Clinical Trial Results:
A 64-Week (12-week core phase and 52-week safety extension), Phase II, Multicenter, Randomized, Open Label Study to Evaluate the Safety, Tolerability and Efficacy of Weekly TV-1106 in Adults with Growth Hormone Deficiency
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Summary
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EudraCT number |
2012-004975-37 |
Trial protocol |
HU CZ SK GR SI DE SE |
Global end of trial date |
23 Jun 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
14 Jul 2016
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First version publication date |
14 Jul 2016
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Other versions |
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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-GHD-201
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01811576 | ||
WHO universal trial number (UTN) |
- | ||
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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,
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Public contact |
Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., 001 215-591-3000, ustevatrials@tevapharm.com
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Scientific contact |
Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., 001 215-591-3000, ustevatrials@tevapharm.com
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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 |
19 May 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 |
23 Jun 2015
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Was the trial ended prematurely? |
No
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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 evaluate the clinical effect of weekly doses of Albutropin (TV-1106), as measured by the change from baseline in insulin-like growth factor 1 (IGF-I), in growth hormone deficient (GHD) adults following 12 weeks of treatment.
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Protection of trial subjects |
This study was conducted in full accordance with the International Conference on Harmonisation
(ICH) Good Clinical Practice (GCP) Consolidated Guideline (E6) and any applicable national
and local laws and regulations (eg, Code of Federal Regulations [CFR] Title 21, Parts 50, 54, 56,
312, and 314; European Union (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 |
05 Aug 2013
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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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 |
Israel: 1
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Country: Number of subjects enrolled |
Serbia: 3
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Country: Number of subjects enrolled |
United States: 2
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Country: Number of subjects enrolled |
Slovakia: 12
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Country: Number of subjects enrolled |
Slovenia: 4
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Country: Number of subjects enrolled |
Czech Republic: 2
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Country: Number of subjects enrolled |
Germany: 4
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Country: Number of subjects enrolled |
Greece: 3
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Country: Number of subjects enrolled |
Hungary: 21
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Worldwide total number of subjects |
52
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EEA total number of subjects |
46
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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) |
49
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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 |
A total of 93 patients with GHD were screened for enrollment into this study. Of the 93 patients screened, 52 patients at 16 centers in Europe, the Middle East and the US met entry criteria. | |||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
Of the 41 patients not enrolled, 32 were excluded due to inclusion/exclusion criteria, 3 withdrew consent, 2 were lost to follow-up before the baseline visit, 1 experienced an AE, and 3 were excluded for ‘other’ reasons. Eligible patients were randomized on a 4:1 basis to either albutropin or genotropin. | |||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Core Study
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | |||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Albutropin | |||||||||||||||||||||||||||
Arm description |
Patients began with a starting weekly dose of Albutropin based on the conversion calculations (previous daily rhGH dose ×28 ×0.6). Up or down titration was allowed based on the IGF-1 SDS obtained on day 7 of weeks 3, 6, and 9 with the goal for each patient to achieve an IGF-1 SDS by the time of trough level during week 12 that was within ±0.5 SDS of the patient’s pre-washout IGF-1 SDS and a Cmax IGF-1 SDS level during week 12 that was below +2.0 SDS. Doses increased or decreased by 2.8 mg if the current dose was < 15 mg, and adjusted by 5.8 mg otherwise. At the end of week 12, patients were expected to continue into the extension phase on their current dose of weekly Albutropin. | |||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||
Investigational medicinal product name |
Albutropin
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Investigational medicinal product code |
TV-1106
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Other name |
human serum albumin-human growth hormone (HSA-hGH)
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Pharmaceutical forms |
Powder for solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
The dose and titration dose levels of Albutropin were up to 50 mg given as weekly subcutaneous (sc) injections in the formulation buffer. Doses in excess of 50 mg
were not allowed for titration and resulted in early termination. Except on in-clinic visit days, the patient was responsible for injections of the specified dose of Albutropin once weekly between 6:00 and 10:00 AM in the abdomen or thigh, rotating the site with each injection.
The starting Albutropin dose was 60% of the albutropin dose considered ‘comparable’ to the dose of rhGH previously administered.
Dose adjustments were accomplished using a titration algorithm based on IGF-1 levels evaluated by a central reader who directed the investigator in choosing the titration dose. Ultimately, the investigator was responsible for making the final decision regarding the dose administered.
