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    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

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    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
    Belgium: 2
    Country: Number of subjects enrolled
    Canada: 12
    Country: Number of subjects enrolled
    United States: 88
    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

    Subject disposition

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    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.

    Number of subjects in period 1
    		Somavaratan rhGH
    Started
    104
    32
    Received a Least 1 Dose of Study Drug
    104
    32
    Completed
    98
    29
    Not completed
    6
    3
         Consent withdrawn by subject
    2
    1
         Adverse event, non-fatal
    1
    -
         Non-compliance With Study Drug
    -
    1
         Poor Growth
    3
    -
         Lost to follow-up
    -
    1

    Baseline characteristics

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    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.

    Reporting group values
    		 Somavaratan rhGH Total
    Number of subjects
    		 104 32 136
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 7.0 ( 2.03 ) 6.9 ( 2.38 ) -
    Gender categorical
    Units: Subjects
        Female
    		 46 10 56
        Male
    		 58 22 80
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 8 3 11
        Not Hispanic or Latino
    		 96 29 125
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 1 0 1
        Asian
    		 5 0 5
        Black or African American
    		 1 0 1
        White
    		 91 31 122
        Unknown or Not Reported
    		 6 1 7

    End points

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    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.

    Primary: Annual Height Velocity

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    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.
    End point values
    		 Somavaratan rhGH
    Number of subjects analysed
    104
    34
    Units: cm/year
        least squares mean (standard error)
    9.43 ( 0.28 )
    10.70 ( 0.48 )
    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

    Secondary: Change From Baseline in Height Standard Deviation Score (SDS) at Month 12

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    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
    End point values
    		 Somavaratan rhGH
    Number of subjects analysed
    98
    30
    Units: SD score
        arithmetic mean (standard deviation)
    0.8 ( 0.53 )
    1.0 ( 0.51 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Bone Age Relative to Chronological Age at Month 12, as Assessed by Central Reader

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    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
    End point values
    		 Somavaratan rhGH
    Number of subjects analysed
    98
    29
    Units: months
        arithmetic mean (standard deviation)
    1.1 ( 0.47 )
    1.3 ( 0.55 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Body Mass Index (BMI) at Month 12

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    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
    End point values
    		 Somavaratan rhGH
    Number of subjects analysed
    99
    30
    Units: kilograms (kg)/square meter (m^2)
        arithmetic mean (standard deviation)
    1.1 ( 0.86 )
    -0.1 ( 0.95 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Body Weight at Month 12

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    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
    End point values
    		 Somavaratan rhGH
    Number of subjects analysed
    100
    30
    Units: kg
        arithmetic mean (standard deviation)
    4.9 ( 1.87 )
    3.8 ( 1.64 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Insulin-like Growth Factor 1 (IGF-I) SDS at Month 12

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    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
    End point values
    		 Somavaratan rhGH
    Number of subjects analysed
    98
    28
    Units: SD score
        arithmetic mean (standard deviation)
    0.9 ( 0.99 )
    1.8 ( 0.72 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Insulin-like Growth Factor Binding Protein 3 (IGFBP-3) at Month 12

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    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
    End point values
    		 Somavaratan rhGH
    Number of subjects analysed
    90
    26
    Units: nanomoles (nmol)/milliliter (mL)
        arithmetic mean (standard deviation)
    32.2 ( 30.2 )
    49.8 ( 19.1 )
    No statistical analyses for this end point

    Secondary: Number of Participants With Adverse Events (AEs)

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    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
    End point values
    		 Somavaratan rhGH
    Number of subjects analysed
    104
    32
    Units: participants
    80
    22
    No statistical analyses for this end point

    Adverse events

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    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.

    Serious adverse events
    		 Somavaratan rhGH
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 104 (5.77%)
    0 / 32 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Congenital, familial and genetic disorders
    Arnold-Chiari malformation
         subjects affected / exposed
    2 / 104 (1.92%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Syringomyelia
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Glomerulonephritis
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Otitis media
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Somavaratan rhGH
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    59 / 104 (56.73%)
    16 / 32 (50.00%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    16 / 104 (15.38%)
    4 / 32 (12.50%)
         occurrences all number
    58
    15
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    18 / 104 (17.31%)
    4 / 32 (12.50%)
         occurrences all number
    28
    6
    Injection site pain
         subjects affected / exposed
    18 / 104 (17.31%)
    3 / 32 (9.38%)
         occurrences all number
    25
    5
    Injection site haematoma
         subjects affected / exposed
    6 / 104 (5.77%)
    1 / 32 (3.13%)
         occurrences all number
    6
    1
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    12 / 104 (11.54%)
    5 / 32 (15.63%)
         occurrences all number
    19
    8
    Diarrhoea
         subjects affected / exposed
    7 / 104 (6.73%)
    1 / 32 (3.13%)
         occurrences all number
    7
    1
    Nausea
         subjects affected / exposed
    5 / 104 (4.81%)
    3 / 32 (9.38%)
         occurrences all number
    8
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    15 / 104 (14.42%)
    2 / 32 (6.25%)
         occurrences all number
    18
    2
    Oropharyngeal pain
         subjects affected / exposed
    7 / 104 (6.73%)
    1 / 32 (3.13%)
         occurrences all number
    10
    1
    Nasal congestion
         subjects affected / exposed
    2 / 104 (1.92%)
    2 / 32 (6.25%)
         occurrences all number
    2
    3
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    2 / 104 (1.92%)
    2 / 32 (6.25%)
         occurrences all number
    2
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    11 / 104 (10.58%)
    3 / 32 (9.38%)
         occurrences all number
    17
    4
    Pain in extremity
         subjects affected / exposed
    12 / 104 (11.54%)
    1 / 32 (3.13%)
         occurrences all number
    20
    1
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    12 / 104 (11.54%)
    3 / 32 (9.38%)
         occurrences all number
    17
    6
    Nasopharyngitis
         subjects affected / exposed
    7 / 104 (6.73%)
    2 / 32 (6.25%)
         occurrences all number
    12
    3
    Otitis media
         subjects affected / exposed
    7 / 104 (6.73%)
    0 / 32 (0.00%)
         occurrences all number
    7
    0
    Ear infection
         subjects affected / exposed
    6 / 104 (5.77%)
    0 / 32 (0.00%)
         occurrences all number
    6
    0

    More information

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    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
    Date
    Interruption
    Restart date
    17 Feb 2015
    Enrollment paused on 17 Feb 2015 for FDA Partial Clinical Hold. All issues resolved and enrollment resumed on 23 June 2015.
    23 Jun 2015

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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