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    Clinical Trial Results:
    A Phase 2, Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of Palovarotene in Subjects with Multiple Osteochondromas

    Summary
    EudraCT number
    		 2017-002751-28
    Trial protocol
    		 ES   GB   PT   FR   IT   NL   BE   Outside EU/EEA  
    Global end of trial date
    30 Oct 2020

    Results information
    Results version number
    		 v2(current)
    This version publication date
    23 Jul 2022
    First version publication date
    29 Aug 2021
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    Additional analyses provided

    Trial information

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    Trial identification
    Sponsor protocol code
    PVO-2A-201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03442985
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Clementia Pharmaceuticals Inc.
    Sponsor organisation address
    1000 De La Gauchetière West, Suite 1200, Montreal, Quebec, Canada, H3B 4W5
    Public contact
    Medical Director, Ipsen, clinical.trials@ipsen.com
    Scientific contact
    Medical Director, Ipsen, clinical.trials@ipsen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001662-PIP03-17
    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
    30 Oct 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Oct 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to compare the efficacy of 2 dosage regimens of palovarotene with placebo in preventing the formation of new osteochondromas (OCs) in participants with multiple osteochondromas (MO) due to exostosin 1 (EXT1) or exostosin 2 (EXT2) mutations.
    Protection of trial subjects
    The clinical study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, inclusive of any subsequent amendment(s), and that are consistent with the International Council for Harmonization Good Clinical Practice (E6), European Union (EU) Directive 2001/20/EC, United States Food and Drug Administration Code of Federal Regulations, and other applicable local regulatory requirements, whichever affords the greater participant protection.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Mar 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 2
    Country: Number of subjects enrolled
    Canada: 13
    Country: Number of subjects enrolled
    Japan: 7
    Country: Number of subjects enrolled
    Turkey: 9
    Country: Number of subjects enrolled
    United States: 122
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    Netherlands: 5
    Country: Number of subjects enrolled
    Portugal: 6
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    United Kingdom: 16
    Worldwide total number of subjects
    193
    EEA total number of subjects
    24
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    174
    Adolescents (12-17 years)
    19
    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 Phase 2 placebo-controlled study was conducted in pediatric participants with MO at 29 study sites in 11 countries. For sites in the EU, participants from 7 to <15 years of age were enrolled first and participants from 2 to <7 years of age were enrolled after the 6-month bone safety data from at least 20 skeletally immature participants.

    Pre-assignment
    Screening details
    		 Study consisted of a screening period (up to 35 days), followed by a double-blind treatment period (24 months) and follow-up period (6 months). Participants were randomized in a 1:1:1 ratio to palovarotene 2.5 milligram (mg) or 5.0 mg or placebo. A total of 193 participants received at least 1 dose of study drug and were included in study analysis.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants were to receive placebo matching with palovarotene capsules orally once daily, for up to 24 months.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo (matching with palovarotene) capsules were to administer at approximately the same time each day, preferably immediately after the first meal of the day up to 24 months. Participants who had difficulty swallowing intact capsules were permitted to sprinkle the contents of the capsule onto a spoonful of specific foods and eaten.

    Arm title
    		 Palovarotene 2.5 mg
    Arm description
    		 Participants were to receive weight-adjusted dose equivalent of palovarotene 2.5 mg capsules orally once daily, for up to 24 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Palovarotene
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Palovarotene 2.5 mg capsules were to administer at approximately the same time each day, preferably immediately after the first meal of the day up to 24 months. Participants who had difficulty swallowing intact capsules were permitted to sprinkle the contents of the capsule onto a spoonful of specific foods and eaten.

    Arm title
    		 Palovarotene 5.0 mg
    Arm description
    		 Participants were to receive weight-adjusted dose equivalent of palovarotene 5.0 mg capsules orally once daily, for up to 24 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Palovarotene
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Palovarotene 5.0 mg capsules were to administer at approximately the same time each day, preferably immediately after the first meal of the day up to 24 months. Participants who had difficulty swallowing intact capsules were permitted to sprinkle the contents of the capsule onto a spoonful of specific foods and eaten.

