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    Clinical Trial Results:
    A Phase 3 Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Efficacy and Safety of BMN 111 in Children with Achondroplasia.

    Summary
    EudraCT number
    2015-003836-11
    Trial protocol
    GB   ES   DE  
    Global end of trial date
    30 Oct 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    24 Sep 2020
    First version publication date
    24 Sep 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    111-301
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03197766
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    BioMarin Pharmaceutical Inc
    Sponsor organisation address
    105 Digital Drive, Novato, United States, 94949
    Public contact
    Clinical Trials Information, BioMarin Pharmaceutical Inc., MedInfo@bmrn.com
    Scientific contact
    Clinical Trials Information, BioMarin Pharmaceutical Inc., MedInfo@bmrn.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-002033-PIP01-16
    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
    21 Apr 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Oct 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Oct 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Evaluate change from baseline in annualized growth velocity at 52 weeks in subjects treated with BMN 111 compared with control subjects in the placebo group
    Protection of trial subjects
    This clinical study was designed, conducted, recorded, and reported in compliance with the principles of Good Clinical Practice (GCP) guidelines. These guidelines are stated in U.S. federal regulations as well as “Guidance for Good Clinical Practice,” International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    12 Dec 2016
    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
    Australia: 22
    Country: Number of subjects enrolled
    Japan: 7
    Country: Number of subjects enrolled
    Turkey: 3
    Country: Number of subjects enrolled
    United States: 53
    Country: Number of subjects enrolled
    Spain: 13
    Country: Number of subjects enrolled
    United Kingdom: 13
    Country: Number of subjects enrolled
    Germany: 10
    Worldwide total number of subjects
    121
    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)
    96
    Adolescents (12-17 years)
    25
    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
    Study was conducted at 24 study centers in 7 countries.

    Pre-assignment
    Screening details
    A total of 121 subjects were enrolled into the study; 61 subjects were randomized to receive placebo and 60 subjects to receive vosoritide.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Subjects received a placebo single daily subcutaneous injection for 52 weeks
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received a placebo single daily subcutaneous injection for 52 weeks

    Arm title
    Vosoritide 15 μg/kg
    Arm description
    Subjects received a 15 μg/kg vosoritide single daily subcutaneous injection for 52 weeks
    Arm type
    Active comparator

    Investigational medicinal product name
    Vosoritide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received a 15 μg/kg vosoritide single daily subcutaneous injection for 52 weeks

    Number of subjects in period 1
    Placebo Vosoritide 15 μg/kg
    Started
    61
    60
    Completed
    61
    58
    Not completed
    0
    2
         Consent withdrawn by subject
    -
    1
         Adverse Event
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received a placebo single daily subcutaneous injection for 52 weeks

    Reporting group title
    Vosoritide 15 μg/kg
    Reporting group description
    Subjects received a 15 μg/kg vosoritide single daily subcutaneous injection for 52 weeks

    Reporting group values
    Placebo Vosoritide 15 μg/kg Total
    Number of subjects
    61 60 121
    Age categorical
    Units: Subjects
        ≥ 5 to < 8 years
    24 31 55
        ≥ 8 to < 11 years
    24 17 41
        ≥ 11 to < 15 years
    13 12 25
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    9.06 ± 2.47 8.35 ± 2.43 -
    Gender categorical
    Units: Subjects
        Female
    28 29 57
        Male
    33 31 64
    Race
    Units: Subjects
        White
    41 45 86
        Asian - Other
    9 7 16
        Asian - Japanese
    4 3 7
        Multiple
    5 2 7
        Black or African American
    2 3 5
    Ethnicity
    Units: Subjects
        Not Hispanic Or Latino
    55 59 114
        Hispanic Or Latino
    6 1 7

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received a placebo single daily subcutaneous injection for 52 weeks

    Reporting group title
    Vosoritide 15 μg/kg
    Reporting group description
    Subjects received a 15 μg/kg vosoritide single daily subcutaneous injection for 52 weeks

    Primary: Change from baseline of annualized growth velocity (AGV)

