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    Clinical Trial Results:
    A Phase 2 Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Evaluate the Safety and Efficacy of BMN 111 in Infants and Young Children with Achondroplasia, Age 0 to < 60 Months

    Summary
    EudraCT number
    2016-003826-18
    Trial protocol
    GB  
    Global end of trial date
    26 Jan 2022

    Results information
    Results version number
    v1(current)
    This version publication date
    28 Mar 2023
    First version publication date
    28 Mar 2023
    Other versions
    Summary report(s)
    Secondary Endpoints_ITQOL Tables
    PK parameter Endpoints tables

    Trial information

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    Trial identification
    Sponsor protocol code
    BMN 111-206
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03583697
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    BioMarin Pharmaceutical Inc
    Sponsor organisation address
    105 Digital Drive, Novato, CA, United States, 94949
    Public contact
    Clinical Trials Information, BioMarin Pharmaceutical Inc., clinicaltrials@bmrn.com
    Scientific contact
    Clinical Trials Information, BioMarin Pharmaceutical Inc., clinicaltrials@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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    26 Jan 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Jan 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Jan 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of the study were to: - Evaluate the safety and tolerability of Vosoritide in children aged 0 to < 60 months with ACH - Evaluate the effect of Vosoritide on change from baseline in length/height Z-score
    Protection of trial subjects
    This clinical study was designed, implemented and reported in accordance with the protocol and also with the following: • European Clinical Trial Directive 2001/20/EC and Good Clinical Practice (GCP) Directive 2005/28/EC, for studies conducted within any European country • United States (US) Code of Federal Regulations (CFR) sections that address clinical research studies, and/or other national and local regulations, as applicable • International Council on Harmonisation, Harmonised Tripartite Guideline: Guideline for GCP E6 (ICH E6) • The ethical principles established by the Declaration of Helsinki
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    13 Jun 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    19 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 18
    Country: Number of subjects enrolled
    Japan: 8
    Country: Number of subjects enrolled
    United States: 41
    Country: Number of subjects enrolled
    United Kingdom: 8
    Worldwide total number of subjects
    75
    EEA total number of subjects
    0
    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)
    40
    Children (2-11 years)
    35
    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
    This was a multi-center study conducted by 16 principal investigators at 16 study centers in four countries (United States, Australia, United Kingdom and Japan).

    Pre-assignment
    Screening details
    A total of 75 participants (full analysis set [FAS]) were enrolled into the study, of which 11 participants were enrolled to receive vosoritide (sentinel participants). 64 participants were randomized to receive vosoritide or placebo (32 randomized for vosoritide and 32 for placebo), which constituted the FAS (randomized).

    Period 1
    Period 1 title
    Overall period
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Participants & site members were blinded to study treatment. The investigator and staff involved with the study also remained blinded to the treatment randomization code. In an emergency medical situation where participant management would be determined or significantly altered by knowing the treatment assignment, the investigator could be unblinded without prior written approval from the Medical Monitor.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Sentinel
    Arm description
    Cohort 1 Sentinel: Participants stratified by age >= 24 to < 60 months, received vosoritide 15 µg/kg/day (n=4) Cohort 2 Sentinel: Participants stratified by age >= 6 to < 24 months, received vosoritide 15 µg/kg/day & 30 µg/kg/day (n=4) Cohort 3 Sentinel: Participants stratified by age 0 to < 6 months, received vosoritide 30 µg/kg/day (n=3)
    Arm type
    Active comparator

    Investigational medicinal product name
    BMN 111
    Investigational medicinal product code
    Other name
    Vosoritide
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Cohort 1 Sentinel participants received a 15 μg/kg vosoritide single daily subcutaneous injection for 52 weeks. Cohort 2 Sentinel participants Initially dosed with single daily subcutaneous injection of vosoritide 15 µg/kg/day and were adjusted to 30 µg/kg/day following the review of safety and PK data then adjusted to 15 µg/kg/day during the visit immediately preceding the 2-year birthday. Cohort 3 Sentinel participants received a 30 μg/kg vosoritide single daily subcutaneous injection for 52 weeks.

    Arm title
    Randomized Vosoritide
    Arm description
    Cohort 1: Vosoritide 15 µg/kg/day (n=15) Cohort 2: Vosoritide 15 µg/kg/day & 30 µg/kg/day (n=8) Cohort 3: Vosoritide 30 µg/kg/day (n=9)
    Arm type
    Experimental

    Investigational medicinal product name
    BMN 111
    Investigational medicinal product code
    Other name
    Vosoritide
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Cohort 1: Participants received a vosoritide 15 μg/kg daily subcutaneous injection for 52 weeks. Cohort 2: Participants received vosoritide 15 μg/kg to 30 μg/kg daily subcutaneous injection for 52 weeks. Cohort 3: Participants received vosoritide 30 μg/kg daily subcutaneous injection for 52 weeks.

    Arm title
    Randomized Placebo
    Arm description
    Cohort 1: Placebo (n=16) Cohort 2: Placebo (n=8) Cohort 3: Placebo (n=8)
    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
    Participants received a placebo single daily subcutaneous injection for 52 weeks.

    Number of subjects in period 1
    Sentinel Randomized Vosoritide Randomized Placebo
    Started
    11
    32
    32
    Completed
    11
    31
    31
    Not completed
    0
    1
    1
         Consent withdrawn by subject
    -
    -
    1
         AE of sudden infant death syndrome, not related
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sentinel
    Reporting group description
    Cohort 1 Sentinel: Participants stratified by age >= 24 to < 60 months, received vosoritide 15 µg/kg/day (n=4) Cohort 2 Sentinel: Participants stratified by age >= 6 to < 24 months, received vosoritide 15 µg/kg/day & 30 µg/kg/day (n=4) Cohort 3 Sentinel: Participants stratified by age 0 to < 6 months, received vosoritide 30 µg/kg/day (n=3)

    Reporting group title
    Randomized Vosoritide
    Reporting group description
    Cohort 1: Vosoritide 15 µg/kg/day (n=15) Cohort 2: Vosoritide 15 µg/kg/day & 30 µg/kg/day (n=8) Cohort 3: Vosoritide 30 µg/kg/day (n=9)

    Reporting group title
    Randomized Placebo
    Reporting group description
    Cohort 1: Placebo (n=16) Cohort 2: Placebo (n=8) Cohort 3: Placebo (n=8)

    Reporting group values
    Sentinel Randomized Vosoritide Randomized Placebo Total
    Number of subjects
    11 32 32 75
    Age categorical
    Units: Subjects
    Age continuous
    Age at Screening, months Full analysis population (FAS).
    Units: months
        arithmetic mean (standard deviation)
    23.4 ± 21.0 23.0 ± 16.9 26.5 ± 19.3 -
    Gender categorical
    Full analysis population (FAS).
    Units: Subjects
        Female
    3 15 19 37
        Male
    8 17 13 38
    Race
    Full analysis population (FAS).
    Units: Subjects
        White
    8 21 25 54
        Asian-Other
    1 6 2 9
        Asian-Japanese
    0 4 4 8
        Multiple
    2 1 0 3
        Native Hawaiian or Other Pacific Islander
    0 0 1 1
    Ethnicity
    Full analysis population (FAS).
    Units: Subjects
        Not Hispanic or Latino
    11 29 29 69
        Hispanic or Latino
    0 3 3 6
    Age continuous
    Age on Day 1, months. Full analysis population (FAS).
    Units: Months
        arithmetic mean (standard deviation)
    24.71 ± 20.79 24.39 ± 16.83 27.82 ± 19.25 -
    Weight
    Full analysis population (FAS).
    Units: Kg
        arithmetic mean (standard deviation)
    10.12 ± 3.70 10.20 ± 3.83 10.55 ± 4.31 -
    Weight Z-Score
    Full analysis population (FAS).
    Units: Z-Score
        arithmetic mean (standard deviation)
    -1.41 ± 0.73 -1.49 ± 1.26 -1.59 ± 1.44 -
    BMI
    Body Mass Index (BMI) Full analysis population (FAS).
    Units: kg/m^2
        arithmetic mean (standard deviation)
    20.06 ± 1.87 19.48 ± 2.45 20.14 ± 2.39 -
    BMI Z-Score
    Baseline is defined as Day 1 or screening if a Day 1 assessment is not available. Z-Scores were derived using age-sex specific reference data (means and SDs) for average stature children per the Centers for Disease Control and Prevention. For height used for BMI calculation, participants aged < 24 months, body length takes precedence over standing height. Participants aged < 24 months at baseline and >= 24 months at Week 52, body length takes precedence. BMI Z-Scores were derived only for participants aged 24 months or older. BMI Z-Score: (n=Sentinel 4, Vosoritide 15, Placebo 16)
    Units: Z-Score
        arithmetic mean (standard deviation)
    2.79 ± 0.98 2.52 ± 1.15 2.77 ± 0.75 -

    End points

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    End points reporting groups
    Reporting group title
    Sentinel
    Reporting group description
    Cohort 1 Sentinel: Participants stratified by age >= 24 to < 60 months, received vosoritide 15 µg/kg/day (n=4) Cohort 2 Sentinel: Participants stratified by age >= 6 to < 24 months, received vosoritide 15 µg/kg/day & 30 µg/kg/day (n=4) Cohort 3 Sentinel: Participants stratified by age 0 to < 6 months, received vosoritide 30 µg/kg/day (n=3)

    Reporting group title
    Randomized Vosoritide
    Reporting group description
    Cohort 1: Vosoritide 15 µg/kg/day (n=15) Cohort 2: Vosoritide 15 µg/kg/day & 30 µg/kg/day (n=8) Cohort 3: Vosoritide 30 µg/kg/day (n=9)

    Reporting group title
    Randomized Placebo
    Reporting group description
    Cohort 1: Placebo (n=16) Cohort 2: Placebo (n=8) Cohort 3: Placebo (n=8)

    Subject analysis set title
    Cohort 1: Placebo
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Cohort 1 included participants stratified by age >=24 to <36 months and >=36 to <60 months. The Full Analysis Set (FAS) was defined according to the intent-to-treat principle and included all enrolled sentinel and randomized participants with a signed informed consent

    Subject analysis set title
    Cohort 1: Vosoritide
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Cohort 1 included participants stratified by age >=24 to <36 months and >=36 to <60 months. Vosoritide 15 μg/kg/day The Full Analysis Set (FAS) was defined according to the intent-to-treat principle and included all enrolled sentinel and randomized participants with a signed informed consent.

    Subject analysis set title
    Cohort 2: Placebo
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Cohort 2 included participants stratified by age >=6 to <15 months and >=15 months to <24 months). The Full Analysis Set (FAS) was defined according to the intent-to-treat principle and included all enrolled sentinel and randomized participants with a signed informed consent

    Subject analysis set title
    Cohort 2: Vosoritide
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Cohort 2 included participants stratified by age >=6 to <15 months and >=15 months to <24 months). Vosoritide 15 μg/kg/day & 30 μg/kg/day The Full Analysis Set (FAS) was defined according to the intent-to-treat principle and included all enrolled sentinel and randomized participants with a signed informed consent

    Subject analysis set title
    Cohort 3: Placebo
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Cohort 3 included participants stratified by age 0 to < 6 months. The Full Analysis Set (FAS) was defined according to the intent-to-treat principle and included all enrolled sentinel and randomized participants with a signed informed consent

    Subject analysis set title
    Cohort 3: Vosoritide
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Cohort 3 included participants stratified by age 0 to < 6 months. Vosoritide 30 μg/kg/day The Full Analysis Set (FAS) was defined according to the intent-to-treat principle and included all enrolled sentinel and randomized participants with a signed informed consent

    Subject analysis set title
    All Vosoritide
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The Full Analysis Set (FAS) was defined according to the intent-to-treat principle and included all enrolled sentinel and randomized participants with a signed informed consent.

    Subject analysis set title
    Placebo
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The Full Analysis Set (FAS) was defined according to the intent-to-treat principle and included all enrolled sentinel and randomized participants with a signed informed consent.

