Clinical Trial Results:
A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Efficacy, Safety and Tolerability Study of TV-1106 in Growth Hormone Deficient Adults Who Are Not Current Users of rhGH Treatment
Summary
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EudraCT number |
2014-003796-32 |
Trial protocol |
DE HU CZ IT AT ES SI LT GR PL BG RO SK HR |
Global end of trial date |
18 Dec 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
26 Dec 2016
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First version publication date |
26 Dec 2016
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
TV1106-IMM-30021
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02410343 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Teva Pharmaceutical Industries Ltd.
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Sponsor organisation address |
5 Bazel St., Petach Tikva, Israel, 49131
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Public contact |
Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., 001 215-591-3000, info-era-clinical@teva.de
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Scientific contact |
Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., 001 215-591-3000, info-era-clinical@teva.de
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
01 Sep 2016
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
18 Dec 2015
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Was the trial ended prematurely? |
Yes
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General information about the trial
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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.
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.
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Protection of trial subjects |
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.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
01 Apr 2015
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Austria: 1
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Country: Number of subjects enrolled |
Greece: 2
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Country: Number of subjects enrolled |
Hungary: 2
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Country: Number of subjects enrolled |
United States: 9
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Worldwide total number of subjects |
14
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EEA total number of subjects |
5
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
11
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From 65 to 84 years |
3
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85 years and over |
0
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Recruitment
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Recruitment details |
Of the 46 patients screened, 14 patients at 10 centers located in the US and Europe (Austria, Greece, Hungary) met entry criteria and were considered eligible for randomization. Of the 32 patients not randomly assigned to study treatment, 26 were excluded on the basis of inclusion/exclusion criteria and 6 were excluded for "other" reasons | ||||||||||||||||||
Pre-assignment
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Screening details |
Participants were randomly allocated to 1 of 2 treatment groups (TV-1106 or placebo) in a 2:1 allocation to prevent selection bias. | ||||||||||||||||||
Period 1
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Period 1 title |
Core Period (24 Weeks)
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Is this the baseline period? |
Yes | ||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||
Roles blinded |
Subject, Investigator, Monitor | ||||||||||||||||||
Blinding implementation details |
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.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Placebo | ||||||||||||||||||
Arm description |
Placebo was injected subcutaneously once weekly on the same day and time for 24 weeks during the Core Period. To maintain the blind, placebo could be titrated by an unblinded central reader on weeks 4, 8, 12 and 16 to match the effect of dose titration. Participants who completed the Core Period were eligible to enter an open-label extension phase for 12 additional months where all participants received treatment with TV-1106. | ||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
Matching placebo
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Placebo treatment was administered in a blinded fashion and titrated on weeks 4, 8, 12 and 16 to mimic the active treatment.
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Arm title
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TV-1106 | ||||||||||||||||||
Arm description |
TV-1106 was injected subcutaneously once weekly on the same day and time for 24 weeks during the Core Period. A common starting dose was 5.0 mg. Doses 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. Participants who completed the Core Period were eligible to enter an open-label extension phase for 12 additional months where all participants received treatment with TV-1106. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
TV-1106
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Investigational medicinal product code |
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Other name |
long-acting growth hormone, albutropin
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
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.
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Period 2
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Period 2 title |
Extension Period (12 Months)
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Is this the baseline period? |
No | ||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||
Arms
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Arm title
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TV-1106 - Extension Period | ||||||||||||||||||
Arm description |
Participants from both the Placebo and TV-1106 groups who completed the Core Period were eligible to enter an open-label extension phase for 12 additional months where all participants received treatment with TV-1106. Due to early termination of the study, two participants spent a maximum of two weeks in the extension period. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
TV-1106
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Investigational medicinal product code |
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Other name |
long-acting growth hormone, albutropin
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
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.
