Clinical Trial Results:
Comparison of Somavaratan (VRS-317), a Long-acting Human Growth Hormone, to Daily rhGH in a Phase 3, Randomized, One-year, Open-label, Multi-center, Non-inferiority Trial in Pre-pubertal Children With Growth Hormone Deficiency
Summary
|
|
EudraCT number |
2014-004525-41 |
Trial protocol |
SE BE NL PL |
Global end of trial date |
23 Aug 2017
|
Results information
|
|
Results version number |
v1(current) |
This version publication date |
14 Dec 2022
|
First version publication date |
14 Dec 2022
|
Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
|
|||
Trial identification
|
|||
Sponsor protocol code |
0014VR4
|
||
Additional study identifiers
|
|||
ISRCTN number |
- | ||
US NCT number |
NCT02339090 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
|
|||
Sponsor organisation name |
Versartis, Inc.
|
||
Sponsor organisation address |
3730 Kirby Drive, Suite 1200, Houston, Texas, United States, 77098
|
||
Public contact |
Chief Operating Officer, Versartis, Inc., +1 (936) 355-1910, clinicaltrials@aravive.com
|
||
Scientific contact |
Chief Operating Officer, Versartis, Inc., +1 (936) 355-1910, clinicaltrials@aravive.com
|
||
Paediatric regulatory details
|
|||
Is trial part of an agreed paediatric investigation plan (PIP) |
No
|
||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
Results analysis stage
|
|||
Analysis stage |
Final
|
||
Date of interim/final analysis |
23 Aug 2017
|
||
Is this the analysis of the primary completion data? |
Yes
|
||
Primary completion date |
23 Aug 2017
|
||
Global end of trial reached? |
Yes
|
||
Global end of trial date |
23 Aug 2017
|
||
Was the trial ended prematurely? |
No
|
||
General information about the trial
|
|||
Main objective of the trial |
The primary objective of the study was to compare the safety and efficacy of subcutaneous somavaratan and daily recombinant human growth hormone (rhGH) during 12 months of treatment.
|
||
Protection of trial subjects |
The study was performed in compliance the Food & Drug Administration Code of Federal Regulations for Good Clinical Practice (GCP) and the International Conference on Harmonisation (ICH) Regulations.
|
||
Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
26 Aug 2015
|
||
Long term follow-up planned |
No
|
||
Independent data monitoring committee (IDMC) involvement? |
Yes
|
||
Population of trial subjects
|
|||
Number of subjects enrolled per country |
|||
Country: Number of subjects enrolled |
Poland: 31
|
||
Country: Number of subjects enrolled |
Sweden: 3
|
||
Country: Number of subjects enrolled |
Canada: 12
|
||
Country: Number of subjects enrolled |
United States: 88
|
||
Country: Number of subjects enrolled |
Belgium: 2
|
||
Worldwide total number of subjects |
136
|
||
EEA total number of subjects |
36
|
||
Number of subjects enrolled per age group |
|||
In utero |
0
|
||
Preterm newborn - gestational age < 37 wk |
0
|
||
Newborns (0-27 days) |
0
|
||
Infants and toddlers (28 days-23 months) |
0
|
||
Children (2-11 years) |
136
|
||
Adolescents (12-17 years) |
0
|
||
Adults (18-64 years) |
0
|
||
From 65 to 84 years |
0
|
||
85 years and over |
0
|
|
|||||||||||||||||||||||||||||||
Recruitment
|
|||||||||||||||||||||||||||||||
Recruitment details |
34 participants randomized in rhGH group, out of which 32 participants received treatment. | ||||||||||||||||||||||||||||||
Pre-assignment
|
|||||||||||||||||||||||||||||||
Screening details |
Participants were stratified by region (North America and Europe), age (above and below anticipated median age of 7.5 years) and baseline Insulin-like growth factor-I (IGF-I) standard deviation score (SDS) (above and below anticipated median of -1.7) and randomized in a 3:1 ratio to receive either somavaratan or rhGH. | ||||||||||||||||||||||||||||||
Period 1
|
|||||||||||||||||||||||||||||||
Period 1 title |
Overall Study (overall period)
|
||||||||||||||||||||||||||||||
Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
|
||||||||||||||||||||||||||||||
Blinding used |
Not blinded | ||||||||||||||||||||||||||||||
Arms
|
|||||||||||||||||||||||||||||||
Are arms mutually exclusive |
Yes
|
||||||||||||||||||||||||||||||
Arm title
|
Somavaratan | ||||||||||||||||||||||||||||||
Arm description |
Participants received somavaratan 3.5 milligrams (mg)/kilogram (kg) subcutaneous (SC) bolus injection twice monthly for 12 months. | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Somavaratan
|
||||||||||||||||||||||||||||||
Investigational medicinal product code |
VRS-317
|
||||||||||||||||||||||||||||||
Other name |
Long-acting recombinant human growth hormone
|
||||||||||||||||||||||||||||||
Pharmaceutical forms |
Injection
|
||||||||||||||||||||||||||||||
Routes of administration |
Subcutaneous use
|
||||||||||||||||||||||||||||||
Dosage and administration details |
Somavaratan was administered per dose and schedule specified in the arm description.
