<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/NCT02190747</url>
  </required_header>
  <id_info>
    <org_study_id>PVO-1A-201</org_study_id>
    <secondary_id>2014-001453-17</secondary_id>
    <nct_id>NCT02190747</nct_id>
  </id_info>
  <brief_title>An Efficacy and Safety Study of Palovarotene to Treat Preosseous Flare-ups in FOP Subjects</brief_title>
  <official_title>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)</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 painful, recurrent episodes of soft tissue swelling (flare-ups) that result&#xD;
      in abnormal bone formation in muscles, tendons, and ligaments. Flare-ups begin early in life&#xD;
      and may occur spontaneously or after soft tissue trauma, vaccinations, or influenza&#xD;
      infections. Recurrent flare-ups progressively restrict movement by locking joints leading to&#xD;
      cumulative loss of function and disability. Mouse models of FOP have demonstrated the ability&#xD;
      of retinoic acid receptor (RAR) gamma agonists to prevent heterotopic ossification (HO)&#xD;
      following injury. The purpose of the study is to evaluate whether palovarotene, an RAR gamma&#xD;
      agonist, will prevent HO during and following a flare-up in subjects with FOP.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The primary objective is to evaluate the ability of different doses of palovarotene to&#xD;
      prevent HO at the flare-up site in subjects with FOP as assessed by plain radiographs.&#xD;
&#xD;
      This is a Phase 2, multi-center, randomized, double-blind, sponsor-unblinded,&#xD;
      placebo-controlled study. Two cohorts of subjects will be randomized into different dosing&#xD;
      regimens of palovarotene for a 6-week (42 days) treatment period. The study will consist of&#xD;
      three periods:&#xD;
&#xD;
        1. A Screening period to occur within 7 days of a distinct flare-up. The first dose of&#xD;
           study drug will be taken within 7 days of the flare-up initiation.&#xD;
&#xD;
        2. A double-blind treatment period of 6 weeks (42 days) duration.&#xD;
&#xD;
        3. A follow-up period of 6 weeks (42 days) duration.&#xD;
&#xD;
      An initial cohort (Cohort 1) of subjects will be randomly assigned 3:1 to either palovarotene&#xD;
      or placebo daily for 42 days. Subjects randomized to palovarotene in Cohort 1 will receive an&#xD;
      initial daily dose of 10 mg for 14 days followed by 5 mg daily for 28 days.&#xD;
&#xD;
      In Cohort 2, new FOP subjects meeting all inclusion/exclusion criteria will be randomly&#xD;
      assigned 3:3:2 to two dose regimens of palovarotene (10 mg for 14 days and 5 mg for 28 days;&#xD;
      5 mg for 14 days and 2.5 mg for 28 days) or placebo daily for 42 days. Doses will be&#xD;
      weight-adjusted and subjects randomized within three weight-range categories (20 to &lt;40 kg,&#xD;
      40 to &lt;60 kg, and ≥60 kg).&#xD;
&#xD;
      Subjects completing the study and still meeting eligibility requirements will be given the&#xD;
      opportunity to enroll into an open-label extension study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">July 14, 2014</start_date>
  <completion_date type="Actual">May 23, 2016</completion_date>
  <primary_completion_date type="Actual">May 23, 2016</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Percentage of Responders at Week 6</measure>
    <time_frame>Baseline (Day 1) and Week 6 (Day 42)</time_frame>
    <description>A responder was defined as a subject with no or minimal new heterotopic ossification (HO) at flare-up site versus baseline as assessed by plain radiographs at Week 6. Minimal new HO is defined as new HO with an HO score &lt;=3 in both anterior/posterior (AP) and lateral projections (or if one view is non-interpretable or non-evaluable, then remaining evaluable view is used). The HO score ranges from 0 to 6 where, 0 = no HO and 6 = single contiguous HO with longest dimension &gt;2 diameters of reference normotopic bone in any projection. The highest HO score from the 2 projections was used. Results from Primary Read reviews are presented. The Primary Read process included a double-read radiology review paradigm with consensus adjudication. Radiography and CT scans were examined independently by scan type, flare-up region, and imaging time point in order to determine whether radiography would be sufficient to measure new HO formation. Only subjects with interpretable outcomes were evaluated.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Percentage of Subjects With New HO at Weeks 6 and 12</measure>
    <time_frame>Weeks 6 and 12 (Day 84)</time_frame>
    <description>Low dose CT scan was used as a secondary imaging assessment of HO and was performed at the same time points as plain radiographs. The percentage of subjects with new HO (regardless of the amount of new HO) at the flare-up site as assessed by CT scan and/or plain radiographs at Weeks 6 and 12 were analysed. The results are from Global Read reviews. The holistic Global Read process allowed concurrent review of all modalities across all time points, and provided access to selected clinical data at the time of review.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Amount (Area) of New HO Formed at the Flare-up Site at Weeks 6 and 12</measure>
    <time_frame>Baseline, Weeks 6 and 12</time_frame>
    <description>Interpretation of plain radiographs document the amount (area) of HO on both the AP and lateral radiograph views. The area for each view was a sum of all the new HO at the flare-up location (and thus if there are multiple HO lesions, the area of each lesion was determined and then the total across all lesions were summed to obtain a total new HO). This total new HO sum was used in the analysis of the area of new HO. Results from Primary Read reviews are presented.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Responders at Week 12</measure>
    <time_frame>Baseline and Week 12</time_frame>
    <description>A responder was defined as a subject with no or minimal new HO at the flare-up site versus baseline as assessed by plain radiographs at Week 12. Minimal new HO is defined as new HO with an HO score &lt;=3 in both the AP and lateral projections (or if one view is non-interpretable or non-evaluable, then the remaining evaluable view is used). The HO score ranges from 0 to 6 where, 0 = no HO and 6 = single contiguous HO with longest dimension &gt;2 diameters of the reference normotopic bone in any projection. The highest HO score from the 2 projections was used. Results from the Primary Read reviews are presented. The Primary Read process included a double-read radiology review paradigm with consensus adjudication. Radiography and CT scans were examined independently by scan type, flare-up region, and imaging time point in order to determine whether radiography would be sufficient to measure new HO formation.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Bone Specific Alkaline Phosphatase at Weeks 2, 4, 6 and 12</measure>
    <time_frame>Baseline, Weeks 2, 4, 6 and 12</time_frame>
    <description>Blood and urine samples for analysis of cartilage, bone, angiogenesis, and inflammation biomarkers were collected. Bone specific alkaline phosphatase was analysed as a bone and cartilage biomarker.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in C-Reactive Protein at Weeks 2, 4, 6 and 12</measure>
    <time_frame>Baseline, Weeks 2, 4, 6 and 12</time_frame>
    <description>Blood and urine samples for analysis of cartilage, bone, angiogenesis, and inflammation biomarkers were collected. C-reactive protein was analysed as a inflammation biomarker.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in C-Terminal Telopeptide at Weeks 2, 4, 6 and 12</measure>
    <time_frame>Baseline, Weeks 2, 4, 6 and 12</time_frame>
    <description>Blood and urine samples for analysis of cartilage, bone, angiogenesis, and inflammation biomarkers were collected. C-terminal telopeptide was analysed as a bone and cartilage biomarker.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Procollagen Type 1 N-Terminal Propeptide at Weeks 2, 4, 6 and 12</measure>
    <time_frame>Baseline, Weeks 2, 4, 6 and 12</time_frame>
    <description>Blood and urine samples for analysis of cartilage, bone, angiogenesis, and inflammation biomarkers were collected. Procollagen type 1 N-terminal propeptide was analysed as a bone and cartilage biomarker.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Procollagen Type 1 C-Terminal Propeptide Biomarker at Weeks 2, 4, 6 and 12</measure>
    <time_frame>Baseline, Weeks 2, 4, 6 and 12</time_frame>
    <description>Blood and urine samples for analysis of cartilage, bone, angiogenesis, and inflammation biomarkers were collected. Procollagen type 1 C-terminal propeptide was analysed as a bone and cartilage biomarker.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Amount of Bone Formation (Volume) at Weeks 6 and 12</measure>
    <time_frame>Baseline, Weeks 6 and 12</time_frame>
    <description>Low dose CT scan were used as a secondary imaging assessment of HO, and was performed at the same time points as plain radiographs. Interpretation of the CT scan documented the amount (volume) and grade of HO. The independent reviewer scored HO lesions according to the following scale for HO on CT. Grade 1 = fluid attenuation without evidence of calcification at CT, Grade 2 = calcification of soft tissues without evidence of bone formation, Grade 3 = immature bone formation, and Grade 4 = mature bone with cortical differentiation. Volume of new HO was determined according to the following steps: (1) calculate volume of new HO compared to baseline for each reviewer/HO ID, (2) sum the volume of new HO across HO IDs for each reviewer, and (3) average the volume of new HO across reviewers. Results from Primary Read reviews are presented.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Subjects With Soft Tissue Swelling and Cartilage Formation Assessed by Magnetic Resonance Imaging (MRI) or Ultrasound (US) at Weeks 6 and 12</measure>
    <time_frame>Weeks 6 and 12</time_frame>
    <description>The MRI was utilized to evaluate the presence of soft tissue swelling/edema (and volume of the swelling/edema) and presence of cartilage formation (yes or no). For subjects who could not have an MRI, US was used to assess edema severity for the sub-set of subjects enrolled after this opinion was introduced in a protocol amendment. Imaging film from MRI was assessed by two independent readers. When there was sufficient agreement between the independent readers on volume, both of the independent readings were used for analysis with the volume measurements averaged. When there was insufficient agreement between the independent readers, an adjudication reading was provided and used for analysis. The US was used for soft tissue swelling/edema but not cartilage formation. Percentage calculated as % = 100 x n/N' where N' is the number of subjects with interpretable outcomes. Results from Primary Read reviews are presented.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Percent of Normal Arc of Motion at the Primary Joint (Flare-up Site) at Weeks 6 and 12</measure>
    <time_frame>Baseline, Weeks 6 and 12</time_frame>
    <description>Active range of motion, expressed as the percent of normal arc of motion, measurements at the primary joint associated with the flare-up and adjoining joints was assessed by goniometer.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Subject and Investigator Global Assessment of Movement at Weeks 6 and 12</measure>
    <time_frame>Weeks 6 and 12</time_frame>
    <description>Flare-up movement outcomes were independently assessed by both the subject (or parent of a subject under 8 years of age) and the Investigator at Weeks 6 and 12 by completing the global assessment of movement. The subject/parent completed the global assessment first. Prior to reviewing the subject's assessment, the Investigator completed his/her own assessment of the flare-up outcome. Subjects were assessed how the flare-up affected their movement on a scale ranging 1 to 5 where, 1 = severely worse movement and 5 = better movement compared with study Day 1 (day of first dose of study drug). Investigators were assessed how the flare-up affected the subject's movement on a scale ranging 1 to 5 where, 1 = severely worse movement and 5 = better movement compared with baseline (day of screening physical examination).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Flare-Up Pain and Swelling at Weeks 2, 4, 6, 9 and 12</measure>
    <time_frame>Baseline, Weeks 2, 4, 6, 9 and 12</time_frame>
    <description>The pain and swelling associated with flare-ups was evaluated using 2 separate numeric rating scales, one for pain and one for swelling. The pain scale ranges from 0 to 10 where, 0 = no pain and 10 = worst pain ever experienced. The swelling scale ranges from 0 to 10 where, 0 = no swelling and 10 = worst swelling ever experienced. The Faces Pain Scale - Revised (FPS-R) was used for children less than 8 years old. The FPS-R ranges from 0 to 10 where, 0 = no pain and 10 = very much pain in two-point increments.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Subjects Who Used Any Assistive Devices and Adaptations for Daily Living at Weeks 6 and 12</measure>
    <time_frame>Weeks 6 and 12</time_frame>
    <description>Subjects were given a list of FOP assistive devices and adaptations and asked to select those they use for daily living. The FOP assistive devices and adaptations included mobility aids, care attendants, eating tools, personal care tools/aids, bathroom aids and devices, bedroom aids and devices, home adaptations, work environment adaptations, technology adaptations, sports and recreation adaptations, school, and medical therapies for daily living.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of Active Symptomatic Flare-up</measure>
    <time_frame>From Day 1 to Day 84</time_frame>
    <description>The duration of active symptomatic flare-up was defined as the number of days the subject reported the presence of symptoms in the diary ('Is your flare-up ongoing today?') from Day 1 to study completion at Day 84. The mean number of days of active, symptomatic flare-up is presented for subjects with evaluable diary data.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Percentage of Worst Total Score for FOP-Specific Physical Function Questionnaire (FOP-PFQ) at Weeks 2, 4, 6, 9 and 12</measure>
    <time_frame>Baseline, Weeks 2, 4, 6, 9 and 12</time_frame>
    <description>The FOP-PFQ consists of 28 questions rated on scales from 1 to 5, with lower scores denoting more difficulty. The adult form of the FOP-PFQ was administered to subjects 15 years of age and older. There are two Pediatric FOP-PFQ (FOP-PFQ-P) forms: a self-completed form for 8 to 14 year-olds and a parent proxy-completed form for 5 to 14 year-olds. For subjects between 8 to 14 years of age, both the self-completed (for 8 to 14 year-olds) and the proxy-completed (for 5 to 14 year olds) forms of the FOP-PFQ-P were administered. However, only the proxy-completed form was used for analysis. Percentage of worst scores ranges from 0% to 100% with 0% = best possible function and 100% = worst possible function. Change from baseline for each time point is presented.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12</measure>
    <time_frame>Baseline, Weeks 2, 4, 6, 9 and 12</time_frame>