    Number of subjects in period 1
    		Placebo Palovarotene 2.5 mg Palovarotene 5.0 mg
    Started
    62
    66
    65
    Completed
    0
    0
    0
    Not completed
    62
    66
    65
         Consent withdrawn by subject
    2
    3
    4
         Adverse event, non-fatal
    -
    1
    -
         Lost to follow-up
    5
    2
    7
         Sponsor Request
    55
    60
    54

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants were to receive placebo matching with palovarotene capsules orally once daily, for up to 24 months.

    Reporting group title
    Palovarotene 2.5 mg
    Reporting group description
    		 Participants were to receive weight-adjusted dose equivalent of palovarotene 2.5 mg capsules orally once daily, for up to 24 months.

    Reporting group title
    Palovarotene 5.0 mg
    Reporting group description
    		 Participants were to receive weight-adjusted dose equivalent of palovarotene 5.0 mg capsules orally once daily, for up to 24 months.

    Reporting group values
    		 Placebo Palovarotene 2.5 mg Palovarotene 5.0 mg Total
    Number of subjects
    		 62 66 65 193
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 56 58 60 174
        Adolescents (12-17 years)
    		 6 8 5 19
        Adults (18-64 years)
    		 0 0 0 0
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 7.9 ( 2.5 ) 7.8 ( 3.1 ) 7.4 ( 3.1 ) -
    Gender categorical
    Units: Subjects
        Female
    		 23 26 27 76
        Male
    		 39 40 38 117
    Race
    Units: Subjects
        White
    		 48 50 52 150
        Black Or African American
    		 0 2 2 4
        Asian
    		 5 3 3 11
        American Indian Or Alaska Native
    		 0 1 0 1
        Multiple
    		 6 7 5 18
        Other
    		 0 0 1 1
        Missing
    		 3 3 2 8
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 6 7 7 20
        Not Hispanic or Latino
    		 56 58 57 171
        Missing
    		 0 1 1 2

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants were to receive placebo matching with palovarotene capsules orally once daily, for up to 24 months.

    Reporting group title
    Palovarotene 2.5 mg
    Reporting group description
    		 Participants were to receive weight-adjusted dose equivalent of palovarotene 2.5 mg capsules orally once daily, for up to 24 months.

    Reporting group title
    Palovarotene 5.0 mg
    Reporting group description
    		 Participants were to receive weight-adjusted dose equivalent of palovarotene 5.0 mg capsules orally once daily, for up to 24 months.

    Primary: Annualized Rate of New OCs

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    End point title
    		 Annualized Rate of New OCs
    End point description
    The annualized rate of new OCs was assessed by whole-body magnetic resonance imaging (MRI) (that is, the total number of new OCs divided by the time in years between the baseline and latest post-baseline MRI). The Full Analysis Set (FAS) included randomized participants who received at least 1 dose of study drug. Only data from the 56 participants for whom Month 12 efficacy imaging data were available were included in the analysis.
    End point type
    Primary
    End point timeframe
    Month 12
    End point values
    		 Placebo Palovarotene 2.5 mg Palovarotene 5.0 mg
    Number of subjects analysed
    16
    17
    23
    Units: number of new OCs per year
        least squares mean (confidence interval 95%)
    0.119 (0.031 to 0.461)
    0.363 (0.148 to 0.888)
    0.172 (0.073 to 0.404)
    Statistical analysis title
    		 Risk ratio for annualized rate of new OCs 1
    Statistical analysis description
    The annualized rate for number of new OCs was estimated using an unadjusted negative binomial regression model, offsetted by log-transformed follow-up time (years) to obtain annualized rate.
    Comparison groups
    Palovarotene 2.5 mg v Palovarotene 5.0 mg
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2556 [1]
    Method
    		 Negative binomial regression model
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    2.109
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.583
         upper limit
    		 7.638
    Notes
    [1] - The p-values were not adjusted for multiple testing due to small sample size.
    Statistical analysis title
    		 Risk ratio for annualized rate of new OCs 2
    Statistical analysis description
    The annualized rate for number of new OCs was estimated using an unadjusted negative binomial regression model, offsetted by log-transformed follow-up time (years) to obtain annualized rate.
    Comparison groups
    Palovarotene 2.5 mg v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1788 [2]
    Method
    		 Negative binomial regression model
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    3.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.601
         upper limit
    		 15.373
    Notes
    [2] - The p-values were not adjusted for multiple testing due to small sample size.
    Statistical analysis title
    		 Risk ratio for annualized rate of new OCs 3
    Statistical analysis description
    The annualized rate for number of new OCs was estimated using an unadjusted negative binomial regression model, offsetted by log-transformed follow-up time (years) to obtain annualized rate.
    Comparison groups
    Palovarotene 5.0 mg v Placebo
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.657 [3]
    Method
    		 Negative binomial regression model
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.441
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.287
         upper limit
    		 7.234
    Notes
    [3] - The p-values were not adjusted for multiple testing due to small sample size.

