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    Clinical Trial Results:
    A Phase 3, Efficacy and Safety Study of Oral Palovarotene for the Treatment of Fibrodysplasia Ossificans Progressiva (FOP)

    Summary
    EudraCT number
    		 2017-002541-29
    Trial protocol
    		 GB   SE   ES   DE   FR   NL   IT   Outside EU/EEA  
    Global end of trial date
    07 Sep 2022

    Results information
    Results version number
    		 v3
    This version publication date
    23 Sep 2023
    First version publication date
    20 Mar 2023
    Other versions
    		 v1 , v2 , v4
    Version creation reason
    • New data added to full data set
    Record update to include new data

    Trial information

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    Trial identification
    Sponsor protocol code
    PVO-1A-301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03312634
    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-PIP01-14
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    07 Sep 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Sep 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of palovarotene in decreasing heterotopic ossification (HO) in adult and pediatric participants with fibrodysplasia ossificans progressiva (FOP) as assessed by low-dose, whole body computed tomography (WBCT), excluding head, as compared to untreated participants from Clementia’s FOP natural history study (Study PVO-1A-001). To evaluate the safety of palovarotene in adult and pediatric participants with FOP.
    Protection of trial subjects
    The 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 Harmonisation Good Clinical Practice (E6), EU Directive 2001/20/EC, United States Food and Drug Administration Code of Federal Regulations, and other applicable local regulatory requirements, which ever affords the greater participant protection.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Nov 2017
    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
    Argentina: 24
    Country: Number of subjects enrolled
    Australia: 13
    Country: Number of subjects enrolled
    Brazil: 5
    Country: Number of subjects enrolled
    Canada: 5
    Country: Number of subjects enrolled
    France: 25
    Country: Number of subjects enrolled
    Italy: 20
    Country: Number of subjects enrolled
    Japan: 4
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    Sweden: 8
    Country: Number of subjects enrolled
    United Kingdom: 27
    Country: Number of subjects enrolled
    United States: 84
    Worldwide total number of subjects
    221
    EEA total number of subjects
    59
    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)
    81
    Adolescents (12-17 years)
    65
    Adults (18-64 years)
    75
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This Phase 3, open-label study was conducted in adult and pediatric participants with FOP at 16 centers in 11 countries (Argentina, Australia, Brazil, Canada, France, Italy, Japan, Spain, Sweden, the United Kingdom, and the US). Two other sites in Germany and Netherland were envisaged as participating countries but did not recruit any participants.

    Pre-assignment
    Screening details
    		 This study included 3 parts: Part A, the main part of the study, Part B, the 24-month extension and Part C, up to 2 year post last dose of study treatment follow-up. A total of 107 participants were enrolled and treated in this study. Data from participants in PVO-1A-001 were used as an external control for only primary endpoint of this study.

    Period 1
    Period 1 title
    Overall (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Palovarotene
    Arm description
    		 Participants were administered 5 milligram (mg) palovarotene orally once daily up to 48 months. Participants with flare-up symptoms or traumatic events received palovarotene 20 mg once daily for 4 weeks after the flare-up confirmation by the Investigator. Followed by palovarotene 10 mg once daily for 8 weeks.
    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 mg once daily up to 48 months. Palovarotene 20 mg once daily for 4 weeks then followed by 10 mg once daily for 8 weeks for participants with flare-up or traumatic symptoms. Flare-up dose was weight-adjusted for skeletally immature participants.