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    End point title
    Change from baseline of annualized growth velocity (AGV)
    End point description
    Annualized growth velocity (AGV) = Standing Height at Date 2 - Standing Height at Date 1/Interval Lenght (Days) x 365.25 The Full Analysis Set (FAS) was defined according to the intention to treat and included all randomized consented subjects. The FAS use to present the baseline characteristics and efficacy data by randomized treatment group. Two subjects in the vosoritide group discontinued from the study before Week 52. The values for these 2 subjects were imputed for this analysis. The type I error was controlled using hierarchical testing.
    End point type
    Primary
    End point timeframe
    At Baseline and Week 52
    End point values
    Placebo Vosoritide 15 μg/kg
    Number of subjects analysed
    61
    60
    Units: cm/year
    arithmetic mean (standard deviation)
        Baseline (n = 61, 60)
    4.06 ± 1.20
    4.26 ± 1.53
        Change from Baseline to Week 52 (n = 60, 58)
    -0.12 ± 1.74
    1.35 ± 1.71
    Statistical analysis title
    Annualized Growth Velocity - Placebo Vs Vosoritide
    Comparison groups
    Placebo v Vosoritide 15 μg/kg
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Confidence interval

    Secondary: Change from baseline of height Z-score

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    End point title
    Change from baseline of height Z-score
    End point description
    Standing Height converted to an age-and sex-appropriate standard deviation score (SDS), also referred to as a Z-score, by comparison with reference data available for average stature children from the Centers for Disease Control and Prevention(CDC). Full Analysis Set(FAS) population Two subjects in the vosoritide group discontinued from the study before Week 52. The values for these 2 subjects were imputed for this analysis. The type I error was controlled using hierarchical testing.
    End point type
    Secondary
    End point timeframe
    At Baseline and Week 52
    End point values
    Placebo Vosoritide 15 μg/kg
    Number of subjects analysed
    61
    60
    Units: Z-score
    arithmetic mean (standard deviation)
        Baseline (n = 61, 60)
    -5.14 ± 1.07
    -5.13 ± 1.11
        Change from Baseline to Week 52 (n = 61, 60)
    0.00 ± 0.28
    0.24 ± 0.32
    Statistical analysis title
    Height Z-Score - Placebo Vs Vosoritide
    Comparison groups
    Placebo v Vosoritide 15 μg/kg
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Confidence interval

    Secondary: Change from baseline of upper to lower body segment ratio

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    End point title
    Change from baseline of upper to lower body segment ratio
    End point description
    Full Analysis Set (FAS) population. Two subjects in the vosoritide group discontinued from the study before Week 52. The values for these 2 subjects were imputed for this analysis. The type I error was controlled using hierarchical testing.
    End point type
    Secondary
    End point timeframe
    At Baseline and Week 52
    End point values
    Placebo Vosoritide 15 μg/kg
    Number of subjects analysed
    61
    60
    Units: Ratio
    arithmetic mean (standard deviation)
        Baseline (n = 61, 60)
    2.01 ± 0.21
    1.98 ± 0.20
        Change from Baseline to Week 52 (n = 60, 58)
    -0.03 ± 0.09
    -0.03 ± 0.11
    Statistical analysis title
    Upper to Lower Body Ratio - Placebo Vs Vosoritide
    Comparison groups
    Placebo v Vosoritide 15 μg/kg
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.506
    Method
    ANCOVA
    Confidence interval

    Secondary: Time taken to reach peak concentration (Tmax) of vosoritide at week 52

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    End point title
    Time taken to reach peak concentration (Tmax) of vosoritide at week 52 [1]
    End point description
    Pharmacokinetics (PK) Parameter Time taken to reach Peak Concentration (Tmax) At week 52: number of PK parameters used in the calculation of the statistics = 56
    End point type
    Secondary
    End point timeframe
    At week 52.
    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: Results summarised using descriptive statistics only
    End point values
    Vosoritide 15 μg/kg
    Number of subjects analysed
    58
    Units: min
        arithmetic mean (standard deviation)
    16.8 ± 11.7
    No statistical analyses for this end point

    Secondary: Maximum plasma concentration (Cmax) of vosoritide at week 52

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    End point title
    Maximum plasma concentration (Cmax) of vosoritide at week 52 [2]
    End point description
    Pharmacokinetics (PK) Parameter Maximum Plasma Concentration (Cmax). At week 52: number of PK parameters used in the calculation of the statistics = 56
    End point type
    Secondary
    End point timeframe
    At Week 52.
    Notes
    [2] - 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: Results summarised using descriptive statistics only
    End point values
    Vosoritide 15 μg/kg
    Number of subjects analysed
    58
    Units: pg/mL
        arithmetic mean (standard deviation)
    5800 ± 3680
    No statistical analyses for this end point