    Secondary: Mean Change From Baseline in the Total Volume of New OCs at Month 12

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    End point title
    		 Mean Change From Baseline in the Total Volume of New OCs at Month 12
    End point description
    The change from baseline in the total volume of OCs was assessed by whole-body MRI. Baseline was defined as the last available value prior to first administration of study drug. The FAS included randomized participants who received at least 1 dose of study drug. Only data from the 56 participants for whom Month 12 efficacy imaging data were available were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Month 12
    End point values
    		 Placebo Palovarotene 2.5 mg Palovarotene 5.0 mg
    Number of subjects analysed
    16
    17
    23
    Units: cubic millimeter
        arithmetic mean (standard deviation)
    10476.7 ( 23294.9 )
    5250.5 ( 11754.7 )
    10911.0 ( 35869.6 )
    Statistical analysis title
    		 Risk ratio for total volume of new OCs 1
    Statistical analysis description
    The mean difference in the change from baseline for total OC volume was estimated using an unadjusted estimation equation model with independent working covariance matrix to address potential correlation within the same family members.
    Comparison groups
    Palovarotene 2.5 mg v Palovarotene 5.0 mg
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.4252 [4]
    Method
    		 Unadjusted estimation equation model
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    -4412.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15257.3
         upper limit
    		 6432.1
    Notes
    [4] - The p-values were not adjusted for multiple testing due to small sample size.
    Statistical analysis title
    		 Risk ratio for total volume of new OCs 2
    Statistical analysis description
    The mean difference in the change from baseline for total OC volume was estimated using an unadjusted estimation equation model with independent working covariance matrix to address potential correlation within the same family members.
    Comparison groups
    Palovarotene 2.5 mg v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.4053 [5]
    Method
    		 Unadjusted estimation equation model
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    -4640.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15570.8
         upper limit
    		 6289
    Notes
    [5] - The p-values were not adjusted for multiple testing due to small sample size.
    Statistical analysis title
    		 Risk ratio for total volume of new OCs 3
    Statistical analysis description
    The mean difference in the change from baseline for total OC volume was estimated using an unadjusted estimation equation model with independent working covariance matrix to address potential correlation within the same family members.
    Comparison groups
    Palovarotene 5.0 mg v Placebo
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.9677 [6]
    Method
    		 Unadjusted estimation equation model
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    -228.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11265
         upper limit
    		 10808.4
    Notes
    [6] - The p-values were not adjusted for multiple testings due to small sample size.

    Secondary: Percentage of Participants With No New OCs

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    End point title
    		 Percentage of Participants With No New OCs
    End point description
    The percentage of participants with no new OCs as assessed by whole-body MRI. Participants with new OCs not identified by MRI due to surgical resection during the treatment period were categorized as having new OCs for this analysis. The FAS included randomized participants who received at least 1 dose of study drug. Only data from the 56 participants for whom Month 12 efficacy imaging data were available were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    		 Placebo Palovarotene 2.5 mg Palovarotene 5.0 mg
    Number of subjects analysed
    16
    17
    23
    Units: percentage of participants
        number (not applicable)
    62.5
    47.1
    56.5
    Statistical analysis title
    		 Odds ratio for participants with no new OCs 1
    Comparison groups
    Palovarotene 2.5 mg v Palovarotene 5.0 mg
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.5025 [7]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.643
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.177
         upper limit
    		 2.335
    Notes
    [7] - Logistic regression was adjusted for the following covariates: baseline age, sex, and Ext1/2 mutation status.
    Statistical analysis title
    		 Odds ratio for participants with no new OCs 2
    Comparison groups
    Palovarotene 2.5 mg v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3763 [8]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.528
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.128
         upper limit
    		 2.175
    Notes
    [8] - Logistic regression was adjusted for the following covariates: baseline age, sex, and Ext1/2 mutation status.
    Statistical analysis title
    		 Odds ratio for participants with no new OCs 3
    Comparison groups
    Palovarotene 5.0 mg v Placebo
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7714 [9]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.215
         upper limit
    		 3.123
    Notes
    [9] - Logistic regression was adjusted for the following covariates: baseline age, sex, and Ext1/2 mutation status.