    Arm title
    		 Untreated (PVO-1A-001)
    Arm description
    		 Participants from study PVO-1A-001 (NCT02322255) were included with FOP caused by the R206H mutation and with baseline data. Participants were not administered palovarotene in this study and only compared as external control.
    Arm type
    		 External control

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Palovarotene Untreated (PVO-1A-001)
    Started
    107
    114
    Completed
    49
    33
    Not completed
    58
    81
         Physician decision
    1
    -
         Enrolled in study at time of a flare-up
    -
    9
         Enrolled into noninterventional study
    -
    5
         Consent withdrawn by subject
    31
    9
         Adverse event, non-fatal
    11
    -
         Death
    -
    1
         Sponsor request
    2
    -
         Worsening clinical condition
    -
    1
         Non-compliance
    -
    2
         Participant did not want to travel
    -
    1
         Unspecified
    13
    -
         Enrolled in an interventional study
    -
    52
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Palovarotene
    Reporting group description
    		 Participants were administered 5 milligram (mg) palovarotene orally once daily up to 48 months. Participants with flare-up symptoms or traumatic events received palovarotene 20 mg once daily for 4 weeks after the flare-up confirmation by the Investigator. Followed by palovarotene 10 mg once daily for 8 weeks.

    Reporting group title
    Untreated (PVO-1A-001)
    Reporting group description
    		 Participants from study PVO-1A-001 (NCT02322255) were included with FOP caused by the R206H mutation and with baseline data. Participants were not administered palovarotene in this study and only compared as external control.

    Reporting group values
    		 Palovarotene Untreated (PVO-1A-001) Total
    Number of subjects
    		 107 114 221
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 45 36 81
        Adolescents (12-17 years)
    		 35 30 65
        Adults (18-64 years)
    		 27 48 75
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 49 52 101
        Male
    		 58 62 120
    Race
    Units: Subjects
        White
    		 78 84 162
        Black or African American
    		 1 0 1
        Asian
    		 9 8 17
        American Indian or Alaska Native
    		 0 1 1
        Native Hawaiian or other Pacific Islander
    		 1 0 1
        Multiple
    		 6 2 8
        Other
    		 1 4 5
        Unknown
    		 11 15 26
    Ethnicity
    Units: Subjects
        Hispanic Or Latino
    		 19 23 42
        Not Hispanic Or Latino
    		 77 73 150
        Not Reported
    		 11 18 29

    End points

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    End points reporting groups
    Reporting group title
    Palovarotene
    Reporting group description
    		 Participants were administered 5 milligram (mg) palovarotene orally once daily up to 48 months. Participants with flare-up symptoms or traumatic events received palovarotene 20 mg once daily for 4 weeks after the flare-up confirmation by the Investigator. Followed by palovarotene 10 mg once daily for 8 weeks.

    Reporting group title
    Untreated (PVO-1A-001)
    Reporting group description
    		 Participants from study PVO-1A-001 (NCT02322255) were included with FOP caused by the R206H mutation and with baseline data. Participants were not administered palovarotene in this study and only compared as external control.

    Subject analysis set title
    Palovarotene
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants were administered 5 mg palovarotene orally once daily up to 48 months. Participants with flare-up symptoms or traumatic events received palovarotene 20 mg once daily for 4 weeks after the flare-up confirmation by the Investigator. Followed by palovarotene 10 mg once daily for 8 weeks.

    Subject analysis set title
    Untreated (PVO-1A-001)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants from study PVO-1A-001 (NCT02322255) were included with FOP caused by the R206H mutation and with baseline data. Participants were not administered palovarotene and compared as external control.

    Primary: Annualized New Heterotopic Ossification (HO)

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    End point title
    		 Annualized New Heterotopic Ossification (HO) [1]
    End point description
    The annualized new HO was assessed by low-dose, whole body computed tomography (WBCT), excluding head. The weighted linear mixed effect method without square-root transformation and negatives included was used for annualized new HO analysis. The Principal Full Analysis Set (FAS) included all enrolled participants in the Principal EP who had a baseline HO volume measurement and at least 1 post-baseline HO volume measurement in PVO-1A-301.For study PVO-1A-001, the Principal FAS included participants enrolled with available baseline and at least 1 post-baseline HO volume measurement. Study PVO-1A-001 was used as an external control. Results are presented for overall intent to treat (ITT) period.
    End point type
    Primary
    End point timeframe
    From Baseline (within one month of screening/Day 1) up to end of 4-year follow-up period (approximately 57 months)
    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: No additional statistical analysis was prespecified for this endpoint.
    End point values
    		 Palovarotene Untreated (PVO-1A-001)
    Number of subjects analysed
    97
    101
    Units: cubic millimeters (mm^3)
        arithmetic mean (standard error)
    13316.2 ± 3358.3
    23656.4 ± 4837.7
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Any New HO