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Baseline characteristics reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Placebo was injected subcutaneously once weekly on the same day and time for 24 weeks during the Core Period. To maintain the blind, placebo could be titrated by an unblinded central reader on weeks 4, 8, 12 and 16 to match the effect of dose titration. Participants who completed the Core Period were eligible to enter an open-label extension phase for 12 additional months where all participants received treatment with TV-1106. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
TV-1106
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Reporting group description |
TV-1106 was injected subcutaneously once weekly on the same day and time for 24 weeks during the Core Period. A common starting dose was 5.0 mg. Doses 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. Participants who completed the Core Period were eligible to enter an open-label extension phase for 12 additional months where all participants received treatment with TV-1106. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Placebo was injected subcutaneously once weekly on the same day and time for 24 weeks during the Core Period. To maintain the blind, placebo could be titrated by an unblinded central reader on weeks 4, 8, 12 and 16 to match the effect of dose titration. Participants who completed the Core Period were eligible to enter an open-label extension phase for 12 additional months where all participants received treatment with TV-1106. | ||
Reporting group title |
TV-1106
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Reporting group description |
TV-1106 was injected subcutaneously once weekly on the same day and time for 24 weeks during the Core Period. A common starting dose was 5.0 mg. Doses 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. Participants who completed the Core Period were eligible to enter an open-label extension phase for 12 additional months where all participants received treatment with TV-1106. | ||
Reporting group title |
TV-1106 - Extension Period
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Reporting group description |
Participants from both the Placebo and TV-1106 groups who completed the Core Period were eligible to enter an open-label extension phase for 12 additional months where all participants received treatment with TV-1106. Due to early termination of the study, two participants spent a maximum of two weeks in the extension period. |
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End point title |
Body Fat Mass at Baseline, Week 24 and Endpoint in Core Period [1] | |||||||||||||||||||||
End point description |
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.
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End point type |
Primary
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End point timeframe |
Baseline (Day 1, pre-dose), Week 24, Endpoint in Core period
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Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: As the study was terminated early, limited efficacy analyses are included. Because the study was terminated while enrollment was ongoing, the sample size was smaller than planned; 14 patients enrolled, 6 of whom received placebo and 8 of whom received TV-1106 during the core phase of the study. Thus, limited efficacy analyses were completed and, as only 2 patients (1 in each treatment group) completed the core phase of the study, no efficacy conclusions were reached. |
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Notes [2] - Intent to treat population (ITT) [3] - Intent to treat population (ITT) |
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No statistical analyses for this end point |
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End point title |
Total Trunk Fat at Baseline, Week 24 and Endpoint in Core Period | |||||||||||||||||||||
End point description |
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.
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End point type |
Secondary
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End point timeframe |
Baseline (Day 1, pre-dose), Week 24, Endpoint in Core Period
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Notes [4] - ITT [5] - ITT |
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No statistical analyses for this end point |
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End point title |
Insulin-Like Growth Factor 1 Standard Deviation Score (IGF-I SDS) at Baseline, Week 24 and Endpoint in Core Period | |||||||||||||||||||||
End point description |
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.
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End point type |
Secondary
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End point timeframe |
Baseline (Day 1, pre-dose), Week 24, Endpoint in Core Period
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Notes [6] - ITT [7] - ITT |
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No statistical analyses for this end point |
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End point title |
Scored Analysis of Quality of Life Assessment of GH Deficiency in Adults (QoL-AGHDA) at Baseline, Week 24 and Endpoint in Core Period | |||||||||||||||||||||
End point description |
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.
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End point type |
Secondary
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End point timeframe |
Baseline (Day 1, pre-dose), Week 24, Endpoint in Core Period
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Notes [8] - ITT [9] - ITT |
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No statistical analyses for this end point |
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End point title |
Participants With Adverse Events During the Core Period | |||||||||||||||||||||||||||
End point description |
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.
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End point type |
Secondary
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End point timeframe |
Day 1 up to 24 Weeks
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Notes [10] - Safety population [11] - Safety population |
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No statistical analyses for this end point |
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End point title |
Participants With Potentially Clinically Significant Abnormal Blood and Urine Test Results | |||||||||||||||||||||||||||||||||
End point description |
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.
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End point type |
Secondary
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End point timeframe |
Day 1 up to 24 Weeks
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Notes [12] - Safety [13] - Safety |
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No statistical analyses for this end point |
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End point title |
Shift From Baseline To Endpoint in Core Period in Electrocardiogram Findings | |||||||||||||||||||||||||||
End point description |
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.
