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    Summary
    EudraCT Number:2014-002496-28
    Sponsor's Protocol Code Number:PVO-1A-202
    Clinical Trial Type:Outside EU/EEA
    Date on which this record was first entered in the EudraCT database:2021-07-15
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    H.4 THIRD COUNTRY IN WHICH THE TRIAL WAS FIRST AUTHORISED
    Expand All   Collapse All
    A. Protocol Information
    A.2EudraCT number2014-002496-28
    A.3Full title of the trial
    A Phase 2, Open-Label Extension, Efficacy and Safety Study of a RARĪ³-Specific Agonist (Palovarotene) in the Treatment of Preosseous Flare-ups in Subjects with Fibrodysplasia Ossificans Progressiva (FOP).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Extension Study of an Investigational Drug, Palovarotene, in the Treatment of Preosseous Flare-ups in Subjects with Fibrodysplasia Ossificans Progressiva (FOP)
    A.4.1Sponsor's protocol code numberPVO-1A-202
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02279095
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/121/2018
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorClementia Pharmaceuticals Inc.
    B.1.3.4CountryCanada
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportClementia Pharmaceuticals Inc.
    B.4.2CountryCanada
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationIpsen
    B.5.2Functional name of contact pointGlobal Medical Affairs
    B.5.3 Address:
    B.5.3.1Street Address65 quai Georges Gorse
    B.5.3.2Town/ cityBoulogne Billancourt Cedex
    B.5.3.3Post code92650
    B.5.3.4CountryFrance
    B.5.6E-mailclinical.trials@ipsen.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/14/1368
    D.3 Description of the IMP
    D.3.1Product namePalovarotene
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPalovarotene
    D.3.9.1CAS number 410528-02-8
    D.3.9.3Other descriptive namePALOVAROTENE
    D.3.9.4EV Substance CodeSUB75998
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number1.5 to 10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Fibrodysplasia Ossificans Progressiva (FOP) is a rare, severely disabling disease characterized by painful, recurrent episodes of soft tissue swelling (flare-ups) and abnormal heterotopic ossification (HO) in muscles, tendons, and ligaments. Lesions begin in early childhood and lead to progressive ankyloses of major joints with resultant loss of movement. Prognosis is poor and median life expectancy is 40 years.
    E.1.1.1Medical condition in easily understood language
    FOP is a rare, severely disabling disease characterized by painful, recurrent episodes of soft tissue swelling (flare-ups) and abnormal heterotopic ossification in muscles, tendons, and ligaments.
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10068715
    E.1.2Term Fibrodysplasia ossificans progressiva
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    •To evaluate the safety and efficacy of different palovarotene dosing regimens in subjects with FOP. Efficacy will be based on the ability of palovarotene to prevent heterotopic ossification (HO) as assessed by low dose whole body computed tomography (WBCT) scan excluding head.
    E.2.2Secondary objectives of the trial
    •To evaluate the effect of palovarotene on range of motion (ROM) as assessed by the Cumulative Analogue Joint Involvement Scale for FOP (CAJIS).
    •To evaluate the effect of palovarotene on physical function using age-appropriate forms of the FOP Physical Function Questionnaire (PFQ).
    •To evaluate the effect of palovarotene on physical and mental health using age-appropriate forms of the Patient Reported Outcome Measurement Information System (PROMIS) Global Health Scale.
    •To evaluate the pharmacokinetics of palovarotene.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Study Population (Adult and Pediatric Cohorts -Part B)
    1.Completion of Study PVO-1A-201 (through Study Day 84); or Adult Cohort subjects not enrolled in Study PVO-1A-201, have the confirmed R206H genetic mutation consistent with FOP, have had at least two acute symptomatic flare-ups in the past 2 years but no flare-up symptoms within the past 4 weeks, including at the time of enrollment, have a CAJIS score of 6 to 16, inclusive, and must be able to receive non-flare-up based dosing.
    2.For the Adult Cohort, subjects under the age of 18 must have knee and hand/wrist radiographs confirming ≥ 90% skeletal maturity.
    3.Written, signed, and dated subject/parent informed consent; and, for subjects who are minors, age appropriate assent (this must be performed according to local regulations).