    <description>The PROMIS Global Health contains 10 questions which are rated on scales from 1 to 5 or 0 to 10. Global physical health scores were calculated as the sum of scores from parameters 3, 6, 7, and 8 and ranges from 4 to 20 where, 4 = worse health and 20 = better health. Global mental health scores were calculated as the sum of scores from parameters 2, 4, 5, and 10 and ranges from 4 to 20 where, 4 = worse health and 20 = better health. For paediatric subjects, the PROMIS was administered as per the adult version. However, there is a single total score for the paediatric PROMIS (as opposed to global physical and global mental health scores as are in the adult version). The total score were converted to a T-score. A T-score of 50 is normal and increments of 10 are +/- 1 standard deviation away from the norm. A T-score &lt;50 indicates worse health, while a T-score &gt;50 indicates better health. The higher values (positive changes) indicate better health.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maximum Measured Plasma Concentration (Cmax) of Palovarotene</measure>
    <time_frame>Pre-dose and 3, 6, 10, and 24 hours (hrs) post-dose at Week 2, and at Week 4 or 6</time_frame>
    <description>The Cmax of palovarotene was determined.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Minimum Measured Plasma Concentration (Cmin) of Palovarotene</measure>
    <time_frame>Pre-dose and 3, 6, 10, and 24 hrs post-dose at Week 2, and at Week 4 or 6</time_frame>
    <description>The Cmin of palovarotene was determined.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time of Maximum Measured Plasma Concentration (Tmax) of Palovarotene</measure>
    <time_frame>Pre-dose and 3, 6, 10, and 24 hrs post-dose at Week 2, and at Week 4 or 6</time_frame>
    <description>The Tmax obtained by inspection of palovarotene was determined.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Apparent Terminal Elimination Half-life (t1/2) of Palovarotene</measure>
    <time_frame>Pre-dose and 3, 6, 10, and 24 hrs post-dose at Week 2, and at Week 4 or 6</time_frame>
    <description>The t1/2 was calculated as ln(2)/ λz. The number of data points included in the regression was determined by visual inspection, but a minimum of three data points in the terminal phase, excluding Cmax, was required to estimate λz.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area Under the Plasma Concentration Versus Time Curve Over the 24-hr Dosing Interval (AUC[0-24hr]) of Palovarotene</measure>
    <time_frame>Pre-dose and 3, 6, 10, and 24 hrs post-dose at Week 2, and at Week 4 or 6</time_frame>
    <description>The AUC(0-24hr) was calculated using linear trapezoid rule.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Apparent Clearance of Palovarotene (CL/F)</measure>
    <time_frame>Pre-dose and 3, 6, 10, and 24 hrs post-dose at Week 2, and at Week 4 or 6</time_frame>
    <description>The CL/F was defined as dose/AUC0-24hr.</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">40</enrollment>
  <condition>Fibrodysplasia Ossificans Progressiva</condition>
  <arm_group>
    <arm_group_label>Palovarotene dose level 1 (Cohort 1)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Doses of palovarotene in dose level 1 are 10 mg once daily for 14 days, followed by 5 mg once daily for 28 days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Palovarotene dose level 2 (Cohort 2)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Weight-adjusted doses of palovarotene in dose level 2 are 10 mg palovarotene once daily, followed by 5 mg once daily for 28 days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Palovarotene dose level 3 (Cohort 2)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Weight-adjusted doses of palovarotene in dose level 3 are 5 mg palovarotene once daily, followed by 2.5 mg once daily for 28 days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Sugar pill</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>The placebo comparator will be taken once daily for the same duration as the palovarotene dose groups in both Cohorts 1 and 2.</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. Powder filled hard gelatin capsules will be opened and the contents added onto specific food.</description>
    <arm_group_label>Palovarotene dose level 1 (Cohort 1)</arm_group_label>
    <arm_group_label>Palovarotene dose level 2 (Cohort 2)</arm_group_label>
    <arm_group_label>Palovarotene dose level 3 (Cohort 2)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <arm_group_label>Sugar pill</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Written, signed, and dated informed subject/parent consent or age-appropriate assent.&#xD;
&#xD;
          -  Subjects clinically diagnosed with classic Fibrodysplasia Ossificans Progressiva&#xD;
             (FOP).&#xD;
&#xD;
          -  Symptomatic onset of a distinct flare-up within 7 days of Study Day 1 (start of study&#xD;
             drug) and defined by the presence of at least two of six of the following symptoms:&#xD;
             pain, soft tissue swelling, decreased range of motion, stiffness, redness, and warmth.&#xD;
             Flare-up must be confirmed by the physician at the Screening visit.&#xD;
&#xD;
          -  Flare-up is at an appendicular area (upper or lower extremity), abdomen, or chest; and&#xD;
             subject has received, is receiving, or is willing to receive treatment per standard of&#xD;
             care, which may or may not include oral prednisone (2 mg/kg PO to a maximum dose of&#xD;
             100 mg daily) for 4 days.&#xD;
&#xD;
          -  Abstinent or using two highly effective forms of birth control.&#xD;
&#xD;
          -  Subjects must be accessible for treatment and follow-up. Subjects living at distant&#xD;
             locations from the investigational site must be able and willing to travel to a site&#xD;
             for the initial and all follow-up visits.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Weight &lt;20 kg.&#xD;
&#xD;
          -  Intercurrent non-healed fracture at any location.&#xD;
&#xD;
          -  Complete immobilization of joint at site of flare-up.&#xD;
&#xD;
          -  The inability of the subject to undergo imaging assessments using plain radiographs.&#xD;
&#xD;
          -  If currently using vitamin A or beta carotene, multivitamins containing vitamin A or&#xD;
             beta carotene, or herbal preparations, fish oil, and unable or unwilling to&#xD;
             discontinue use of these products for the duration of the study.&#xD;
&#xD;
          -  Exposure to synthetic oral retinoids in the past 30 days prior to Screening (signature&#xD;
             of the informed consent).&#xD;
&#xD;
          -  Concurrent treatment with tetracycline due to the potential increased risk of&#xD;
             pseudotumor cerebri.&#xD;
&#xD;
          -  History of allergy or hypersensitivity to retinoids or lactose.&#xD;
&#xD;
          -  Concomitant medications that are inhibitors or inducers of CYP450 3A4 activity.&#xD;
&#xD;
          -  Amylase or lipase &gt;1.5x above the upper limit of normal or with a history of chronic&#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;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>6 Years</minimum_age>
    <maximum_age>N/A</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>University of California San Francisco, Division of Endocrinology and Metabolism</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94143</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Pennsylvania, Center for Research in FOP &amp; Related Disorders</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hôpital Necker-Enfants Malades, Department of Genetics</name>
      <address>
        <city>Paris</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Royal National Orthopaedic Hospital, Brockley Hill</name>
      <address>
        <city>Stanmore</city>
        <state>Middlesex</state>
        <zip>HA7 4LP</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
    <country>United Kingdom</country>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://ifopa.org</url>
    <description>Website for the International FOP Association</description>
  </link>
  <link>
    <url>http://clementiapharma.com/</url>
    <description>Click here for more information about this study: 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 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>January 2021</verification_date>
  <study_first_submitted>July 13, 2014</study_first_submitted>
  <study_first_submitted_qc>July 14, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 15, 2014</study_first_posted>
  <results_first_submitted>June 3, 2020</results_first_submitted>
  <results_first_submitted_qc>June 3, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">June 24, 2020</results_first_posted>
  <disposition_first_submitted>October 20, 2017</disposition_first_submitted>
  <disposition_first_submitted_qc>October 20, 2017</disposition_first_submitted_qc>
  <disposition_first_posted type="Actual">October 23, 2017</disposition_first_posted>
  <last_update_submitted>January 29, 2021</last_update_submitted>
  <last_update_submitted_qc>January 29, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">February 16, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Intervention 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 acid receptor agonist</keyword>
  <keyword>Retinoic acid receptor gamma agonist</keyword>
  <keyword>Clementia</keyword>
  <keyword>Myositis Ossificans Progressiva</keyword>
  <keyword>Munchmeyer's Disease</keyword>
  <keyword>FOP</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Myositis Ossificans</mesh_term>
  </condition_browse>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Eight subjects were randomized 3:1 to either palovarotene or placebo in Cohort 1; 8 additional subjects were randomized 3:1 in an interim period between Cohorts 1 and 2. In Cohort 2, 24 additional fibrodysplasia ossificans progressiva (FOP) subjects were randomized 3:3:2 across 2 weight-based regimens of palovarotene or placebo.</recruitment_details>
      <pre_assignment_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.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Palovarotene 10/5 mg</title>
          <description>Subjects received palovarotene 10 milligram (mg) orally for 14 days followed by 5 mg orally 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.</description>
        </group>
        <group group_id="P2">
          <title>Palovarotene 5/2.5 mg</title>
          <description>Subjects received palovarotene 5 mg orally for 14 days followed by 2.5 mg orally 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.</description>
        </group>
        <group group_id="P3">
          <title>Placebo</title>
          <description>Subjects received placebo (matching with palovarotene) 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.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="21"/>
                <participants group_id="P2" count="9"/>
                <participants group_id="P3" count="10"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="21"/>
                <participants group_id="P2" count="9"/>
                <participants group_id="P3" count="10"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>The safety population included all subjects who received at least 1 dose of study drug (placebo or palovarotene).</population>
      <group_list>
        <group group_id="B1">
          <title>Palovarotene 10/5 mg</title>
          <description>Subjects received palovarotene 10 mg orally for 14 days followed by 5 mg orally 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.</description>
        </group>
        <group group_id="B2">
          <title>Palovarotene 5/2.5 mg</title>
          <description>Subjects received palovarotene 5 mg orally for 14 days followed by 2.5 mg orally 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.</description>
        </group>
        <group group_id="B3">
          <title>Placebo</title>
          <description>Subjects received placebo (matching with palovarotene) 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.</description>
        </group>
        <group group_id="B4">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="21"/>
            <count group_id="B2" value="9"/>
            <count group_id="B3" value="10"/>
            <count group_id="B4" value="40"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="22.8" spread="10.3"/>
                    <measurement group_id="B2" value="17.9" spread="8.6"/>
                    <measurement group_id="B3" value="21.2" spread="13.7"/>
                    <measurement group_id="B4" value="21.3" spread="10.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age, Customized</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Children (2-11 years)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Adolescents (12-17 years)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="4"/>
                    <measurement group_id="B4" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Adults (18-64 years)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="4"/>
                    <measurement group_id="B4" value="22"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="7"/>
                    <measurement group_id="B4" value="22"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="3"/>
                    <measurement group_id="B4" value="18"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="6"/>
                    <measurement group_id="B4" value="27"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="3"/>
                    <measurement group_id="B4" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>White</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="6"/>
                    <measurement group_id="B4" value="25"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Black or African American</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Asian</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Multiple</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Not available</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="3"/>
                    <measurement group_id="B4" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Percentage of Responders at Week 6</title>
        <description>A responder was defined as a subject with no or minimal new heterotopic ossification (HO) at flare-up site versus baseline as assessed by plain radiographs at Week 6. Minimal new HO is defined as new HO with an HO score &lt;=3 in both anterior/posterior (AP) and lateral projections (or if one view is non-interpretable or non-evaluable, then remaining evaluable view is used). The HO score ranges from 0 to 6 where, 0 = no HO and 6 = single contiguous HO with longest dimension &gt;2 diameters of reference normotopic bone in any projection. The highest HO score from the 2 projections was used. Results from Primary Read reviews are presented. The Primary Read process included a double-read radiology review paradigm with consensus adjudication. Radiography and CT scans were examined independently by scan type, flare-up region, and imaging time point in order to determine whether radiography would be sufficient to measure new HO formation. Only subjects with interpretable outcomes were evaluated.</description>
        <time_frame>Baseline (Day 1) and Week 6 (Day 42)</time_frame>
        <population>The Per Protocol (PP) population included all subjects who were eligible for full analysis set (FAS) population, completed Week 6 study visit with no major protocol deviations with at least 80% compliance with study drug, and had an evaluable radiograph or computed tomography (CT) at Week 6 sufficient to allow determination of HO at flare-up site.</population>
        <group_list>
          <group group_id="O1">
            <title>Palovarotene 10/5 mg</title>
            <description>Subjects received palovarotene 10 mg orally for 14 days followed by 5 mg orally 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.</description>