    Secondary: Annualized Rate of New or Worsening Deformities

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    End point title
    		 Annualized Rate of New or Worsening Deformities
    End point description
    The annualized rate of new or worsening deformities as assessed by radiographic imaging of both upper and lower limbs. The FAS included randomized participants who received at least 1 dose of study drug. Only data from the 56 participants for whom Month 12 efficacy imaging data were available were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    		 Placebo Palovarotene 2.5 mg Palovarotene 5.0 mg
    Number of subjects analysed
    16
    18
    22
    Units: number of deformities per year
        least squares mean (confidence interval 95%)
    1.797 (1.272 to 2.537)
    1.802 (1.209 to 2.684)
    1.895 (1.584 to 2.266)
    Statistical analysis title
    		 Risk ratio for new or worsening deformities 1
    Statistical analysis description
    The annualized rate for number of new or worsening deformities was estimated using an unadjusted negative binomial regression model, offsetted by log-transformed follow-up time (years) to obtain annualized rate.
    Comparison groups
    Palovarotene 2.5 mg v Palovarotene 5.0 mg
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.8155 [10]
    Method
    		 Negative binomial regression model
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.951
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.623
         upper limit
    		 1.451
    Notes
    [10] - The p-values were not adjusted for multiple testing due to small sample size. The correlation matrix type = compound symmetry was used.
    Statistical analysis title
    		 Risk ratio for new or worsening deformities 2
    Statistical analysis description
    The annualized rate for number of new or worsening deformities was estimated using an unadjusted negative binomial regression model, offsetted by log-transformed follow-up time (years) to obtain annualized rate.
    Comparison groups
    Palovarotene 2.5 mg v Placebo
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.9918 [11]
    Method
    		 Negative binomial regression model
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.003
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.592
         upper limit
    		 1.699
    Notes
    [11] - The p-values were not adjusted for multiple testing due to small sample size. The correlation matrix type = compound symmetry was used.
    Statistical analysis title
    		 Risk ratio for new or worsening deformities 3
    Statistical analysis description
    The annualized rate for number of new or worsening deformities was estimated using an unadjusted negative binomial regression model, offsetted by log-transformed follow-up time (years) to obtain annualized rate.
    Comparison groups
    Palovarotene 5.0 mg v Placebo
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7997 [12]
    Method
    		 Negative binomial regression model
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.055
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 1.589
    Notes
    [12] - The p-values were not adjusted for multiple testing due to small sample size. The correlation matrix type = compound symmetry was used.