    Study Population for Non Flare-Up Based Treatment
    (Adult Cohort-Part B)
    1.Females of child-bearing potential (FOCBP) must have a negative blood or urine pregnancy test (with sensitivity of at least 50 mIU/mL) prior to administration of palovarotene. Male and FOCBP subjects must agree to remain abstinent during treatment and for 1 month after treatment or, if sexually active, to use two highly effective methods of birth control during and for 1 month after treatment. Additionally, sexually active FOCBP subjects must already be using two highly effective methods of birth control 1 month before treatment is to start. Specific risk of the use of retinoids during pregnancy, and the agreement to remain abstinent or use two highly effective methods of birth control will be clearly defined in the informed consent and the subject or legally authorized representatives (eg, parents, caregivers, or legal guardians) must specifically sign this section.
    2.Subjects must be accessible for treatment with palovarotene and follow up. Subjects living at distant locations from the investigational site must be able and willing to travel to a site for the initial and all on site follow-up visits.

    Study Population for Flare Up Based Treatment
    (Adult and Pediatric Cohorts-Part B)
    1.Symptomatic onset of a flare-up within 7 days before the first dose of study drug and defined by the presence of at least two of the following symptoms: pain, soft tissue swelling, decreased ROM, stiffness, redness, and warmth. Symptoms must be reported by the subject, be consistent with their previous flare-ups, and include a subject reported onset date, and flare-up must be confirmed by the Investigator.
    2.Flare-up is at an appendicular area (upper or lower extremity), abdomen, chest, neck, or lower back; and subject has received, is receiving, or is willing to receive treatment per standard of care, which may or may not include prednisone (2 mg/kg PO to a maximum dose of 100 mg daily) for 4 days.
    3.Females of child-bearing potential (FOCBP) must have a negative blood or urine pregnancy test (with sensitivity of at least 50 mIU/mL) prior to administration of palovarotene. Male and FOCBP subjects must agree to remain abstinent during treatment and for 1 month after treatment or, if sexually active, to use two highly effective methods of birth control during and for 1 month after treatment. Additionally, sexually active FOCBP subjects must already be using two highly effective methods of birth control 1 month before treatment is to start. Specific risk of the use of retinoids during pregnancy, and the agreement to remain abstinent or use two highly effective methods of birth control will be clearly defined in the informed consent and the subject or legally authorized representatives (eg, parents, caregivers, or legal guardians) must specifically sign this section.
    4.Subjects must be accessible for treatment with palovarotene and follow up. Subjects living at distant locations from the investigational site must be able and willing to travel to a site for the initial and all on site follow-up visits.

    Study Population
    (All Subjects -Part C)
    1. Prior participation in Part B of the current study (PVO-1A-202).
    2. Written, signed, and dated subject/parent informed consent; and, for subjects who are minors, age-appropriate assent (this must be performed according to local regulations).
    3. Females of child-bearing potential must have a negative pregnancy test (blood/urine) prior to administration of IMP. Male & FOCBP subjects must remain abstinent or use 2 methods of birth control during treatment & for 1 month after treatment. Sexually active FOCBP subjects must already be using 2 methods of birth control 1 month before treatment.

    Study Population of Subjects Starting Non-Flare-Up Based Treatment During Part C
    1. Subjects must be accessible for treatment with palovarotene and follow-up. Subjects living at distant locations from the investigational site must be able and willing to travel to a site for the initial and all on-site follow-up visits.
    2. Subjects must be able to undergo low-dose WBCT scan, excluding head.
    E.4Principal exclusion criteria
    Study Population
    (Adult and Pediatric Cohorts-Part B)
    1.Simultaneous participation in another clinical research study (except for Studies PVO-1A-201, PVO-1A-203, or PVO-1A-001) within 4 weeks prior to Part B Screening.
    2.Any reason that, in the opinion of the Investigator, would lead to the inability of the subject and/or family to comply with the protocol.

    Study Population for Non Flare-Up Based Treatment
    (Adult Cohort-Part B)
    1.Weight <20 kg.
    2.Intercurrent known or suspected non-healed fracture at any location.
    3.If currently using vitamin A or beta carotene, multivitamins containing vitamin A or beta carotene, or herbal preparations, fish oil, and unable or unwilling to discontinue use of these products during palovarotene treatment.
    4.Exposure to synthetic oral retinoids other than palovarotene in the past 30 days prior to Part B Screening (signature of the informed consent).
    5.Concurrent treatment with tetracycline or any tetracycline derivatives due to the potential increased risk of pseudotumor cerebri.
    6.History of allergy or hypersensitivity to retinoids or lactose.
    7.Concomitant medications that are inhibitors or inducers of cytochrome P450 (CYP450) 3A4 activity (see Section 5.4).
    8.Amylase or lipase >2x above the upper limit of normal (ULN) or with a history of chronic pancreatitis.
    9.Elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5x ULN.
    10.Fasting triglycerides >400 mg/dL with or without therapy.
    11.Female subjects who are breastfeeding.
    12.Subjects with uncontrolled cardiovascular, hepatic, pulmonary, gastrointestinal, endocrine, metabolic, ophthalmologic, immunologic, psychiatric, or other significant disease.
    13.Subjects experiencing suicidal ideation (type 4 or 5) or any suicidal behavior within the past month as defined by the Columbia Suicide Severity Rating Scale (C-SSRS).

