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