    Primary: Number of participants with adverse events (AEs) by severity grade and study drug treatment-emergent adverse events (TEAEs)

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    End point title
    Number of participants with adverse events (AEs) by severity grade and study drug treatment-emergent adverse events (TEAEs) [1]
    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. A severity grade was defined by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. As per CTCAE, Grade 1 scales as Mild; Grade 2 scales as Moderate; Grade 3 scales as severe or medically significant but not immediately life threatening; Grade 4 scales as life-threatening consequences; and Grade 5 scales as death related to AE. Safety Population includes all sentinel and randomized participants in the FAS who received at least one dose of vosoritide or placebo in this study. Serious adverse event (SAE)
    End point type
    Primary
    End point timeframe
    Up to Week 56 (Safety Follow-Up +/-7d)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was analyzed for this endpoint.
    End point values
    Sentinel Randomized Vosoritide Randomized Placebo
    Number of subjects analysed
    11
    32
    32
    Units: Numbers
        Participants with any AE
    11
    32
    32
        Participants with any SAE
    0
    3
    6
        Participants with any treatment-related AE
    8
    29
    17
        Participants with any treatment-related SAEs
    0
    0
    0
        Participants with any AE of CTCAE grade >=3
    0
    2
    3
        Participants who died
    0
    1
    0
    No statistical analyses for this end point

    Primary: Change from baseline in height Z-score at Week 52

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    End point title
    Change from baseline in height Z-score at Week 52 [2]
    End point description
    Standing Height/body length was 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). The primary efficacy analysis population was the subset of randomized participants in the FAS. The Full Analysis Set (FAS) was defined according to the intent-to-treat principle and included all enrolled sentinel and randomized participants with a signed informed consent. FAS Randomized population includes randomized vosoritide (32 participants) and randomized placebo (32 participants). FAS analysis population includes All vosoritide (43 participants) and Placebo (32 participants).
    End point type
    Primary
    End point timeframe
    Baseline to 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: Statistical analysis for FAS (All Vosoritide and Placebo) includes Sentinel participants.
    End point values
    Randomized Vosoritide Randomized Placebo All Vosoritide Placebo
    Number of subjects analysed
    32
    32
    43
    32
    Units: Z-score
        least squares mean (confidence interval 95%)
    -0.06 (-0.26 to 0.15)
    -0.31 (-0.48 to -0.13)
    0.01 (-0.15 to 0.17)
    -0.30 (-0.47 to -0.13)
    Statistical analysis title
    Height Z-Score-Placebo Vs Vosoritide(FAS Random)
    Statistical analysis description
    Z-Scores were derived using age-sex specific reference data (means and SDs) for average stature children per the Centers for Disease Control and Prevention. Participants aged < 24 months, body length takes precedence over standing height. Participants aged < 24 months at baseline and >= 24 months at Week 52, body length takes precedence. Difference in LS means were obtained from an analysis of covariance model.
    Comparison groups
    Randomized Vosoritide v Randomized Placebo
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    other [3]
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    0.25
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.02
         upper limit
    0.53
    Notes
    [3] - Covariance model
    Statistical analysis title
    Height Z-Score - Placebo Vs Vosoritide (FAS)
    Statistical analysis description
    Z-Scores were derived using age-sex specific reference data (means and SDs) for average stature children per the Centers for Disease Control and Prevention. Participants aged < 24 months, body length takes precedence over standing height. Participants aged < 24 months at baseline and >= 24 months at Week 52, body length takes precedence. Difference in LS means were obtained from an analysis of covariance model.
    Comparison groups
    All Vosoritide v Placebo
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    other [4]
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.07
         upper limit
    0.54
    Notes
    [4] - Covariance model

    Secondary: Change from baseline in height at Week 52

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    End point title
    Change from baseline in height at Week 52 [5]
    End point description
    FAS Randomized population includes randomized vosoritide (32 participants) and randomized placebo (32 participants). FAS analysis population includes All vosoritide (43 participants) and Placebo (32 participants).
    End point type
    Secondary
    End point timeframe
    Baseline to 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: Statistical analysis for FAS (All Vosoritide and Placebo) includes Sentinel participants.
    End point values
    Randomized Vosoritide Randomized Placebo All Vosoritide Placebo
    Number of subjects analysed
    32
    32
    43
    32
    Units: cm
        least squares mean (confidence interval 95%)
    8.15 (7.55 to 8.75)
    7.38 (6.87 to 7.89)
    8.41 (7.93 to 8.89)
    7.45 (6.95 to 7.95)
    Statistical analysis title
    Height-Placebo Vs Vosoritide(FAS Randomized)
    Statistical analysis description
    Difference in LS means were obtained from an analysis of covariance model.
    Comparison groups
    Randomized Vosoritide v Randomized Placebo
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    other [6]
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    0.77
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.02
         upper limit
    1.56
    Notes
    [6] - Covariance model.
    Statistical analysis title
    Height - Placebo Vs Vosoritide (FAS)
    Statistical analysis description
    Difference in LS means were obtained from an analysis of covariance model.
    Comparison groups
    All Vosoritide v Placebo
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    other [7]
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    0.96
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.26
         upper limit
    1.66
    Notes
    [7] - Covariance model.

    Secondary: Change from baseline in annualized growth velocity (AGV) at Week 52

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    End point title
    Change from baseline in annualized growth velocity (AGV) at Week 52 [8]
    End point description
    AGV was derived over 12-month intervals starting from the baseline visit. Annualized growth velocity (AGV) = Standing Height at Date 2 - Standing Height at Date 1/Interval Lenght (Days) x 365.25. FAS Randomized population includes randomized vosoritide (32 participants) and randomized placebo (32 participants). FAS analysis population includes All vosoritide (43 participants) and Placebo (32 participants).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    Notes
    [8] - 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: Statistical analysis for FAS (All Vosoritide and Placebo) includes Sentinel participants.
    End point values
    Randomized Vosoritide Randomized Placebo All Vosoritide Placebo
    Number of subjects analysed
    32
    32
    43
    32
    Units: cm/year
        least squares mean (confidence interval 95%)
    -2.17 (-2.76 to -1.58)
    -2.95 (-3.45 to -2.45)
    -2.41 (-2.88 to -1.94)
    -3.32 (-3.81 to -2.84)
    Statistical analysis title
    AGV - Placebo Vs Vosoritide(FAS Randomized)
    Statistical analysis description
    Difference in LS means were obtained from an analysis of covariance model.
    Comparison groups
    Randomized Vosoritide v Randomized Placebo
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    other [9]
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    0.78
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.02
         upper limit
    1.54
    Notes
    [9] - Covariance model.
    Statistical analysis title
    AGV - Placebo Vs Vosoritide (FAS)
    Statistical analysis description
    Difference in LS means were obtained from an analysis of covariance model.
    Comparison groups
    All Vosoritide v Placebo
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    0.92
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.24
         upper limit
    1.59

    Secondary: Change from baseline in upper to lower body segment ratio at Week 52

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    End point title
    Change from baseline in upper to lower body segment ratio at Week 52 [10]
    End point description
    Upper to Lower Body ratio=Sitting Height / (Standing Height – Sitting Height). The ratio of derived sitting height and derived standing height was also calculated. FAS Randomized population includes randomized vosoritide (32 participants) and randomized placebo (32 participants). FAS analysis population includes All vosoritide (43 participants) and Placebo (32 participants).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    Notes
    [10] - 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: Statistical analysis for FAS (All Vosoritide and Placebo) includes Sentinel participants.
    End point values
    Randomized Vosoritide Randomized Placebo All Vosoritide Placebo
    Number of subjects analysed
    32
    32
    43
    32
    Units: Ratio
        least squares mean (confidence interval 95%)
    -0.20 (-0.28 to -0.13)
    -0.13 (-0.21 to -0.06)
    -0.19 (-0.25 to -0.13)
    -0.13 (-0.20 to -0.06)
    Statistical analysis title
    Upper-Lower Body Placebo Vs Vosoritide (FAS Rand)
    Statistical analysis description
    Upper to lower body segment ratio. Difference in LS means were obtained from an analysis of covariance model.
    Comparison groups
    Randomized Vosoritide v Randomized Placebo
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    other [11]
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.17
         upper limit
    0.04
    Notes
    [11] - Covariance model.
    Statistical analysis title
    Upper-Lower Body Ratio Placebo Vs Vosoritide (FAS)
    Statistical analysis description
    Upper to lower body segment ratio. Difference in LS means were obtained from an analysis of covariance model.
    Comparison groups
    All Vosoritide v Placebo
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    other [12]
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.06
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.15
         upper limit
    0.03
    Notes
    [12] - Covariance model.

    Secondary: Change from baseline in other growth measures (upper body length, head circumference, arm span, upper arm length, lower arm length, Lower Body Length, upper leg length, knee to heel length, and tibial length) at Week 52

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    End point title
    Change from baseline in other growth measures (upper body length, head circumference, arm span, upper arm length, lower arm length, Lower Body Length, upper leg length, knee to heel length, and tibial length) at Week 52
    End point description
    Change from baseline in other growth measures (upper body length, head circumference, arm span, upper arm length, lower arm (Forearm) length, Lower Body Length, Upper Leg Length (Thigh), knee to heel length, and tibial length) at Week 52. The number of participants analyzed is reported in sequence: (n=Cohort 1 Placebo, Cohort 1 Vosoritide, Cohort 2 Placebo, Cohort 2 Vosoritide, Cohort 3 Placebo, Cohort 3 Vosoritide) vosoritide including sentinel and randomized participants for each category. Upper body length: (n=16, 19, 7, 12, 8, 11) Head Circumference: (n=16, 19, 7, 11, 8, 11) Arm Span: (n=16, 19, 7, 10, 8, 10) Upper Arm Length: (n=16, 19, 7, 11, 8, 11) Lower Arm (Forearm) Length : (n=16, 19, 7, 10, 8, 11) Lower Body Length: (n=16, 19, 7, 12, 8, 11) Upper Leg Length (Thigh): (n=16, 19, 7, 10, 8, 11) Knee to Heel Length: (n=16, 19, 7, 11, 8, 11) Tibial Length: (n=16, 19, 7, 11, 8, 11)
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    Cohort 1: Placebo Cohort 1: Vosoritide Cohort 2: Placebo Cohort 2: Vosoritide Cohort 3: Placebo Cohort 3: Vosoritide
    Number of subjects analysed
    16
    19
    8
    12
    8
    12
    Units: cm
    arithmetic mean (standard deviation)
        Upper body length
    3.04 ± 1.52
    3.54 ± 1.81
    5.45 ± 1.75
    5.20 ± 1.50
    6.58 ± 0.99
    6.75 ± 0.86
        Head Circumference
    0.68 ± 0.66
    0.74 ± 0.49
    2.29 ± 1.28
    3.10 ± 1.45
    5.35 ± 0.71
    6.29 ± 0.81
        Arm Span
    4.86 ± 1.99
    5.82 ± 3.65
    7.13 ± 1.59
    7.22 ± 1.45
    8.22 ± 1.93
    8.99 ± 4.77
        Upper Arm Length
    1.02 ± 1.13
    0.77 ± 0.96
    1.08 ± 0.93
    1.44 ± 1.26
    1.95 ± 1.23
    1.44 ± 1.33
        Lower Arm (Forearm) Length
    0.49 ± 0.96
    0.79 ± 0.90
    1.78 ± 0.44
    1.57 ± 0.98
    1.66 ± 0.82
    1.49 ± 0.79
        Lower Body Length
    2.41 ± 1.31
    2.89 ± 1.99
    2.39 ± 1.27
    3.79 ± 1.56
    3.86 ± 1.55
    4.41 ± 1.53
        Upper Leg Length (Thigh)
    0.82 ± 1.75
    1.55 ± 1.46
    0.38 ± 1.71
    1.10 ± 1.42
    1.98 ± 2.21
    1.93 ± 1.65
        Knee to Heel Length
    1.52 ± 0.76
    2.21 ± 0.67
    2.70 ± 0.75
    2.29 ± 1.91
    2.93 ± 0.68
    3.12 ± 0.85
        Tibial Length
    0.85 ± 0.69
    1.16 ± 1.35
    1.97 ± 1.49
    1.99 ± 0.80
    1.83 ± 0.88
    1.39 ± 0.77
    No statistical analyses for this end point

    Secondary: Change from baseline in other body proportion ratios (arm span to height ratio, upper arm length to lower arm [forearm] length ratio, upper leg length [thigh] to knee to heel length ratio, and upper leg length (thigh) to tibial length ratio) at Week 52