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    End point title
    		 Percentage of Participants With Any New HO
    End point description
    The new HO was assessed by WBCT scan. The percentage of participants with any new HO (volume > 0 mm^3) were analyzed using the Bayesian distribution. The Principal FAS included all enrolled participants in the Principal EP who had a baseline HO volume measurement and at least 1 post-baseline HO volume measurement in study PVO-1A-301. Results are presented for overall ITT period.
    End point type
    Secondary
    End point timeframe
    From Baseline (Day 1) up to end of 4-year follow-up period (approximately 57 months)
    End point values
    		 Palovarotene
    Number of subjects analysed
    97
    Units: percentage of participants
        number (not applicable)
    83.5
    No statistical analyses for this end point

    Secondary: Number of Body Regions With New HO

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    End point title
    		 Number of Body Regions With New HO
    End point description
    All participants were analyzed for number of body regions with any new HO (new HO > 0 mm^3). The presence of HO across various body regions was analyzed using WBCT scan. The Principal FAS included all enrolled participants in the Principal EP who had a baseline HO volume measurement and at least 1 post-baseline HO volume measurement in the study PVO-1A-301. Results are presented for overall ITT period. Only data from the participants analyzed were reported.
    End point type
    Secondary
    End point timeframe
    From Baseline (Day 1) up to end of 4-year follow-up period (approximately 57 months)
    End point values
    		 Palovarotene
    Number of subjects analysed
    81
    Units: body regions
        arithmetic mean (standard deviation)
    3.0 ± 1.68
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Flare-Ups

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    End point title
    		 Percentage of Participants With Flare-Ups
    End point description
    Flare-up as an event with one or more flare-up symptoms, and regardless of flare-up symptom onset. Flare-up was evaluated remotely, or by telephone or video-conferencing, unless the Investigator deemed that a site visit was necessary. The Principal SS included all enrolled participants in the Principal EP set (ie, participants with the R206H ACVR1 mutation) receiving at least 1 dose of palovarotene in study PVO-1A-301. Only data from the participants analyzed at Month 12 reported.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    		 Palovarotene
    Number of subjects analysed
    99
    Units: percentage of participants
        number (not applicable)
    64.6
    No statistical analyses for this end point

    Secondary: Ratio of Flare-Up Per Participant-Month of Exposure

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    End point title
    		 Ratio of Flare-Up Per Participant-Month of Exposure
    End point description
    Flare-up as an event with one or more flare-up symptoms, and regardless of flare-up symptom onset. Flare-up was evaluated remotely, or by telephone or video-conferencing, unless the Investigator deemed that a site visit was necessary. The flare-up rate per participant-month exposure was analyzed using a negative binomial regression. The Safety analysis set included all enrolled participants who received at least 1 dose of palovarotene in study PVO-1A-301. Results are presented for overall ITT period.
    End point type
    Secondary
    End point timeframe
    From Baseline (Day 1) up to end of 4-year follow-up period (approximately 57 months)
    End point values
    		 Palovarotene
    Number of subjects analysed
    107
    Units: ratio of flare-up
        arithmetic mean (standard deviation)
    0.2 ± 0.40
    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 are collected from first date of palovarotene intake up to 4-year follow-up (approximately 57 months) for study PVO-1A-301. Adverse events (AEs) were collected from study day 1 up to approximately 37 months (PVO-1A-001).
    Adverse event reporting additional description
    The Safety analysis set included all enrolled participants who received at least 1 dose of palovarotene in study PVO-1A-301. The FAS included all participants in the Enrolled Analysis Set with FOP caused by the R206H mutation and who had baseline data in study PVO-1A-001. MedDRA version 21.0 for PVO-1A-001 study.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Palovarotene 5 mg
    Reporting group description
    		 Participants were administered 5 mg palovarotene orally once daily up to 48 months.