          </group>
          <group group_id="O2">
            <title>Palovarotene 5/2.5 mg</title>
            <description>Subjects received palovarotene 5 mg orally for 14 days followed by 2.5 mg orally 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.</description>
          </group>
          <group group_id="O3">
            <title>Placebo</title>
            <description>Subjects received placebo (matching with palovarotene) 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.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Responders at Week 6</title>
          <description>A responder was defined as a subject with no or minimal new heterotopic ossification (HO) at flare-up site versus baseline as assessed by plain radiographs at Week 6. Minimal new HO is defined as new HO with an HO score &lt;=3 in both anterior/posterior (AP) and lateral projections (or if one view is non-interpretable or non-evaluable, then remaining evaluable view is used). The HO score ranges from 0 to 6 where, 0 = no HO and 6 = single contiguous HO with longest dimension &gt;2 diameters of reference normotopic bone in any projection. The highest HO score from the 2 projections was used. Results from Primary Read reviews are presented. The Primary Read process included a double-read radiology review paradigm with consensus adjudication. Radiography and CT scans were examined independently by scan type, flare-up region, and imaging time point in order to determine whether radiography would be sufficient to measure new HO formation. Only subjects with interpretable outcomes were evaluated.</description>
          <population>The Per Protocol (PP) population included all subjects who were eligible for full analysis set (FAS) population, completed Week 6 study visit with no major protocol deviations with at least 80% compliance with study drug, and had an evaluable radiograph or computed tomography (CT) at Week 6 sufficient to allow determination of HO at flare-up site.</population>
          <units>percentage of subjects</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="9"/>
                <count group_id="O3" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="100"/>
                    <measurement group_id="O2" value="88.9"/>
                    <measurement group_id="O3" value="88.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>Cochran-Armitage test of trend (one-sided). The Cochran-Armitage test of trend assessed the overall trend of response across the dose groups (from the lowest dose [or placebo], to the highest dose).</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.1664</p_value>
            <method>Cochran-Armitage test of trend</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Subjects With New HO at Weeks 6 and 12</title>
        <description>Low dose CT scan was used as a secondary imaging assessment of HO and was performed at the same time points as plain radiographs. The percentage of subjects with new HO (regardless of the amount of new HO) at the flare-up site as assessed by CT scan and/or plain radiographs at Weeks 6 and 12 were analysed. The results are from Global Read reviews. The holistic Global Read process allowed concurrent review of all modalities across all time points, and provided access to selected clinical data at the time of review.</description>
        <time_frame>Weeks 6 and 12 (Day 84)</time_frame>
        <population>The PP population included all subjects who were eligible for the FAS population, completed Week 6 study visit with no major protocol deviations with at least 80% compliance with study drug, and had an evaluable radiograph or CT at Week 6 sufficient to allow determination of HO at flare-up site.</population>
        <group_list>
          <group group_id="O1">
            <title>Palovarotene 10/5 mg</title>
            <description>Subjects received palovarotene 10 mg orally for 14 days followed by 5 mg orally 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.</description>
          </group>
          <group group_id="O2">
            <title>Palovarotene 5/2.5 mg</title>
            <description>Subjects received palovarotene 5 mg orally for 14 days followed by 2.5 mg orally 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.</description>
          </group>
          <group group_id="O3">
            <title>Placebo</title>
            <description>Subjects received placebo (matching with palovarotene) 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.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Subjects With New HO at Weeks 6 and 12</title>
          <description>Low dose CT scan was used as a secondary imaging assessment of HO and was performed at the same time points as plain radiographs. The percentage of subjects with new HO (regardless of the amount of new HO) at the flare-up site as assessed by CT scan and/or plain radiographs at Weeks 6 and 12 were analysed. The results are from Global Read reviews. The holistic Global Read process allowed concurrent review of all modalities across all time points, and provided access to selected clinical data at the time of review.</description>
          <population>The PP population included all subjects who were eligible for the FAS population, completed Week 6 study visit with no major protocol deviations with at least 80% compliance with study drug, and had an evaluable radiograph or CT at Week 6 sufficient to allow determination of HO at flare-up site.</population>
          <units>percentage of subjects</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="9"/>
                <count group_id="O3" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Week 6</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="15.0"/>
                    <measurement group_id="O2" value="22.2"/>
                    <measurement group_id="O3" value="30.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 12</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="15.0"/>
                    <measurement group_id="O2" value="44.4"/>
                    <measurement group_id="O3" value="40.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>Week 6: Cochran-Armitage test of trend (one-sided). The Cochran-Armitage test of trend assessed the overall trend of response across the dose groups (from the lowest dose [or placebo], to the highest dose).</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.2335</p_value>
            <method>Cochran-Armitage test of trend</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>Week 12: Cochran-Armitage test of trend (one-sided). The Cochran-Armitage test of trend assessed the overall trend of response across the dose groups (from the lowest dose [or placebo], to the highest dose).</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0837</p_value>
            <method>Cochran-Armitage test of trend</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Amount (Area) of New HO Formed at the Flare-up Site at Weeks 6 and 12</title>
        <description>Interpretation of plain radiographs document the amount (area) of HO on both the AP and lateral radiograph views. The area for each view was a sum of all the new HO at the flare-up location (and thus if there are multiple HO lesions, the area of each lesion was determined and then the total across all lesions were summed to obtain a total new HO). This total new HO sum was used in the analysis of the area of new HO. Results from Primary Read reviews are presented.</description>
        <time_frame>Baseline, Weeks 6 and 12</time_frame>
        <population>The PP population included all subjects who were eligible for the FAS population, completed Week 6 study visit with no major protocol deviations with at least 80% compliance with study drug, and had an evaluable radiograph or CT at Week 6 sufficient to allow determination of HO at flare-up site.</population>
        <group_list>
          <group group_id="O1">
            <title>Palovarotene 10/5 mg</title>
            <description>Subjects received palovarotene 10 mg orally for 14 days followed by 5 mg orally 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.</description>
          </group>
          <group group_id="O2">
            <title>Palovarotene 5/2.5 mg</title>
            <description>Subjects received palovarotene 5 mg orally for 14 days followed by 2.5 mg orally 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.</description>
          </group>
          <group group_id="O3">
            <title>Placebo</title>
            <description>Subjects received placebo (matching with palovarotene) 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.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Amount (Area) of New HO Formed at the Flare-up Site at Weeks 6 and 12</title>
          <description>Interpretation of plain radiographs document the amount (area) of HO on both the AP and lateral radiograph views. The area for each view was a sum of all the new HO at the flare-up location (and thus if there are multiple HO lesions, the area of each lesion was determined and then the total across all lesions were summed to obtain a total new HO). This total new HO sum was used in the analysis of the area of new HO. Results from Primary Read reviews are presented.</description>
          <population>The PP population included all subjects who were eligible for the FAS population, completed Week 6 study visit with no major protocol deviations with at least 80% compliance with study drug, and had an evaluable radiograph or CT at Week 6 sufficient to allow determination of HO at flare-up site.</population>
          <units>square millimeters (mm)</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="9"/>
                <count group_id="O3" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Week 6</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="20"/>
                    <count group_id="O2" value="9"/>
                    <count group_id="O3" value="9"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.00" spread="0.000"/>
                    <measurement group_id="O2" value="38.85" spread="116.542"/>
                    <measurement group_id="O3" value="75.89" spread="176.744"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 12</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="20"/>
                    <count group_id="O2" value="9"/>
                    <count group_id="O3" value="9"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="19.00" spread="84.955"/>
                    <measurement group_id="O2" value="71.22" spread="213.650"/>
                    <measurement group_id="O3" value="621.71" spread="1287.519"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>Week 6: Analysis of area of new HO</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.6984</p_value>
            <method>Pairwise test</method>
            <param_type>Least square (LS) mean</param_type>
            <param_value>-86.35</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>220.570</dispersion_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>Week 6: Analysis of area of new HO</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.8811</p_value>
            <method>Pairwise test</method>
            <param_type>LS mean</param_type>
            <param_value>-38.07</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>252.192</dispersion_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>Week 12: Analysis of area of new HO</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0017</p_value>
            <method>Pairwise test</method>
            <param_type>LS mean</param_type>
            <param_value>-764.38</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>220.570</dispersion_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>Week 12: Analysis of area of new HO</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0094</p_value>
            <method>Pairwise test</method>
            <param_type>LS mean</param_type>
            <param_value>-703.43</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>252.192</dispersion_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Responders at Week 12</title>
        <description>A responder was defined as a subject with no or minimal new HO at the flare-up site versus baseline as assessed by plain radiographs at Week 12. Minimal new HO is defined as new HO with an HO score &lt;=3 in both the AP and lateral projections (or if one view is non-interpretable or non-evaluable, then the remaining evaluable view is used). The HO score ranges from 0 to 6 where, 0 = no HO and 6 = single contiguous HO with longest dimension &gt;2 diameters of the reference normotopic bone in any projection. The highest HO score from the 2 projections was used. Results from the Primary Read reviews are presented. The Primary Read process included a double-read radiology review paradigm with consensus adjudication. Radiography and CT scans were examined independently by scan type, flare-up region, and imaging time point in order to determine whether radiography would be sufficient to measure new HO formation.</description>
        <time_frame>Baseline and Week 12</time_frame>
        <population>The PP population included all subjects who were eligible for FAS population, completed Week 6 study visit with no major protocol deviations with at least 80% compliance with study drug, and had an evaluable radiograph or CT at Week 6 sufficient to allow determination of HO at flare-up site. Only subjects with interpretable outcomes were evaluated.</population>
        <group_list>
          <group group_id="O1">
            <title>Palovarotene 10/5 mg</title>
            <description>Subjects received palovarotene 10 mg orally for 14 days followed by 5 mg orally 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.</description>
          </group>
          <group group_id="O2">
            <title>Palovarotene 5/2.5 mg</title>
            <description>Subjects received palovarotene 5 mg orally for 14 days followed by 2.5 mg orally 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.</description>
          </group>
          <group group_id="O3">
            <title>Placebo</title>
            <description>Subjects received placebo (matching with palovarotene) 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.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Responders at Week 12</title>
          <description>A responder was defined as a subject with no or minimal new HO at the flare-up site versus baseline as assessed by plain radiographs at Week 12. Minimal new HO is defined as new HO with an HO score &lt;=3 in both the AP and lateral projections (or if one view is non-interpretable or non-evaluable, then the remaining evaluable view is used). The HO score ranges from 0 to 6 where, 0 = no HO and 6 = single contiguous HO with longest dimension &gt;2 diameters of the reference normotopic bone in any projection. The highest HO score from the 2 projections was used. Results from the Primary Read reviews are presented. The Primary Read process included a double-read radiology review paradigm with consensus adjudication. Radiography and CT scans were examined independently by scan type, flare-up region, and imaging time point in order to determine whether radiography would be sufficient to measure new HO formation.</description>
          <population>The PP population included all subjects who were eligible for FAS population, completed Week 6 study visit with no major protocol deviations with at least 80% compliance with study drug, and had an evaluable radiograph or CT at Week 6 sufficient to allow determination of HO at flare-up site. Only subjects with interpretable outcomes were evaluated.</population>
          <units>percentage of subjects</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="9"/>