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    End point title
    Change from baseline in other body proportion ratios (arm span to height ratio, upper arm length to lower arm [forearm] length ratio, upper leg length [thigh] to knee to heel length ratio, and upper leg length (thigh) to tibial length ratio) at Week 52
    End point description
    The number of participant analyzed is reported in sequence: (n=Cohort 1 Placebo, Cohort 1 Vosoritide, Cohort 2 Placebo, Cohort 2 Vosoritide, Cohort 3 Placebo, Cohort 3 Vosoritide) vosoritide including sentinel and randomized participants for each category. Upper Arm Length to Lower Arm (Forearm) Length Ratio: (n=16, 19, 7, 10, 8, 11) Upper Leg Length(Thigh)-Knee to Heel Length Ratio: (n=16, 19, 7, 10, 8, 11) Upper Leg Length (Thigh) to Tibial Length Ratio: (n=16, 19, 7, 10, 8, 11) Arm Span to Standing Height Ratio: (n=16,19, 7, 10, 8, 10)
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    Cohort 1: Placebo Cohort 1: Vosoritide Cohort 2: Placebo Cohort 2: Vosoritide Cohort 3: Placebo Cohort 3: Vosoritide
    Number of subjects analysed
    16
    19
    7
    10
    8
    12
    Units: Ratio
    arithmetic mean (standard deviation)
        Upper Arm Length to Lower Arm(Forearm)Length Ratio
    0.05 ± 0.15
    0.00 ± 0.12
    -0.09 ± 0.06
    0.01 ± 0.10
    0.02 ± 0.11
    -0.01 ± 0.12
        Upper Leg Length(Thigh)-Knee to Heel Length Ratio
    -0.01 ± 0.08
    0.01 ± 0.07
    -0.09 ± 0.10
    -0.03 ± 0.08
    0.01 ± 0.16
    -0.02 ± 0.11
        Upper Leg Length (Thigh) to Tibial Length Ratio
    0.00 ± 0.12
    0.02 ± 0.17
    -0.16 ± 0.24
    -0.10 ± 0.07
    0.00 ± 0.29
    0.04 ± 0.22
        Arm Span to Standing Height Ratio
    0.00 ± 0.02
    0.00 ± 0.06
    0.00 ± 0.02
    -0.01 ± 0.02
    -0.01 ± 0.04
    -0.02 ± 0.07
    No statistical analyses for this end point

    Secondary: Change from baseline in body mass index (BMI) at Week 52

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    End point title
    Change from baseline in body mass index (BMI) at Week 52
    End point description
    Body Mass Index (BMI): For height used for BMI calculation, participants aged < 24 months, body length takes precedence over standing height. Participants aged < 24 months at baseline and >= 24 months at Week 52, body length takes precedence. There were no meaningful differences in BMI between treatment groups from baseline to Week 52 (change of <1 BMI score at Week 52 across all cohorts).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    Cohort 1: Placebo Cohort 1: Vosoritide Cohort 2: Placebo Cohort 2: Vosoritide Cohort 3: Placebo Cohort 3: Vosoritide
    Number of subjects analysed
    16
    19
    8
    12
    8
    12
    Units: kg/m^2
        arithmetic mean (standard deviation)
    0.20 ± 1.34
    -0.45 ± 0.94
    0.55 ± 1.17
    0.08 ± 0.75
    0.74 ± 1.70
    0.94 ± 1.42
    No statistical analyses for this end point

    Secondary: Change from baseline in BMI Z-score at Week 52

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    End point title
    Change from baseline in BMI Z-score at Week 52
    End point description
    BMI Z-Scores were derived using age-sex specific reference data (means and SDs) for average stature children per the Centers for Disease Control and Prevention. BMI Z-scores are derived only for participants aged 24 months or older, the change from baseline to Week 52 in BMI Z-score is summarized for Cohort 1 only as no participants in Cohort 2 or Cohort 3 were 24 months at baseline.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    Cohort 1: Placebo Cohort 1: Vosoritide
    Number of subjects analysed
    16
    19
    Units: Z-Score
        arithmetic mean (standard deviation)
    -0.12 ± 0.48
    -0.18 ± 0.65
    No statistical analyses for this end point

    Secondary: Change from baseline in weight Z-score at Week 52

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    End point title
    Change from baseline in weight Z-score at Week 52
    End point description
    Z-Scores were derived using age-sex specific reference data (means and SDs) for average stature children per the Centers for Disease Control and Prevention.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    Cohort 1: Placebo Cohort 1: Vosoritide Cohort 2: Placebo Cohort 2: Vosoritide Cohort 3: Placebo Cohort 3: Vosoritide
    Number of subjects analysed
    16
    19
    7
    12
    8
    11
    Units: Z-score
        arithmetic mean (standard deviation)
    0.14 ± 0.44
    0.14 ± 0.42
    0.74 ± 0.82
    0.70 ± 0.64
    -0.81 ± 0.49
    -0.66 ± 0.77
    No statistical analyses for this end point

    Secondary: Change from baseline in Infant Toddler Quality of Life (ITQoL) scores at Week 52

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    End point title
    Change from baseline in Infant Toddler Quality of Life (ITQoL) scores at Week 52
    End point description
    # of participants analyzed reported in sequence:(n=C1 Placebo,C1 Vosoritide,C2 Placebo,C2 Vosoritide,C3 Placebo,C3 Vosoritide)incl sentinel for each category. Overall Health Score:(n=12, 15, 5,10, 6, 10) Physical Abilities Score:(n=14, 17, 7, 12, 7, 6) Growth and Development Scores:(n=14, 17, 7, 12, 8, 10) Pain Score:(n=14, 17, 7,12, 8, 10) Temperament and mood Score:(n=14, 17, 7,12, 8, 10) Behavior score:(n=13, 17, 5, 8, 0, 1) Ref PDF Global behavior score:(n=13, 17, 5, 9, 0, 1) Ref PDF Getting on with others score:(n=12, 17, 5, 8, 0,0) Ref PDF Global health perceptions score:(n=13, 17, 7, 12, 8, 9) Change in health score:(n=13, 16, 5, 6, 0, 1) Ref PDF Parental impact emotional score:(n=14, 17, 7, 12, 8, 10) Parental Impact Time Score:(n=14, 17, 7, 12, 8, 10) Family Cohesion Score:(n=14, 16, 7, 12, 8, 10) 97(ITQOL) item full-length version was used. For each concept, item responses are scored, summed, & transformed on a scale from 0(worst health) to 100(best health)
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    Cohort 1: Placebo Cohort 1: Vosoritide Cohort 2: Placebo Cohort 2: Vosoritide Cohort 3: Placebo Cohort 3: Vosoritide
    Number of subjects analysed
    16
    19
    8
    12
    8
    12
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Overall Health Score
    3.75 ± 17.60
    4.33 ± 15.10
    -5.00 ± 15.41
    -3.50 ± 14.15
    -5.00 ± 7.75
    0.50 ± 13.01
        Physical Abilities Score
    -6.01 ± 9.83
    8.82 ± 23.06
    3.36 ± 8.62
    1.30 ± 16.05
    2.35 ± 29.29
    -15.91 ± 22.74
        Growth and Development Scores
    4.82 ± 11.62
    4.34 ± 9.40
    -0.71 ± 8.75
    1.46 ± 26.01
    3.57 ± 6.35
    -3.50 ± 13.19
        Pain Score
    -1.19 ± 20.37
    -1.47 ± 18.22
    -1.19 ± 18.90
    -7.64 ± 27.63
    -4.69 ± 27.77
    2.50 ± 22.58
        Temperament and mood Score
    4.79 ± 9.60
    0.54 ± 5.40
    0.66 ± 7.18
    -0.49 ± 9.78
    -2.43 ± 6.76
    4.62 ± 10.48
        Global health perceptions score
    -1.07 ± 15.43
    2.24 ± 12.37
    -2.73 ± 11.29
    -4.55 ± 12.18
    -2.84 ± 13.62
    0.50 ± 17.11
        Parental impact emotional score
    2.04 ± 23.13
    -0.84 ± 8.89
    0.51 ± 14.64
    -6.85 ± 11.94
    9.82 ± 20.89
    -2.50 ± 19.05
        Parental Impact Time Score
    9.52 ± 29.06
    4.76 ± 10.78
    -8.05 ± 19.70
    -2.38 ± 35.61
    -10.7 ± 17.59
    2.38 ± 14.93
        Family Cohesion Score
    1.79 ± 13.53
    -1.25 ± 10.72
    0.00 ± 15.00
    -7.08 ± 28.08
    -3.13 ± 8.84
    -4.50 ± 15.54
    No statistical analyses for this end point

    Secondary: Change from Baseline in functional independence measure for children (WeeFIM-II) Score at Week 52

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    End point title
    Change from Baseline in functional independence measure for children (WeeFIM-II) Score at Week 52
    End point description
    The Pediatric Functional Independence Measure-II (WeeFIM®-II) is designed to measure the functional independence of children between the ages of 6 months and 18 years who have physical or general developmental limitations (Msall 1994b). The WeeFIM-II is comprised of 3 domains that are rated by clinicians based on information obtained from parents/caregivers (self-care [score range 8 to 56], mobility [score range 8 to 35], and cognition [score range 8 to 35]) and provides a total score between 18 (worst) and 126 (Best). The Wee-FIM-II is only validated in children ages 6 months to 18 years. Therefore results for Cohort 3 is not summarized. The number of participants analyzed is reported in sequence: (n=Cohort 1 Placebo, Cohort 1 Vosoritide, Cohort 2 Placebo, Cohort 2 Vosoritide) incl sentinel for each category. WeeFIM-II Total Score: (n=14, 19, 6,11) WeeFIM : Self-Care Score: (n=14, 19, 6, 11) WeeFIM: Mobility Score: (n=14, 19, 6, 11) WeeFIM: Cognitive Score: (n=14, 19, 6, 11)
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    Cohort 1: Placebo Cohort 1: Vosoritide Cohort 2: Placebo Cohort 2: Vosoritide
    Number of subjects analysed
    16
    19
    8
    12
    Units: Score on a scale
    arithmetic mean (standard deviation)
        WeeFIM-II Total Score
    11.2 ± 11.1
    14.7 ± 17.3
    16.2 ± 14.6
    16.5 ± 28.1
        WeeFIM : Self-Care Score
    6.4 ± 6.0
    6.6 ± 7.2
    3.7 ± 2.3
    5.6 ± 14.1
        WeeFIM: Mobility Score
    2.2 ± 3.4
    4.5 ± 5.6
    7.0 ± 7.5
    6.7 ± 9.4
        WeeFIM: Cognitive Score
    2.6 ± 4.0
    3.6 ± 6.0
    5.5 ± 7.6
    4.2 ± 8.4
    No statistical analyses for this end point

    Secondary: Change from baseline in Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) scores at Week 52

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    End point title
    Change from baseline in Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) scores at Week 52
    End point description
    The number of participants analyzed is reported in sequence: (n=Cohort 1 Placebo, Cohort 1 Vosoritide, Cohort 2 Placebo, Cohort 2 Vosoritide, Cohort 3 Placebo, Cohort 3 Vosoritide) for each category. Motor Composite Score: (n=2, 4, 4, 9, 5,8) Cognitive scaled score: (n=2, 4, 3, 8, 6,9) Cognitive composite score: (n=2, 4, 3, 8, 6, 9) Receptive communication language scaled score: (n=2, 4, 3, 9, 5,9) Expressive communication language scaled score: (n=2, 4, 4, 8, 5, 8) Language sum of scaled score: (n=2, 4, 4, 9, 6,9) Language composite score: (n=2, 4, 4, 9, 5, 9) Fine motor scaled score: (n=2, 4, 4, 9, 5, 8) Gross motor scaled score: (n=2, 4, 4, 9, 5, 9) BSID-III is performance-based clinician-reported outcome assessment for use in children from 1 to 42 months (1 month to 3.5 years). individually administered by the trained clinician to the participant/child. Each (sub)scale yields a total raw score, standardized according to the participant’s chronological age (scaled scores)
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    Cohort 1: Placebo Cohort 1: Vosoritide Cohort 2: Placebo Cohort 2: Vosoritide Cohort 3: Placebo Cohort 3: Vosoritide
    Number of subjects analysed
    16
    19
    8
    12
    8
    12
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Motor Composite Score
    -2.0 ± 5.7
    4.8 ± 11.5
    12.0 ± 17.5
    -2.3 ± 12.3
    5.4 ± 22.2
    11.1 ± 18.1
        Cognitive scaled score
    -1.0 ± 2.8
    -0.5 ± 1.7
    3.3 ± 4.9
    0.6 ± 3.2
    1.5 ± 1.9
    2.1 ± 4.4
        Cognitive composite score
    -5.0 ± 14.1
    -2.5 ± 8.7
    16.7 ± 24.7
    3.1 ± 16.0
    7.5 ± 9.4
    10.6 ± 22.1
        Receptive communication language scaled score
    -1.0 ± 0.0
    -1.8 ± 2.5
    3.3 ± 4.0
    1.0 ± 1.2
    -3.0 ± 2.1
    0.7 ± 5.2
        Expressive communication language scaled score
    2.5 ± 0.7
    0.3 ± 1.3
    2.8 ± 2.9
    -0.1 ± 2.2
    -1.8 ± 1.6
    -0.1 ± 3.3
        Language sum of scaled score
    1.5 ± 0.7
    -1.5 ± 3.3
    6.0 ± 5.2
    1.8 ± 4.0
    -7.3 ± 6.4
    -0.3 ± 6.6
        Language composite score
    4.5 ± 2.1
    -4.5 ± 9.9
    17.8 ± 15.2
    5.3 ± 12.1
    -13.4 ± 5.8
    -0.9 ± 19.5
        Fine motor scaled score
    -0.5 ± 3.5
    0.0 ± 2.9
    1.5 ± 3.3
    -2.1 ± 2.5
    2.2 ± 4.8
    2.6 ± 2.7
        Gross motor scaled score
    0.0 ± 5.7
    1.0 ± 0.8
    2.8 ± 3.2
    1.3 ± 2.8
    -0.2 ± 3.1
    0.1 ± 3.0
    No statistical analyses for this end point

