TV1106-IMM-30021

Teva Pharmaceutical Industries Ltd.

5 Bazel St., Petach Tikva, Israel, 49131

Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., 001 215-591-3000, info-era-clinical@teva.de

Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., 001 215-591-3000, info-era-clinical@teva.de

No

No

No

Final

01 Sep 2016

No

Yes

18 Dec 2015

Yes

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. Based on evolving data from the two ongoing global Phase III studies in adults (TV1106-IMM-30021 and -30022) and the ongoing pediatric Phase II study (TV1106-IMM-20001) and as well as the recently completed adult Phase II study (TV1106-GHD-201), the Sponsor Teva Pharmaceuticals Ltd. reassessed the benefit/risk balance of TV-1106 and the likelihood of regulatory success for TV-1106. As a consequence of this reassessment, the Sponsor took the decision to terminate the development of TV-1106 and stop all ongoing clinical trials. Notably, no new safety issues were identified with the administration of TV-1106.

This study was conducted in full accordance with the International Council for Harmonisation (ICH) Good Clinical Practice (GCP) Consolidated Guideline (E6) and any applicable national and local laws and regulations (eg, Code of Federal Regulations Title 21, Parts 50, 54, 56, 312, and 314; EU Directive 2001/20/EC on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of GCP in the conduct of clinical trials on medicinal products for human use). Written and/or oral information about the study was provided to all patients in a language understandable by the patients. The information included an adequate explanation of the aims, methods, anticipated benefits, potential hazards, and insurance arrangements in force. Written informed consent was obtained from each patient before any study procedures or assessments were done. It was explained to the patients that they were free to refuse entry into the study and free to withdraw from the study at any time without prejudice to future treatment. Each patient’s willingness to participate in the study was documented in writing in a consent form that was signed by the patient with the date of that signature indicated. Each investigator kept the original consent forms, and copies were given to the patients.

01 Apr 2015

No

No

Austria: 1

Greece: 2

Hungary: 2

United States: 9

14

5

0

0

0

0

0

0

11

3

0

Core Period (24 Weeks)

Randomised - controlled

The 24-week core phase of the study was double-blind, and therefore, the sponsor, investigators, patients, and site staff did not have knowledge of treatment assignment. Blinded persons remained blinded until last patient randomized completed the core phase, at which time analysis of the accrued data from the core phase was to be performed.The central reader was unblinded, as were the bioanalytical scientists. The 48-week extension phase of the study was open-label.

Yes

Placebo

Matching placebo

Solution for injection

Subcutaneous use

Placebo treatment was administered in a blinded fashion and titrated on weeks 4, 8, 12 and 16 to mimic the active treatment.

TV-1106

long-acting growth hormone, albutropin

Solution for injection

Intravenous use

A starting dose of 5.0 mg was expected to be appropriate for most patients because the daily recommended starting dose of recombinant human growth hormone (rhGH) treatments (e.g. somatropin) is 0.2 mg/day, and the conversion factor was 28. Dosage could be titrated by an unblinded central reader on weeks 4, 8, 12 and 16 until the participant's insulin-like growth factor 1 (IGF-1) standard deviation score (SDS) was within the range of -0.5 to +1.5.

Extension Period (12 Months)

Not applicable

TV-1106

long-acting growth hormone, albutropin

Solution for injection

Intravenous use

After completion of the core phase and at initiation of the extension phase (visit 7), all patients were to revert to the starting dose of TV-1106, as determined by the unblinded central reader, to ensure the core phase of the study remained blinded during the transition to the open-label period.

Placebo

TV-1106

Placebo

TV-1106

TV-1106 - Extension Period

The primary efficacy measure for the study was body fat mass (kg) measured by DXA imaging. The primary outcome as defined in the protocol was the change from baseline to week 24 in body fat mass. Due to the early termination of the study, observed values including endpoint values are reported. Endpoint is the last observed value. Values of 999 indicate not estimable due to single patient being reported.