                <count group_id="O3" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="95.0"/>
                    <measurement group_id="O2" value="88.9"/>
                    <measurement group_id="O3" value="77.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>Cochran-Armitage test of trend (one-sided). The Cochran-Armitage test of trend assessed the overall trend of response across the dose groups (from the lowest dose [or placebo], to the highest dose).</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.1503</p_value>
            <method>Cochran-Armitage test of trend</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Bone Specific Alkaline Phosphatase at Weeks 2, 4, 6 and 12</title>
        <description>Blood and urine samples for analysis of cartilage, bone, angiogenesis, and inflammation biomarkers were collected. Bone specific alkaline phosphatase was analysed as a bone and cartilage biomarker.</description>
        <time_frame>Baseline, Weeks 2, 4, 6 and 12</time_frame>
        <population>The FAS population included all subjects who received at least 1 dose of study drug and had at least 1 evaluable post-baseline radiograph or CT sufficient to allow determination of HO at the flare-up site.</population>
        <group_list>
          <group group_id="O1">
            <title>Palovarotene 10/5 mg</title>
            <description>Subjects received palovarotene 10 mg orally for 14 days followed by 5 mg orally 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.</description>
          </group>
          <group group_id="O2">
            <title>Palovarotene 5/2.5 mg</title>
            <description>Subjects received palovarotene 5 mg orally for 14 days followed by 2.5 mg orally 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.</description>
          </group>
          <group group_id="O3">
            <title>Placebo</title>
            <description>Subjects received placebo (matching with palovarotene) 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.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Bone Specific Alkaline Phosphatase at Weeks 2, 4, 6 and 12</title>
          <description>Blood and urine samples for analysis of cartilage, bone, angiogenesis, and inflammation biomarkers were collected. Bone specific alkaline phosphatase was analysed as a bone and cartilage biomarker.</description>
          <population>The FAS population included all subjects who received at least 1 dose of study drug and had at least 1 evaluable post-baseline radiograph or CT sufficient to allow determination of HO at the flare-up site.</population>
          <units>microgram per liter (mcg/L)</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="21"/>
                <count group_id="O2" value="9"/>
                <count group_id="O3" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Week 2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="15"/>
                    <count group_id="O2" value="4"/>
                    <count group_id="O3" value="6"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-1.33" spread="13.267"/>
                    <measurement group_id="O2" value="-3.18" spread="4.619"/>
                    <measurement group_id="O3" value="12.02" spread="35.263"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 4</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="15"/>
                    <count group_id="O2" value="7"/>
                    <count group_id="O3" value="6"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-1.41" spread="8.328"/>
                    <measurement group_id="O2" value="3.80" spread="12.072"/>
                    <measurement group_id="O3" value="7.53" spread="10.208"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 6</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="17"/>
                    <count group_id="O2" value="7"/>
                    <count group_id="O3" value="7"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-2.53" spread="8.157"/>
                    <measurement group_id="O2" value="0.74" spread="3.316"/>
                    <measurement group_id="O3" value="6.23" spread="6.851"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 12</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="16"/>
                    <count group_id="O2" value="7"/>
                    <count group_id="O3" value="7"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.49" spread="5.506"/>
                    <measurement group_id="O2" value="0.89" spread="6.738"/>
                    <measurement group_id="O3" value="10.00" spread="10.091"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in C-Reactive Protein at Weeks 2, 4, 6 and 12</title>
        <description>Blood and urine samples for analysis of cartilage, bone, angiogenesis, and inflammation biomarkers were collected. C-reactive protein was analysed as a inflammation biomarker.</description>
        <time_frame>Baseline, Weeks 2, 4, 6 and 12</time_frame>
        <population>The FAS population included all subjects who received at least 1 dose of study drug and had at least 1 evaluable post-baseline radiograph or CT sufficient to allow determination of HO at the flare-up site.</population>
        <group_list>
          <group group_id="O1">
            <title>Palovarotene 10/5 mg</title>
            <description>Subjects received palovarotene 10 mg orally for 14 days followed by 5 mg orally 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.</description>
          </group>
          <group group_id="O2">
            <title>Palovarotene 5/2.5 mg</title>
            <description>Subjects received palovarotene 5 mg orally for 14 days followed by 2.5 mg orally 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.</description>
          </group>
          <group group_id="O3">
            <title>Placebo</title>
            <description>Subjects received placebo (matching with palovarotene) 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.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in C-Reactive Protein at Weeks 2, 4, 6 and 12</title>
          <description>Blood and urine samples for analysis of cartilage, bone, angiogenesis, and inflammation biomarkers were collected. C-reactive protein was analysed as a inflammation biomarker.</description>
          <population>The FAS population included all subjects who received at least 1 dose of study drug and had at least 1 evaluable post-baseline radiograph or CT sufficient to allow determination of HO at the flare-up site.</population>
          <units>mg/L</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="21"/>
                <count group_id="O2" value="9"/>
                <count group_id="O3" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Week 2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="13"/>
                    <count group_id="O2" value="6"/>
                    <count group_id="O3" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8.62" spread="28.085"/>
                    <measurement group_id="O2" value="0.09" spread="2.370"/>
                    <measurement group_id="O3" value="-1.59" spread="1.909"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 4</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="15"/>
                    <count group_id="O2" value="7"/>
                    <count group_id="O3" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.48" spread="4.924"/>
                    <measurement group_id="O2" value="23.26" spread="38.311"/>
                    <measurement group_id="O3" value="2.34" spread="3.704"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 6</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="15"/>
                    <count group_id="O2" value="7"/>
                    <count group_id="O3" value="6"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.14" spread="3.419"/>
                    <measurement group_id="O2" value="2.70" spread="7.984"/>
                    <measurement group_id="O3" value="1.20" spread="1.319"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 12</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="15"/>
                    <count group_id="O2" value="7"/>
                    <count group_id="O3" value="6"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.82" spread="11.762"/>
                    <measurement group_id="O2" value="1.27" spread="1.789"/>
                    <measurement group_id="O3" value="-0.30" spread="2.951"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in C-Terminal Telopeptide at Weeks 2, 4, 6 and 12</title>
        <description>Blood and urine samples for analysis of cartilage, bone, angiogenesis, and inflammation biomarkers were collected. C-terminal telopeptide was analysed as a bone and cartilage biomarker.</description>
        <time_frame>Baseline, Weeks 2, 4, 6 and 12</time_frame>
        <population>The FAS population included all subjects who received at least 1 dose of study drug and had at least 1 evaluable post-baseline radiograph or CT sufficient to allow determination of HO at the flare-up site.</population>
        <group_list>
          <group group_id="O1">
            <title>Palovarotene 10/5 mg</title>
            <description>Subjects received palovarotene 10 mg orally for 14 days followed by 5 mg orally 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.</description>
          </group>
          <group group_id="O2">
            <title>Palovarotene 5/2.5 mg</title>
            <description>Subjects received palovarotene 5 mg orally for 14 days followed by 2.5 mg orally 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.</description>
          </group>
          <group group_id="O3">
            <title>Placebo</title>
            <description>Subjects received placebo (matching with palovarotene) 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.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in C-Terminal Telopeptide at Weeks 2, 4, 6 and 12</title>
          <description>Blood and urine samples for analysis of cartilage, bone, angiogenesis, and inflammation biomarkers were collected. C-terminal telopeptide was analysed as a bone and cartilage biomarker.</description>
          <population>The FAS population included all subjects who received at least 1 dose of study drug and had at least 1 evaluable post-baseline radiograph or CT sufficient to allow determination of HO at the flare-up site.</population>
          <units>mcg/L</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="21"/>
                <count group_id="O2" value="9"/>
                <count group_id="O3" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Week 2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="15"/>
                    <count group_id="O2" value="5"/>
                    <count group_id="O3" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.020" spread="0.290"/>
                    <measurement group_id="O2" value="0.118" spread="0.359"/>
                    <measurement group_id="O3" value="0.071" spread="0.342"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 4</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="16"/>
                    <count group_id="O2" value="8"/>
                    <count group_id="O3" value="6"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.015" spread="0.337"/>
                    <measurement group_id="O2" value="0.095" spread="0.380"/>
                    <measurement group_id="O3" value="0.188" spread="0.219"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 6</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="19"/>
                    <count group_id="O2" value="8"/>
                    <count group_id="O3" value="8"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.105" spread="0.304"/>
                    <measurement group_id="O2" value="0.078" spread="0.293"/>
                    <measurement group_id="O3" value="0.125" spread="0.351"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 12</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="18"/>
                    <count group_id="O2" value="8"/>
                    <count group_id="O3" value="7"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.116" spread="0.241"/>
                    <measurement group_id="O2" value="0.054" spread="0.285"/>
                    <measurement group_id="O3" value="0.126" spread="0.197"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Procollagen Type 1 N-Terminal Propeptide at Weeks 2, 4, 6 and 12</title>
        <description>Blood and urine samples for analysis of cartilage, bone, angiogenesis, and inflammation biomarkers were collected. Procollagen type 1 N-terminal propeptide was analysed as a bone and cartilage biomarker.</description>
        <time_frame>Baseline, Weeks 2, 4, 6 and 12</time_frame>
        <population>The FAS population included all subjects who received at least 1 dose of study drug and had at least 1 evaluable post-baseline radiograph or CT sufficient to allow determination of HO at the flare-up site.</population>
        <group_list>
          <group group_id="O1">
            <title>Palovarotene 10/5 mg</title>
            <description>Subjects received palovarotene 10 mg orally for 14 days followed by 5 mg orally 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.</description>
          </group>
          <group group_id="O2">
            <title>Palovarotene 5/2.5 mg</title>
            <description>Subjects received palovarotene 5 mg orally for 14 days followed by 2.5 mg orally 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.</description>
          </group>
          <group group_id="O3">
            <title>Placebo</title>
            <description>Subjects received placebo (matching with palovarotene) 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.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Procollagen Type 1 N-Terminal Propeptide at Weeks 2, 4, 6 and 12</title>
          <description>Blood and urine samples for analysis of cartilage, bone, angiogenesis, and inflammation biomarkers were collected. Procollagen type 1 N-terminal propeptide was analysed as a bone and cartilage biomarker.</description>
          <population>The FAS population included all subjects who received at least 1 dose of study drug and had at least 1 evaluable post-baseline radiograph or CT sufficient to allow determination of HO at the flare-up site.</population>
          <units>mcg/L</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="21"/>
                <count group_id="O2" value="9"/>
                <count group_id="O3" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Week 2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="14"/>
                    <count group_id="O2" value="4"/>
                    <count group_id="O3" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="53.022" spread="72.091"/>
                    <measurement group_id="O2" value="78.930" spread="113.443"/>
                    <measurement group_id="O3" value="42.058" spread="77.358"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 4</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="15"/>
                    <count group_id="O2" value="8"/>
                    <count group_id="O3" value="6"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="123.986" spread="207.513"/>
                    <measurement group_id="O2" value="117.476" spread="169.238"/>
                    <measurement group_id="O3" value="194.193" spread="318.920"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 6</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="18"/>
                    <count group_id="O2" value="8"/>
                    <count group_id="O3" value="6"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="141.304" spread="206.163"/>