    Reporting group title
    Palovarotene 20/10 mg
    Reporting group description
    		 Participants with flare-up symptoms or traumatic events received palovarotene 20 mg once daily for 4 weeks after the flare-up confirmation by the Investigator. Followed by palovarotene 10 mg once daily for 8 weeks.

    Reporting group title
    Untreated (PVO-1A-001)
    Reporting group description
    		 Participants from study PVO-1A-001 (NCT02322255) were included with FOP caused by the R206H mutation and with baseline data. Participants were not administered palovarotene in this study and only compared as external control. While no pharmacological intervention was applied in this observational study, safety issues resulting only from any study-related procedure were recorded as AEs.

    Serious adverse events
    		 Palovarotene 5 mg Palovarotene 20/10 mg Untreated (PVO-1A-001)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    34 / 107 (31.78%)
    19 / 81 (23.46%)
    0 / 114 (0.00%)
         number of deaths (all causes)
    0
    0
    1
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Uterine leiomyoma
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 81 (0.00%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Radius fracture
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 81 (0.00%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Traumatic fracture
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 81 (1.23%)
    0 / 114 (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
    Exposure to communicable disease
         subjects affected / exposed
    3 / 107 (2.80%)
    0 / 81 (0.00%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural haematoma
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 81 (0.00%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Lymphoedema
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 81 (0.00%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 81 (0.00%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 81 (1.23%)
    0 / 114 (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
    General disorders and administration site conditions
    Condition aggravated
         subjects affected / exposed
    2 / 107 (1.87%)
    3 / 81 (3.70%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 81 (0.00%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 81 (0.00%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 81 (0.00%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 81 (1.23%)
    0 / 114 (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
    Epiphyseal disorder
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 81 (0.00%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epiphyses premature fusion
         subjects affected / exposed
    11 / 107 (10.28%)
    10 / 81 (12.35%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    11 / 11
    10 / 10
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mobility decreased
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 81 (1.23%)
    0 / 114 (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
    Aneurysmal bone cyst
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 81 (0.00%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 81 (0.00%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 81 (0.00%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 81 (0.00%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 81 (1.23%)
    0 / 114 (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
    Escherichia sepsis
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 81 (1.23%)
    0 / 114 (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
    Klebsiella bacteraemia
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 81 (0.00%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mycoplasma infection
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 81 (1.23%)
    0 / 114 (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
    Pneumonia
         subjects affected / exposed
    1 / 107 (0.93%)
    1 / 81 (1.23%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 81 (1.23%)
    0 / 114 (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
    Corona virus infection
         subjects affected / exposed