    Secondary: Area under the concentration-time curve from time zero to time of last measurable concentration (AUC0-t) of vosoritide at week 52

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    End point title
    Area under the concentration-time curve from time zero to time of last measurable concentration (AUC0-t) of vosoritide at week 52 [3]
    End point description
    Pharmacokinetics (PK) Parameter Area under the concentration-time curve from time zero to time of last measurable concentration (AUC0-t). At week 52: number of PK parameters used in the calculation of the statistics = 56
    End point type
    Secondary
    End point timeframe
    At week 52.
    Notes
    [3] - 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: Results summarised using descriptive statistics only
    End point values
    Vosoritide 15 μg/kg
    Number of subjects analysed
    58
    Units: pg-min/mL
        arithmetic mean (standard deviation)
    290000 ± 235000
    No statistical analyses for this end point

    Secondary: Area under the concentration-time curve from time zero to infinity (AUC0-∞) of vosoritide at week 52

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    End point title
    Area under the concentration-time curve from time zero to infinity (AUC0-∞) of vosoritide at week 52 [4]
    End point description
    Pharmacokinetics (PK) Parameter Area Under the Concentration-time Curve From Time 0 to Infinity (AUC0-∞). At week 52: number of PK parameters used in the calculation of the statistics = 48
    End point type
    Secondary
    End point timeframe
    At week 52.
    Notes
    [4] - 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: Results summarised using descriptive statistics only
    End point values
    Vosoritide 15 μg/kg
    Number of subjects analysed
    58
    Units: pg-min/mL
        arithmetic mean (standard deviation)
    276000 ± 187000
    No statistical analyses for this end point

    Secondary: Apparent clearance (CL/F) of vosoritide at week 52

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    End point title
    Apparent clearance (CL/F) of vosoritide at week 52 [5]
    End point description
    Pharmacokinetics(PK) Parameter Apparent Clearance (CL/F) At week 52: number of PK parameters used in the calculation of the statistics = 48
    End point type
    Secondary
    End point timeframe
    At week 52.
    Notes
    [5] - 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: Results summarised using descriptive statistics only
    End point values
    Vosoritide 15 μg/kg
    Number of subjects analysed
    58
    Units: mL/min/kg
        arithmetic mean (standard deviation)
    79.4 ± 53.0
    No statistical analyses for this end point

    Secondary: Apparent volume of distribution (Vz/F) of vosoritide at week 52

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    End point title
    Apparent volume of distribution (Vz/F) of vosoritide at week 52 [6]
    End point description
    Pharmacokinetics (PK) Parameter Apparent Volume of Distribution (Vz/F) At week 52: number of PK parameters used in the calculation of the statistics = 48
    End point type
    Secondary
    End point timeframe
    At week 52.
    Notes
    [6] - 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: Results summarised using descriptive statistics only
    End point values
    Vosoritide 15 μg/kg
    Number of subjects analysed
    58
    Units: mL/kg
        arithmetic mean (standard deviation)
    2910 ± 1660
    No statistical analyses for this end point

    Secondary: Plasma half life (t1/2) of vosoritide at week 52

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    End point title
    Plasma half life (t1/2) of vosoritide at week 52 [7]
    End point description
    Pharmacokinetics (PK) Parameter Plasma Half Life (t1/2). At week 52: number of PK parameters used in the calculation of the statistics = 48
    End point type
    Secondary
    End point timeframe
    At week 52.
    Notes
    [7] - 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: Results summarised using descriptive statistics only
    End point values
    Vosoritide 15 μg/kg
    Number of subjects analysed
    58
    Units: min
        arithmetic mean (standard deviation)
    27.9 ± 9.91
    No statistical analyses for this end point

    Secondary: Number of subjects with treatment emergent adverse events (TEAEs)

