<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02979769</url>
  </required_header>
  <id_info>
    <org_study_id>PVO-1A-204</org_study_id>
    <secondary_id>2016-002526-36</secondary_id>
    <nct_id>NCT02979769</nct_id>
  </id_info>
  <brief_title>An Open-Label Extension Study of Palovarotene to Prevent Heterotopic Ossification in People With Fibrodysplasia Ossificans Progressiva (FOP) in France</brief_title>
  <official_title>A Phase 2, Open-Label Extension, Efficacy and Safety Study of a Retinoic Acid Receptor Gamma (RARγ)-Specific Agonist (Palovarotene) in the Treatment of Preosseous Flare-ups in Subjects With Fibrodysplasia Ossificans Progressiva (FOP)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Clementia Pharmaceuticals Inc.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Ipsen</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Fibrodysplasia Ossificans Progressiva (FOP) is a rare, severely disabling disease&#xD;
      characterized by heterotopic ossification (HO), i.e., abnormal bone formation, often&#xD;
      associated with painful, recurrent episodes of soft tissue swelling (flare-ups). Lesions&#xD;
      begin in early childhood and lead to progressive ankyloses of major joints with resultant&#xD;
      loss of movement.&#xD;
&#xD;
      In this study, the ability of different palovarotene dosing regimens to prevent the formation&#xD;
      of new HO will be evaluated in adult and pediatric participants with FOP in France.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The main objective of this Phase 2, open-label study is to evaluate the safety and efficacy&#xD;
      of different palovarotene dosing regimens in participants with FOP in France. Efficacy will&#xD;
      be assessed based on the ability of palovarotene to prevent the formation of new heterotopic&#xD;
      ossification (HO) as assessed by low-dose whole body computed tomography (WBCT) scan,&#xD;
      excluding head.&#xD;
&#xD;
      Participants who successfully completed study PVO-1A-201 as well as up to two new adult&#xD;
      participants were followed for up to 24 months. Participants under Amendment 1 will be&#xD;
      followed for up to an additional 48 months. No new participants will be enrolled.&#xD;
&#xD;
      The Adult Cohort will include all participants with at least 90% skeletal maturity,&#xD;
      regardless of age. The Pediatric Cohort will include all participants with less than 90%&#xD;
      skeletal maturity. Any Pediatric Cohort participants who achieves ≥90% skeletal maturity&#xD;
      during the study can be considered for enrollment into the Adult Cohort at the discretion of&#xD;
      then Investigator.&#xD;
&#xD;
      Participants that were skeletally immature at their last assessment will be invited back to&#xD;
      participate in a safety follow-up (Part D) that includes yearly visits for up to a 2-year&#xD;
      follow-up period following last dose. No dosing will occur in Part D.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 28, 2016</start_date>
  <completion_date type="Actual">June 28, 2022</completion_date>
  <primary_completion_date type="Actual">June 28, 2022</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Annualized change in new HO volume</measure>
    <time_frame>Every 12 months until the end of the study (up to 72 months)</time_frame>
    <description>Assessed by low-dose whole body computed tomography (WBCT) (excluding head)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Percent of participants with new HO</measure>
    <time_frame>Every 12 months for up to 72 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline in range of motion (ROM)</measure>
    <time_frame>Every 6 months for up to 72 months</time_frame>
    <description>Assessed by Cumulative Analogue Joint Involvement Scale (CAJIS)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline in physical function</measure>
    <time_frame>Every 6 months for up to 72 months</time_frame>
    <description>Assessed by age-appropriate forms of the FOP-Physical Function Questionnaire (FOP-PFQ)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline in physical and mental function for participants ≥15 years old and mental function for participants &lt;15 years old</measure>
    <time_frame>Every 6 months for up to 72 months</time_frame>
    <description>Assessed by age-appropriate forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">9</enrollment>
  <condition>Fibrodysplasia Ossificans Progressiva</condition>
  <arm_group>
    <arm_group_label>Palovarotene</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>All participants will receive non-flare-up based treatment of 5 mg palovarotene once daily for 24 months.&#xD;
Participants who continued non-flare-up based treatment under Amendment 1 will receive non-flare-up based treatment for up to an additional 48 months (therefore 72 months over the entire study).&#xD;
Participants who start non-flare-up based treatment under Amendment 1 will receive non-flare-up based treatment for up to 48 months.&#xD;
Participants that are skeletally immature will receive weight-adjusted doses.&#xD;
In the event of an eligible flare-up all participants will receive 20 mg palovarotene for 28 days, followed by 10 mg palovarotene for 56 days. Participants under the age of 18 years will receive weight-adjusted doses.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Palovarotene</intervention_name>
    <description>Palovarotene will be taken orally once daily at approximately the same time each day.</description>
    <arm_group_label>Palovarotene</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Prior participation in Amendment 1 of the current study (PVO-1A-204).&#xD;
&#xD;