    10 / 107 (9.35%)
    2 / 81 (2.47%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Malnutrition
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 81 (1.23%)
    0 / 114 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Palovarotene 5 mg Palovarotene 20/10 mg Untreated (PVO-1A-001)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    105 / 107 (98.13%)
    77 / 81 (95.06%)
    0 / 114 (0.00%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 107 (0.93%)
    5 / 81 (6.17%)
    0 / 114 (0.00%)
         occurrences all number
    1
    5
    0
    Bone density decreased
         subjects affected / exposed
    8 / 107 (7.48%)
    5 / 81 (6.17%)
    0 / 114 (0.00%)
         occurrences all number
    8
    5
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    9 / 107 (8.41%)
    6 / 81 (7.41%)
    0 / 114 (0.00%)
         occurrences all number
    12
    6
    0
    Fall
         subjects affected / exposed
    10 / 107 (9.35%)
    7 / 81 (8.64%)
    0 / 114 (0.00%)
         occurrences all number
    12
    12
    0
    Skin abrasion
         subjects affected / exposed
    8 / 107 (7.48%)
    9 / 81 (11.11%)
    0 / 114 (0.00%)
         occurrences all number
    11
    13
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    10 / 107 (9.35%)
    7 / 81 (8.64%)
    0 / 114 (0.00%)
         occurrences all number
    13
    7
    0
    General disorders and administration site conditions
    Peripheral swelling
         subjects affected / exposed
    3 / 107 (2.80%)
    6 / 81 (7.41%)
    0 / 114 (0.00%)
         occurrences all number
    3
    7
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    6 / 107 (5.61%)
    1 / 81 (1.23%)
    0 / 114 (0.00%)
         occurrences all number
    7
    1
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    7 / 107 (6.54%)
    0 / 81 (0.00%)
    0 / 114 (0.00%)
         occurrences all number
    8
    0
    0
    Eye disorders
    Dry eye
         subjects affected / exposed
    8 / 107 (7.48%)
    11 / 81 (13.58%)
    0 / 114 (0.00%)
         occurrences all number
    8
    14
    0
    Gastrointestinal disorders
    Chapped lips
         subjects affected / exposed
    6 / 107 (5.61%)
    10 / 81 (12.35%)
    0 / 114 (0.00%)
         occurrences all number
    7
    11
    0
    Cheilitis
         subjects affected / exposed
    3 / 107 (2.80%)
    8 / 81 (9.88%)
    0 / 114 (0.00%)
         occurrences all number
    3
    13
    0
    Diarrhoea
         subjects affected / exposed
    6 / 107 (5.61%)
    2 / 81 (2.47%)
    0 / 114 (0.00%)
         occurrences all number
    6
    2
    0
    Lip dry
         subjects affected / exposed
    37 / 107 (34.58%)
    17 / 81 (20.99%)
    0 / 114 (0.00%)
         occurrences all number
    38
    17
    0
    Nausea
         subjects affected / exposed
    9 / 107 (8.41%)
    3 / 81 (3.70%)
    0 / 114 (0.00%)
         occurrences all number
    9
    3
    0
    Vomiting
         subjects affected / exposed
    11 / 107 (10.28%)
    5 / 81 (6.17%)
    0 / 114 (0.00%)
         occurrences all number
    14
    5
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    7 / 107 (6.54%)
    5 / 81 (6.17%)
    0 / 114 (0.00%)
         occurrences all number
    7
    5
    0
    Epistaxis
         subjects affected / exposed
    6 / 107 (5.61%)
    3 / 81 (3.70%)
    0 / 114 (0.00%)
         occurrences all number
    14
    3
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    19 / 107 (17.76%)
    21 / 81 (25.93%)
    0 / 114 (0.00%)
         occurrences all number
    23
    28
    0
    Dermatitis
         subjects affected / exposed
    3 / 107 (2.80%)
    7 / 81 (8.64%)
    0 / 114 (0.00%)
         occurrences all number
    3
    8
    0
    Drug eruption
         subjects affected / exposed
    15 / 107 (14.02%)
    26 / 81 (32.10%)
    0 / 114 (0.00%)
         occurrences all number
    24
    40
    0
    Dry skin
         subjects affected / exposed
    60 / 107 (56.07%)
    37 / 81 (45.68%)
    0 / 114 (0.00%)
         occurrences all number
    95
    77
    0
    Erythema
         subjects affected / exposed
    11 / 107 (10.28%)
    16 / 81 (19.75%)
    0 / 114 (0.00%)
         occurrences all number
