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    Clinical Trial Results:
    A Phase 2 Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of a RARγ-Specific Agonist (Palovarotene) in the Treatment of Preosseous Flare-ups in Subjects with Fibrodysplasia Ossificans Progressiva (FOP).

    Summary
    EudraCT number
    		 2014-001453-17
    Trial protocol
    		 GB  
    Global end of trial date
    23 May 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Jun 2018
    First version publication date
    01 Jun 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PVO-1A-201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02190747
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Clementia Pharmaceuticals Inc.
    Sponsor organisation address
    4150 Sainte-Catherine Street West, Suite 550, Montreal, Canada, H3Z 2Y5
    Public contact
    Clinical Trials Information, Clementia Pharmaceuticals Inc., clinicaltrials@clementiapharma.com
    Scientific contact
    Clinical Trials Information, Clementia Pharmaceuticals Inc., clinicaltrials@clementiapharma.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
    14 Nov 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 May 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    23 May 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective was to evaluate the ability of different doses of palovarotene to prevent heterotopic ossification (HO) at the flare-up site in subjects with FOP as assessed by plain radiographs. Images were evaluated for HO and soft tissue edema by a central imaging laboratory using two independent treatment-blinded procedures: Primary Reads and Global Reads. For Primary Reads, two musculoskeletal radiologists independently evaluated the volume of HO and soft tissue edema from each relevant imaging modality with no comparisons across modalities. Global Reads were performed by one of these radiologists, an independent musculoskeletal consultant radiologist, an independent consultant ultrasound radiologist, and the Investigators. From Global Reads, HO was evaluated only after the review of all images across all modalities and time points. Primary Reads were used to assess primary outcomes, per protocol. Global Reads were more holistic, and used to elucidate efficacy results.
    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 ICH Good Clinical Practice (ICH GCP), EU Directive 2001/20/EC, US Food and Drug Administration (FDA) Code of Federal Regulations and other applicable local regulatory requirements, which ever afforded the greater subject protection. The study protocol and informed consent (ICF)/assent documents to be used in the clinical study were approved by an IRB/IEC prior to initiation of the study. The ICF was written in a language and in a form understandable to the subjects/parents.
    Background therapy
    		 -
    Evidence for comparator
    		 Not Applicable
    Actual start date of recruitment
    14 Jul 2014
    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
    United States: 29
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    France: 9
    Worldwide total number of subjects
    40
    EEA total number of subjects
    11
    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)
    9
    Adolescents (12-17 years)
    9
    Adults (18-64 years)
    22
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Eight subjects aged ≥15 years were randomized 3:1 to palovarotene:placebo in Cohort 1; 8 additional subjects were randomised 3:1 in an interim period between Cohorts 1 and 2 (included in the description of Cohort 1). In Cohort 2, additional FOP subjects aged ≥6 years were randomized 3:3:2 across two weight-based regimens of palovarotene or placebo.

    Pre-assignment
    Screening details
    		 The study included clinically diagnosed FOP subjects at least 6 years of age (Cohort 2) or 15 years of age and older (Cohort 1) with symptomatic onset of a flare-up within 7 days of treatment start and accessible for treatment and follow-up.

    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
    		 Investigator, Monitor, Data analyst, Carer, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Palovarotene 10/5 mg
    Arm description
    		 Subjects received palovarotene 10 mg for 14 days followed by 5 mg for 28 days during flare-ups (10/5-mg regimen). The subjects were followed for an additional 42 days without treatment. Subjects in Cohort 1 and Cohort 2 contributed to this arm.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Palovarotene
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 10 mg once daily for 14 days followed by 5 mg once daily for 28 days (or weight-adjusted equivalent for skeletally immature subjects) during flare-ups, totaling 42 days of treatment. Palovarotene was to be taken orally with food at approximately the same time each day.

    Arm title
    		 Palovarotene 5/2.5 mg
    Arm description
    		 Subjects received palovarotene 5 mg for 14 days followed by 2.5 mg for 28 days during flare-ups (5/2.5-mg regimen). The subjects were followed for an additional 42 days without treatment. Only subjects in Cohort 2 contributed to this arm.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Palovarotene
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a palovarotene 5 mg daily for 14 days followed by 2.5 mg daily for 28 days (or weight-adjusted equivalent for skeletally immature subjects) during flare-ups, totaling 42 days of treatment. Palovarotene was to be taken orally with food at approximately the same time each day.

    Arm title
    		 Placebo
    Arm description
    		 Subjects received placebo for 42 days during flare-ups. Subjects were followed for an additional 42 days without treatment. Subjects in Cohort 1 and Cohort 2 contributed to this arm.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was taken orally with food at approximately the same time once daily for 42 days during flare-ups.