          -  Written, signed, and dated informed consent and, for participants who are minors,&#xD;
             age-appropriate participant assent (performed according to local regulations).&#xD;
&#xD;
          -  Accessible for treatment with palovarotene and follow-up (able and willing to travel&#xD;
             to a site for the initial and all follow-up clinic visits).&#xD;
&#xD;
          -  Able to undergo low-dose, WBCT scan, excluding head.&#xD;
&#xD;
          -  Females of child-bearing potential (FOCBP) must have a negative blood or urine&#xD;
             pregnancy test (with sensitivity of at least 50 mIU/mL) prior to administration of&#xD;
             palovarotene.&#xD;
&#xD;
          -  Male and FOCBP participants must agree to remain abstinent from heterosexual sex&#xD;
             during treatment and for 1 month after treatment or, if sexually active, to use two&#xD;
             effective methods of birth control during and for 1 month after treatment.&#xD;
             Additionally, sexually active FOCBP participants must already be using two effective&#xD;
             methods of birth control 1 month before treatment is to start. Specific risk of the&#xD;
             use of retinoids during pregnancy, and the agreement to remain abstinent or use two&#xD;
             effective methods of birth control will be clearly defined in the informed consent and&#xD;
             the participant or legally authorized representatives.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any reason that, in the opinion of the Investigator, would lead to the inability of&#xD;
             the participant and/or family to comply with the protocol.&#xD;
&#xD;
          -  Amylase or lipase &gt;2x above the upper limit of normal or with a history of&#xD;
             pancreatitis.&#xD;
&#xD;
          -  Elevated aspartate aminotransferase or alanine aminotransferase &gt;2.5x the upper limit&#xD;
             of normal.&#xD;
&#xD;
          -  Fasting triglycerides &gt;400 mg/dL with or without therapy.&#xD;
&#xD;
          -  If currently using vitamin A or beta carotene, multivitamins containing vitamin A or&#xD;
             beta carotene, herbal preparations containing vitamin A or beta carotene, or fish oil,&#xD;
             and unable or unwilling to discontinue use of these products during palovarotene&#xD;
             treatment.&#xD;
&#xD;
          -  Participants experiencing suicidal ideation (type 4 or 5) or any suicidal behavior&#xD;
             within the past month as defined by the Columbia Suicide Severity Rating Scale&#xD;
             (C-SSRS).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>6 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ipsen Medical Director</last_name>
    <role>Study Director</role>
    <affiliation>Ipsen</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hôpital Necker-Enfants Malades, Department of Genetics</name>
      <address>
        <city>Paris</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <link>
    <url>http://ifopa.org</url>
    <description>Website for the International FOP Association</description>
  </link>
  <link>
    <url>http://fopfrance.fr</url>
    <description>Website for the French FOP Association</description>
  </link>
  <link>
    <url>http://clementiapharma.com</url>
    <description>Click here for more information about this study: A Phase 2, Open-Label Extension, Efficacy and Safety Study of a RARγ-Specific Agonist (Palovarotene) in the Treatment of Preosseous Flare-ups in Subjects with Fibrodysplasia Ossificans Progressiva (FOP)</description>
  </link>
  <reference>
    <citation>Shimono K, Tung WE, Macolino C, Chi AH, Didizian JH, Mundy C, Chandraratna RA, Mishina Y, Enomoto-Iwamoto M, Pacifici M, Iwamoto M. Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-gamma agonists. Nat Med. 2011 Apr;17(4):454-60. doi: 10.1038/nm.2334. Epub 2011 Apr 3. Erratum In: Nat Med. 2012 Oct;18(10):1592.</citation>
    <PMID>21460849</PMID>
  </reference>
  <verification_date>July 2022</verification_date>
  <study_first_submitted>November 23, 2016</study_first_submitted>
  <study_first_submitted_qc>November 29, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 2, 2016</study_first_posted>
  <last_update_submitted>July 28, 2022</last_update_submitted>
  <last_update_submitted_qc>July 28, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">July 29, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Open-label extension study</keyword>
  <keyword>Clinical trial Phase 2</keyword>
  <keyword>Efficacy and safety</keyword>
  <keyword>Heterotopic ossification</keyword>
  <keyword>Flare-up</keyword>
  <keyword>Palovarotene</keyword>
  <keyword>Retinoic acide receptor agonist</keyword>
  <keyword>Retinoic acide receptor gamma agonist</keyword>
  <keyword>Clementia</keyword>
  <keyword>Myositis Ossificans</keyword>
  <keyword>Munchmeyer's Disease</keyword>
  <keyword>FOP</keyword>
  <keyword>Ipsen</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Myositis Ossificans</mesh_term>
  </condition_browse>
  <pending_results>
    <submitted>June 22, 2023</submitted>
    <returned>July 12, 2023</returned>
    <submitted>July 31, 2023</submitted>
    <returned>August 24, 2023</returned>
  </pending_results>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02979769
org study id: PVO-1A-204
secondary id: 2016-002526-36
nct id: NCT02979769
lead sponsor: 
has dmc: Yes
Fibrodysplasia Ossificans Progressiva (FOP) is a rare, severely disabling disease
      characterized by heterotopic ossification (HO), i.e., abnormal bone formation, often
      associated with painful, recurrent episodes of soft tissue swelling (flare-ups). Lesions
      begin in early childhood and lead to progressive ankyloses of major joints with resultant
      loss of movement.