                    <measurement group_id="O2" value="147.409" spread="246.219"/>
                    <measurement group_id="O3" value="252.328" spread="389.359"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 12</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="17"/>
                    <count group_id="O2" value="8"/>
                    <count group_id="O3" value="6"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="120.489" spread="211.565"/>
                    <measurement group_id="O2" value="25.766" spread="233.860"/>
                    <measurement group_id="O3" value="141.367" spread="213.926"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Procollagen Type 1 C-Terminal Propeptide Biomarker at Weeks 2, 4, 6 and 12</title>
        <description>Blood and urine samples for analysis of cartilage, bone, angiogenesis, and inflammation biomarkers were collected. Procollagen type 1 C-terminal propeptide was analysed as a bone and cartilage biomarker.</description>
        <time_frame>Baseline, Weeks 2, 4, 6 and 12</time_frame>
        <population>The FAS population included all subjects who received at least 1 dose of study drug and had at least 1 evaluable post-baseline radiograph or CT sufficient to allow determination of HO at the flare-up site.</population>
        <group_list>
          <group group_id="O1">
            <title>Palovarotene 10/5 mg</title>
            <description>Subjects received palovarotene 10 mg orally for 14 days followed by 5 mg orally 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.</description>
          </group>
          <group group_id="O2">
            <title>Palovarotene 5/2.5 mg</title>
            <description>Subjects received palovarotene 5 mg orally for 14 days followed by 2.5 mg orally 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.</description>
          </group>
          <group group_id="O3">
            <title>Placebo</title>
            <description>Subjects received placebo (matching with palovarotene) 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.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Procollagen Type 1 C-Terminal Propeptide Biomarker at Weeks 2, 4, 6 and 12</title>
          <description>Blood and urine samples for analysis of cartilage, bone, angiogenesis, and inflammation biomarkers were collected. Procollagen type 1 C-terminal propeptide was analysed as a bone and cartilage biomarker.</description>
          <population>The FAS population included all subjects who received at least 1 dose of study drug and had at least 1 evaluable post-baseline radiograph or CT sufficient to allow determination of HO at the flare-up site.</population>
          <units>mcg/L</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="21"/>
                <count group_id="O2" value="9"/>
                <count group_id="O3" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Week 2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="15"/>
                    <count group_id="O2" value="5"/>
                    <count group_id="O3" value="6"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="22.12" spread="61.976"/>
                    <measurement group_id="O2" value="23.26" spread="11.585"/>
                    <measurement group_id="O3" value="82.93" spread="109.010"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 4</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="15"/>
                    <count group_id="O2" value="8"/>
                    <count group_id="O3" value="7"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="72.16" spread="98.697"/>
                    <measurement group_id="O2" value="76.10" spread="110.041"/>
                    <measurement group_id="O3" value="140.26" spread="155.036"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 6</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="18"/>
                    <count group_id="O2" value="8"/>
                    <count group_id="O3" value="8"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="73.36" spread="130.437"/>
                    <measurement group_id="O2" value="87.19" spread="96.451"/>
                    <measurement group_id="O3" value="125.31" spread="110.389"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 12</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="17"/>
                    <count group_id="O2" value="8"/>
                    <count group_id="O3" value="7"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="51.21" spread="82.901"/>
                    <measurement group_id="O2" value="47.30" spread="112.113"/>
                    <measurement group_id="O3" value="96.49" spread="92.215"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Amount of Bone Formation (Volume) at Weeks 6 and 12</title>
        <description>Low dose CT scan were used as a secondary imaging assessment of HO, and was performed at the same time points as plain radiographs. Interpretation of the CT scan documented the amount (volume) and grade of HO. The independent reviewer scored HO lesions according to the following scale for HO on CT. Grade 1 = fluid attenuation without evidence of calcification at CT, Grade 2 = calcification of soft tissues without evidence of bone formation, Grade 3 = immature bone formation, and Grade 4 = mature bone with cortical differentiation. Volume of new HO was determined according to the following steps: (1) calculate volume of new HO compared to baseline for each reviewer/HO ID, (2) sum the volume of new HO across HO IDs for each reviewer, and (3) average the volume of new HO across reviewers. Results from Primary Read reviews are presented.</description>
        <time_frame>Baseline, Weeks 6 and 12</time_frame>
        <population>The PP population included all subjects who were eligible for the FAS population, completed Week 6 study visit with no major protocol deviations with at least 80% compliance with study drug, and had an evaluable radiograph or CT at Week 6 sufficient to allow determination of HO at flare-up site.</population>
        <group_list>
          <group group_id="O1">
            <title>Palovarotene 10/5 mg</title>
            <description>Subjects received palovarotene 10 mg orally for 14 days followed by 5 mg orally 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.</description>
          </group>
          <group group_id="O2">
            <title>Palovarotene 5/2.5 mg</title>
            <description>Subjects received palovarotene 5 mg orally for 14 days followed by 2.5 mg orally 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.</description>
          </group>
          <group group_id="O3">
            <title>Placebo</title>
            <description>Subjects received placebo (matching with palovarotene) 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.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Amount of Bone Formation (Volume) at Weeks 6 and 12</title>
          <description>Low dose CT scan were used as a secondary imaging assessment of HO, and was performed at the same time points as plain radiographs. Interpretation of the CT scan documented the amount (volume) and grade of HO. The independent reviewer scored HO lesions according to the following scale for HO on CT. Grade 1 = fluid attenuation without evidence of calcification at CT, Grade 2 = calcification of soft tissues without evidence of bone formation, Grade 3 = immature bone formation, and Grade 4 = mature bone with cortical differentiation. Volume of new HO was determined according to the following steps: (1) calculate volume of new HO compared to baseline for each reviewer/HO ID, (2) sum the volume of new HO across HO IDs for each reviewer, and (3) average the volume of new HO across reviewers. Results from Primary Read reviews are presented.</description>
          <population>The PP population included all subjects who were eligible for the FAS population, completed Week 6 study visit with no major protocol deviations with at least 80% compliance with study drug, and had an evaluable radiograph or CT at Week 6 sufficient to allow determination of HO at flare-up site.</population>
          <units>cubic mm</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="9"/>
                <count group_id="O3" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Week 6</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="19"/>
                    <count group_id="O2" value="9"/>
                    <count group_id="O3" value="10"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2820.53" spread="11078.233"/>
                    <measurement group_id="O2" value="326.58" spread="979.733"/>
                    <measurement group_id="O3" value="11459.42" spread="29759.691"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 12</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="17"/>
                    <count group_id="O2" value="9"/>
                    <count group_id="O3" value="10"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3857.95" spread="11860.978"/>
                    <measurement group_id="O2" value="1184.99" spread="3188.020"/>
                    <measurement group_id="O3" value="16181.64" spread="41643.976"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Subjects With Soft Tissue Swelling and Cartilage Formation Assessed by Magnetic Resonance Imaging (MRI) or Ultrasound (US) at Weeks 6 and 12</title>
        <description>The MRI was utilized to evaluate the presence of soft tissue swelling/edema (and volume of the swelling/edema) and presence of cartilage formation (yes or no). For subjects who could not have an MRI, US was used to assess edema severity for the sub-set of subjects enrolled after this opinion was introduced in a protocol amendment. Imaging film from MRI was assessed by two independent readers. When there was sufficient agreement between the independent readers on volume, both of the independent readings were used for analysis with the volume measurements averaged. When there was insufficient agreement between the independent readers, an adjudication reading was provided and used for analysis. The US was used for soft tissue swelling/edema but not cartilage formation. Percentage calculated as % = 100 x n/N' where N' is the number of subjects with interpretable outcomes. Results from Primary Read reviews are presented.</description>
        <time_frame>Weeks 6 and 12</time_frame>
        <population>The FAS population included all subjects who received at least 1 dose of study drug and had at least 1 evaluable post-baseline radiograph or CT sufficient to allow determination of HO at the flare-up site.</population>
        <group_list>
          <group group_id="O1">
            <title>Palovarotene 10/5 mg</title>
            <description>Subjects received palovarotene 10 mg orally for 14 days followed by 5 mg orally 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.</description>
          </group>
          <group group_id="O2">
            <title>Palovarotene 5/2.5 mg</title>
            <description>Subjects received palovarotene 5 mg orally for 14 days followed by 2.5 mg orally 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.</description>
          </group>
          <group group_id="O3">
            <title>Placebo</title>
            <description>Subjects received placebo (matching with palovarotene) 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.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Subjects With Soft Tissue Swelling and Cartilage Formation Assessed by Magnetic Resonance Imaging (MRI) or Ultrasound (US) at Weeks 6 and 12</title>
          <description>The MRI was utilized to evaluate the presence of soft tissue swelling/edema (and volume of the swelling/edema) and presence of cartilage formation (yes or no). For subjects who could not have an MRI, US was used to assess edema severity for the sub-set of subjects enrolled after this opinion was introduced in a protocol amendment. Imaging film from MRI was assessed by two independent readers. When there was sufficient agreement between the independent readers on volume, both of the independent readings were used for analysis with the volume measurements averaged. When there was insufficient agreement between the independent readers, an adjudication reading was provided and used for analysis. The US was used for soft tissue swelling/edema but not cartilage formation. Percentage calculated as % = 100 x n/N' where N' is the number of subjects with interpretable outcomes. Results from Primary Read reviews are presented.</description>
          <population>The FAS population included all subjects who received at least 1 dose of study drug and had at least 1 evaluable post-baseline radiograph or CT sufficient to allow determination of HO at the flare-up site.</population>
          <units>percentage of subjects</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="21"/>
                <count group_id="O2" value="9"/>
                <count group_id="O3" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Soft tissue swelling: Week 6</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="16"/>
                    <count group_id="O2" value="8"/>
                    <count group_id="O3" value="9"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="50.0"/>
                    <measurement group_id="O2" value="50.0"/>
                    <measurement group_id="O3" value="66.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Soft tissue swelling: Week 12</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="15"/>
                    <count group_id="O2" value="9"/>
                    <count group_id="O3" value="9"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="60.0"/>
                    <measurement group_id="O2" value="66.7"/>
                    <measurement group_id="O3" value="66.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Cartilage formation: Week 6</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="13"/>
                    <count group_id="O2" value="3"/>
                    <count group_id="O3" value="4"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="15.4"/>
                    <measurement group_id="O2" value="0.0"/>
                    <measurement group_id="O3" value="0.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Cartilage formation: Week 12</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="12"/>
                    <count group_id="O2" value="3"/>
                    <count group_id="O3" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8.3"/>
                    <measurement group_id="O2" value="0.0"/>
                    <measurement group_id="O3" value="0.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Percent of Normal Arc of Motion at the Primary Joint (Flare-up Site) at Weeks 6 and 12</title>
        <description>Active range of motion, expressed as the percent of normal arc of motion, measurements at the primary joint associated with the flare-up and adjoining joints was assessed by goniometer.</description>
        <time_frame>Baseline, Weeks 6 and 12</time_frame>
        <population>The FAS population included all subjects who received at least 1 dose of study drug and had at least 1 evaluable post-baseline radiograph or CT sufficient to allow determination of HO at the flare-up site.</population>
        <group_list>
          <group group_id="O1">
            <title>Palovarotene 10/5 mg</title>
            <description>Subjects received palovarotene 10 mg orally for 14 days followed by 5 mg orally 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.</description>
          </group>
          <group group_id="O2">
            <title>Palovarotene 5/2.5 mg</title>
            <description>Subjects received palovarotene 5 mg orally for 14 days followed by 2.5 mg orally 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.</description>