    Study Population for Flare Up Based Treatment
    (Adult and Pediatric Cohorts-Part B)
    1.Weight <20 kg.
    2.Intercurrent known or suspected non-healed fracture at any location.
    3.Complete immobilization of joint at site of flare-up.
    4.Inability of the subject to undergo imaging assessments using plain radiographs.
    5.Currently using vitamin A or beta carotene, multivitamins containing vitamin A or beta carotene, or herbal preparations, fish oil, and unable or unwilling to discontinue use of these products during palovarotene treatment.
    6.Exposure to synthetic oral retinoids other than palovarotene in the past 30 days prior to Flare-up Screening (signature of the informed consent).
    7.Concurrent treatment with tetracycline or any tetracycline derivatives due to the potential increased risk of pseudotumor cerebri.
    8.History of allergy or hypersensitivity to retinoids or lactose.
    9.Concomitant medications that are inhibitors or inducers of CYP450 3A4 activity (see Section 5.4.1).
    10.Any subject with clinically significant elevations in amylase, lipase, AST, ALT, or fasting triglycerides during the most recent clinical laboratory assessment will require re-test prior to immediate flare-up based dosing with palovarotene per the Investigator. If upon re-test, the laboratory value in question remains clinically significantly abnormal, then the subject will not receive flare-up based treatment for this flare-up.
    11.Female subjects who are breastfeeding.
    12.Subjects with uncontrolled cardiovascular, hepatic, pulmonary, gastrointestinal, endocrine, metabolic, ophthalmologic, immunologic, psychiatric, or other significant disease.
    13.Subjects experiencing suicidal ideation (type 4 or 5) or any suicidal behavior within the past month as defined by the C-SSRS
    14.Any reason that, in the opinion of the Investigator, would lead to the inability of the subject and/or family to comply with the protocol.

    Study Population (All Subjects – Part C)
    1. Any reason that, in the opinion of the Investigator, would lead to the
    inability of the subject and/or family to comply with the protocol.
    2. If currently using vitamin A or beta carotene, multivitamins containing vitamin A or beta carotene, herbal preparations containing vitamin A or beta carotene, or fish oil, and unable or unwilling to discontinue use of these products during palovarotene treatment.

    Study Population of Subjects Starting Non-Flare-Up Based Treatment During Part C
    1. Amylase or lipase >2x above the upper limit of normal (ULN) or with a history of chronic pancreatitis.
    2. Elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5x ULN.
    3. Fasting triglycerides >400 mg/dL with or without therapy.
    4. Subjects experiencing suicidal ideation (type 4 or 5) or any suicidal behavior within the past month as defined by the Columbia Suicide Severity Rating Scale (C-SSRS).
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the annualized change in new HO volume as assessed by low-dose WBCT scan, excluding head. The annualized change from Parts B and C will be compared to data collected from the NHS.
    E.5.1.1Timepoint(s) of evaluation of this end point
    End of treatment
    E.5.2Secondary end point(s)
    Baseline is Non-flare-up Day 1.
    Note: Some subjects may be assessed for up to 60 months.
    1. Percent of subjects with new HO at Months 12, 24, 36, and overall.
    2. Change from baseline in ROM as assessed by CAJIS at Study Months 6, 12, 18, 24, 30, and 36.
    3. Change from baseline in physical function using age appropriate forms of the FOP-PFQ at Months 6, 12, 18, 24, 30, and 36.
    4. Change from baseline in physical and mental function for subjects ≥15 years old and mental function for subjects <15 years old using age appropriate forms of the PROMIS Global Health Scale at Months 6, 12, 18, 24, 30, and 36.
    E.5.2.1Timepoint(s) of evaluation of this end point
    6, 12, 18,24, 30, 36 months
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Use of Assistive Devices
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial4
    E.8.3 Will this trial be conducted at a single site globally? No
    E.8.4 Will this trial be conducted at multiple sites globally? Yes
    E.8.6 Trial involving sites outside the EEA
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3Specify the countries outside of the EEA in which trial sites are planned
    Australia
    United States
    Argentina
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    last patient last visit
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.2In all countries concerned by the trial years7
    E.8.9.2In all countries concerned by the trial days22
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 20
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 8
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 12
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 40
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 60
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    none
    G. Investigator Networks to be involved in the Trial
    H.4 Third Country in which the Trial was first authorised
    H.4.1Third Country in which the trial was first authorised: United States
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