    Secondary: Change from Baseline in Child Behaviour Checklist (CBCL) at Week 52

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    End point title
    Change from Baseline in Child Behaviour Checklist (CBCL) at Week 52
    End point description
    The number of participants analyzed is reported in sequence: (n=Cohort 1 Placebo, Cohort 1 Vosoritide, Cohort 2 Placebo, Cohort 2 Vosoritide) vosoritide including sentinel and randomized participants for each category. Emotionally Reactive Total: (n=15, 18, 4, 5) Anxious/Depressed Total: (n=15, 18, 4, 5) Withdrawn Total: (n=15, 18, 4, 5) Somatic Complaints Total: (n=15, 18, 4, 5) Sleep Problems Total: (n=15, 18, 4, 5) Attention Problems Total: (n=15, 18, 4, 5) Aggressive Behavior Total: (n=15, 18, 4, 5) Total Problems Total: (n=15, 18, 4, 5) The CBCL 1.5-5 years old consists of 100 questions, scored on a three-point Likert scale (0=Not True (as far as you know), 1= Somewhat or Sometimes True, 2=Very True or Often True). The time frame for item responses was the past 2 months. Raw scores, t-scores, and percentiles are calculated for all subscales and syndromes, with higher scores indicating higher problems.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    Cohort 1: Placebo Cohort 1: Vosoritide Cohort 2: Placebo Cohort 2: Vosoritide
    Number of subjects analysed
    16
    19
    8
    12
    Units: Score on a scale
    arithmetic mean (standard deviation)
        CBCL Pre-School : Emotionally Reactive Total
    -0.2 ± 1.5
    0.1 ± 1.4
    1.0 ± 2.0
    1.0 ± 3.9
        CBCL Pre-School : Anxious/Depressed Total
    0.3 ± 1.7
    0.2 ± 1.4
    0.0 ± 2.2
    0.8 ± 3.1
        CBCL Pre-School : Withdrawn Total
    -0.6 ± 1.7
    0.6 ± 1.5
    0.8 ± 2.2
    -0.2 ± 1.6
        CBCL Pre-School : Somatic Complaints Total
    0.1 ± 1.7
    0.3 ± 1.0
    0.5 ± 1.0
    1.8 ± 4.1
        CBCL Pre-School : Sleep Problems Total
    -0.3 ± 3.2
    0.1 ± 1.9
    -0.3 ± 1.7
    1.4 ± 4.3
        CBCL Pre-School : Attention Problems Total
    -0.1 ± 1.9
    -0.1 ± 1.6
    -0.3 ± 1.0
    -0.2 ± 2.0
        CBCL Pre-School : Aggressive Behavior Total
    -1.1 ± 2.4
    0.3 ± 4.1
    -0.8 ± 1.5
    -0.4 ± 2.7
        CBCL Pre-School : Total Problems Total
    -3.0 ± 13.0
    2.8 ± 11.7
    -2.3 ± 6.0
    3.6 ± 23.2
    No statistical analyses for this end point

    Secondary: Change from baseline in bilateral X-rays of lower extremities at Wee 52

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    End point title
    Change from baseline in bilateral X-rays of lower extremities at Wee 52
    End point description
    The number of participants analyzed is reported in sequence: (n= All Vosoritide, Placebo) for each category. Left Femur Length: (n= 17, 14) Right Femur Length: (n= 17, 14) Left Fibula Length: (n= 40,,27) Right Fibula Length: (n= 39, 27) Left Tibia Length: (n= 40, 27) Right Tibia Length: (n= 39, 27) Left Distance Between Ankle Joint and Distal Growth Plate of Fibula: (n= 38, 26) Right Distance Between Ankle Joint and Distal Growth Plate of Fibula: (n= 37, 26) Left Lower Extremity: (n= 18, 14) Right Lower Extremity: (n= 18, 14)
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    All Vosoritide Placebo
    Number of subjects analysed
    43
    32
    Units: cm
    arithmetic mean (standard deviation)
        Left Femur Length
    2.29 ± 0.58
    2.01 ± 0.62
        Right Femur Length
    2.35 ± 0.49
    2.20 ± 0.73
        Left Fibula Length
    2.00 ± 0.61
    1.97 ± 0.69
        Right Fibula Length
    2.00 ± 0.64
    1.89 ± 0.75
        Left Tibia Length
    1.92 ± 0.55
    1.69 ± 0.70
        Right Tibia Length
    1.96 ± 0.57
    1.68 ± 0.77
        Lt Dis btw Ankle Joint&Distal Growth Plate Fibula
    -0.02 ± 0.23
    0.07 ± 0.23
        Rt Dis btw Ankle Joint&Distal Growth Plate Fibula
    -0.05 ± 0.23
    0.05 ± 0.22
        Left Lower Extremity
    6.02 ± 6.67
    3.87 ± 1.56
        Right Lower Extremity
    6.08 ± 6.54
    4.26 ± 1.85
    No statistical analyses for this end point

    Secondary: Change from baseline in bilateral X-rays of Left/Right Tibia bowing angle at Week 52

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    End point title
    Change from baseline in bilateral X-rays of Left/Right Tibia bowing angle at Week 52
    End point description
    The number of participants analyzed is reported in sequence: (n=All vosoritide , Placebo) for each category. Left Tibia Bowing Angle : (n= 39, 27) Right Tibia Bowing Angle : (n=38, 27)
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    All Vosoritide Placebo
    Number of subjects analysed
    43
    32
    Units: Degrees
    arithmetic mean (standard deviation)
        Left Tibia Bowing Angle
    -0.97 ± 5.88
    1.07 ± 5.38
        Right Tibia Bowing Angle
    -2.34 ± 5.37
    -0.93 ± 5.54
    No statistical analyses for this end point

    Secondary: Change from baseline in bilateral X-rays of Left Femur Length (cm) to Tibia Length (cm) Ratio and Right Femur Length (cm) to Tibia Length (cm) Ratio & Right Femur Length (cm) to Tibia Length (cm) Ratio at Week 52

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    End point title
    Change from baseline in bilateral X-rays of Left Femur Length (cm) to Tibia Length (cm) Ratio and Right Femur Length (cm) to Tibia Length (cm) Ratio & Right Femur Length (cm) to Tibia Length (cm) Ratio at Week 52
    End point description
    The number of participants analyzed is reported in sequence: (n= All Vosoritide, Placebo) Left Femur Length (cm) to Tibia Length (cm) Ratio : (n= 17, 14) Right Femur Length (cm) to Tibia Length (cm) Ratio: (n= 17, 14)
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    All Vosoritide Placebo
    Number of subjects analysed
    43
    32
    Units: Ratio
    arithmetic mean (standard deviation)
        Left Femur Length (cm) to Tibia Length (cm) Ratio
    -0.03 ± 0.06
    -0.05 ± 0.05
        Right Femur Length (cm) to Tibia Length (cm) Ratio
    -0.05 ± 0.06
    -0.02 ± 0.03
    No statistical analyses for this end point

    Secondary: Change from baseline in bilateral X-rays of Left Tibia Length (cm) to Fibula Length (cm) Ratio & Right Tibia Length (cm) to Fibula Length (cm) Ratio at Week 52

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    End point title
    Change from baseline in bilateral X-rays of Left Tibia Length (cm) to Fibula Length (cm) Ratio & Right Tibia Length (cm) to Fibula Length (cm) Ratio at Week 52
    End point description
    The number of participants analyzed is reported in sequence: (n= All vosoritide, Placebo) Left Tibia Length (cm) to Fibula Length (cm) Ratio: (n=40, 27) Right Tibia Length (cm) to Fibula Length (cm) Ratio: (n=39, 27)
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    All Vosoritide Placebo
    Number of subjects analysed
    43
    32
    Units: Ratio
    arithmetic mean (standard deviation)
        Left Tibia Length (cm) to Fibula Length (cm) Ratio
    -0.02 ± 0.04
    -0.04 ± 0.04
        Right Tibia Length (cm) to Fibula Length(cm) Ratio
    -0.02 ± 0.05
    -0.03 ± 0.04
    No statistical analyses for this end point

    Secondary: Change from baseline in X-ray of Lumbar spine vertebral ratios at Week 52

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    End point title
    Change from baseline in X-ray of Lumbar spine vertebral ratios at Week 52
    End point description
    The number of participants analyzed is reported in sequence: (n= All Vosoritide, Placebo) for each category. Anterior Height to Medial Height Ratio (L1): (n= 30, 23) Anterior Height to Medial Height Ratio (L2): (n= 23, 13) Anterior Height to Medial Height Ratio (L3): (n= 19, 11) Anterior Height to Medial Height Ratio (L4): (n=26, 15) Anterior Height to Medial Height Ratio (L5): (n=27, 12) Anterior Height to Posterior Height Ratio (L1): (n= 40, 27) Anterior Height to Posterior Height Ratio (L2): (n= 40, 27) Anterior Height to Posterior Height Ratio (L3): (n= 40, 27) Anterior Height to Posterior Height Ratio (L4): (n= 40, 27) Anterior Height to Posterior Height Ratio (L5): (n= 40, 27) Medial Height to Posterior Height Ratio (L1): (n= 30, 23) Medial Height to Posterior Height Ratio (L2): (n= 23, 13) Medial Height to Posterior Height Ratio (L3): (n= 19, 11) Medial Height to Posterior Height Ratio (L4): (n= 26, 15) Medial Height to Posterior Height Ratio (L5):(n= 27,12)
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    All Vosoritide Placebo
    Number of subjects analysed
    43
    32
    Units: Ratio
    arithmetic mean (standard deviation)
        Anterior Height to Medial Height Ratio (L1)
    -0.04 ± 0.16
    -0.04 ± 0.20
        Anterior Height to Medial Height Ratio (L2)
    -0.06 ± 0.16
    -0.07 ± 0.16
        Anterior Height to Medial Height Ratio (L3)
    -0.02 ± 0.19
    0.04 ± 0.09
        Anterior Height to Medial Height Ratio (L4)
    0.02 ± 0.12
    -0.01 ± 0.11
        Anterior Height to Medial Height Ratio (L5)
    -0.02 ± 0.15
    0.04 ± 0.17
        Anterior Height to Posterior Height Ratio (L1)
    -0.03 ± 0.13
    -0.08 ± 0.17
        Anterior Height to Posterior Height Ratio (L2)
    -0.02 ± 0.13
    -0.03 ± 0.12
        Anterior Height to Posterior Height Ratio (L3)
    -0.01 ± 0.16
    0.04 ± 0.12
        Anterior Height to Posterior Height Ratio (L4)
    0.03 ± 0.11
    0.02 ± 0.13
        Anterior Height to Posterior Height Ratio (L5)
    0.01 ± 0.13
    0.02 ± 0.15
        Medial Height to Posterior Height Ratio (L1)
    -0.01 ± 0.15
    -0.04 ± 0.12
        Medial Height to Posterior Height Ratio (L2)
    0.05 ± 0.11
    0.03 ± 0.09
        Medial Height to Posterior Height Ratio (L3)
    -0.02 ± 0.10
    -0.02 ± 0.10
        Medial Height to Posterior Height Ratio (L4)
    -0.03 ± 0.13
    0.04 ± 0.10
        Medial Height to Posterior Height Ratio (L5)
    0.02 ± 0.16
    -0.04 ± 0.21
    No statistical analyses for this end point

    Secondary: Change from baseline in X-ray of Lumbar Spine Transverse Diameter at Week 52