          </group>
          <group group_id="O3">
            <title>Placebo</title>
            <description>Subjects received placebo (matching with palovarotene) 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.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Percent of Normal Arc of Motion at the Primary Joint (Flare-up Site) at Weeks 6 and 12</title>
          <description>Active range of motion, expressed as the percent of normal arc of motion, measurements at the primary joint associated with the flare-up and adjoining joints was assessed by goniometer.</description>
          <population>The FAS population included all subjects who received at least 1 dose of study drug and had at least 1 evaluable post-baseline radiograph or CT sufficient to allow determination of HO at the flare-up site.</population>
          <units>percent of normal arc of motion</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="21"/>
                <count group_id="O2" value="9"/>
                <count group_id="O3" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Week 6</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="20"/>
                    <count group_id="O2" value="8"/>
                    <count group_id="O3" value="10"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.40" spread="9.574"/>
                    <measurement group_id="O2" value="-1.36" spread="21.336"/>
                    <measurement group_id="O3" value="-0.99" spread="18.951"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 12</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="20"/>
                    <count group_id="O2" value="8"/>
                    <count group_id="O3" value="10"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.58" spread="15.079"/>
                    <measurement group_id="O2" value="-4.23" spread="26.791"/>
                    <measurement group_id="O3" value="-2.31" spread="18.963"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Subject and Investigator Global Assessment of Movement at Weeks 6 and 12</title>
        <description>Flare-up movement outcomes were independently assessed by both the subject (or parent of a subject under 8 years of age) and the Investigator at Weeks 6 and 12 by completing the global assessment of movement. The subject/parent completed the global assessment first. Prior to reviewing the subject's assessment, the Investigator completed his/her own assessment of the flare-up outcome. Subjects were assessed how the flare-up affected their movement on a scale ranging 1 to 5 where, 1 = severely worse movement and 5 = better movement compared with study Day 1 (day of first dose of study drug). Investigators were assessed how the flare-up affected the subject's movement on a scale ranging 1 to 5 where, 1 = severely worse movement and 5 = better movement compared with baseline (day of screening physical examination).</description>
        <time_frame>Weeks 6 and 12</time_frame>
        <population>The FAS population included all subjects who received at least 1 dose of study drug and had at least 1 evaluable post-baseline radiograph or CT sufficient to allow determination of HO at the flare-up site. Only subjects with non-missing values were presented.</population>
        <group_list>
          <group group_id="O1">
            <title>Palovarotene 10/5 mg</title>
            <description>Subjects received palovarotene 10 mg orally for 14 days followed by 5 mg orally 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.</description>
          </group>
          <group group_id="O2">
            <title>Palovarotene 5/2.5 mg</title>
            <description>Subjects received palovarotene 5 mg orally for 14 days followed by 2.5 mg orally 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.</description>
          </group>
          <group group_id="O3">
            <title>Placebo</title>
            <description>Subjects received placebo (matching with palovarotene) 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.</description>
          </group>
        </group_list>
        <measure>
          <title>Subject and Investigator Global Assessment of Movement at Weeks 6 and 12</title>
          <description>Flare-up movement outcomes were independently assessed by both the subject (or parent of a subject under 8 years of age) and the Investigator at Weeks 6 and 12 by completing the global assessment of movement. The subject/parent completed the global assessment first. Prior to reviewing the subject's assessment, the Investigator completed his/her own assessment of the flare-up outcome. Subjects were assessed how the flare-up affected their movement on a scale ranging 1 to 5 where, 1 = severely worse movement and 5 = better movement compared with study Day 1 (day of first dose of study drug). Investigators were assessed how the flare-up affected the subject's movement on a scale ranging 1 to 5 where, 1 = severely worse movement and 5 = better movement compared with baseline (day of screening physical examination).</description>
          <population>The FAS population included all subjects who received at least 1 dose of study drug and had at least 1 evaluable post-baseline radiograph or CT sufficient to allow determination of HO at the flare-up site. Only subjects with non-missing values were presented.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="21"/>
                <count group_id="O2" value="9"/>
                <count group_id="O3" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Subject Global Assessment: Week 6</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="9"/>
                    <count group_id="O2" value="8"/>
                    <count group_id="O3" value="6"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Score 1</title>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Score 2</title>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Score 3</title>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Score 4</title>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="3"/>
                    <measurement group_id="O3" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Score 5</title>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                    <measurement group_id="O2" value="4"/>
                    <measurement group_id="O3" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Subject Global Assessment: Week 12</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="13"/>
                    <count group_id="O2" value="9"/>
                    <count group_id="O3" value="7"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Score 1</title>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Score 2</title>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Score 3</title>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Score 4</title>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                    <measurement group_id="O2" value="2"/>
                    <measurement group_id="O3" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Score 5</title>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                    <measurement group_id="O2" value="5"/>
                    <measurement group_id="O3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Investigator Global Assessment: Week 6</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="9"/>
                    <count group_id="O2" value="8"/>
                    <count group_id="O3" value="6"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Score 1</title>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Score 2</title>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Score 3</title>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Score 4</title>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="2"/>
                    <measurement group_id="O3" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Score 5</title>
                  <measurement_list>
                    <measurement group_id="O1" value="5"/>
                    <measurement group_id="O2" value="5"/>
                    <measurement group_id="O3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Investigator Global Assessment: Week 12</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="13"/>
                    <count group_id="O2" value="9"/>
                    <count group_id="O3" value="7"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Score 1</title>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Score 2</title>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Score 3</title>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Score 4</title>
                  <measurement_list>
                    <measurement group_id="O1" value="8"/>
                    <measurement group_id="O2" value="2"/>
                    <measurement group_id="O3" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Score 5</title>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                    <measurement group_id="O2" value="4"/>
                    <measurement group_id="O3" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Flare-Up Pain and Swelling at Weeks 2, 4, 6, 9 and 12</title>
        <description>The pain and swelling associated with flare-ups was evaluated using 2 separate numeric rating scales, one for pain and one for swelling. The pain scale ranges from 0 to 10 where, 0 = no pain and 10 = worst pain ever experienced. The swelling scale ranges from 0 to 10 where, 0 = no swelling and 10 = worst swelling ever experienced. The Faces Pain Scale - Revised (FPS-R) was used for children less than 8 years old. The FPS-R ranges from 0 to 10 where, 0 = no pain and 10 = very much pain in two-point increments.</description>
        <time_frame>Baseline, Weeks 2, 4, 6, 9 and 12</time_frame>
        <population>The PP population included all subjects who were eligible for the FAS population, completed Week 6 study visit with no major protocol deviations with at least 80% compliance with study drug, and had an evaluable radiograph or CT at Week 6 sufficient to allow determination of HO at flare-up site.</population>
        <group_list>
          <group group_id="O1">
            <title>Palovarotene 10/5 mg</title>
            <description>Subjects received palovarotene 10 mg orally for 14 days followed by 5 mg orally 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.</description>
          </group>
          <group group_id="O2">
            <title>Palovarotene 5/2.5 mg</title>
            <description>Subjects received palovarotene 5 mg orally for 14 days followed by 2.5 mg orally 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.</description>
          </group>
          <group group_id="O3">
            <title>Placebo</title>
            <description>Subjects received placebo (matching with palovarotene) 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.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Flare-Up Pain and Swelling at Weeks 2, 4, 6, 9 and 12</title>
          <description>The pain and swelling associated with flare-ups was evaluated using 2 separate numeric rating scales, one for pain and one for swelling. The pain scale ranges from 0 to 10 where, 0 = no pain and 10 = worst pain ever experienced. The swelling scale ranges from 0 to 10 where, 0 = no swelling and 10 = worst swelling ever experienced. The Faces Pain Scale - Revised (FPS-R) was used for children less than 8 years old. The FPS-R ranges from 0 to 10 where, 0 = no pain and 10 = very much pain in two-point increments.</description>
          <population>The PP population included all subjects who were eligible for the FAS population, completed Week 6 study visit with no major protocol deviations with at least 80% compliance with study drug, and had an evaluable radiograph or CT at Week 6 sufficient to allow determination of HO at flare-up site.</population>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="9"/>
                <count group_id="O3" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Flare-up pain: Week 2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="20"/>
                    <count group_id="O2" value="9"/>
                    <count group_id="O3" value="10"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-2.5" spread="2.50"/>
                    <measurement group_id="O2" value="0.0" spread="2.40"/>
                    <measurement group_id="O3" value="-2.0" spread="1.76"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Flare-up pain: Week 4</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="20"/>
                    <count group_id="O2" value="9"/>
                    <count group_id="O3" value="10"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-3.2" spread="2.46"/>
                    <measurement group_id="O2" value="-1.3" spread="1.58"/>
                    <measurement group_id="O3" value="-1.9" spread="3.14"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Flare-up pain: Week 6</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="20"/>
                    <count group_id="O2" value="9"/>
                    <count group_id="O3" value="10"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-3.5" spread="2.78"/>
                    <measurement group_id="O2" value="-1.3" spread="1.58"/>
                    <measurement group_id="O3" value="-2.4" spread="2.91"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Flare-up pain: Week 9</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="19"/>
                    <count group_id="O2" value="8"/>
                    <count group_id="O3" value="10"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-3.8" spread="2.62"/>
                    <measurement group_id="O2" value="-1.1" spread="1.64"/>
                    <measurement group_id="O3" value="-2.1" spread="1.85"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Flare-up pain: Week 12</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="20"/>
                    <count group_id="O2" value="9"/>
                    <count group_id="O3" value="10"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-3.6" spread="2.72"/>
                    <measurement group_id="O2" value="-1.9" spread="2.42"/>
                    <measurement group_id="O3" value="-2.2" spread="2.53"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Flare-up swelling: Week 2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="20"/>
                    <count group_id="O2" value="7"/>
                    <count group_id="O3" value="10"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-1.4" spread="2.76"/>
                    <measurement group_id="O2" value="-1.3" spread="2.93"/>
                    <measurement group_id="O3" value="-2.3" spread="2.79"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Flare-up swelling: Week 4</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="19"/>
                    <count group_id="O2" value="8"/>
                    <count group_id="O3" value="10"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-1.7" spread="3.30"/>
                    <measurement group_id="O2" value="-1.9" spread="1.81"/>
                    <measurement group_id="O3" value="-2.0" spread="3.30"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Flare-up swelling: Week 6</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="20"/>
                    <count group_id="O2" value="8"/>
                    <count group_id="O3" value="10"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-2.2" spread="3.32"/>
                    <measurement group_id="O2" value="-2.0" spread="2.45"/>
                    <measurement group_id="O3" value="-2.6" spread="3.50"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Flare-up swelling: Week 9</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="19"/>