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Arm title
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Genotropin | |||||||||||||||||||||||||||
Arm description |
The initial dose of Genotropin was based on the previous daily rhGH dose in use prior to washout. Up and down titrations were performed at the same time points and according to the same algorithm as that described for Albutropin, using either 0.2 mg/day of the Genotropin if the current dose of Genotropin was greater than 0.5 mg/day or 0.1 mg/day if the current dose of Genotropin was less than or equal to 0.5 mg/day. At the end of week 12, patients were expected to continue into the extension phase on their current daily dose of Genotropin. | |||||||||||||||||||||||||||
Arm type |
Active comparator | |||||||||||||||||||||||||||
Investigational medicinal product name |
Genotropin
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Investigational medicinal product code |
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Other name |
somatropin (rDNA origin), rhGH (recombinant human Growth Hormone)
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Pharmaceutical forms |
Solution for injection in pre-filled syringe
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Patients injected their specified dose of Genotropin once daily between 6:00 and 10:00 AM except on days of in-clinic visits when the dose was injected in the arm by a qualified site staff member after the planned activities were performed by the site staff. The dose levels available for achieving the appropriate final daily dose ranged from 0.2 mg to 1.8 mg and were administered using a variable, multi-dose injection device.
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Period 2
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Period 2 title |
Extension Phase
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Is this the baseline period? |
No | |||||||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | |||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Albutropin | |||||||||||||||||||||||||||
Arm description |
At the end of week 12, patients were expected to continue into the extension phase on their current dose of weekly Albutropin for an additional 52 weeks. | |||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||
Investigational medicinal product name |
Albutropin
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Investigational medicinal product code |
TV-1106
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Other name |
human serum albumin-human growth hormone (HSA-hGH)
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Pharmaceutical forms |
Powder for solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
The dose and titration dose levels of Albutropin were up to 50 mg given as weekly subcutaneous (sc) injections in the formulation buffer. Except on in-clinic visit days, the patient was responsible for injections of the specified dose of Albutropin once weekly between 6:00 and 10:00 AM in the abdomen or thigh, rotating the site with each injection.
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Arm title
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Genotropin | |||||||||||||||||||||||||||
Arm description |
At the end of week 12, patients were expected to continue into the extension phase on their current daily dose of Genotropin for an additional 52 weeks. | |||||||||||||||||||||||||||
Arm type |
Active comparator | |||||||||||||||||||||||||||
Investigational medicinal product name |
Genotropin
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Investigational medicinal product code |
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Other name |
somatropin (rDNA origin), rhGH (recombinant human Growth Hormone)
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Pharmaceutical forms |
Solution for injection in pre-filled syringe
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Patients injected their specified dose of Genotropin once daily between 6:00 and 10:00 AM except on days of in-clinic visits when the dose was injected in the arm by a qualified site staff member after the planned activities were performed by the site staff. The dose levels available for achieving the appropriate final daily dose ranged from 0.2 mg to 1.8 mg and were administered using a variable, multi-dose injection device.