    Secondary: Annualized Rate of MO-Related Surgeries

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    End point title
    		 Annualized Rate of MO-Related Surgeries
    End point description
    The MO-related surgeries included any procedure indicated for the treatment of MO, such as an excision of a symptomatic OC or correction of a limb deformity. The FAS included randomized participants who received at least 1 dose of study drug. Participants with planned surgeries within 6 months of enrollment to remove symptomatic OCs or to correct deformities present at baseline, and/or had surgical procedures that were a continuation of a previous procedure were excluded in the analysis.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    		 Placebo Palovarotene 2.5 mg Palovarotene 5.0 mg
    Number of subjects analysed
    4
    8
    7
    Units: number of MO-related surgeries per year
        least squares mean (confidence interval 95%)
    2.087 (1.099 to 3.964)
    3.454 (1.850 to 6.451)
    2.231 (1.638 to 3.038)
    Statistical analysis title
    		 Risk ratio for MO-Related Surgeries 1
    Statistical analysis description
    The annualized rate for number of MO-related surgeries was estimated using an unadjusted poisson regression model, offsetted by log-transformed follow-up time (years) to obtain annualized rate.
    Comparison groups
    Palovarotene 2.5 mg v Palovarotene 5.0 mg
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2186 [13]
    Method
    		 Poisson regression model
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.548
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.772
         upper limit
    		 3.108
    Notes
    [13] - The p-values were not adjusted for multiple testing due to small sample size. The correlation matrix type = independent was used.
    Statistical analysis title
    		 Risk ratio for MO-Related Surgeries 2
    Statistical analysis description
    The annualized rate for number of MO-related surgeries was estimated using an unadjusted poisson regression model, offsetted by log-transformed follow-up time (years) to obtain annualized rate.
    Comparison groups
    Palovarotene 2.5 mg v Placebo
    Number of subjects included in analysis
    12
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.27 [14]
    Method
    		 Poisson regression model
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.655
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.676
         upper limit
    		 4.052
    Notes
    [14] - The p-values were not adjusted for multiple testing due to small sample size. The correlation matrix type = independent was used.
    Statistical analysis title
    		 Risk ratio for MO-Related Surgeries 3
    Statistical analysis description
    The annualized rate for number of MO-related surgeries was estimated using an unadjusted poisson regression model, offsetted by log-transformed follow-up time (years) to obtain annualized rate.
    Comparison groups
    Palovarotene 5.0 mg v Placebo
    Number of subjects included in analysis
    11
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.8546 [15]
    Method
    		 Poisson regression model
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.069
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.524
         upper limit
    		 2.178
    Notes
    [15] - The p-values were not adjusted for multiple testing due to small sample size. The correlation matrix type = independent was used.

    Secondary: Maximum Observed Plasma Drug Concentrations at Steady State (Cmax,ss) of Palovarotene

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    End point title
    		 Maximum Observed Plasma Drug Concentrations at Steady State (Cmax,ss) of Palovarotene [16]
    End point description
    The Cmax,ss of palovarotene was evaluated. The pharmacokinetic (PK) sampling was performed at Month 1. If samples could not be obtained at Month 1, then one additional attempt was made at a subsequent visit. The Pharmacokinetic Set (PKS) included participants receiving treatment with palovarotene and with evaluable PK data.
    End point type
    Secondary
    End point timeframe
    Month 1: pre-dose and 3, 6, 10 and 24 hours post-dose
    Notes
    [16] - 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: Only reporting groups in which participants received palovarotene were evaluated for this PK endpoint.
    End point values
    		 Palovarotene 2.5 mg Palovarotene 5.0 mg
    Number of subjects analysed
    49
    52
    Units: nanogram per milliliter (ng/mL)
        geometric mean (geometric coefficient of variation)
    18.0 ( 50.2 )
    34.9 ( 63.3 )
    No statistical analyses for this end point

    Secondary: Minimum Observed Plasma Drug Concentrations at Steady State (Cmin,ss) of Palovarotene

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    End point title
    		 Minimum Observed Plasma Drug Concentrations at Steady State (Cmin,ss) of Palovarotene [17]
    End point description
    The Cmin,ss of palovarotene was evaluated. The PK sampling was performed at Month 1. If samples could not be obtained at Month 1, then one additional attempt was made at a subsequent visit. The PKS included participants receiving treatment with palovarotene and with evaluable PK data.
    End point type
    Secondary
    End point timeframe
    Month 1: pre-dose and 3, 6, 10 and 24 hours post-dose
    Notes
    [17] - 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: Only reporting groups in which participants received palovarotene were evaluated for this PK endpoint.
    End point values
    		 Palovarotene 2.5 mg Palovarotene 5.0 mg
    Number of subjects analysed
    49
    53
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    0.314 ( 86.1 )
    0.674 ( 83.3 )
    No statistical analyses for this end point

    Secondary: Time to Maximum Observed Drug Concentration at Steady State (Tmax,ss) of Palovarotene

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    End point title
    		 Time to Maximum Observed Drug Concentration at Steady State (Tmax,ss) of Palovarotene [18]
    End point description
    The Tmax,ss of palovarotene was evaluated. The PK sampling was performed at Month 1. If samples could not be obtained at Month 1, then one additional attempt was made at a subsequent visit. The PKS included participants receiving treatment with palovarotene and with evaluable PK data.
    End point type
    Secondary
    End point timeframe
    Month 1: pre-dose and 3, 6, 10 and 24 hours post-dose
    Notes
    [18] - 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: Only reporting groups in which participants received palovarotene were evaluated for this PK endpoint.
    End point values
    		 Palovarotene 2.5 mg Palovarotene 5.0 mg
    Number of subjects analysed
    49
    52
    Units: hour
        median (full range (min-max))
    3.00 (2.47 to 10.00)
    3.01 (2.42 to 24.25)
    No statistical analyses for this end point