    15
    21
    0
    Pruritus
         subjects affected / exposed
    19 / 107 (17.76%)
    14 / 81 (17.28%)
    0 / 114 (0.00%)
         occurrences all number
    29
    16
    0
    Pruritus generalised
         subjects affected / exposed
    16 / 107 (14.95%)
    11 / 81 (13.58%)
    0 / 114 (0.00%)
         occurrences all number
    21
    19
    0
    Rash
         subjects affected / exposed
    25 / 107 (23.36%)
    11 / 81 (13.58%)
    0 / 114 (0.00%)
         occurrences all number
    40
    22
    0
    Rash generalised
         subjects affected / exposed
    6 / 107 (5.61%)
    4 / 81 (4.94%)
    0 / 114 (0.00%)
         occurrences all number
    9
    5
    0
    Skin exfoliation
         subjects affected / exposed
    11 / 107 (10.28%)
    11 / 81 (13.58%)
    0 / 114 (0.00%)
         occurrences all number
    14
    23
    0
    Skin irritation
         subjects affected / exposed
    6 / 107 (5.61%)
    5 / 81 (6.17%)
    0 / 114 (0.00%)
         occurrences all number
    9
    6
    0
    Ingrowing nail
         subjects affected / exposed
    6 / 107 (5.61%)
    4 / 81 (4.94%)
    0 / 114 (0.00%)
         occurrences all number
    8
    5
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    32 / 107 (29.91%)
    15 / 81 (18.52%)
    0 / 114 (0.00%)
         occurrences all number
    49
    24
    0
    Back pain
         subjects affected / exposed
    8 / 107 (7.48%)
    3 / 81 (3.70%)
    0 / 114 (0.00%)
         occurrences all number
    13
    4
    0
    Musculoskeletal pain
         subjects affected / exposed
    7 / 107 (6.54%)
    5 / 81 (6.17%)
    0 / 114 (0.00%)
         occurrences all number
    9
    5
    0
    Neck pain
         subjects affected / exposed
    6 / 107 (5.61%)
    6 / 81 (7.41%)
    0 / 114 (0.00%)
         occurrences all number
    6
    9
    0
    Pain in extremity
         subjects affected / exposed
    21 / 107 (19.63%)
    9 / 81 (11.11%)
    0 / 114 (0.00%)
         occurrences all number
    33
    13
    0
    Pain in jaw
         subjects affected / exposed
    6 / 107 (5.61%)
    2 / 81 (2.47%)
    0 / 114 (0.00%)
         occurrences all number
    7
    2
    0
    Joint range of motion decreased
         subjects affected / exposed
    6 / 107 (5.61%)
    3 / 81 (3.70%)
    0 / 114 (0.00%)
         occurrences all number
    9
    3
    0
    Myalgia
         subjects affected / exposed
    6 / 107 (5.61%)
    2 / 81 (2.47%)
    0 / 114 (0.00%)
         occurrences all number
    6
    2
    0
    Infections and infestations
    Ear infection
         subjects affected / exposed
    5 / 107 (4.67%)
    6 / 81 (7.41%)
    0 / 114 (0.00%)
         occurrences all number
    5
    7
    0
    Gastroenteritis
         subjects affected / exposed
    6 / 107 (5.61%)
    2 / 81 (2.47%)
    0 / 114 (0.00%)
         occurrences all number
    8
    2
    0
    Nasopharyngitis
         subjects affected / exposed
    14 / 107 (13.08%)
    9 / 81 (11.11%)
    0 / 114 (0.00%)
         occurrences all number
    26
    12
    0
    Paronychia
         subjects affected / exposed
    9 / 107 (8.41%)
    10 / 81 (12.35%)
    0 / 114 (0.00%)
         occurrences all number
    13
    15
    0
    Upper respiratory tract infection
         subjects affected / exposed
    23 / 107 (21.50%)
    6 / 81 (7.41%)
    0 / 114 (0.00%)
         occurrences all number
    30
    7
    0
    Urinary tract infection
         subjects affected / exposed
    6 / 107 (5.61%)
    1 / 81 (1.23%)
    0 / 114 (0.00%)
         occurrences all number
    6
    2
    0
    Influenza
         subjects affected / exposed
    7 / 107 (6.54%)
    4 / 81 (4.94%)
    0 / 114 (0.00%)
         occurrences all number
    7
    4
    0
    Otitis media
         subjects affected / exposed
    6 / 107 (5.61%)
    3 / 81 (3.70%)
    0 / 114 (0.00%)
         occurrences all number
    7
    3
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Mar 2018