      In this study, the ability of different palovarotene dosing regimens to prevent the formation
      of new HO will be evaluated in adult and pediatric participants with FOP in France.
The main objective of this Phase 2, open-label study is to evaluate the safety and efficacy
      of different palovarotene dosing regimens in participants with FOP in France. Efficacy will
      be assessed based on the ability of palovarotene to prevent the formation of new heterotopic
      ossification (HO) as assessed by low-dose whole body computed tomography (WBCT) scan,
      excluding head.

      Participants who successfully completed study PVO-1A-201 as well as up to two new adult
      participants were followed for up to 24 months. Participants under Amendment 1 will be
      followed for up to an additional 48 months. No new participants will be enrolled.

      The Adult Cohort will include all participants with at least 90% skeletal maturity,
      regardless of age. The Pediatric Cohort will include all participants with less than 90%
      skeletal maturity. Any Pediatric Cohort participants who achieves ≥90% skeletal maturity
      during the study can be considered for enrollment into the Adult Cohort at the discretion of
      then Investigator.

      Participants that were skeletally immature at their last assessment will be invited back to
      participate in a safety follow-up (Part D) that includes yearly visits for up to a 2-year
      follow-up period following last dose. No dosing will occur in Part D.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Annualized change in new HO volume
time frame: Every 12 months until the end of the study (up to 72 months)
description: Assessed by low-dose whole body computed tomography (WBCT) (excluding head)
measure: Percent of participants with new HO
time frame: Every 12 months for up to 72 months
measure: Change from baseline in range of motion (ROM)
time frame: Every 6 months for up to 72 months
description: Assessed by Cumulative Analogue Joint Involvement Scale (CAJIS)
measure: Change from baseline in physical function
time frame: Every 6 months for up to 72 months
description: Assessed by age-appropriate forms of the FOP-Physical Function Questionnaire (FOP-PFQ)
measure: Change from baseline in physical and mental function for participants ≥15 years old and mental function for participants <15 years old
time frame: Every 6 months for up to 72 months
description: Assessed by age-appropriate forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale
arm group label: Palovarotene
arm group type: Experimental
description: All participants will receive non-flare-up based treatment of 5 mg palovarotene once daily for 24 months.
Participants who continued non-flare-up based treatment under Amendment 1 will receive non-flare-up based treatment for up to an additional 48 months (therefore 72 months over the entire study).
Participants who start non-flare-up based treatment under Amendment 1 will receive non-flare-up based treatment for up to 48 months.
Participants that are skeletally immature will receive weight-adjusted doses.
In the event of an eligible flare-up all participants will receive 20 mg palovarotene for 28 days, followed by 10 mg palovarotene for 56 days. Participants under the age of 18 years will receive weight-adjusted doses.
intervention type: Drug
intervention name: Palovarotene
description: Palovarotene will be taken orally once daily at approximately the same time each day.
arm group label: Palovarotene
criteria: 
gender: All
minimum age: 6 Years
maximum age: 65 Years
healthy volunteers: No
last name: Ipsen Medical Director
role: Study Director
affiliation: Ipsen
facility: 
country: France
url: http://ifopa.org
description: Website for the International FOP Association
url: http://fopfrance.fr
description: Website for the French FOP Association
url: http://clementiapharma.com
description: Click here for more information about this study: A Phase 2, Open-Label Extension, Efficacy and Safety Study of a RARγ-Specific Agonist (Palovarotene) in the Treatment of Preosseous Flare-ups in Subjects with Fibrodysplasia Ossificans Progressiva (FOP)
citation: Shimono K, Tung WE, Macolino C, Chi AH, Didizian JH, Mundy C, Chandraratna RA, Mishina Y, Enomoto-Iwamoto M, Pacifici M, Iwamoto M. Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-gamma agonists. Nat Med. 2011 Apr;17(4):454-60. doi: 10.1038/nm.2334. Epub 2011 Apr 3. Erratum In: Nat Med. 2012 Oct;18(10):1592.
PMID: 21460849
responsible party type: Sponsor
mesh term: Myositis Ossificans
submitted: June 22, 2023
returned: July 12, 2023
submitted: July 31, 2023
returned: August 24, 2023