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    End point title
    Number of subjects with treatment emergent adverse events (TEAEs)
    End point description
    A treatment-emergent Adverse Events (TEAE) is any Adverse Events that newly appeared, increased in frequency or worsened in severity following initiation of study drug administration. Safety Population are those all subjects in the FAS who received at least one dose of double-blind vosoritide or placebo in this study. Safety Population used to present the safety summaries by actual treatment received.
    End point type
    Secondary
    End point timeframe
    Up to Week 56
    End point values
    Placebo Vosoritide 15 μg/kg
    Number of subjects analysed
    61
    60
    Units: participants
        Subjects with any Adverse Event
    60
    59
        Subjects with any Serious Adverse Event
    4
    3
        Subjects with any treatment-related Adverse Event
    51
    53
        Any treatment-related Serious Adverse Event
    0
    0
        Death
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Week 56
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    -

    Reporting group title
    Vosoritide 15 μg/kg
    Reporting group description
    -

    Serious adverse events
    Placebo Vosoritide 15 μg/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 61 (6.56%)
    3 / 60 (5.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Radius fracture
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Adenoidal hypertrophy
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Intracranial pressure increased
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 60 (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
    Influenza
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 60 (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
    Placebo Vosoritide 15 μg/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    60 / 61 (98.36%)
    59 / 60 (98.33%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    4 / 61 (6.56%)
    4 / 60 (6.67%)
         occurrences all number
    5
    5
    Investigations
    Blood pressure decreased
         subjects affected / exposed
    3 / 61 (4.92%)
    7 / 60 (11.67%)
         occurrences all number
    3
    10
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    1 / 61 (1.64%)
    4 / 60 (6.67%)
         occurrences all number
    1
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 61 (13.11%)
    7 / 60 (11.67%)
         occurrences all number
    10
    8
    Oropharyngeal pain
         subjects affected / exposed
    4 / 61 (6.56%)
    6 / 60 (10.00%)
         occurrences all number
    4
    13
    Nasal congestion
         subjects affected / exposed
    4 / 61 (6.56%)
    3 / 60 (5.00%)
         occurrences all number
    5
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    16 / 61 (26.23%)
    14 / 60 (23.33%)
         occurrences all number
    30
    23
    Dizziness
         subjects affected / exposed
    1 / 61 (1.64%)
    4 / 60 (6.67%)
         occurrences all number
    1
    4
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    3 / 61 (4.92%)
    6 / 60 (10.00%)
         occurrences all number
    3
    11
    General disorders and administration site conditions
    Injection site reaction
         subjects affected / exposed
    29 / 61 (47.54%)
    44 / 60 (73.33%)
         occurrences all number
    229
    2280
    Injection site erythema
         subjects affected / exposed
    40 / 61 (65.57%)
    41 / 60 (68.33%)
         occurrences all number
    1215
    3987
    Injection site swelling
         subjects affected / exposed
    6 / 61 (9.84%)
    23 / 60 (38.33%)
         occurrences all number
    53
    322
    Pyrexia
         subjects affected / exposed
    13 / 61 (21.31%)
    10 / 60 (16.67%)
         occurrences all number
    22
    11
    Injection site urticaria
         subjects affected / exposed
    2 / 61 (3.28%)
    8 / 60 (13.33%)
         occurrences all number
    5
    71
    Injection site bruising
         subjects affected / exposed
    8 / 61 (13.11%)
    5 / 60 (8.33%)
         occurrences all number
    16
    19
    Fatigue
         subjects affected / exposed
    0 / 61 (0.00%)
    4 / 60 (6.67%)
         occurrences all number
    0
    4
    Injection site mass
         subjects affected / exposed
    1 / 61 (1.64%)
    4 / 60 (6.67%)
         occurrences all number
    1
    34
    Injection site haemorrhage
         subjects affected / exposed
    7 / 61 (11.48%)
    2 / 60 (3.33%)
         occurrences all number
    15
    4
    Injection site pruritus
         subjects affected / exposed
    4 / 61 (6.56%)
    1 / 60 (1.67%)
         occurrences all number
    102
    220
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    12 / 61 (19.67%)
    16 / 60 (26.67%)
         occurrences all number
    16
    25
    Diarrhoea
         subjects affected / exposed
    2 / 61 (3.28%)
    6 / 60 (10.00%)
         occurrences all number
    2
    8
    Nausea
         subjects affected / exposed
    4 / 61 (6.56%)
    3 / 60 (5.00%)
         occurrences all number
    6
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 61 (6.56%)
    9 / 60 (15.00%)
         occurrences all number
    7
    11
    Pain in extremity
         subjects affected / exposed
    4 / 61 (6.56%)
    5 / 60 (8.33%)
         occurrences all number
    4
    8
    Metabolism and nutrition disorders
    Vitamin D deficiency
         subjects affected / exposed
    7 / 61 (11.48%)
    3 / 60 (5.00%)
         occurrences all number
    7
    3
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    18 / 61 (29.51%)
    16 / 60 (26.67%)
         occurrences all number
    29
    26
    Upper respiratory tract infection
         subjects affected / exposed
    10 / 61 (16.39%)
    8 / 60 (13.33%)
         occurrences all number
    12
    8
    Ear infection
         subjects affected / exposed
    6 / 61 (9.84%)
    6 / 60 (10.00%)
         occurrences all number
    6
    8
    Influenza
         subjects affected / exposed
    3 / 61 (4.92%)
    6 / 60 (10.00%)
         occurrences all number
    3
    8
    Otitis media
         subjects affected / exposed
    6 / 61 (9.84%)
    6 / 60 (10.00%)
         occurrences all number
    9
    7
    Viral infection
         subjects affected / exposed
    3 / 61 (4.92%)
    5 / 60 (8.33%)
         occurrences all number
    5
    11
    Gastroenteritis
         subjects affected / exposed
    3 / 61 (4.92%)
    4 / 60 (6.67%)
         occurrences all number
    3
    4
    Gastroenteritis viral
         subjects affected / exposed
    1 / 61 (1.64%)
    4 / 60 (6.67%)
         occurrences all number
    1
    4
    Pharyngitis
         subjects affected / exposed
    4 / 61 (6.56%)
    1 / 60 (1.67%)
         occurrences all number
    7
    1