                    <count group_id="O2" value="7"/>
                    <count group_id="O3" value="10"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-2.7" spread="3.32"/>
                    <measurement group_id="O2" value="-2.3" spread="2.43"/>
                    <measurement group_id="O3" value="-1.9" spread="4.41"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Flare-up swelling: Week 12</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="20"/>
                    <count group_id="O2" value="8"/>
                    <count group_id="O3" value="10"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-2.1" spread="3.73"/>
                    <measurement group_id="O2" value="-2.5" spread="2.20"/>
                    <measurement group_id="O3" value="-2.3" spread="3.16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Subjects Who Used Any Assistive Devices and Adaptations for Daily Living at Weeks 6 and 12</title>
        <description>Subjects were given a list of FOP assistive devices and adaptations and asked to select those they use for daily living. The FOP assistive devices and adaptations included mobility aids, care attendants, eating tools, personal care tools/aids, bathroom aids and devices, bedroom aids and devices, home adaptations, work environment adaptations, technology adaptations, sports and recreation adaptations, school, and medical therapies for daily living.</description>
        <time_frame>Weeks 6 and 12</time_frame>
        <population>The FAS population included all subjects who received at least 1 dose of study drug and had at least 1 evaluable post-baseline radiograph or CT sufficient to allow determination of HO at the flare-up site.</population>
        <group_list>
          <group group_id="O1">
            <title>Palovarotene 10/5 mg</title>
            <description>Subjects received palovarotene 10 mg orally for 14 days followed by 5 mg orally 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.</description>
          </group>
          <group group_id="O2">
            <title>Palovarotene 5/2.5 mg</title>
            <description>Subjects received palovarotene 5 mg orally for 14 days followed by 2.5 mg orally 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.</description>
          </group>
          <group group_id="O3">
            <title>Placebo</title>
            <description>Subjects received placebo (matching with palovarotene) 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.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Subjects Who Used Any Assistive Devices and Adaptations for Daily Living at Weeks 6 and 12</title>
          <description>Subjects were given a list of FOP assistive devices and adaptations and asked to select those they use for daily living. The FOP assistive devices and adaptations included mobility aids, care attendants, eating tools, personal care tools/aids, bathroom aids and devices, bedroom aids and devices, home adaptations, work environment adaptations, technology adaptations, sports and recreation adaptations, school, and medical therapies for daily living.</description>
          <population>The FAS population included all subjects who received at least 1 dose of study drug and had at least 1 evaluable post-baseline radiograph or CT sufficient to allow determination of HO at the flare-up site.</population>
          <units>percentage of subjects</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="21"/>
                <count group_id="O2" value="9"/>
                <count group_id="O3" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Week 6</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="20"/>
                    <count group_id="O2" value="9"/>
                    <count group_id="O3" value="10"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="85.0"/>
                    <measurement group_id="O2" value="100.0"/>
                    <measurement group_id="O3" value="100.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 12</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="21"/>
                    <count group_id="O2" value="9"/>
                    <count group_id="O3" value="10"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="90.5"/>
                    <measurement group_id="O2" value="100.0"/>
                    <measurement group_id="O3" value="100.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Duration of Active Symptomatic Flare-up</title>
        <description>The duration of active symptomatic flare-up was defined as the number of days the subject reported the presence of symptoms in the diary ('Is your flare-up ongoing today?') from Day 1 to study completion at Day 84. The mean number of days of active, symptomatic flare-up is presented for subjects with evaluable diary data.</description>
        <time_frame>From Day 1 to Day 84</time_frame>
        <population>The PP population included all subjects who were eligible for the FAS population, completed Week 6 study visit with no major protocol deviations with at least 80% compliance with study drug, and had an evaluable radiograph or CT at Week 6 sufficient to allow determination of HO at flare-up site.</population>
        <group_list>
          <group group_id="O1">
            <title>Palovarotene 10/5 mg</title>
            <description>Subjects received palovarotene 10 mg orally for 14 days followed by 5 mg orally 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.</description>
          </group>
          <group group_id="O2">
            <title>Palovarotene 5/2.5 mg</title>
            <description>Subjects received palovarotene 5 mg orally for 14 days followed by 2.5 mg orally 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.</description>
          </group>
          <group group_id="O3">
            <title>Placebo</title>
            <description>Subjects received placebo (matching with palovarotene) 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.</description>
          </group>
        </group_list>
        <measure>
          <title>Duration of Active Symptomatic Flare-up</title>
          <description>The duration of active symptomatic flare-up was defined as the number of days the subject reported the presence of symptoms in the diary ('Is your flare-up ongoing today?') from Day 1 to study completion at Day 84. The mean number of days of active, symptomatic flare-up is presented for subjects with evaluable diary data.</description>
          <population>The PP population included all subjects who were eligible for the FAS population, completed Week 6 study visit with no major protocol deviations with at least 80% compliance with study drug, and had an evaluable radiograph or CT at Week 6 sufficient to allow determination of HO at flare-up site.</population>
          <units>days</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="17"/>
                <count group_id="O2" value="9"/>
                <count group_id="O3" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="22.1" spread="20.53"/>
                    <measurement group_id="O2" value="44.1" spread="38.36"/>
                    <measurement group_id="O3" value="34.4" spread="34.15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Percentage of Worst Total Score for FOP-Specific Physical Function Questionnaire (FOP-PFQ) at Weeks 2, 4, 6, 9 and 12</title>
        <description>The FOP-PFQ consists of 28 questions rated on scales from 1 to 5, with lower scores denoting more difficulty. The adult form of the FOP-PFQ was administered to subjects 15 years of age and older. There are two Pediatric FOP-PFQ (FOP-PFQ-P) forms: a self-completed form for 8 to 14 year-olds and a parent proxy-completed form for 5 to 14 year-olds. For subjects between 8 to 14 years of age, both the self-completed (for 8 to 14 year-olds) and the proxy-completed (for 5 to 14 year olds) forms of the FOP-PFQ-P were administered. However, only the proxy-completed form was used for analysis. Percentage of worst scores ranges from 0% to 100% with 0% = best possible function and 100% = worst possible function. Change from baseline for each time point is presented.</description>
        <time_frame>Baseline, Weeks 2, 4, 6, 9 and 12</time_frame>
        <population>The FAS population included all subjects who received at least 1 dose of study drug and had at least 1 evaluable post-baseline radiograph or CT sufficient to allow determination of HO at the flare-up site.</population>
        <group_list>
          <group group_id="O1">
            <title>Palovarotene 10/5 mg</title>
            <description>Subjects received palovarotene 10 mg orally for 14 days followed by 5 mg orally 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.</description>
          </group>
          <group group_id="O2">
            <title>Palovarotene 5/2.5 mg</title>
            <description>Subjects received palovarotene 5 mg orally for 14 days followed by 2.5 mg orally 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.</description>
          </group>
          <group group_id="O3">
            <title>Placebo</title>
            <description>Subjects received placebo (matching with palovarotene) 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.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Percentage of Worst Total Score for FOP-Specific Physical Function Questionnaire (FOP-PFQ) at Weeks 2, 4, 6, 9 and 12</title>
          <description>The FOP-PFQ consists of 28 questions rated on scales from 1 to 5, with lower scores denoting more difficulty. The adult form of the FOP-PFQ was administered to subjects 15 years of age and older. There are two Pediatric FOP-PFQ (FOP-PFQ-P) forms: a self-completed form for 8 to 14 year-olds and a parent proxy-completed form for 5 to 14 year-olds. For subjects between 8 to 14 years of age, both the self-completed (for 8 to 14 year-olds) and the proxy-completed (for 5 to 14 year olds) forms of the FOP-PFQ-P were administered. However, only the proxy-completed form was used for analysis. Percentage of worst scores ranges from 0% to 100% with 0% = best possible function and 100% = worst possible function. Change from baseline for each time point is presented.</description>
          <population>The FAS population included all subjects who received at least 1 dose of study drug and had at least 1 evaluable post-baseline radiograph or CT sufficient to allow determination of HO at the flare-up site.</population>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="21"/>
                <count group_id="O2" value="9"/>
                <count group_id="O3" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Week 2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="21"/>
                    <count group_id="O2" value="9"/>
                    <count group_id="O3" value="10"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.95" spread="5.484"/>
                    <measurement group_id="O2" value="0.31" spread="3.818"/>
                    <measurement group_id="O3" value="2.11" spread="6.659"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 4</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="20"/>
                    <count group_id="O2" value="9"/>
                    <count group_id="O3" value="10"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.42" spread="7.932"/>
                    <measurement group_id="O2" value="2.67" spread="7.200"/>
                    <measurement group_id="O3" value="2.91" spread="8.427"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 6</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="21"/>
                    <count group_id="O2" value="9"/>
                    <count group_id="O3" value="9"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.79" spread="7.787"/>
                    <measurement group_id="O2" value="2.88" spread="7.550"/>
                    <measurement group_id="O3" value="1.75" spread="5.980"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 9</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="19"/>
                    <count group_id="O2" value="8"/>
                    <count group_id="O3" value="10"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.89" spread="5.432"/>
                    <measurement group_id="O2" value="-0.52" spread="7.881"/>
                    <measurement group_id="O3" value="4.91" spread="13.185"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 12</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="20"/>
                    <count group_id="O2" value="9"/>
                    <count group_id="O3" value="10"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.22" spread="7.915"/>
                    <measurement group_id="O2" value="1.08" spread="8.724"/>
                    <measurement group_id="O3" value="3.02" spread="9.587"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12</title>
        <description>The PROMIS Global Health contains 10 questions which are rated on scales from 1 to 5 or 0 to 10. Global physical health scores were calculated as the sum of scores from parameters 3, 6, 7, and 8 and ranges from 4 to 20 where, 4 = worse health and 20 = better health. Global mental health scores were calculated as the sum of scores from parameters 2, 4, 5, and 10 and ranges from 4 to 20 where, 4 = worse health and 20 = better health. For paediatric subjects, the PROMIS was administered as per the adult version. However, there is a single total score for the paediatric PROMIS (as opposed to global physical and global mental health scores as are in the adult version). The total score were converted to a T-score. A T-score of 50 is normal and increments of 10 are +/- 1 standard deviation away from the norm. A T-score &lt;50 indicates worse health, while a T-score &gt;50 indicates better health. The higher values (positive changes) indicate better health.</description>
        <time_frame>Baseline, Weeks 2, 4, 6, 9 and 12</time_frame>
        <population>The FAS population included all subjects who received at least 1 dose of study drug and had at least 1 evaluable post-baseline radiograph or CT sufficient to allow determination of HO at the flare-up site.</population>
        <group_list>
          <group group_id="O1">
            <title>Palovarotene 10/5 mg</title>
            <description>Subjects received palovarotene 10 mg orally for 14 days followed by 5 mg orally 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.</description>
          </group>
          <group group_id="O2">
            <title>Palovarotene 5/2.5 mg</title>
            <description>Subjects received palovarotene 5 mg orally for 14 days followed by 2.5 mg orally 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.</description>
          </group>
          <group group_id="O3">
            <title>Placebo</title>
            <description>Subjects received placebo (matching with palovarotene) 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.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12</title>
          <description>The PROMIS Global Health contains 10 questions which are rated on scales from 1 to 5 or 0 to 10. Global physical health scores were calculated as the sum of scores from parameters 3, 6, 7, and 8 and ranges from 4 to 20 where, 4 = worse health and 20 = better health. Global mental health scores were calculated as the sum of scores from parameters 2, 4, 5, and 10 and ranges from 4 to 20 where, 4 = worse health and 20 = better health. For paediatric subjects, the PROMIS was administered as per the adult version. However, there is a single total score for the paediatric PROMIS (as opposed to global physical and global mental health scores as are in the adult version). The total score were converted to a T-score. A T-score of 50 is normal and increments of 10 are +/- 1 standard deviation away from the norm. A T-score &lt;50 indicates worse health, while a T-score &gt;50 indicates better health. The higher values (positive changes) indicate better health.</description>