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Baseline characteristics reporting groups
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Reporting group title |
Albutropin
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Reporting group description |
Patients began with a starting weekly dose of Albutropin based on the conversion calculations (previous daily rhGH dose ×28 ×0.6). Up or down titration was allowed based on the IGF-1 SDS obtained on day 7 of weeks 3, 6, and 9 with the goal for each patient to achieve an IGF-1 SDS by the time of trough level during week 12 that was within ±0.5 SDS of the patient’s pre-washout IGF-1 SDS and a Cmax IGF-1 SDS level during week 12 that was below +2.0 SDS. Doses increased or decreased by 2.8 mg if the current dose was < 15 mg, and adjusted by 5.8 mg otherwise. At the end of week 12, patients were expected to continue into the extension phase on their current dose of weekly Albutropin. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Genotropin
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Reporting group description |
The initial dose of Genotropin was based on the previous daily rhGH dose in use prior to washout. Up and down titrations were performed at the same time points and according to the same algorithm as that described for Albutropin, using either 0.2 mg/day of the Genotropin if the current dose of Genotropin was greater than 0.5 mg/day or 0.1 mg/day if the current dose of Genotropin was less than or equal to 0.5 mg/day. At the end of week 12, patients were expected to continue into the extension phase on their current daily dose of Genotropin. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Albutropin
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Reporting group description |
Patients began with a starting weekly dose of Albutropin based on the conversion calculations (previous daily rhGH dose ×28 ×0.6). Up or down titration was allowed based on the IGF-1 SDS obtained on day 7 of weeks 3, 6, and 9 with the goal for each patient to achieve an IGF-1 SDS by the time of trough level during week 12 that was within ±0.5 SDS of the patient’s pre-washout IGF-1 SDS and a Cmax IGF-1 SDS level during week 12 that was below +2.0 SDS. Doses increased or decreased by 2.8 mg if the current dose was < 15 mg, and adjusted by 5.8 mg otherwise. At the end of week 12, patients were expected to continue into the extension phase on their current dose of weekly Albutropin. | ||
Reporting group title |
Genotropin
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Reporting group description |
The initial dose of Genotropin was based on the previous daily rhGH dose in use prior to washout. Up and down titrations were performed at the same time points and according to the same algorithm as that described for Albutropin, using either 0.2 mg/day of the Genotropin if the current dose of Genotropin was greater than 0.5 mg/day or 0.1 mg/day if the current dose of Genotropin was less than or equal to 0.5 mg/day. At the end of week 12, patients were expected to continue into the extension phase on their current daily dose of Genotropin. | ||
Reporting group title |
Albutropin
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Reporting group description |
At the end of week 12, patients were expected to continue into the extension phase on their current dose of weekly Albutropin for an additional 52 weeks. | ||
Reporting group title |
Genotropin
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Reporting group description |
At the end of week 12, patients were expected to continue into the extension phase on their current daily dose of Genotropin for an additional 52 weeks. | ||
Subject analysis set title |
Albutropin: Baseline
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
A paired t-test in Albutropin subjects to assess the magnitude of change from baseline to maximum IGF-1 SDS (Cmax) value during week 12. Baseline data are reported in this column.
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Subject analysis set title |
Albutropin: Cmax at Week 12
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
A paired t-test in Albutropin subjects to assess the magnitude of change from baseline to maximum IGF-1 SDS (Cmax) value during week 12. IGF-1 SDS data at maximum concentration during Week 12 are reported in this column.
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End point title |
Insulin-Like Growth Factor 1 (IGF-1) Standard Deviation Score (SDS) at Baseline and Cmax Level During Week 12 | ||||||||||||
End point description |
The study hypotheses are defined as follows:
H0: μD = 0
H1: μD ≠ 0
Where μD = expected value of IGF-1 SDS difference (Cmax at week 12 - baseline) in Albutropin group.
Observed values are reported here. The statistical analysis was based on the within-subject change from baseline to Cmax during week 12.
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End point type |
Primary
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End point timeframe |
Baseline (Day 0), Week 12; samples drawn between 6:00 and 10:00 AM prior to dosing on Days 0, 78, 79, 80, 81 and 84
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Statistical analysis title |
IGF-1 SDS Change Baseline to Cmax Week 12 | ||||||||||||
Statistical analysis description |
The null hypothesis was tested based on a paired t – test with n-1 degrees of freedom, where n refers to the total number of subjects in the Albutropin group with baseline and Cmax at week 12.
n=41 since this is a within subject change.
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Comparison groups |
Albutropin: Baseline v Albutropin: Cmax at Week 12
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Number of subjects included in analysis |
82
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 [1] | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Confidence interval |
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| Notes [1] - The significance level of the paired t-test was 5% (2-sided). |
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End point title |
Percentage of Patients Whose Week 12 Trough IGF-1 SDS Value Is Within +/- 0.5 of screening IGF-1 SDS Value and Cmax <+2.0 | ||||||||||||
End point description |
Percentage of patients who meet both conditions:
1) Week 12 trough IGF-1 SDS within +/- 0.5 of screening IGF-1 SDS
2) Cmax Level During Week 12 Is Below +2.0 SDS.
Both protocol and SAP document that 95% CI ranges will only be calculated for the Albutropin group. Values of 9999 indicate values were not calculated.