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End point type |
Secondary
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End point timeframe |
Baseline (Day 1, pre-dose), up to Week 24
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Notes [14] - Safety [15] - Safety |
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No statistical analyses for this end point |
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End point title |
Thyroid Stimulating Hormone (TSH) at Baseline and Endpoint | ||||||||||||||||||
End point description |
Observed values of TSH which is the first of three thyroid hormones measured.
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End point type |
Secondary
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End point timeframe |
Baseline (Day 1, pre-dose), Endpoint (up to Week 24)
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Notes [16] - Safety [17] - Safety |
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No statistical analyses for this end point |
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End point title |
Free Thyroxin (Free T4) at Baseline and Endpoint | ||||||||||||||||||
End point description |
Observed values of Free T4 which is the second of three thyroid hormones measured.
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End point type |
Secondary
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End point timeframe |
Baseline (Day 1, pre-dose), Endpoint (up to Week 24)
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Notes [18] - Safety [19] - Safety |
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No statistical analyses for this end point |
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End point title |
Triiodothyronine (Total T3) at Baseline and Endpoint | ||||||||||||||||||
End point description |
Observed values of Total T3 which is the third of three thyroid hormones measured.
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End point type |
Secondary
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End point timeframe |
Baseline (Day 1, pre-dose), Endpoint (up to Week 24)
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Notes [20] - Safety [21] - Safety |
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No statistical analyses for this end point |
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End point title |
Glycated Hemoglobin (HbA1c) at Baseline and Endpoint | ||||||||||||||||||
End point description |
Glycated Hemoglobin (HbA1c) is a measure of glucose homeostasis.
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End point type |
Secondary
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End point timeframe |
Baseline (Day 1, pre-dose), Endpoint (up to Week 24)
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Notes [22] - Safety population [23] - Safety population |
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No statistical analyses for this end point |
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End point title |
Fasting Blood Glucose at Baseline and Endpoint | ||||||||||||||||||
End point description |
Fasting blood glucose is another measure of glucose homeostasis.
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End point type |
Secondary
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End point timeframe |
Baseline (Day 1, pre-dose), Endpoint (up to Week 24)
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Notes [24] - Safety [25] - Safety |
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No statistical analyses for this end point |
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End point title |
Insulin at Baseline and Endpoint | ||||||||||||||||||
End point description |
Insulin is another measure of glucose homeostasis.
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End point type |
Secondary
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End point timeframe |
Baseline (Day 1, pre-dose), Endpoint (up to Week 24)
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Notes [26] - Safety [27] - Safety |
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No statistical analyses for this end point |
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End point title |
Local Tolerability Assessed by Injection Site Reactions | ||||||||||||||||||||||||
End point description |
Participants reporting at least one injection site reaction.
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End point type |
Secondary
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End point timeframe |
Day 1 up to Week 24
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Notes [28] - Safety [29] - Safety |
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No statistical analyses for this end point |
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End point title |
Pharmacokinetic Serum Concentration of TV1106 by Nominal Sampling Timepoints | ||||||||||||||||||||||||||||||
End point description |
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.
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End point type |
Secondary
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End point timeframe |
Baseline (Day 1, pre-dose), Weeks 4, 8, 12, 16, 24
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Notes [30] - Not performed on placebo group [31] - Safety |
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
Core Period: Day 1 to Week 24
Extension Period: Week 25-26
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
17.1
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Reporting groups
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Reporting group title |
Placebo - Core Period
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Reporting group description |
Placebo was injected subcutaneously once weekly on the same day and time for 24 weeks during the Core Period. To maintain the blind, placebo could be titrated by an unblinded central reader on weeks 4, 8, 12 and 16 to match the effect of dose titration. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
TV-1106 - Core Period
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Reporting group description |
TV-1106 was injected subcutaneously once weekly on the same day and time for 24 weeks during the Core Period. A common starting dose was 5.0 mg. Doses 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
TV-1106 - Extension Period
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Reporting group description |
Participants from both the Placebo and TV-1106 groups who completed the Core Period were eligible to enter an open-label extension phase for 12 additional months where all participants received treatment with TV-1106. Due to early termination of the study, two participants spent a maximum of two weeks in the extension period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
The sample size was smaller than the planned; 14 patients enrolled. Limited efficacy analyses were completed; as only 2 patients (1 in each treatment group) completed the core phase of the study, no efficacy conclusions were reached. |