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    End point title
    Change from baseline in X-ray of Lumbar Spine Transverse Diameter at Week 52
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    All Vosoritide Placebo
    Number of subjects analysed
    40
    27
    Units: cm
    arithmetic mean (standard deviation)
        Transverse Diameter (L1)
    0.12 ± 0.17
    0.12 ± 0.11
        Transverse Diameter (L2)
    0.12 ± 0.16
    0.09 ± 0.13
        Transverse Diameter (L3)
    0.08 ± 0.15
    0.09 ± 0.12
        Transverse Diameter (L4)
    0.09 ± 0.13
    0.06 ± 0.11
        Transverse Diameter (L5)
    0.10 ± 0.13
    0.05 ± 0.14
    No statistical analyses for this end point

    Secondary: Change from baseline in X-ray of Lumbar Spine Sagittal Width and Week 52

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    End point title
    Change from baseline in X-ray of Lumbar Spine Sagittal Width and Week 52
    End point description
    The number of participants analyzed is reported in sequence: (n=All Vosoritide, Placebo) for each category. Sagittal Width (L1): (n=34, 26) Sagittal Width (L2): (n=34, 26) Sagittal Width (L3): (n=34, 26) Sagittal Width (L4): (n=34, 26) Sagittal Width (L5): (n=31, 25)
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    All Vosoritide Placebo
    Number of subjects analysed
    43
    32
    Units: cm
    arithmetic mean (standard deviation)
        Sagittal Width (L1)
    0.07 ± 0.26
    0.00 ± 0.22
        Sagittal Width (L2)
    0.05 ± 0.18
    0.01 ± 0.18
        Sagittal Width (L3)
    0.08 ± 0.20
    0.04 ± 0.19
        Sagittal Width (L4)
    0.16 ± 0.24
    0.03 ± 0.16
        Sagittal Width (L5)
    0.13 ± 0.34
    0.06 ± 0.26
    No statistical analyses for this end point

    Secondary: Change from baseline in X-ray of Lumbar Spine Angles at Week 52

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    End point title
    Change from baseline in X-ray of Lumbar Spine Angles at Week 52
    End point description
    The number of participants analyzed is reported in sequence: (n=All Vosoritide, Placebo) Sacral Tilt: (n= 40, 27) Lordosis Angle: (n= 40, 27) Kyphosis Angle: (n= 39, 27)
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    All Vosoritide Placebo
    Number of subjects analysed
    43
    32
    Units: Degree
    arithmetic mean (standard deviation)
        Sacral Tilt
    10.6 ± 13.2
    5.7 ± 15.9
        Lordosis Angle
    12.5 ± 17.4
    8.4 ± 14.2
        Kyphosis Angle
    -2.2 ± 13.9
    -2.1 ± 10.3
    No statistical analyses for this end point

    Secondary: Changes from Baseline in X-ray of lumbar spine angle changes: Number of participants with an increase in Lumbar Spine Angle at Week 52

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    End point title
    Changes from Baseline in X-ray of lumbar spine angle changes: Number of participants with an increase in Lumbar Spine Angle at Week 52
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    All Vosoritide Placebo
    Number of subjects analysed
    43
    32
    Units: Number of participants
        Increase in sacral tilt (deg) >=5 to <10
    3
    6
        Increase in sacral tilt (deg) >=10
    24
    10
        Increase in lordosis angle (deg) >=5 to <10
    5
    1
        Increase in lordosis angle (deg) >=10
    19
    14
        Increase in kyphosis angle (deg) >=5 to <10
    3
    2
        Increase in kyphosis angle (deg) >=10
    9
    4
    No statistical analyses for this end point

    Secondary: MRI Parameter: Change from baseline to Week 52 for Volume of Face, Sinus, Calvarium, Whole Brain Total Volume, Ventricles Total Volume.

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    End point title
    MRI Parameter: Change from baseline to Week 52 for Volume of Face, Sinus, Calvarium, Whole Brain Total Volume, Ventricles Total Volume.
    End point description
    The number of participants analyzed is reported in sequence: (n=All Vosoritide, Placebo) for each category. Volume of Face: (n=30, 21) Volume of Sinus: (n=35, 24) Volume of Calvarium: (n=34, 24) Whole Brain Total Volume: (n=34, 24) Ventricles Total Volume: (n=34, 25)
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    All Vosoritide Placebo
    Number of subjects analysed
    43
    32
    Units: cm^3
    arithmetic mean (standard deviation)
        Volume of Face
    80.527 ± 59.211
    78.107 ± 33.369
        Volume of Sinus
    2.362 ± 3.578
    1.195 ± 3.769
        Volume of Calvarium
    213.075 ± 202.415
    183.427 ± 183.210
        Whole Brain Total Volume
    175.399 ± 158.088
    146.247 ± 115.274
        Ventricles Total Volume
    11.394 ± 20.416
    8.515 ± 16.325
    No statistical analyses for this end point

    Secondary: MRI Parameter: Change from baseline to Week 52 for area of Area of Foramen Magnum & Area of Spinal Cord at the Foramen Magnum Level

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    End point title
    MRI Parameter: Change from baseline to Week 52 for area of Area of Foramen Magnum & Area of Spinal Cord at the Foramen Magnum Level
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    All Vosoritide Placebo
    Number of subjects analysed
    43
    32
    Units: cm^2
    arithmetic mean (standard deviation)
        Area of Foramen Magnum
    0.002 ± 0.034
    0.006 ± 0.020
        Area of Spinal Cord at the Foramen Magnum Level
    0.001 ± 0.020
    0.007 ± 0.016
    No statistical analyses for this end point

    Secondary: MRI Parameter: Change from baseline to Week 52 for Ratio of Face Volume to Calvarium, Ratio of Area of Spinal Cord to Foramen Magnum, Ratio of Face Volume to Sinus

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    End point title
    MRI Parameter: Change from baseline to Week 52 for Ratio of Face Volume to Calvarium, Ratio of Area of Spinal Cord to Foramen Magnum, Ratio of Face Volume to Sinus
    End point description
    The number of participants analyzed is reported in sequence: (n=All Vosoritide, Placebo) Ratio of face volume to calvarium: (n=29, 20) Ratio of area of spinal cord to foramen magnum: (n=35, 25) Ratio of face volume to sinus: (n=30, 21)
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    All Vosoritide Placebo
    Number of subjects analysed
    43
    32
    Units: Ratio
    arithmetic mean (standard deviation)
        Ratio of face volume to calvarium
    0.002 ± 0.031
    0.003 ± 0.033
        Ratio of area of spinal cord to foramen magnum
    0.005 ± 0.120
    0.037 ± 0.100
        Ratio of face volume to sinus
    -6.798 ± 175.646
    14.505 ± 284.950
    No statistical analyses for this end point

    Secondary: DEXA parameter: Change from baseline to Week 52 for Whole Body Less Head bone mineral content (BMC)

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    End point title
    DEXA parameter: Change from baseline to Week 52 for Whole Body Less Head bone mineral content (BMC)
    End point description
    The number of participants analyzed is reported in sequence: (n=All Vosoritide, Placebo) for each category. GE - Lunar Prodigy: Whole Body Less Head BMC: (n=8, 12) Hologic - Discovery Horizon Whole Body Less Head BMC: (n=18, 8) Dual Energy X-Ray Absorptiometry (DEXA)
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    All Vosoritide Placebo
    Number of subjects analysed
    43
    32
    Units: gm
    arithmetic mean (standard deviation)
        GE - Lunar Prodigy: Whole Body Less Head BMC
    55.87 ± 14.68
    50.26 ± 17.44
        Hologic Discovery Horizon Whole Body Less Head BMC
    44.61 ± 12.62
    47.19 ± 12.55
    No statistical analyses for this end point

    Secondary: DEXA parameter: Change from baseline to Week 52 of Whole Body Less Head bone mineral density (BMD)

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    End point title
    DEXA parameter: Change from baseline to Week 52 of Whole Body Less Head bone mineral density (BMD)
    End point description
    GE - Lunar Prodigy Whole Body Less Head BMD: (n=8,12) Hologic - Discovery Horizon Whole Body Less Head BMD: (18, 8)
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    All Vosoritide Placebo
    Number of subjects analysed
    43
    32
    Units: g/cm^2
    arithmetic mean (standard deviation)
        GE - Lunar Prodigy Whole Body Less Head BMD
    0.04 ± 0.02
    0.05 ± 0.03
        Hologic Discovery Horizon Whole Body Less Head BMD
    0.03 ± 0.01
    0.04 ± 0.02
    No statistical analyses for this end point

    Secondary: DEXA parameter: Change from baseline to Week 52 of Whole Body BMC

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    End point title
    DEXA parameter: Change from baseline to Week 52 of Whole Body BMC
    End point description
    The number of participants analyzed is reported in sequence: (n=All Vosoritide, Placebo) for each category. GE - Lunar Prodigy Whole Body BMC: (n=8, 12) Hologic - Discovery Horizon Whole Body BMC: (n=18, 8)
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    All Vosoritide Placebo
    Number of subjects analysed
    43
    32
    Units: gm
    arithmetic mean (standard deviation)
        GE - Lunar Prodigy Whole Body BMC
    96.85 ± 39.82
    98.99 ± 32.45
        Hologic - Discovery Horizon Whole Body BMC
    87.97 ± 32.35
    101.33 ± 33.34
    No statistical analyses for this end point

    Secondary: DEXA parameter: Change from baseline to Week 52 of Whole Body BMD

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    End point title
    DEXA parameter: Change from baseline to Week 52 of Whole Body BMD
    End point description
    The number of participants analyzed is reported in sequence: (n=All Vosoritide, Placebo) for each category. GE - Lunar Prodigy Whole Body BMD: (n=8, 12) Hologic - Discovery Horizon Whole Body BMD: (n=18, 8)
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    All Vosoritide Placebo
    Number of subjects analysed
    43
    32
    Units: g/cm^2
    arithmetic mean (standard deviation)
        GE - Lunar Prodigy Whole Body BMD
    0.06 ± 0.06
    0.07 ± 0.04
        Hologic - Discovery Horizon Whole Body BMD
    0.05 ± 0.02
    0.07 ± 0.03
    No statistical analyses for this end point

    Secondary: DEXA parameter: Change from baseline to Week 52 of Lumbar Spine BMC

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    End point title
    DEXA parameter: Change from baseline to Week 52 of Lumbar Spine BMC
    End point description
    The number of participants analyzed is reported in sequence: (n=All Vosoritide, Placebo) for each category. GE - Lunar Prodigy Lumbar Spine BMC: (n=9, 10) Hologic - Discovery Horizon Lumbar Spine BMC: (n=27, 13)
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    All Vosoritide Placebo
    Number of subjects analysed
    43
    32
    Units: gm
    arithmetic mean (standard deviation)
        GE - Lunar Prodigy Lumbar Spine BMC
    2.73 ± 0.83
    2.09 ± 0.97
        Hologic - Discovery Horizon Lumbar Spine BMC
    2.19 ± 0.68
    1.94 ± 0.72
    No statistical analyses for this end point

    Secondary: DEXA parameter: Change from baseline to Week 52 of Lumbar Spine BMD

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    End point title
    DEXA parameter: Change from baseline to Week 52 of Lumbar Spine BMD
    End point description
    The number of participants analyzed is reported in sequence: (n=All Vosoritide, Placebo) for each category. GE - Lunar Prodigy Lumbar Spine BMD: (n=9, 10) Hologic - Discovery Horizon Lumbar Spine BMD: (27, 13)
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    All Vosoritide Placebo
    Number of subjects analysed
    43
    32
    Units: g/cm^2
    arithmetic mean (standard deviation)
        GE - Lunar Prodigy Lumbar Spine BMD
    0.07 ± 0.04
    0.05 ± 0.03
        Hologic - Discovery Horizon Lumbar Spine BMD
    0.05 ± 0.03
    0.06 ± 0.04
    No statistical analyses for this end point

    Secondary: Change from baseline to Week 52 in whole body BMD Z-score

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    End point title
    Change from baseline to Week 52 in whole body BMD Z-score
    End point description
    Hologic - Discovery Horizon Whole Body BMD Z-Score
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    All Vosoritide Placebo
    Number of subjects analysed
    6
    4
    Units: Z-score
    arithmetic mean (standard deviation)
        Hologic - Discovery Horizon Whole Body BMD Z-Score
    -0.20 ± 0.35
    0.30 ± 0.47
    No statistical analyses for this end point

    Secondary: Change from baseline to Week 52 in Lumbar Spine BMD Z-Score

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    End point title
    Change from baseline to Week 52 in Lumbar Spine BMD Z-Score
    End point description
    Hologic - Discovery Horizon Lumbar Spine BMD Z-Score
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    All Vosoritide Placebo
    Number of subjects analysed
    7
    4
    Units: Z-score
        arithmetic mean (standard deviation)
    0.17 ± 0.24
    0.03 ± 0.45
    No statistical analyses for this end point