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Nov 2016
    Use of Birth Control During and After Study Participation
    27 Apr 2017
    - Upper limit of age range increased from less than 15 years old to less than 18 years old. - Stratification /randomization to be conducted by Tanner stage rather than by age group. - Criterion for removing subjects from treatment or assessment, “Subject has reached near adult height in the judgment of the investigator” revised to be more specific. - ISR photo language has been revised. - Inclusion criterion #1, regarding informed consent, revised to state the subjects who reach age of 18 years while study is ongoing are asked to provide their own written consent. - Inclusion criteria #4 revised to elaborate on requirements for entering Study 111-301 from 111-901. - New section, Procedures due to Achondroplasia added. - Pregnancy Testing, language added stating that start date of menses is captured. - New section, Events of Special Interest, added. - Statistical Methods and Determination of Sample Size, has been substantially revised.
    05 Jan 2018
    - Evaluation of change from baseline in bone metabolism biomarkers moved from exploratory to secondary objectives. - Exclusion criterion #6 revised to include evidence of decreased growth velocity (AGV < 1.5 cm/year) as assessed over a period of at least 6 months. - Exclusion criterion #15 revised to state that subjects with previous bone-related surgery may enroll if surgery occurred at least 6 months prior to screening, rather than 12 months, excluding tooth extraction. - Salivary cortisol, serum prolactin, FSH/LH, and cognitive assessment with the CBCL added as safety assessments. - Use of Birth Control During and After Study Participation, progestogen-only hormonal contraception removed. - DXA scans to no longer include tibia scans. - Hip Clinical Assessment, requirement to be completed by a physician, i.e., the investigator or sub-investigator changed to assessment by an appropriately qualified health care professional.
    01 Feb 2019
    - The following exploratory objectives moved to secondary: a. Change from baseline in body proportion ratios of the extremities. b. Effect of vosoritide on bone morphology/quality by X-ray and DXA. c. Changes in HRQoL and functional independence. - Contraception in inclusion criteria and birth control during and after the study updated. - Duration of subject participation updated to account for 4-week safety follow-up after Week 52. - Primary and secondary efficacy variables separated so that new secondary variables are incorporated. - Replaced “18 years of age” with “age of majority”. - Inserted “In Japan, subject enrollment was staggered initially, with a minimum of a 2-week window between the first 4 subjects enrolled”.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    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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