| 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 | 18.1 |
| 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 determine the efficacy of 6 months of treatment with TV-1106 compared with placebo on body fat composition. |
|
| E.2.2 | Secondary objectives of the trial |
| The secondary objectives of the study are to assess additional body composition measures, insulin-like growth factor 1 standard deviation score (IGF-I SDS), quality of life (QOL), the safety, and tolerability of treatment, pharmacokinetics, pharmacokinetic/pharmacodynamic analysis, and pharmacogenomics (PGx) with TV-1106. |
|
| 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 |
Pharmacogenomics 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 of the assessment for 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. no history of exposure to any rhGH within the past 12 months prior to screening
f. IGF-I SDS level less than -1.0 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
h. patients 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 participation in the study (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 1 year
g. patients with known allergy or hypersensitivity to rhGH, HSA, yeast-derived products, or any other component of the formulation
h. patients who are unable to undergo scanning by dual-energy x-ray absorptiometry (DXA) (eg, due to excessive body weight or implanted devices which would interfere with DXA)
i. 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.
j. 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
k. patients with untreated or poorly controlled stage 2 hypertension (systolic blood pressure [SBP] ≥150 mmHg and/or diastolic blood pressure [DBP] ≥90 mmHg)
l. 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.
m. patients with type 1 diabetes mellitus or poorly controlled type 2 diabetes mellitus as indicated by a glycated hemoglobin (HBA1c) of ≥8%
n. 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.
o. patients using weight reducing agents or appetite suppressants
p. women who are pregnant or nursing, or planning pregnancy during the study period
q. patients with active or known history of substance abuse that in the investigator’s opinion would affect compliance with the study
r. patients with known tendency to have injection site lipoatrophy |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Efficacy Variables and Endpoints:
The primary endpoint is the change from baseline to week 24 in body fat mass (kg) as measured by DXA.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Efficacy Variables and Endpoints:
The secondary efficacy variables and endpoints for this study are as follows:
- change from baseline to week 24 in total trunk fat (kg) as measured by DXA
- change in IGF-I SDS from baseline to week 24
- change in QOL scores from baseline to week 24 by questionnaire (assessment of GHD in adults [AGHDA])
Other Efficacy Variables and Endpoints:
- change from baseline to week 24 in lean body mass (DXA), percentage body fat (DXA), percentage trunk fat (DXA), and percentage change in trunk fat (DXA)
- proportion of patients with IGF-I SDS within the normal range (-0.5 to +1.5) at week 24
The following endpoints will be analyzed for all patients, and although all patients will receive TV-1106 during the 12-month extension phase, data will be analyzed by the original treatment assignment:
- change from baseline to weeks 24, 48, and 72 in total trunk fat (DXA), lean body mass (DXA), percentage body fat (DXA), percentage trunk fat (DXA), and percentage change in trunk fat from week 24 through 72
- change in IGF-I from baseline to week 24, week 48, and week 72 (IGF-I SDS)
- change in lipids between baseline to week 24 and week 72 (as measured by total cholesterol, low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, triglycerides, and lipoprotein)
- change from baseline to week 48in QOL as measured by questionnaire (AGHDA) scores
Exploratory Efficacy Variables and Endpoints:
- change from baseline in QOL as measured by questionnaire (EQ5D-5L) scores and injection satisfaction questionnaire at all other time points
Safety Variables and Endpoints:
Safety variables and endpoints will include the following:
- 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 hormone [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
- proportion of patients with injection site reactions (patient questionnaire)
- proportion of patients with lipoatrophy |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Week 24, 48 and 72 or throughout the study - as specified above. |
|
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 70 |
| 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 |
| Belarus |
| 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 |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 9 |
| 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 | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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