    Secondary: Immunogenicity: Number of participants with Incidence of Antibody Positivity at Scheduled Visits

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    End point title
    Immunogenicity: Number of participants with Incidence of Antibody Positivity at Scheduled Visits
    End point description
    Number of participants with Incidence of Antibody Positivity at Scheduled Visits for : total antibody (TAb), Neutralizing antibodies (NAb), atrial natriuretic peptide (ANP), B-type Natriuretic Peptide (BNP) & C-type natriuretic peptide (CNP). TAb Titer Positive, NAb Titer Positive, ANP Reactivity Positive, BNP Reactivity Positive & CNP Reactivity Positive. Day 1 is the baseline assessment result taken prior to first dose of study drug. Ever Positive = the number of participants with at least one positive sample result.
    End point type
    Secondary
    End point timeframe
    At Day 1, Week 3, Week 13, Week 26, Week 52, & Ever Positive.
    End point values
    All Vosoritide Placebo
    Number of subjects analysed
    43
    32
    Units: Number of participants
        TAb Titer Positive: Day 1
    0
    0
        TAb Titer Positive: Week 3
    0
    0
        TAb Titer Positive: Week 13
    0
    0
        TAb Titer Positive: Week 26
    2
    0
        TAb Titer Positive: Week 52
    8
    0
        TAb Titer Ever Positive
    8
    0
        NAb Titer Positive: Day 1
    0
    0
        NAb Titer Positive: Week 3
    0
    0
        NAb Titer Positive: Week 13
    0
    0
        NAb Titer Positive: Week 26
    0
    0
        NAb Titer Positive: Week 52
    0
    0
        NAb Titer Ever Positive
    0
    0
        ANP Reactivity Positive: Day 1
    3
    5
        ANP Reactivity Positive: Week 3
    0
    0
        ANP Reactivity Positive: Week 13
    1
    0
        ANP Reactivity Positive: Week 26
    6
    0
        ANP Reactivity Positive: Week 52
    11
    0
        ANP Reactivity Ever Positive
    12
    0
        BNP Reactivity Positive: Day 1
    0
    3
        BNP Reactivity Positive: Week 3
    0
    0
        BNP Reactivity Positive: Week 13
    2
    0
        BNP Reactivity Positive: Week 26
    3
    0
        BNP Reactivity Positive: Week 52
    2
    0
        BNP Reactivity Ever Positive
    3
    0
        CNP Reactivity Positive: Day 1
    0
    1
        CNP Reactivity Positive: Week 3
    0
    0
        CNP Reactivity Positive: Week 13
    1
    0
        CNP Reactivity Positive: Week 26
    2
    0
        CNP Reactivity Positive: Week 52
    4
    0
        CNP Reactivity Ever Positive
    4
    0
    No statistical analyses for this end point

    Secondary: Biomarker: Bone Specific Alkaline Phosphatase (BSAP) overtime

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    End point title
    Biomarker: Bone Specific Alkaline Phosphatase (BSAP) overtime
    End point description
    The number of participants analyzed is reported in sequence: (n=All Vosoritide, Placebo) for each category. Baseline: (n= 43, 32) Day 8: (n=42, 27) Change from baseline to Day 8: (n=42, 27) Week 6: (n=41, 29) Change from baseline to Week 6: (n=41, 29) Week 20: (n=40, 28) Change from baseline to Week 20: (n=40, 28) Week 39: (n=34, 24) Change from baseline to Week 39 : (n=34, 24)
    End point type
    Secondary
    End point timeframe
    At Baseline, Day 8, Week 6, Week 20, & Week 39.
    End point values
    All Vosoritide Placebo
    Number of subjects analysed
    43
    32
    Units: U/L
    arithmetic mean (standard deviation)
        BSAP: Baseline
    140.28 ± 183.23
    113.43 ± 33.56
        BSAP: Day 8
    122.32 ± 99.09
    104.12 ± 29.12
        BSAP: Change from baseline to Day 8
    -19.39 ± 202.90
    -7.67 ± 17.53
        BSAP: Week 6
    130.38 ± 140.08
    109.46 ± 29.04
        BSAP: Change from baseline to Week 6
    2.63 ± 218.60
    -6.17 ± 24.32
        BSAP: Week 20
    109.67 ± 30.88
    104.46 ± 29.69
        BSAP: Change from baseline to Week 20
    -7.21 ± 96.94
    -11.32 ± 18.19
        BSAP: Week 39
    108.49 ± 32.02
    208.13 ± 363.56
        BSAP: Change from baseline to Week 39
    -12.21 ± 105.04
    95.41 ± 352.78
    No statistical analyses for this end point

    Secondary: Biomarker: Type II Collagen C-Telopeptides Normalized for Creatinine (CTX-II)

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    End point title
    Biomarker: Type II Collagen C-Telopeptides Normalized for Creatinine (CTX-II)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52.
    End point values
    All Vosoritide Placebo
    Number of subjects analysed
    31
    24
    Units: ng/ mmol Cr
        arithmetic mean (standard deviation)
    -9364.7 ± 65244.1
    -7607.6 ± 54614.9
    No statistical analyses for this end point

    Secondary: Biomarker: Plasma cGMP Change from Pre-Dose to Maximum Post-Dose at Week 52

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    End point title
    Biomarker: Plasma cGMP Change from Pre-Dose to Maximum Post-Dose at Week 52
    End point description
    End point type
    Secondary
    End point timeframe
    Week 52 Pre-Dose to Week 52 Maximum Post-Dose.
    End point values
    All Vosoritide Placebo
    Number of subjects analysed
    33
    21
    Units: nM
        arithmetic mean (standard deviation)
    39.079 ± 25.706
    9.460 ± 26.307
    No statistical analyses for this end point

    Secondary: Change in Sleep Study Indices at Week 52

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    End point title
    Change in Sleep Study Indices at Week 52
    End point description
    A sleep study was performed in a limited number of qualified sleep centers. A sleep-testing device was used to assess the presence and severity of sleep-disordered breathing by measurement of blood oxygen saturation, pulse rate, and airflow during overnight monitoring. Assessment of episodes of sleep apnea included but were not limited to the number of episodes of apnea and hypopnea per hour (Apnea/Hypopnea Index).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    Cohort 1: Placebo Cohort 1: Vosoritide Cohort 2: Placebo Cohort 2: Vosoritide Cohort 3: Placebo Cohort 3: Vosoritide
    Number of subjects analysed
    14
    16
    5
    9
    7
    10
    Units: Number per Hour
    arithmetic mean (standard deviation)
        Apnea Hypopnea Index
    -0.54 ± 2.70
    -1.45 ± 4.63
    1.06 ± 4.80
    -0.72 ± 1.41
    1.89 ± 6.31
    -0.94 ± 2.78
        Apnea Index
    -1.07 ± 2.12
    -0.83 ± 1.93
    0.40 ± 2.34
    -0.71 ± 1.61
    -1.09 ± 1.22
    -0.36 ± 2.54
        Central Apnea Index
    -1.26 ± 2.66
    -0.74 ± 1.86
    -0.28 ± 0.89
    -0.71 ± 1.61
    -1.00 ± 0.97
    0.50 ± 0.92
        Hypopnea Index
    0.52 ± 1.35
    -0.61 ± 3.63
    0.66 ± 2.53
    -0.01 ± 1.32
    2.97 ± 5.45
    -0.56 ± 0.54
        Desaturation per Hour >=3%
    -0.41 ± 1.51
    -1.24 ± 3.98
    0.98 ± 3.60
    -0.69 ± 1.30
    1.71 ± 6.63
    -0.93 ± 2.60
        Obstructive Index
    0.19 ± 0.73
    -0.09 ± 0.45
    0.68 ± 1.52
    -0.01 ± 0.08
    -0.07 ± 0.64
    -0.86 ± 2.08
    No statistical analyses for this end point

    Secondary: PK parameter: Area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞) at Day1, Week 13, Week 26, Week 39, & Week 52

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    End point title
    PK parameter: Area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞) at Day1, Week 13, Week 26, Week 39, & Week 52
    End point description
    Vosoritide concentrations at 5-, 15- and 30-minute post-dose for one participant on Day 1 were not available, hence PK parameters for this participant were excluded from summary statistics. PK parameters for another participant on Day 1 obtained from extrapolation. AUC0-∞ excluded from summary statistics. PK parameters are not available for this participant at Week 13 due to unsuccessful venipuncture, and Week 26 as post-dose PK samples were not collected. The number of participants analyzed are reported in sequence (n = Day 01, Week 13, Week 26, Week 39, Week 52) Cohort 1 15 µg/kg/day: (n=16, 15, 16, 16, 15) Cohort 2 15 µg/kg/day: (n=1, 1, 4, 4, 3) Refer PDF Cohort 2 30 µg/kg/day: (n=7, 6, 3, 2, 3) Cohort 3 30 µg/kg/day: (n=8, 6, 6, 3,7)
    End point type
    Secondary
    End point timeframe
    At Day1, Week 13, Week 26, Week 39, & Week 52.
    End point values
    All Vosoritide
    Number of subjects analysed
    43
    Units: min*pg/ml
    arithmetic mean (standard deviation)
        Cohort 1 15 µg/kg/day: Day 01
    149000 ± 98000
        Cohort 1 15 µg/kg/day: Week 13
    197000 ± 144000
        Cohort 1 15 µg/kg/day: Week 26
    306000 ± 252000
        Cohort 1 15 µg/kg/day: Week 39
    284000 ± 137000
        Cohort 1 15 µg/kg/day: Week 52
    303000 ± 208000
        Cohort 2 15 µg/kg/day: Week 26
    233000 ± 132000
        Cohort 2 15 µg/kg/day: Week 39
    204000 ± 39700
        Cohort 2 15 µg/kg/day: Week 52
    137000 ± 48900
        Cohort 2 30 µg/kg/day: Day 01
    557000 ± 278000
        Cohort 2 30 µg/kg/day: Week 13
    670000 ± 312000
        Cohort 2 30 µg/kg/day: Week 26
    429000 ± 163000
        Cohort 2 30 µg/kg/day: Week 39
    387000 ± 53800
        Cohort 2 30 µg/kg/day: Week 52
    768000 ± 391000
        Cohort 3 30 µg/kg/day: Day 01
    353000 ± 133000
        Cohort 3 30 µg/kg/day: Week 13
    382000 ± 268000
        Cohort 3 30 µg/kg/day: Week 26
    305000 ± 82100
        Cohort 3 30 µg/kg/day: Week 39
    575000 ± 455000
        Cohort 3 30 µg/kg/day: Week 52
    622000 ± 455000
    No statistical analyses for this end point

    Secondary: PK parameter: Area under the plasma concentration-time curve from time 0 to nominal 120 minutes postdose (AUC 0- 120 min) at Day 01, Week 13, Week 26, Week 39, & Week 52

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    End point title
    PK parameter: Area under the plasma concentration-time curve from time 0 to nominal 120 minutes postdose (AUC 0- 120 min) at Day 01, Week 13, Week 26, Week 39, & Week 52
    End point description
    The number of participants analyzed in Cohort 1 is reported in Cohort 1 Day 01, Week 13, Week 26, Week 39, Week 52) in sequence (n=18, 16, 17, 19, 16), Cohort 2 15 µg/kg/day: (n=3, 2, 5, 5, 5), Cohort 2 30 µg/kg/day: (n=7, 8, 3, 2, 3), & Cohort 3 30 µg/kg/day: (n=11, 7, 6, 4, 8)
    End point type
    Secondary
    End point timeframe
    At Day 01, Week 13, Week 26, Week 39, & Week 52
    End point values
    All Vosoritide
    Number of subjects analysed
    43
    Units: min*pg/ml
    arithmetic mean (standard deviation)
        Cohort 1 15 µg/kg/day: Day 01
    134000 ± 96500
        Cohort 1 15 µg/kg/day: Week 13
    183000 ± 126000
        Cohort 1 15 µg/kg/day: Week 26
    283000 ± 222000
        Cohort 1 15 µg/kg/day: Week 39
    257000 ± 132000
        Cohort 1 15 µg/kg/day: Week 52
    260000 ± 172000
        Cohort 2 15 µg/kg/day: Day 01
    83100 ± 48300
        Cohort 2 15 µg/kg/day: Week 13
    115000 ± 59300
        Cohort 2 15 µg/kg/day: Week 26
    197000 ± 121000
        Cohort 2 15 µg/kg/day: Week 39
    166000 ± 81000
        Cohort 2 15 µg/kg/day: Week 52
    125000 ± 76700
        Cohort 2 30 µg/kg/day: Day 01
    525000 ± 251000
        Cohort 2 30 µg/kg/day: Week 13
    642000 ± 353000
        Cohort 2 30 µg/kg/day: Week 26
    408000 ± 148000
        Cohort 2 30 µg/kg/day: Week 39
    365000 ± 44700
        Cohort 2 30 µg/kg/day: Week 52
    670000 ± 335000
        Cohort 3 30 µg/kg/day: Day 01
    312000 ± 119000
        Cohort 3 30 µg/kg/day: Week 13
    342000 ± 245000
        Cohort 3 30 µg/kg/day: Week 26
    300000 ± 79100
        Cohort 3 30 µg/kg/day: Week 39
    591000 ± 359000
        Cohort 3 30 µg/kg/day: Week 52
    558000 ± 400000
    No statistical analyses for this end point

