| 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 | 14.1 |
| 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 | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of this study is to evaluate the clinical effect of weekly doses of TV-1106, as measured by the change from baseline in IGF-I, in GHD adults following 12 weeks of treatment. |
|
| E.2.2 | Secondary objectives of the trial |
To assess the extent of the adult GHD patient population that responds positively to weekly TV-1106 as demonstrated by an increase in IGF-I standard deviation score (SDS)
To determine the effect of long-term TV-1106 treatment on maintenance of or improvement in the lipid profile of adult GHD patients treated with TV-1106 for 64 weeks |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.) Patient agrees to provide written informed consent and to comply with the study protocol after reading the informed consent and discussing the study with the investigator.
2.) Males and females between 23 and 65 years of age must have a confirmed diagnosis of adult GHD, either adult onset (AO) GHD due to hypothalamic-pituitary disease or childhood onset (CO) GHD that is either idiopathic or due to hypothalamic-pituitary disease or due to genetic causes.
3.) Diagnosis of GH deficiency must be confirmed by documented (medical records) diagnostic testing specified by an accepted guidance (e.g., GH Research Society Consensus guidelines for the diagnosis and treatment of adults with GH deficiency 2007; AACE Clinical Practice Guidelines 2009; Endocrine Society Clinical Practice Guidelines Molitch et.al. 2006 and 2011) in effect at the time of
diagnosis. |
|
| E.4 | Principal exclusion criteria |
1.)Patients with history or clinical evidence of active or chronic diseases that could confound results of the study or put the subject at undue risk as determined by the investigator.
2.) Patients with known active malignancy
3.) Patients with history of malignancy other than intracranial tumor causing GHD (excluding surgically cured basal cell or squamous cell cancer of the skin with documented 6 month remission)
4.) Patients with evidence of pituitary adenoma or other intracranial tumor within 12 months of enrollment, which is on day 0 (baseline, Visit 3)
5.) Patients without magnetic resonance imaging (MRI) or computerized tomography (CT) data to document tumor stability within the 12 months prior to enrollment, which is on day 0 (baseline, Visit 3) (NOTE: please see Restrictions – Medical History, Section 5.2)
6.) 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.
7.) Patients with known history of severe allergic or anaphylactic reactions
8.) Patients with known allergy or hypersensitivity to rhGH, HSA, yeast-derived products, or any other component of the formulation
9.) Patients with antibodies to hGH following the washout period.
10.) Patients who will require a dose of the study drug (TV-1106) in excess of 50 mg/week or of Genotropin® in excess of 1.8 mg/day at baseline visit.
11.) Patients who have had 1 of the following conditions in the noted amount of time prior to screening or between screening and first dosing day: major trauma or surgery within 6 months; acute infection requiring systemic antibiotic treatment within 4 weeks; any acute, severe illness within 6 months
12.) Patients with history of documented increased intracranial pressure (ICP) associated with GH treatment or signs of increased ICP including papilledema based on fundoscopic exam performed by investigator or ophthalmologist during screening.
13.) Patients who have participated in another clinical trial with a new
chemical/biological entity within 3 months of screening
14.) Patients who have clinically significant abnormal electrocardiogram (ECG) as determined by the investigator
15.) Patients with blood pressure (treated) outside the ranges 90 to 139 or mHg systolic or 45 to 89 mmHg diastolic, inclusive.
16.) Patients with abnormal levels [greater than x2 the upper limit of normal (ULN)] of alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT) or total bilirubin at screening or baseline
17.) Patients with known history of or confirmed positive test results for human immunodeficiency virus (HIV) types 1 and 2 at screening
18.) Patients with known history of or a positive test result for hepatitis B (HBsAg) or hepatitis C virus (HCV) at screening
19.) Patients using weight reducing agents or appetite suppressants.
20.) Patients with persistent or recurring migraines, edema, arthralgias (not due to osteoarthritis), myalgias, carpal tunnel syndrome, paresthesias, or other nerve compression symptoms.
21.) Patients with diagnosis of diabetes mellitus or patients with impaired fasting blood glucose (100 – 125 mg/dL, inclusive).
22.) Women who are pregnant or nursing at the time of screening or who intend to be during the study period.
23.) 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. skin creams, eyedrops).
Inhaled budesonide will be permitted at a monthly consumption not to exceed 400 μg/day for 3 days (total 1200 μg/month).
24.) Patients with proliferative retinopathy or severe non-proliferative retinopathy.
25.) Patients with a malignant appearing skin lesion unless it has been evaluated by a dermatologist and confirmed to be non-malignant.
26.) Patients with history of alcoholism or with history or evidence of drug/chemical abuse.
27.) Patients with a psychological condition which may influence compliance with the study requirements. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy variable for this study is IGF-I
concentration (ng/ml). The primary endpoint is the change from baseline in IGF-I SDS to Cmax
level during week 12, for patients treated with TV-1106. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
The secondary efficacy variables and endpoints for this study are as follows:
1. The percentage of patients, treated with TV-1106, who return by the trough level of
IGF-I SDS during study week 12 to their pre-washout (screening) IGF-I SDS level
(± 0.5 SDS) and their Cmax level during week 12 is below +2.0 SDS.
2. Lipid profile assessed by measurement of lipoprotein (a), triglycerides and LDL,
HDL, and total cholesterol after 64 weeks of TV-1106 treatment |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.The percentage of patients, treated with TV-1106, who return by the trough level of
IGF-I SDS during study week 12 to their pre-washout (screening) IGF-I SDS level
(± 0.5 SDS) and their Cmax level during week 12 is below +2.0 SDS.
2.Lipid profile assessed by measurement of lipoprotein (a), triglycerides and LDL,
HDL, and total cholesterol after 64 weeks of TV-1106 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 | No |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| 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 | 31 |
| 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 |
| Czech Republic |
| Denmark |
| France |
| Germany |
| Greece |
| Hungary |
| Slovakia |
| Slovenia |
| Sweden |
|
| 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
|
| Trial will be concluded after a telephone follow up two weeks after the final visit. |
|
| 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 | 1 |
| 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 | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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