    Participants with other FOP variants associated with progressive HO were provided optimal treatment. Enrollment criteria for participants from Study PVO-1A-202 and PVO-1A-204 were specified. Inclusion criterion 6 was modified. Eligibility criterion for enrollment was specified. Primary efficacy analysis for participants with R206H mutation who were not treated with palovarotene were restricted. Primary efficacy endpoint and safety analyses summarization were specified. Baseline assessment of WBCT scan for participants who were enrolled from Phase 2 were specified. Additional clarifications were specified in-order to reduce participant burden. Schedule for linear growth measurements were specified. Blood pressure cuff measurement procedures were added. Pregnancy prevention measures and re-assessments were added to avoid risk of pregnancy. Criterion for serious adverse events follow-up was updated. Participants bone age assessment schedule specified. Additional high-level descriptions included for participant safety monitoring. Hearing tests added at Baseline and months 12 and 24. Daily assessment regarding onset of flare-up symptoms were included participant diary. Safety monitoring procedures clarified on termination of study. Sample determination for primary and secondary endpoints were updated.
    19 Feb 2019
    Schedule for clinical laboratory assessments during chronic treatment were changed. Schedule for clinical laboratory assessment, Columbia-Suicide Severity Rating scale, vital signs and body weight determination during flare-up cycle were changed. Specification for flare-up dosing added. Visit window for flare-up safety visit and final flare-up safety visit changed. Criteria for discontinuation of palovarotene added. Planned enrollment number was increased. Timings of the second and third interim analyses were changed. The frequency of pregnancy testing was emphasized.
    29 Oct 2019
    Extension period for Part B was added. Radiographic assessment of the knee and hand-wrist added in Part A and B. All scheduled assessments during chronic dosing to continue in Part B. Safety assessments schedule updated for Part A and B. Secondary objective for Part B was added. Statistical analyses modified for Part B. Dose modification details revised for partial or complete premature growth plate closure. Updated palovarotene, pharmacokinetics, efficacy, and safety findings from the FOP interventional trials.
    04 Feb 2020
    Additional columns for monthly remote pregnancy testing in Part B were updated. Specified that study continued despite crossing the futility boundary.
    30 Oct 2020
    Part C was added to ensure continued collection of safety data off treatment for participants <14 years of age and any participants who were skeletally immature at the time of their end-of-study visit. Assessments for spinal health carried out on low-dose WBCT scans collected in the study were added. Additional clarification updated for safety measures. Part C added for skeletally immature participants who had stopped taking medications for any reasons before completion of Part A/B. Assessment and duration for Part C were added. Secondary objective added and safety data were summarized for Part C. Editorial changes updated for clarification and consistent presentation. Vendor contact information revised.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    04 Dec 2019
    As of 04 December 2019, all participants <14 years of age were required to interrupt study drug due to a partial clinical hold placed on the palovarotene clinical development program by the FDA. On 24-Jan-2020, treatment was temporarily halted in all participants equal to and over the age of 14 years in the palovarotene FOP trials when the futility boundary was crossed at an interim analysis in the Phase 3 PVO-1A-301 study. After post-hoc analyses showed that the pre-specified analyses may have skewed and negatively affected the results, dosing was re-initiated only in participants 14 years and above that were able and willing to re-start treatment (in the context of COVID-19 conditions, starting 30 April 2020).
    30 Apr 2020

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    A valid comparison of AEs from observational study (PVO-1A-001) was not made since AEs were only captured as related to study procedures.
    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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