    Secondary: PK parameter: Area under the plasma concentration-time curve from time 0 to the time of last measurable concentration (AUC0-t) at Day 01, Week 13, Week 26, Week 39, & Week 52

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    End point title
    PK parameter: Area under the plasma concentration-time curve from time 0 to the time of last measurable concentration (AUC0-t) at Day 01, Week 13, Week 26, Week 39, & Week 52
    End point description
    The number of participants analyzed in Cohort 1 is reported in Cohort 1 Day 01, Week 13, Week 26, Week 39, Week 52) in sequence (n=18, 16, 17, 19, 16), Cohort 2 15 µg/kg/day: (n=3, 2, 5, 5, 5) Cohort 2 30 µg/kg/day: (n=7, 8, 3, 2, 3), & Cohort 3 30 µg/kg/day: (n=11, 7, 6, 4, 8)
    End point type
    Secondary
    End point timeframe
    At Day 01, Week 13, Week 26, Week 39, & Week 52
    End point values
    All Vosoritide
    Number of subjects analysed
    43
    Units: min*pg/ml
    arithmetic mean (standard deviation)
        Cohort 1 15 µg/kg/day: Day 01
    132000 ± 97300
        Cohort 1 15 µg/kg/day: Week 13
    182000 ± 127000
        Cohort 1 15 µg/kg/day: Week 26
    282000 ± 222000
        Cohort 1 15 µg/kg/day: Week 39
    256000 ± 132000
        Cohort 1 15 µg/kg/day: Week 52
    258000 ± 169000
        Cohort 2 15 µg/kg/day: Day 01
    65900 ± 33600
        Cohort 2 15 µg/kg/day: Week 13
    112000 ± 62900
        Cohort 2 15 µg/kg/day: Week 26
    196000 ± 121000
        Cohort 2 15 µg/kg/day: Week 39
    165000 ± 82400
        Cohort 2 15 µg/kg/day: Week 52
    122000 ± 75700
        Cohort 2 30 µg/kg/day: Day 01
    547000 ± 279000
        Cohort 2 30 µg/kg/day: Week 13
    645000 ± 357000
        Cohort 2 30 µg/kg/day: Week 26
    407000 ± 148000
        Cohort 2 30 µg/kg/day: Week 39
    365000 ± 44300
        Cohort 2 30 µg/kg/day: Week 52
    672000 ± 334000
        Cohort 3 30 µg/kg/day: Day 01
    323000 ± 129000
        Cohort 3 30 µg/kg/day: Week 13
    340000 ± 244000
        Cohort 3 30 µg/kg/day: Week 26
    297000 ± 80700
        Cohort 3 30 µg/kg/day: Week 39
    567000 ± 361000
        Cohort 3 30 µg/kg/day: Week 52
    557000 ± 401000
    No statistical analyses for this end point

    Secondary: PK parameter: Maximum observed plasma concentration (Cmax) at Day 01, Week 13, Week 26, Week 39, & Week 52

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    End point title
    PK parameter: Maximum observed plasma concentration (Cmax) at Day 01, Week 13, Week 26, Week 39, & Week 52
    End point description
    The number of participant analyzed in Cohort 1 is reported in Cohort 1 Day 01, Week 13, Week 26, Week 39, Week 52) in sequence (n=18, 16, 17, 19, 16) Cohort 2 15 µg/kg/day: (n=3, 2, 5, 5, 5) Cohort 2 30 µg/kg/day: (n=7, 8, 3, 2, 3), & Cohort 3 30 µg/kg/day: (n=11, 7, 6, 4, 8).
    End point type
    Secondary
    End point timeframe
    At Day 01, Week 13, Week 26, Week 39, & Week 52
    End point values
    All Vosoritide
    Number of subjects analysed
    43
    Units: pg/ml
    arithmetic mean (standard deviation)
        Cohort 1 15 µg/kg/day: Day 01
    4430 ± 3670
        Cohort 1 15 µg/kg/day: Week 13
    4350 ± 1670
        Cohort 1 15 µg/kg/day: Week 26
    5850 ± 3260
        Cohort 1 15 µg/kg/day: Week 39
    5600 ± 2200
        Cohort 1 15 µg/kg/day: Week 52
    5640 ± 2740
        Cohort 2 15 µg/kg/day: Day 01
    2840 ± 1230
        Cohort 2 15 µg/kg/day: Week 13
    5970 ± 2390
        Cohort 2 15 µg/kg/day: Week 26
    6800 ± 3360
        Cohort 2 15 µg/kg/day: Week 39
    4600 ± 2150
        Cohort 2 15 µg/kg/day: Week 52
    3870 ± 2120
        Cohort 2 30 µg/kg/day: Day 01
    14500 ± 5950
        Cohort 2 30 µg/kg/day: Week 13
    13400 ± 6070
        Cohort 2 30 µg/kg/day: Week 26
    10100 ± 2970
        Cohort 2 30 µg/kg/day: Week 39
    6980 ± 1140
        Cohort 2 30 µg/kg/day: Week 52
    12900 ± 6260
        Cohort 3 30 µg/kg/day: Day 01
    13400 ± 5710
        Cohort 3 30 µg/kg/day: Week 13
    10500 ± 6850
        Cohort 3 30 µg/kg/day: Week 26
    11500 ± 4290
        Cohort 3 30 µg/kg/day: Week 39
    18400 ± 11900
        Cohort 3 30 µg/kg/day: Week 52
    13500 ± 6770
    No statistical analyses for this end point

    Secondary: PK parameter: Time to reach maximum concentration (Tmax) at Day 01, Week 13, Week 26, Week 39, & Week 52

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    End point title
    PK parameter: Time to reach maximum concentration (Tmax) at Day 01, Week 13, Week 26, Week 39, & Week 52
    End point description
    The number of participants analyzed in Cohort 1 is reported in Cohort 1 Day 01, Week 13, Week 26, Week 39, Week 52) in sequence (n=18, 16, 17, 19, 16), Cohort 2 15 µg/kg/day: (n=3, 2, 5, 5, 5) Cohort 2 30 µg/kg/day: (n=7, 8, 3, 2, 3), & Cohort 3 30 µg/kg/day: (n=11, 7, 6, 4, 8).
    End point type
    Secondary
    End point timeframe
    At Day 01, Week 13, Week 26, Week 39, & Week 52.
    End point values
    All Vosoritide
    Number of subjects analysed
    43
    Units: min
    arithmetic mean (standard deviation)
        Cohort 1 15 µg/kg/day: Day 01
    13.1 ± 6.33
        Cohort 1 15 µg/kg/day: Week 13
    14.3 ± 5.5
        Cohort 1 15 µg/kg/day: Week 26
    16.1 ± 8.69
        Cohort 1 15 µg/kg/day: Week 39
    17.4 ± 11.9
        Cohort 1 15 µg/kg/day: Week 52
    16.1 ± 6.27
        Cohort 2 15 µg/kg/day: Day 01
    11.3 ± 6.35
        Cohort 2 15 µg/kg/day: Week 13
    6 ± 1.41
        Cohort 2 15 µg/kg/day: Week 26
    10.8 ± 5.5
        Cohort 2 15 µg/kg/day: Week 39
    15.4 ± 11.6
        Cohort 2 15 µg/kg/day: Week 52
    14.2 ± 5.76
        Cohort 2 30 µg/kg/day: Day 01
    12.9 ± 9.1
        Cohort 2 30 µg/kg/day: Week 13
    14 ± 8.42
        Cohort 2 30 µg/kg/day: Week 26
    12 ± 5.2
        Cohort 2 30 µg/kg/day: Week 39
    15 ± 0
        Cohort 2 30 µg/kg/day: Week 52
    14.3 ± 1.53
        Cohort 3 30 µg/kg/day: Day 01
    7.36 ± 3.53
        Cohort 3 30 µg/kg/day: Week 13
    9.43 ± 5.22
        Cohort 3 30 µg/kg/day: Week 26
    9 ± 4.69
        Cohort 3 30 µg/kg/day: Week 39
    11.3 ± 3.59
        Cohort 3 30 µg/kg/day: Week 52
    14.5 ± 3.51
    No statistical analyses for this end point

    Secondary: PK parameter: Apparent clearance (CL/F) at Day 01, Week 13, Week 26, Week 39, & Week 52

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    End point title
    PK parameter: Apparent clearance (CL/F) at Day 01, Week 13, Week 26, Week 39, & Week 52
    End point description
    Vosoritide concentrations at 5-, 15- and 30-minute post-dose for one participant on Day 1 were not available, hence PK parameters for this participant were excluded from summary statistics. PK parameters for another participant on Day 1 obtained from extrapolation. AUC0-∞, CL/F, V/F and t1/2 excluded from summary statistics. PK parameters are not available for this participant at Week 13 due to unsuccessful venipuncture, and Week 26 as post-dose PK samples were not collected. The number of participants analyzed are reported in sequence (n = Day 01, Week 13, Week 26, Week 39, Week 52) Cohort 1 15 µg/kg/day: (n=16, 15, 16, 16, 15) Cohort 2 15 µg/kg/day: (n=1, 1, 4, 4, 3) Refer PDF Cohort 2 30 µg/kg/day: (n=7, 6, 3, 2, 3) Cohort 3 30 µg/kg/day: (n=8, 6, 6, 3, 7)
    End point type
    Secondary
    End point timeframe
    At Day 01, Week 13, Week 26, Week 39, & Week 52.
    End point values
    All Vosoritide
    Number of subjects analysed
    43
    Units: ml/min/kg
    arithmetic mean (standard deviation)
        Cohort 1 15 µg/kg/day: Day 01
    134 ± 59.8
        Cohort 1 15 µg/kg/day: Week 13
    111 ± 58.5
        Cohort 1 15 µg/kg/day: Week 26
    79.8 ± 48.3
        Cohort 1 15 µg/kg/day: Week 39
    65.3 ± 32.7
        Cohort 1 15 µg/kg/day: Week 52
    69 ± 41.2
        Cohort 2 15 µg/kg/day: Week 26
    79.5 ± 38.4
        Cohort 2 15 µg/kg/day: Week 39
    75.5 ± 14.8
        Cohort 2 15 µg/kg/day: Week 52
    122 ± 52.5
        Cohort 2 30 µg/kg/day: Day 01
    65.9 ± 31.6
        Cohort 2 30 µg/kg/day: Week 13
    58.7 ± 40.4
        Cohort 2 30 µg/kg/day: Week 26
    79.4 ± 37.7
        Cohort 2 30 µg/kg/day: Week 39
    78.3 ± 10.9
        Cohort 2 30 µg/kg/day: Week 52
    49.7 ± 32
        Cohort 3 30 µg/kg/day: Day 01
    95.9 ± 34
        Cohort 3 30 µg/kg/day: Week 13
    115 ± 78.1
        Cohort 3 30 µg/kg/day: Week 26
    104 ± 23.2
        Cohort 3 30 µg/kg/day: Week 39
    73.6 ± 41.6
        Cohort 3 30 µg/kg/day: Week 52
    76.5 ± 49.8
    No statistical analyses for this end point

    Secondary: PK parameter: Apparent volume of distribution (Vz/F) at Day 01, Week 13, Week 26, Week 39, & Week 52