    Secondary: Area Under the Plasma Concentration-Time Curve at Steady State From Time 0 to 24 Hours After Dosing (AUC0-24,ss) of Palovarotene

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    End point title
    		 Area Under the Plasma Concentration-Time Curve at Steady State From Time 0 to 24 Hours After Dosing (AUC0-24,ss) of Palovarotene [19]
    End point description
    The AUC0-24,ss of palovarotene was evaluated. The PK sampling was performed at Month 1. If samples could not be obtained at Month 1, then one additional attempt was made at a subsequent visit. The PKS included participants receiving treatment with palovarotene and with evaluable PK data.
    End point type
    Secondary
    End point timeframe
    Month 1: pre-dose and 3, 6, 10 and 24 hours post-dose
    Notes
    [19] - 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: Only reporting groups in which participants received palovarotene were evaluated for this PK endpoint.
    End point values
    		 Palovarotene 2.5 mg Palovarotene 5.0 mg
    Number of subjects analysed
    47
    46
    Units: hour*ng/mL
        geometric mean (geometric coefficient of variation)
    112 ( 29.1 )
    241 ( 42.7 )
    No statistical analyses for this end point

    Secondary: Number of Participants With Palatability of Sprinkled Palovarotene and Placebo

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    End point title
    		 Number of Participants With Palatability of Sprinkled Palovarotene and Placebo
    End point description
    Palatability of palovarotene and placebo when sprinkled on specific foods as assessed with a 5-point hedonic face scale at the first dose (Day 1) and at Month 1 in all participants (including <4 years old) who sprinkled the palovarotene or placebo onto a spoonful of specific foods. The hedonic face scale ranges from 1 to 5 where, 1= dislike very much, 2= dislike slightly, 3= neither like nor dislike, 4= like slightly, 5= like very much. Higher scores indicate positive outcome. The Safety set included randomized participants who received at least 1 dose of study drug. Only data from the participants analyzed at Day 1 and Month 1 were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Day 1 and Month 1
    End point values
    		 Placebo Palovarotene 2.5 mg Palovarotene 5.0 mg
    Number of subjects analysed
    21
    15
    11
    Units: participants
        Day 1: Dislike very much
    0
    1
    0
        Day 1: Dislike a little
    1
    1
    0
        Day 1: Not sure
    6
    3
    3
        Day 1: Like a little
    3
    5
    3
        Day 1: Like very much
    11
    5
    5
        Month 1: Dislike very much
    1
    0
    0
        Month 1: Dislike a little
    1
    1
    1
        Month 1: Not sure
    5
    1
    3
        Month 1: Like a little
    8
    5
    1
        Month 1: Like very much
    6
    8
    6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent adverse events were collected from the start of the first study drug (Day 1) up to 7 days after last study drug intake, assessed until data cut-off for study termination (maximum of 595 days).
    Adverse event reporting additional description
    The Safety set included randomized participants who received at least one dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants were to receive placebo matching with palovarotene capsules orally once daily, for up to 24 months.

    Reporting group title
    Palovarotene 5.0 mg
    Reporting group description
    		 Participants were to receive weight-adjusted dose equivalent of palovarotene 5.0 mg capsules orally once daily, for up to 24 months.

    Reporting group title
    Palovarotene 2.5 mg
    Reporting group description
    		 Participants were to receive weight-adjusted dose equivalent of palovarotene 2.5 mg capsules orally once daily, for up to 24 months.