Primary

Baseline (Day 1, pre-dose), Week 24, Endpoint in Core period

Trunk fat (kg) was assessed based on DXA results. Trunk fat was defined as fat mass - (total arm fat + total leg fat + total head fat). The outcome as defined in the protocol was the within-patient change from baseline to week 24 in trunk fat. Due to the early termination of the study, observed values including endpoint values are reported. Endpoint is the last observed value. Values of 999 indicate not estimable due to reporting a single patient.

Secondary

Baseline (Day 1, pre-dose), Week 24, Endpoint in Core Period

IGF-I SDS, as reported by the central laboratory, was a key secondary variable. The week 24 value is a trough value as it was taken 7 days after the last TV-1106 or placebo injection. The outcome as defined in the protocol was the within-patient change from baseline to week 24. Due to the early termination of the study, observed values including endpoint values are reported. Endpoint is the last observed value and is of variable length of time since last TV-1106 or placebo injection. Values of 999 = not estimable due to reporting a single patient.

Secondary

Baseline (Day 1, pre-dose), Week 24, Endpoint in Core Period

The AGHDA instrument is comprised of 25 questions, with yes or no answers. To each of the 25 questions comprising QOL AGHDA, a score of 1 was assigned if the answer was affirmative and 0 if the answer was negative. Data reported is the total score across the 25 questions for a total range of 0-25 with higher scores representing a poorer quality of life. The outcome as defined in the protocol was the within-patient change from baseline to week 24. Due to the early termination of the study, observed values including endpoint values are reported. Endpoint is the last observed value. Values of 999 = not estimable since reporting on a single patient.

Secondary

Baseline (Day 1, pre-dose), Week 24, Endpoint in Core Period

An adverse event was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an AE which prevents usual activities. Relationship of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes.

Secondary

Day 1 up to 24 Weeks

Parameters with potentially clinically significant abnormal test results include Serum chemistry: blood urea nitrogen, creatinine and bilirubin Hematology: leukocytes, hemoglobin, hematocrit, platelets and neutrophils Urinalysis: none Significance criteria are listed below with the test.

Secondary

Day 1 up to 24 Weeks

Shifts represented as baseline - endpoint value (last observed post-baseline value). Abnormal NCS indicates an abnormal but not clinically significant finding. Abnormal CS indicates an abnormal and clinically significant finding.

Secondary

Baseline (Day 1, pre-dose), up to Week 24

Observed values of TSH which is the first of three thyroid hormones measured.

Secondary

Baseline (Day 1, pre-dose), Endpoint (up to Week 24)

Observed values of Free T4 which is the second of three thyroid hormones measured.

Secondary

Baseline (Day 1, pre-dose), Endpoint (up to Week 24)

Observed values of Total T3 which is the third of three thyroid hormones measured.

Secondary

Baseline (Day 1, pre-dose), Endpoint (up to Week 24)

Glycated Hemoglobin (HbA1c) is a measure of glucose homeostasis.

Secondary

Baseline (Day 1, pre-dose), Endpoint (up to Week 24)

Fasting blood glucose is another measure of glucose homeostasis.

Secondary

Baseline (Day 1, pre-dose), Endpoint (up to Week 24)

Insulin is another measure of glucose homeostasis.

Secondary

Baseline (Day 1, pre-dose), Endpoint (up to Week 24)

Participants reporting at least one injection site reaction.

Secondary

Day 1 up to Week 24

Weeks 4 and 8 serum samples obtained 2 days after TV1106 administration. Weeks 12 and 24 serum samples obtained 7 days after TV1106 administration. Week 16 serum samples obtained 1 day after TV1106 administration. In study documentation, only minimum and maximum values are presented at visits where more than 50% of results are below the limit of quantitation. The lower limit of quantification was 4 ng/mL. However EUdraCT requires a median value so 'zero' has been entered in Baseline, Week 4, Week 12 and Week 24 as a placeholder.

Secondary

Baseline (Day 1, pre-dose), Weeks 4, 8, 12, 16, 24

Core Period: Day 1 to Week 24 Extension Period: Week 25-26

17.1

Placebo - Core Period

TV-1106 - Core Period

TV-1106 - Extension Period