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    End point title
    PK parameter: Apparent volume of distribution (Vz/F) at Day 01, Week 13, Week 26, Week 39, & Week 52
    End point description
    Vosoritide concentrations at 5-, 15- and 30-minute post-dose for one participant on Day 1 were not available, hence PK parameters for this participant were excluded from summary statistics. PK parameters for another participant on Day 1 obtained from extrapolation. V/F excluded from summary statistics. PK parameters are not available for this participant at Week 13 due to unsuccessful venipuncture, and Week 26 as post-dose PK samples were not collected. The number of participants analyzed are reported in sequence (n = Day 01, Week 13, Week 26, Week 39, Week 52) Cohort 1 15 µg/kg/day: (n=16, 15, 16, 16, 15) Cohort 2 15 µg/kg/day: (n=1, 1, 4, 4, 3) Refer PDF Cohort 2 30 µg/kg/day: (n=7, 6, 3, 2, 3) Cohort 3 30 µg/kg/day: (n=8, 6, 6, 3, 7)
    End point type
    Secondary
    End point timeframe
    At Day 01, Week 13, Week 26, Week 39, & Week 52.
    End point values
    All Vosoritide
    Number of subjects analysed
    43
    Units: ml/kg
    arithmetic mean (standard deviation)
        Cohort 1 15 µg/kg/day: Day 01
    4070 ± 2310
        Cohort 1 15 µg/kg/day: Week 13
    3990 ± 2960
        Cohort 1 15 µg/kg/day: Week 26
    3400 ± 2520
        Cohort 1 15 µg/kg/day: Week 39
    2330 ± 1150
        Cohort 1 15 µg/kg/day: Week 52
    2660 ± 1420
        Cohort 2 15 µg/kg/day: Week 26
    3890 ± 2880
        Cohort 2 15 µg/kg/day: Week 39
    2250 ± 284
        Cohort 2 15 µg/kg/day: Week 52
    3770 ± 1410
        Cohort 2 30 µg/kg/day: Day 01
    3190 ± 1790
        Cohort 2 30 µg/kg/day: Week 13
    2090 ± 1360
        Cohort 2 30 µg/kg/day: Week 26
    1960 ± 829
        Cohort 2 30 µg/kg/day: Week 39
    2920 ± 205
        Cohort 2 30 µg/kg/day: Week 52
    3040 ± 2630
        Cohort 3 30 µg/kg/day: Day 01
    5240 ± 1890
        Cohort 3 30 µg/kg/day: Week 13
    4260 ± 2960
        Cohort 3 30 µg/kg/day: Week 26
    2750 ± 710
        Cohort 3 30 µg/kg/day: Week 39
    2200 ± 951
        Cohort 3 30 µg/kg/day: Week 52
    2620 ± 1950
    No statistical analyses for this end point

    Secondary: PK parameter: Elimination half-life (t1/2) at Day 01, Week 13, Week 26, Week 39, & Week 52

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    End point title
    PK parameter: Elimination half-life (t1/2) at Day 01, Week 13, Week 26, Week 39, & Week 52
    End point description
    Vosoritide concentrations at 5-, 15- and 30-minute post-dose for one participant on Day 1 were not available, hence PK parameters for this participant were excluded from summary statistics. PK parameters for another participant on Day 1 obtained from extrapolation. AUC0-∞, CL/F, V/F and t1/2 excluded from summary statistics. PK parameters are not available for this participant at Week 13 due to unsuccessful venipuncture, and Week 26 as post-dose PK samples were not collected. The number of participants analyzed are reported in sequence (n = Day 01, Week 13, Week 26, Week 39, Week 52) Cohort 1 15 µg/kg/day: (n=16, 15, 16, 16, 15) Cohort 2 15 µg/kg/day: (n=1, 1, 4, 4, 3) Refer PDF Cohort 2 30 µg/kg/day: (n=7, 6, 3, 2, 3) Cohort 3 30 µg/kg/day: (n=8, 6, 6, 3, 7)
    End point type
    Secondary
    End point timeframe
    At Day 01, Week 13, Week 26, Week 39, & Week 52.
    End point values
    All Vosoritide
    Number of subjects analysed
    43
    Units: min
    arithmetic mean (standard deviation)
        Cohort 1 15 µg/kg/day: Day 01
    21.7 ± 7.99
        Cohort 1 15 µg/kg/day: Week 13
    25.4 ± 10.7
        Cohort 1 15 µg/kg/day: Week 26
    29.2 ± 7.06
        Cohort 1 15 µg/kg/day: Week 39
    25.7 ± 7.82
        Cohort 1 15 µg/kg/day: Week 52
    29 ± 9.12
        Cohort 2 15 µg/kg/day: Week 26
    32.7 ± 9.62
        Cohort 2 15 µg/kg/day: Week 39
    20.9 ± 2.18
        Cohort 2 15 µg/kg/day: Week 52
    24 ± 12.8
        Cohort 2 30 µg/kg/day: Day 01
    33.3 ± 8.41
        Cohort 2 30 µg/kg/day: Week 13
    25.6 ± 3.59
        Cohort 2 30 µg/kg/day: Week 26
    21 ± 13.1
        Cohort 2 30 µg/kg/day: Week 39
    26.2 ± 5.46
        Cohort 2 30 µg/kg/day: Week 52
    40.1 ± 15.2
        Cohort 3 30 µg/kg/day: Day 01
    41.1 ± 18.8
        Cohort 3 30 µg/kg/day: Week 13
    26.2 ± 7.1
        Cohort 3 30 µg/kg/day: Week 26
    19.2 ± 6.14
        Cohort 3 30 µg/kg/day: Week 39
    22.7 ± 5.36
        Cohort 3 30 µg/kg/day: Week 52
    24.3 ± 6.58
    No statistical analyses for this end point

    Secondary: Biomarker: Bone and Collagen Metabolism Biomarker Over Time-CNP Col X BM

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    End point title
    Biomarker: Bone and Collagen Metabolism Biomarker Over Time-CNP Col X BM
    End point description
    The number of participants analyzed is reported in sequence: (n=All Vosoritide, Placebo) for each category. Baseline: (n= 42, 32) Day 8: (n=42, 24) Change from baseline to Day 8: (n=41, 24) Week 6: (n=41, 29) Change from baseline to Week 6: (n=40, 29) Week 20: (n=42, 29) Change from baseline to Week 20: (n=41, 29) Week 39: (n=33, 22) Change from baseline to Week 39 : (n=32, 22)
    End point type
    Secondary
    End point timeframe
    At Baseline, Day 8, Week 6, Week 20, & Week 39.
    End point values
    All Vosoritide Placebo
    Number of subjects analysed
    43
    32
    Units: pg/mL
    arithmetic mean (standard deviation)
        CNP Col X BM: Baseline
    9833.8 ± 3444.7
    9555.0 ± 4016.7
        CNP Col X BM: Day 8
    12093.8 ± 4443.8
    10017.5 ± 3831.2
        CNP Col X BM: Change from baseline to Day 8
    2139.5 ± 3871.9
    1391.3 ± 3354.2
        CNP Col X BM: Week 6
    13456.3 ± 4763.3
    9464.8 ± 4243.3
        CNP Col X BM: Change from baseline to Week 6
    3400.3 ± 4554.6
    200.3 ± 3867.5
        CNP Col X BM: Week 20
    12833.3 ± 4581.9
    12064.8 ± 5277.3
        CNP Col X BM: Change from baseline to Week 20
    2928.0 ± 4385.9
    2435.5 ± 4666.9
        CNP Col X BM: Week 39
    12249.7 ± 5056.5
    9932.7 ± 4004.4
        CNP Col X BM: Change from baseline to Week 39
    2362.8 ± 5752.9
    946.4 ± 3490.1
    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 Safety Follow-Up.
    Adverse event reporting additional description
    The Safety Population was a subset of the FAS who received at least one dose of vosoritide or placebo in the study.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    -

    Reporting group title
    Vosoritide
    Reporting group description
    -

    Serious adverse events
    Placebo Vosoritide
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 32 (18.75%)
    3 / 43 (6.98%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    1
    Investigations
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Skull fracture
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 43 (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
    Petit mal epilepsy
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Sudden infant death syndrome
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory distress
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Autism spectrum disorder
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 43 (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
    Pneumonia
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus bronchiolitis
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 43 (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
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    32 / 32 (100.00%)
    43 / 43 (100.00%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    3 / 32 (9.38%)
    7 / 43 (16.28%)
         occurrences all number
    5
    9
    Arthropod bite
         subjects affected / exposed
    2 / 32 (6.25%)
    6 / 43 (13.95%)
         occurrences all number
    2
    7
    General disorders and administration site conditions
    Injection site reaction
         subjects affected / exposed
    13 / 32 (40.63%)
    34 / 43 (79.07%)
         occurrences all number
    154
    3057
    Injection site erythema
         subjects affected / exposed
    13 / 32 (40.63%)
    33 / 43 (76.74%)
         occurrences all number
    1738
    5100
    Injection site swelling
         subjects affected / exposed
    2 / 32 (6.25%)
    8 / 43 (18.60%)
         occurrences all number
    3
    36
    Injection site urticaria
         subjects affected / exposed
    1 / 32 (3.13%)
    6 / 43 (13.95%)
         occurrences all number
    1
    22
    Injection site induration
         subjects affected / exposed
    0 / 32 (0.00%)
    5 / 43 (11.63%)
         occurrences all number
    0
    14
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    2 / 32 (6.25%)
    5 / 43 (11.63%)
         occurrences all number
    4
    7
    Respiratory, thoracic and mediastinal disorders
    Sleep apnea syndrome
         subjects affected / exposed
    0 / 32 (0.00%)
    3 / 43 (6.98%)
         occurrences all number
    0
    3
    Epistaxis
         subjects affected / exposed
    0 / 32 (0.00%)
    3 / 43 (6.98%)
         occurrences all number
    0
    3
    Skin and subcutaneous tissue disorders
    Dermatitis Diaper
         subjects affected / exposed
    1 / 32 (3.13%)
    4 / 43 (9.30%)
         occurrences all number
    1
    5
    Infections and infestations
    Viral Infection
         subjects affected / exposed
    4 / 32 (12.50%)
    8 / 43 (18.60%)
         occurrences all number
    8
    28
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 32 (3.13%)
    4 / 43 (9.30%)
         occurrences all number
    3
    4
    Rhinitis
         subjects affected / exposed
    0 / 32 (0.00%)
    4 / 43 (9.30%)
         occurrences all number
    0
    8
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 32 (0.00%)
    3 / 43 (6.98%)
         occurrences all number
    0
    3

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Aug 2018
    • The lower age range of participating participants who have a >= 6-month period of pretreatment growth assessment in 111-901 immediately before study entry was revised from >= 3 months to >= 6 months. • Language updated to state that no two sentinel participants would be dosed on the same day for any cohort. • Echocardiogram would be performed at the Week 56Safety Follow-up and Early Termination visits • Use of residual plasma samples for cGMP PD biomarker assessment in all age groups was added to procedures. • An anti-vosoritide immunogenicity assessment was added at Week 3. • Bone metabolism urine biomarkers, vosoritide pharmacodynamic urine biomarkers, and urine chemistry assessments were added at Week 39. • The sleep study scheduled at the Week 26 visit was removed. • DXA scans would no longer include tibia scans. • If the 111-901 visit at which the participant entered 111-206 and the 111-206 Screening visit were on the same day, the procedures common to both visits were performed one time only. • On days when PK samples were being drawn, ECG would be performed within a 5-minute window prior to the 30-minute PK assessment. • Exclusion criterion #6 was revised from “…as determined by the Investigator based on the following assessments…) to (…as determined by theInvestigator and informed by the following assessments…). The determination about whether presence of cervicomedullary compression is likely to require surgical intervention will be informed by physical exam, polysomnography, and MRI. • Exclusion criterion #15 was revised to include cervicomedullary decompression surgery (Cohorts 2 and 3 only). • Inclusion/exclusion criteria was added for Cohort 3 participants enrolling in the observational period. • A table of restricted medications, including growth hormone, was added. For participants enrolled in Cohort 3 (0 to < 6 months old), the collection period for all AEs was to begin after informed consent is obtained.
    08 Feb 2019
    The following exploratory objectives were revised to secondary objectives. • Evaluate the effect of vosoritide on growth parameters and body proportions, including change from baseline in upper:lower segment ratio • Evaluate the effect of vosoritide on sleep apnea • Evaluate the effect of vosoritide on skull and brain morphology, including foramen magnum, ventricular and brain parenchymal dimensions • Describe the incidence of surgical interventions, including cervical decompression, adenotonsellectomy, and typanostomy The secondary imaging assessment procedures, excluding the MRI assessment, were moved to the secondary safety variables section. The hip imaging assessment was removed, the X-ray assessment was modified to include long bone growth, and the DXA assessment would no longer include the forearm. Also, the paragraph discussing the possibility of non-radiological methods of assessment for participants in Cohort 3 was deleted. The screening baseline hip assessment with pelvis X-ray was removed from the Schedule of Events. Footnotes were changed to modify procedures and to add early termination visits (ETV) for anthropomorphic measurements, DXA, and X-rays.

    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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