    Serious adverse events
    		 Placebo Palovarotene 5.0 mg Palovarotene 2.5 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 62 (0.00%)
    2 / 65 (3.08%)
    2 / 66 (3.03%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Radius Fracture
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 65 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ulna Fracture
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 65 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Status Epilepticus
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 65 (1.54%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Blood Loss Anaemia
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 65 (1.54%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 65 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Palovarotene 5.0 mg Palovarotene 2.5 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    41 / 62 (66.13%)
    56 / 65 (86.15%)
    56 / 66 (84.85%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 62 (9.68%)
    3 / 65 (4.62%)
    4 / 66 (6.06%)
         occurrences all number
    8
    4
    4
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 62 (0.00%)
    9 / 65 (13.85%)
    3 / 66 (4.55%)
         occurrences all number
    0
    9
    3
    Gastrointestinal disorders
    Lip Dry
         subjects affected / exposed
    3 / 62 (4.84%)
    11 / 65 (16.92%)
    6 / 66 (9.09%)
         occurrences all number
    3
    11
    6
    Vomiting
         subjects affected / exposed
    2 / 62 (3.23%)
    7 / 65 (10.77%)
    3 / 66 (4.55%)
         occurrences all number
    2
    9
    4
    Dry Mouth
         subjects affected / exposed
    3 / 62 (4.84%)
    4 / 65 (6.15%)
    4 / 66 (6.06%)
         occurrences all number
    3
    4
    4
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    7 / 62 (11.29%)
    25 / 65 (38.46%)
    17 / 66 (25.76%)
         occurrences all number
    12
    50
    31
    Dry Skin
         subjects affected / exposed
    7 / 62 (11.29%)
    19 / 65 (29.23%)
    16 / 66 (24.24%)
         occurrences all number
    9
    23
    19
    Pruritus
         subjects affected / exposed
    6 / 62 (9.68%)
    7 / 65 (10.77%)
    8 / 66 (12.12%)
         occurrences all number
    7
    9
    9
    Rash Generalised
         subjects affected / exposed
    2 / 62 (3.23%)
    5 / 65 (7.69%)
    3 / 66 (4.55%)
         occurrences all number
    4
    5
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    7 / 62 (11.29%)
    1 / 65 (1.54%)
    3 / 66 (4.55%)
         occurrences all number
    10
    1
    3
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    3 / 62 (4.84%)
    5 / 65 (7.69%)
    3 / 66 (4.55%)
         occurrences all number
    3
    6
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Jul 2018
    Increased screening period from 28 to 35 days to accommodate time required for genetic testing. Added a safety follow-up visit 6 months after end of treatment (EOT) for participants who did not participate in the open-label extension study, as requested by regulatory authorities. Added that additional safety follow-up could be required to ensure that ongoing adverse events were resolved or stabilized. Modified inclusion criteria to require ≥5 clinically evident OCs with one new/enlarging OC in preceding 12 months and one painful OC and to specify disease-causing EXT1 or EXT2 gene mutations. Added the following endpoints as requested by regulatory authorities: proportion of participants with no new OCs as assessed by whole-body MRI at Months 12 and 24; palatability of sprinkled drug product; and OC cartilage cap volume. Added skeletal deformity and long bone length assessments and safety assessment for osteonecrosis, as requested by regulatory authorities. Amended MRI sedation to allow general anesthesia to ensure participant safety and successful image acquisition. Adjusted the timing of safety laboratory tests, dual X-ray absorptiometry (DXA), and hearing and visual acuity testing to decrease participant burden.
    23 Apr 2019
    Stipulated that only clinically significant abnormal clinical laboratory results at the EOT, including hematology parameters, would require retesting at the safety follow-up visit, rather than all abnormal clinical laboratory findings. Changed the definition of female of childbearing potential from Tanner 2+ to age >13 years or postmenarchal, whichever occurred earlier. Added 25-hydroxyl vitamin D assessments at the discretion of the Investigator to evaluate changes in bone mineral density. Amended the requirement for a confirmatory DXA scan to only those that would result in a dose modification (that is, >5% loss in spine areal bone mineral density and -1 change from baseline in height adjusted z-score in lumbar spine bone mineral density). Removed some of the age restrictions on participant enrollment for sites in the EU. Defined effective and highly effective forms of birth control. Added that the Investigator should review the participant’s condition to determine whether a missed clinical laboratory test or non-evaluable test should be repeated for that time point. Stipulated that participants enrolled in Japan would have on-site clinic visits every 3 months.

    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.
    The Sponsor terminated the study early due to a partial clinical hold instituted by the Food and Drug Administration. Recruitment was stopped before full enrollment was reached, and study drug administration was discontinued.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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