|
||||||||||||||||||||||||||||||
Arm title
|
rhGH | ||||||||||||||||||||||||||||||
Arm description |
Participants received commercially available rhGH (genotropin) 34 micrograms (μg)/kg once daily SC bolus injection for 12 months. | ||||||||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
rhGH
|
||||||||||||||||||||||||||||||
Investigational medicinal product code |
|||||||||||||||||||||||||||||||
Other name |
daily growth hormone, recombinant growth hormone therapy
|
||||||||||||||||||||||||||||||
Pharmaceutical forms |
Injection
|
||||||||||||||||||||||||||||||
Routes of administration |
Subcutaneous use
|
||||||||||||||||||||||||||||||
Dosage and administration details |
rhGH was administered per dose and schedule specified in the arm description.
|
||||||||||||||||||||||||||||||
|
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Baseline characteristics reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Somavaratan
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Participants received somavaratan 3.5 milligrams (mg)/kilogram (kg) subcutaneous (SC) bolus injection twice monthly for 12 months. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
rhGH
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Participants received commercially available rhGH (genotropin) 34 micrograms (μg)/kg once daily SC bolus injection for 12 months. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||
End points reporting groups
|
|||
Reporting group title |
Somavaratan
|
||
Reporting group description |
Participants received somavaratan 3.5 milligrams (mg)/kilogram (kg) subcutaneous (SC) bolus injection twice monthly for 12 months. | ||
Reporting group title |
rhGH
|
||
Reporting group description |
Participants received commercially available rhGH (genotropin) 34 micrograms (μg)/kg once daily SC bolus injection for 12 months. | ||
Subject analysis set title |
rhGH
|
||
Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
Participants received commercially available rhGH (genotropin) 34 μg/kg once daily SC bolus injection for 12 months.
|
|
|||||||||||||
End point title |
Annual Height Velocity [1] | ||||||||||||
End point description |
Height measured without shoes in triplicate by stadiometer. Annual height velocity was calculated as (height at Month 12 - height at Baseline)/(Month 12 Date - Baseline Date) * 365.25, where height was expressed as centimetres (cm) so that height velocity is expressed as centimetres per year (cm/yr). Annual height velocity after 12 months continuous treatment with either somavaratan or daily rhGH has been reported. Missing data was imputed using last observation carried forward. Least square (LS) mean was calculated using analysis of covariance (ANCOVA) model. ITT population included all randomized participants.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
12 months
|
||||||||||||
Notes [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The end point is reporting statistics for specified arms only. |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
An ANCOVA model will be used to determine the adjusted (least squares) means and standard error (SE) to determine the confidence interval (CI) of the difference. ANCOVA model included treatment group, region, and gender as fixed effects; with baseline age and baseline IGF-I SDS as covariates.