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End point type |
Secondary
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End point timeframe |
Screening (Weeks -8 to -5), Week 12
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| Notes [2] - ITT [3] - ITT |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Patients with Adverse Events (AE) | |||||||||||||||||||||||||||
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 normal daily 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 to Week 64
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| Notes [4] - Safety [5] - Safety |
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||
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End point title |
Change from Baseline to Endpoint in Lipid Profile | |||||||||||||||||||||||||||
End point description |
Change from baseline to endpoint values are offered for total cholesterol, very-low-density lipoprotein (VLDL) cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides. Endpoint in this context is referring to the last observed, post-baseline value for each patient.
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End point type |
Secondary
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End point timeframe |
Baseline (Day 0), Endpoint (up to Week 64)
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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 |
Patients with Treatment-Emergent Anti-drug Antibodies (ADA) | |||||||||||||||
End point description |
The testing scheme for patients treated with Albutropin (TV-1106) was multi-tiered, with testing for inhibition by TV-1106, by human growth hormone (hGH), and by human serum albumin (HSA). Confirmed positive assays were titered and tested for neutralizing antibodies (NAbs). All patients treated with Genotropin were tested for anti- recombinant human growth hormone (anti-rhGH) ADA.
Values of 9999 = not applicable
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End point type |
Secondary
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End point timeframe |
Day 1 to Week 64
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| Notes [8] - PK analysis set [9] - PK analysis set |
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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 |
Day 1 to Week 64
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
17.0
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Reporting groups
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Reporting group title |
Albutropin
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Reporting group description |
Patients began with a starting weekly dose of Albutropin based on the conversion calculations (previous daily rhGH dose ×28 ×0.6). Up or down titration was allowed based on the IGF-1 SDS obtained on day 7 of weeks 3, 6, and 9 with the goal for each patient to achieve an IGF-1 SDS by the time of trough level during week 12 that was within ±0.5 SDS of the patient’s pre-washout IGF-1 SDS and a Cmax IGF-1 SDS level during week 12 that was below +2.0 SDS. Doses increased or decreased by 2.8 mg if the current dose was < 15 mg, and adjusted by 5.8 mg otherwise. At the end of week 12, patients were expected to continue into the extension phase on their current dose of weekly Albutropin. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Genotropin
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Reporting group description |
The initial dose of Genotropin was based on the previous daily rhGH dose in use prior to washout. Up and down titrations were performed at the same time points and according to the same algorithm as that described for TV-1106, using either 0.2 mg/day of the Genotropin if the current dose of Genotropin was greater than 0.5 mg/day or 0.1 mg/day if the current dose of Genotropin was less than or equal to 0.5 mg/day. At the end of week 12, patients were expected to continue into the extension phase on their current daily dose of genotropin. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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? Yes | |||
Date |
Amendment |
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04 Mar 2013 |
Amendment 1 (dated 04 March 2013) to the protocol was issued before any patients were enrolled into the study.
The following major procedural changes (not all-inclusive) were made to the protocol:
Added monitoring procedures (MRI/CT imaging)
Clarified the inclusion/exclusion criteria
Clarified the study design
Clarified study drug dosing |
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21 Jul 2013 |
Amendment 2 (dated 21 July 2013) to the protocol was issued before any patients were enrolled into the study. Changes to the protocol were considered to have no negative impact on the safety of patients already enrolled into the study.
The following major procedural changes (not all-inclusive) were made to the protocol:
Modified inclusion criterion d: the intent of inclusion criterion d was to establish that patients with GHD had been receiving stable rhGH therapy. However, patients with GHD that had been clinically stable over an extended period of time may have had infrequent monitoring of their IGF-1 levels, and still have been an appropriate clinical candidate for the study. Therefore, clarification of this criterion was necessary to reduce patient burden in terms of time and inconvenience of additional blood draws, as well as to clarify to investigators how to proceed with patients with long standing GHD in whom frequent monitoring was not indicated.
Modified / amended exclusion criteria
Electrocardiography was modified so that the methodology of ECG collection could support further development work for QT analysis. Digital ECGs with a central reader were used for the core phase of the study. For the safety extension phase, traditional ECGs were performed with investigator interpretation. Lipid profile was changed from a secondary endpoint to a safety endpoint .
Clarified that the MRI/CT scan should have been performed prior to baseline (visit 3) so that the results could have been obtained prior to the baseline visit, in which the first dose of study drug was administered. |
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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. | |||
| None reported | |||