    Number of subjects in period 1
    		Palovarotene 10/5 mg Palovarotene 5/2.5 mg Placebo
    Started
    21
    9
    10
    Completed
    21
    9
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Palovarotene 10/5 mg
    Reporting group description
    		 Subjects received palovarotene 10 mg for 14 days followed by 5 mg for 28 days during flare-ups (10/5-mg regimen). The subjects were followed for an additional 42 days without treatment. Subjects in Cohort 1 and Cohort 2 contributed to this arm.

    Reporting group title
    Palovarotene 5/2.5 mg
    Reporting group description
    		 Subjects received palovarotene 5 mg for 14 days followed by 2.5 mg for 28 days during flare-ups (5/2.5-mg regimen). The subjects were followed for an additional 42 days without treatment. Only subjects in Cohort 2 contributed to this arm.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo for 42 days during flare-ups. Subjects were followed for an additional 42 days without treatment. Subjects in Cohort 1 and Cohort 2 contributed to this arm.

    Reporting group values
    		 Palovarotene 10/5 mg Palovarotene 5/2.5 mg Placebo Total
    Number of subjects
    		 21 9 10 40
    Age categorical
    Units: Subjects
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 3 4 2 9
        Adolescents (12-17 years)
    		 5 0 4 9
        Adults (18-64 years)
    		 13 5 4 22
        From 65-84 years
    		 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 9 6 7 22
        Male
    		 12 3 3 18
    Subject analysis sets

    Subject analysis set title
    Full analysis
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Full Analysis Set (FAS) included all subjects who received at least one dose of study drug AND had at least one post-baseline radiograph sufficient for the determination of HO at the flare-up site.

    Subject analysis set title
    Per protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per Protocol (PP) analysis set included all subjects who were eligible for the FAS, with no major protocol deviations, with at least 80% compliance with study medication, and had an evaluable radiograph or CT at Day 42 sufficient for the determination of HO at the flare-up site. Exclusions from the PP analysis set were identified prior to database lock, comprising one subject in the 10/5 mg palovarotene group who received less than 80% of the required dose.

    Subject analysis sets values
    		 Full analysis Per protocol
    Number of subjects
    40
    39
    Age categorical
    Units: Subjects
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    9
    9
        Adolescents (12-17 years)
    9
    8
        Adults (18-64 years)
    22
    22
        From 65-84 years
    0
    0
    Age continuous
    Units:
        
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    22
    22
        Male
    18
    17

    End points

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    End points reporting groups
    Reporting group title
    Palovarotene 10/5 mg
    Reporting group description
    		 Subjects received palovarotene 10 mg for 14 days followed by 5 mg for 28 days during flare-ups (10/5-mg regimen). The subjects were followed for an additional 42 days without treatment. Subjects in Cohort 1 and Cohort 2 contributed to this arm.

    Reporting group title
    Palovarotene 5/2.5 mg
    Reporting group description
    		 Subjects received palovarotene 5 mg for 14 days followed by 2.5 mg for 28 days during flare-ups (5/2.5-mg regimen). The subjects were followed for an additional 42 days without treatment. Only subjects in Cohort 2 contributed to this arm.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo for 42 days during flare-ups. Subjects were followed for an additional 42 days without treatment. Subjects in Cohort 1 and Cohort 2 contributed to this arm.

    Subject analysis set title
    Full analysis
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Full Analysis Set (FAS) included all subjects who received at least one dose of study drug AND had at least one post-baseline radiograph sufficient for the determination of HO at the flare-up site.

    Subject analysis set title
    Per protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per Protocol (PP) analysis set included all subjects who were eligible for the FAS, with no major protocol deviations, with at least 80% compliance with study medication, and had an evaluable radiograph or CT at Day 42 sufficient for the determination of HO at the flare-up site. Exclusions from the PP analysis set were identified prior to database lock, comprising one subject in the 10/5 mg palovarotene group who received less than 80% of the required dose.