|
||||||||||||
Comparison groups |
Somavaratan v rhGH
|
||||||||||||
Number of subjects included in analysis |
138
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
non-inferiority [2] | ||||||||||||
Method |
|||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-1.28
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-2.32 | ||||||||||||
upper limit |
-0.24 | ||||||||||||
Notes [2] - Threshold for significance: annualized height velocity between somavaratan and daily rhGH ≤ -2.0 cm/year |
|
|||||||||||||
End point title |
Change From Baseline in Height Standard Deviation Score (SDS) at Month 12 | ||||||||||||
End point description |
Height SDS was determined using the Center for Disease Control (CDC) Clinical Growth Charts; 2000. The SD score was calculated as the participant’s height value minus the mean divided by the standard deviation (SD). The mean and the SD vary depending on the age and sex of the participant. Mean change from baseline in height SDS at Month 12 is presented. ITT population included all randomized participants. Here, ‘overall number of participants analyzed’ signifies participants evaluable for this outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Month 12
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change From Baseline in Bone Age Relative to Chronological Age at Month 12, as Assessed by Central Reader | ||||||||||||
End point description |
Bone age was assessed from a radiograph of the left hand and wrist by central reader. ITT population included all randomized participants. Here, ‘overall number of participants analyzed’ signifies participants evaluable for this outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Month 12
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change From Baseline in Body Mass Index (BMI) at Month 12 | ||||||||||||
End point description |
The BMI is a person’s weight in kilograms divided by the square of height in meters. ITT population included all randomized participants. Here, ‘overall number of participants analyzed’ signifies participants evaluable for this outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Month 12
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change From Baseline in Body Weight at Month 12 | ||||||||||||
End point description |
Body weight measured in light clothing and without shoes. ITT population included all randomized participants. Here, ‘overall number of participants analyzed’ signifies participants evaluable for this outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Month 12
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change From Baseline in Insulin-like Growth Factor 1 (IGF-I) SDS at Month 12 | ||||||||||||
End point description |
The SD score was calculated as the actual value of IGF-I minus mean reference value of IGF-I divided by reference standard deviation of IGF-I. The mean and the SD vary depending on the age and sex of the participant. Change in IGF-I level (SD score) at Month 12 from Baseline was assessed. A higher score reflects a better outcome. ITT population included all randomized participants. Here, ‘overall number of participants analyzed’ signifies participants evaluable for this outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Month 12
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change From Baseline in Insulin-like Growth Factor Binding Protein 3 (IGFBP-3) at Month 12 | ||||||||||||
End point description |
ITT population included all randomized participants. Here, ‘overall number of participants analyzed’ signifies participants evaluable for this outcome measure.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Month 12
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
||||||||||
End point title |
Number of Participants With Adverse Events (AEs) | |||||||||
End point description |
An AE 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. SAEs included 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 participant and required medical intervention to prevent 1 of the outcomes listed in this definition. A summary of serious and non-serious AEs regardless of causality is located in ‘Reported Adverse Events module’. Safety population included all participants who received any amount of study drug.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
Baseline up to Month 12
|
|||||||||
|
||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Baseline up to Month 12
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
Safety population included all participants who received any amount of study drug.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
20
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting groups
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Somavaratan
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Participants received somavaratan 3.5 mg/kg SC bolus injection twice monthly for 12 months. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
rhGH
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Participants received commercially available rhGH (genotropin) 34 μg/kg once daily SC bolus injection for 12 months. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||
Substantial protocol amendments (globally) |
|||||||
Were there any global substantial amendments to the protocol? Yes | |||||||
Date |
Amendment |
||||||
15 Dec 2014 |
The protocol was revised to modify the protocol-specified criteria for routine funduscopy in sites located outside of North America. |
||||||
17 Jul 2015 |
- A new stopping criteria was added: Individual participants with confirmed positive neutralizing antibody and a change in height standard deviation score (HT-SDS) ≤ 0 in the past 6 months may be withdrawn from treatment at the discretion of the Principal Investigator and Medical Monitor.
- A new activity 12-lead electrocardiogram (ECG) (triplicate tracings) was added. |
||||||
05 Apr 2017 |
Changes were made to align this protocol with other somavaratan pediatric growth hormone deficiency (GHD) study protocols, all of which were intended to enhance safety of participants. The primary change was the removal of an interim analysis. |
||||||
Interruptions (globally) |
|||||||
Were there any global interruptions to the trial? Yes | |||||||
|
|||||||
Limitations and caveats |
|||||||
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||||||
None reported |