    Primary: Percentage of Responders (Subjects with No/Minimal New Flare-up Heterotopic Ossification Versus Baseline)

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    End point title
    		 Percentage of Responders (Subjects with No/Minimal New Flare-up Heterotopic Ossification Versus Baseline)
    End point description
    Percentage of responders defined by no or minimal new heterotopic ossification at the flare-up site versus baseline as assessed by plain radiographs at Day 42. Analysis was performed on the FAS. Results from the Primary Read reviews are presented.
    End point type
    Primary
    End point timeframe
    Day 42
    End point values
    		 Palovarotene 10/5 mg Palovarotene 5/2.5 mg Placebo
    Number of subjects analysed
    21
    9
    10
    Units: Percentage of subjects
        number (not applicable)
    100
    88.9
    88.9
    Statistical analysis title
    		 Overall trend test
    Statistical analysis description
    Cochran-Armitage test of trend (one-sided).
    Comparison groups
    Palovarotene 10/5 mg v Palovarotene 5/2.5 mg v Placebo
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.16
    Method
    		 Cochran-Armitage test of trend-one-sided
    Confidence interval

    Secondary: Percentage of Subjects With New HO at Day 84

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    End point title
    		 Percentage of Subjects With New HO at Day 84
    End point description
    Low dose CT scan was used as a secondary imaging assessment of heterotopic ossification and was performed at the same time points as plain radiographs. The percentage of subjects with new heterotopic ossification at the flare-up site as assessed by CT scan or plain radiographs at Day 84 was analysed. The analysis was performed on the per-protocol analysis set. The results are from Global Read reviews.
    End point type
    Secondary
    End point timeframe
    Day 84
    End point values
    		 Palovarotene 10/5 mg Palovarotene 5/2.5 mg Placebo Per protocol
    Number of subjects analysed
    20
    9
    10
    39
    Units: Percentage of subjects
        number (not applicable)
    15
    44
    40
    39
    Statistical analysis title
    		 Overall trend test
    Statistical analysis description
    Cochran-Armitage test of trend (one-sided) using the per-protocol population.
    Comparison groups
    Palovarotene 10/5 mg v Palovarotene 5/2.5 mg v Placebo
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.08
    Method
    		 Cochran-Armitage test of trend-one-sided
    Confidence interval

    Secondary: Volume of New Heterotopic Ossification From CT Scan at Day 84

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    End point title
    		 Volume of New Heterotopic Ossification From CT Scan at Day 84
    End point description
    Low dose CT scan was used as a secondary imaging assessment of heterotopic ossification (HO) and was performed at the same time points as plain radiographs. Interpretation of the CT scan documented the amount (volume) of HO at Screening/Baseline and the amount (volume) of new HO at Day 84. Analysis was performed on the PP analysis set. The results of new HO volume are from Primary Read reviews.
    End point type
    Secondary
    End point timeframe
    Day 84
    End point values
    		 Palovarotene 10/5 mg Palovarotene 5/2.5 mg Placebo
    Number of subjects analysed
    4
    2
    3
    Units: mm3
        number (not applicable)
    16396
    5332
    53939
    Statistical analysis title
    		 T test
    Comparison groups
    Palovarotene 10/5 mg v Placebo
    Number of subjects included in analysis
    7
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.17
    Method
    		 t-test, 2-sided
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AEs) were recorded from the time informed consent is signed through Study Day 84.
    Adverse event reporting additional description
    Treatment-emergent AEs were those with a start date/time after the first dose of study medication. All AEs reported after the first dose and up to and including the Day 84 visit were considered treatment-emergent.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Palovarotene 10/5 mg
    Reporting group description
    		 Subjects received palovarotene 10 mg for 14 days followed by 5 mg for 28 days during flare-ups (or weight adjusted equivalent for skeletally immature subjects). The subjects were followed for an additional 42 days without treatment. Subjects in Cohort 1 and Cohort 2 contributed to this arm.

    Reporting group title
    Palovarotene 5/2.5 mg
    Reporting group description
    		 Subjects received palovarotene 5 mg for 14 days followed by 2.5 mg for 28 days (or weight adjusted equivalent for skeletally immature subjects) during flare-ups. The subjects were followed for an additional 42 days without treatment. Only subjects in Cohort 2 contributed to this arm.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo for 42 days during flare-ups. Subjects were followed for an additional 42 days without treatment. Subjects in Cohort 1 and Cohort 2 contributed to this arm.

    Serious adverse events
    		 Palovarotene 10/5 mg Palovarotene 5/2.5 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Nervous system disorders
    Myoclonus
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 9 (0.00%)
    0 / 10 (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
    General disorders and administration site conditions
    Condition aggravated
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Haemorrhagic ovarian cyst
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (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
    Respiratory, thoracic and mediastinal disorders
    Asthmatic crisis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         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
    		 Palovarotene 10/5 mg Palovarotene 5/2.5 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 21 (100.00%)
    9 / 9 (100.00%)
    10 / 10 (100.00%)
    Vascular disorders
    Pallor
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    General disorders and administration site conditions
    Condition aggravated
         subjects affected / exposed
    11 / 21 (52.38%)
    2 / 9 (22.22%)
    3 / 10 (30.00%)
         occurrences all number
    27
    2
    3
    Pyrexia
         subjects affected / exposed
    1 / 21 (4.76%)
    3 / 9 (33.33%)
    1 / 10 (10.00%)
         occurrences all number
    2
    4
    1
    Application site erythema
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Fatigue
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Feeling cold
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Vessel puncture site bruise
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Chest pain
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Nasal congestion
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Epistaxis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    0
    Irritability
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    0
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Lipase increased
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    5
    0
    5
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    1
    Blood bilirubin increased
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    2
    Blood thyroid stimulating hormone decreased
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Amylase increased
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    3
    Blood potassium increased
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Thyroxine free increased
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Thyroxine increased
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Excoriation
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    3
    0
    0
    Post-traumatic pain
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    4
    0
    0
    Fall
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 21 (38.10%)
    1 / 9 (11.11%)
    3 / 10 (30.00%)
         occurrences all number
    9
    1
    5
    Dizziness
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    2
    2
    0
    Hypoaesthesia
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 9 (22.22%)
    2 / 10 (20.00%)
         occurrences all number
    0
    3
    5
    Migraine
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Blood and lymphatic system disorders
    Leukocytosis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Thrombocytopenia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Eye disorders
    Dry eye
         subjects affected / exposed
    1 / 21 (4.76%)
    2 / 9 (22.22%)
    0 / 10 (0.00%)
         occurrences all number
    1
    2
    0
    Eye pruritus
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Vision blurred
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Lip dry
         subjects affected / exposed
    7 / 21 (33.33%)
    5 / 9 (55.56%)
    1 / 10 (10.00%)
         occurrences all number
    8
    5
    1
    Nausea
         subjects affected / exposed
    6 / 21 (28.57%)
    1 / 9 (11.11%)
    2 / 10 (20.00%)
         occurrences all number
    7
    1
    2
    Chapped lips
         subjects affected / exposed
    5 / 21 (23.81%)
    0 / 9 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    6
    0
    2
    Diarrhoea
         subjects affected / exposed
    4 / 21 (19.05%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    4
    0
    1
    Dry mouth
         subjects affected / exposed
    3 / 21 (14.29%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    3
    1
    0
    Abdominal pain
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    1
    Vomiting
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 9 (11.11%)
    2 / 10 (20.00%)
         occurrences all number
    1
    1
    2
    Constipation
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Flatulence
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Frequent bowel movements
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    17 / 21 (80.95%)
    5 / 9 (55.56%)
    3 / 10 (30.00%)
         occurrences all number
    38
    5
    3
    Erythema
         subjects affected / exposed
    3 / 21 (14.29%)
    2 / 9 (22.22%)
    0 / 10 (0.00%)
         occurrences all number
    6
    2
    0
    Pruritus generalised
         subjects affected / exposed
    4 / 21 (19.05%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    5
    1
    0
    Dermatitis acneiform
         subjects affected / exposed
    4 / 21 (19.05%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    5
    0
    0
    Pruritus
         subjects affected / exposed
    4 / 21 (19.05%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    5
    0
    0
    Eczema
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    3
    2
    0
    Rash maculo-papular
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    0
    Skin exfoliation
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    0
    Dandruff
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Dermatitis contact
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    0
    2
    0
    Ecchymosis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Rash
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    0
    2
    0
    Macule
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Pain of skin
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Skin hypopigmentation
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    2 / 21 (9.52%)
    2 / 9 (22.22%)
    0 / 10 (0.00%)
         occurrences all number
    3
    2
    0
    Haematuria
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Polyuria
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Glycosuria
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    10 / 21 (47.62%)
    1 / 9 (11.11%)
    6 / 10 (60.00%)
         occurrences all number
    13
    4
    14
    Pain in extremity
         subjects affected / exposed
    2 / 21 (9.52%)
    3 / 9 (33.33%)
    2 / 10 (20.00%)
         occurrences all number
    2
    4
    3
    Joint swelling
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    2
    2
    0
    Joint stiffness
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    0
    Musculoskeletal stiffness
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    0
    Neck pain
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Back pain
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 9 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    1
    0
    2
    Groin pain
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Bone pain
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Myalgia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Muscle spasms
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    3
    0
    1
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 21 (4.76%)
    2 / 9 (22.22%)
    0 / 10 (0.00%)
         occurrences all number
    1
    2
    0
    Influenza
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    0
    Pharyngitis
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Oral candidiasis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Increased appetite
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Feb 2015
    Changes in the conduct of the study.
    29 May 2015
    Changes in the conduct of the study.

    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.
    Radiography was less sensitive than CT for detecting new HO. Also, some subjects had new HO only at Week 12. Thus, Global Read data are presented where available using more sensitive CT scans at Week 12 in the PP population.
    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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