          <population>The FAS population included all subjects who received at least 1 dose of study drug and had at least 1 evaluable post-baseline radiograph or CT sufficient to allow determination of HO at the flare-up site.</population>
          <units>t-score</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="21"/>
                <count group_id="O2" value="9"/>
                <count group_id="O3" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Adult-only: Global Physical Health T-Score: Week 2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="17"/>
                    <count group_id="O2" value="5"/>
                    <count group_id="O3" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.76" spread="5.308"/>
                    <measurement group_id="O2" value="0.00" spread="1.768"/>
                    <measurement group_id="O3" value="5.90" spread="2.087"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Adult-only: Global Physical Health T-Score: Week 4</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="17"/>
                    <count group_id="O2" value="5"/>
                    <count group_id="O3" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.66" spread="6.590"/>
                    <measurement group_id="O2" value="2.66" spread="4.345"/>
                    <measurement group_id="O3" value="5.56" spread="2.904"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Adult-only: Global Physical Health T-Score: Week 6</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="17"/>
                    <count group_id="O2" value="5"/>
                    <count group_id="O3" value="4"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.69" spread="5.585"/>
                    <measurement group_id="O2" value="7.08" spread="6.591"/>
                    <measurement group_id="O3" value="5.73" spread="2.750"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Adult-only: Global Physical Health T-Score: Week 9</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="15"/>
                    <count group_id="O2" value="4"/>
                    <count group_id="O3" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.96" spread="5.489"/>
                    <measurement group_id="O2" value="5.58" spread="3.381"/>
                    <measurement group_id="O3" value="4.94" spread="3.135"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Adult-only:Global Physical Health T-Score: Week 12</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="16"/>
                    <count group_id="O2" value="5"/>
                    <count group_id="O3" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.97" spread="6.764"/>
                    <measurement group_id="O2" value="4.98" spread="6.246"/>
                    <measurement group_id="O3" value="3.78" spread="3.883"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Adult-only: Global Mental Health T-Score: Week 2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="17"/>
                    <count group_id="O2" value="5"/>
                    <count group_id="O3" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.66" spread="5.216"/>
                    <measurement group_id="O2" value="3.20" spread="2.024"/>
                    <measurement group_id="O3" value="1.98" spread="3.124"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Adult-only: Global Mental Health T-Score: Week 4</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="17"/>
                    <count group_id="O2" value="5"/>
                    <count group_id="O3" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.32" spread="5.066"/>
                    <measurement group_id="O2" value="2.28" spread="2.700"/>
                    <measurement group_id="O3" value="7.30" spread="5.609"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Adult-only: Global Mental Health T-Score: Week 6</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="17"/>
                    <count group_id="O2" value="5"/>
                    <count group_id="O3" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.15" spread="6.878"/>
                    <measurement group_id="O2" value="2.54" spread="4.980"/>
                    <measurement group_id="O3" value="4.34" spread="5.850"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Adult-only: Global Mental Health T-Score: Week 9</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="15"/>
                    <count group_id="O2" value="4"/>
                    <count group_id="O3" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.62" spread="7.684"/>
                    <measurement group_id="O2" value="1.68" spread="3.641"/>
                    <measurement group_id="O3" value="5.38" spread="5.438"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Adult-only: Global Mental Health T-Score: Week 12</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="16"/>
                    <count group_id="O2" value="5"/>
                    <count group_id="O3" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.33" spread="7.527"/>
                    <measurement group_id="O2" value="3.10" spread="4.127"/>
                    <measurement group_id="O3" value="1.04" spread="3.664"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Paediatric-only: Global Health T-Score: Week 2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="3"/>
                    <count group_id="O2" value="4"/>
                    <count group_id="O3" value="3"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-2.27" spread="4.278"/>
                    <measurement group_id="O2" value="1.05" spread="2.352"/>
                    <measurement group_id="O3" value="-1.80" spread="4.668"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Paediatric-only: Global Health T-Score: Week 4</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="3"/>
                    <count group_id="O2" value="4"/>
                    <count group_id="O3" value="3"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.57" spread="2.499"/>
                    <measurement group_id="O2" value="1.43" spread="6.352"/>
                    <measurement group_id="O3" value="-6.40" spread="4.314"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Paediatric-only: Global Health T-Score: Week 6</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="3"/>
                    <count group_id="O2" value="4"/>
                    <count group_id="O3" value="3"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-2.23" spread="3.499"/>
                    <measurement group_id="O2" value="2.80" spread="4.955"/>
                    <measurement group_id="O3" value="-3.30" spread="7.826"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Paediatric-only: Global Health T-Score: Week 9</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="3"/>
                    <count group_id="O2" value="4"/>
                    <count group_id="O3" value="3"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.17" spread="2.021"/>
                    <measurement group_id="O2" value="1.83" spread="1.434"/>
                    <measurement group_id="O3" value="-3.50" spread="4.668"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Paediatric-only: Global Health T-Score: Week 12</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="3"/>
                    <count group_id="O2" value="4"/>
                    <count group_id="O3" value="3"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.17" spread="7.572"/>
                    <measurement group_id="O2" value="-2.13" spread="2.964"/>
                    <measurement group_id="O3" value="-6.57" spread="1.950"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Maximum Measured Plasma Concentration (Cmax) of Palovarotene</title>
        <description>The Cmax of palovarotene was determined.</description>
        <time_frame>Pre-dose and 3, 6, 10, and 24 hours (hrs) post-dose at Week 2, and at Week 4 or 6</time_frame>
        <population>The Pharmacokinetic (PK) population included all subjects who had sufficient blood samples collected for valid estimation of PK parameters.</population>
        <group_list>
          <group group_id="O1">
            <title>Palovarotene 10/5 mg</title>
            <description>Subjects received palovarotene 10 mg orally for 14 days followed by 5 mg orally 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.</description>
          </group>
          <group group_id="O2">
            <title>Palovarotene 5/2.5 mg</title>
            <description>Subjects received palovarotene 5 mg orally for 14 days followed by 2.5 mg orally 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.</description>
          </group>
        </group_list>
        <measure>
          <title>Maximum Measured Plasma Concentration (Cmax) of Palovarotene</title>
          <description>The Cmax of palovarotene was determined.</description>
          <population>The Pharmacokinetic (PK) population included all subjects who had sufficient blood samples collected for valid estimation of PK parameters.</population>
          <units>picograms per milliliter (pg/mL)</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Week 2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="15"/>
                    <count group_id="O2" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="95620.00" spread="30296.77"/>
                    <measurement group_id="O2" value="35620.00" spread="19882.08"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 4/Week 6</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="17"/>
                    <count group_id="O2" value="7"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="45505.88" spread="17061.05"/>
                    <measurement group_id="O2" value="18958.57" spread="9238.62"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Minimum Measured Plasma Concentration (Cmin) of Palovarotene</title>
        <description>The Cmin of palovarotene was determined.</description>
        <time_frame>Pre-dose and 3, 6, 10, and 24 hrs post-dose at Week 2, and at Week 4 or 6</time_frame>
        <population>The PK population included all subjects who had sufficient blood samples collected for valid estimation of PK parameters.</population>
        <group_list>
          <group group_id="O1">
            <title>Palovarotene 10/5 mg</title>
            <description>Subjects received palovarotene 10 mg orally for 14 days followed by 5 mg orally 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.</description>
          </group>
          <group group_id="O2">
            <title>Palovarotene 5/2.5 mg</title>
            <description>Subjects received palovarotene 5 mg orally for 14 days followed by 2.5 mg orally 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.</description>
          </group>
        </group_list>
        <measure>
          <title>Minimum Measured Plasma Concentration (Cmin) of Palovarotene</title>
          <description>The Cmin of palovarotene was determined.</description>
          <population>The PK population included all subjects who had sufficient blood samples collected for valid estimation of PK parameters.</population>
          <units>pg/mL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Week 2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="15"/>
                    <count group_id="O2" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3128.53" spread="2358.88"/>
                    <measurement group_id="O2" value="1739.40" spread="963.68"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 4/Week 6</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="17"/>
                    <count group_id="O2" value="7"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3879.00" spread="7042.29"/>
                    <measurement group_id="O2" value="614.14" spread="289.72"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Time of Maximum Measured Plasma Concentration (Tmax) of Palovarotene</title>
        <description>The Tmax obtained by inspection of palovarotene was determined.</description>
        <time_frame>Pre-dose and 3, 6, 10, and 24 hrs post-dose at Week 2, and at Week 4 or 6</time_frame>
        <population>The PK population included all subjects who had sufficient blood samples collected for valid estimation of PK parameters.</population>
        <group_list>
          <group group_id="O1">
            <title>Palovarotene 10/5 mg</title>
            <description>Subjects received palovarotene 10 mg orally for 14 days followed by 5 mg orally 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.</description>
          </group>
          <group group_id="O2">
            <title>Palovarotene 5/2.5 mg</title>
            <description>Subjects received palovarotene 5 mg orally for 14 days followed by 2.5 mg orally 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.</description>
          </group>
        </group_list>
        <measure>
          <title>Time of Maximum Measured Plasma Concentration (Tmax) of Palovarotene</title>
          <description>The Tmax obtained by inspection of palovarotene was determined.</description>
          <population>The PK population included all subjects who had sufficient blood samples collected for valid estimation of PK parameters.</population>
          <units>hr</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Week 2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="15"/>
                    <count group_id="O2" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.00" lower_limit="2.83" upper_limit="6.03"/>
                    <measurement group_id="O2" value="2.77" lower_limit="2.08" upper_limit="5.88"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 4/Week 6</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="17"/>
                    <count group_id="O2" value="7"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.00" lower_limit="2.75" upper_limit="6.00"/>
                    <measurement group_id="O2" value="3.00" lower_limit="3.00" upper_limit="6.00"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Apparent Terminal Elimination Half-life (t1/2) of Palovarotene</title>
        <description>The t1/2 was calculated as ln(2)/ λz. The number of data points included in the regression was determined by visual inspection, but a minimum of three data points in the terminal phase, excluding Cmax, was required to estimate λz.</description>
        <time_frame>Pre-dose and 3, 6, 10, and 24 hrs post-dose at Week 2, and at Week 4 or 6</time_frame>
        <population>The PK population included all subjects who had sufficient blood samples collected for valid estimation of PK parameters.</population>
        <group_list>
          <group group_id="O1">
            <title>Palovarotene 10/5 mg</title>
            <description>Subjects received palovarotene 10 mg orally for 14 days followed by 5 mg orally 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.</description>
          </group>
          <group group_id="O2">
            <title>Palovarotene 5/2.5 mg</title>
            <description>Subjects received palovarotene 5 mg orally for 14 days followed by 2.5 mg orally 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.</description>
          </group>
        </group_list>
        <measure>
          <title>Apparent Terminal Elimination Half-life (t1/2) of Palovarotene</title>
          <description>The t1/2 was calculated as ln(2)/ λz. The number of data points included in the regression was determined by visual inspection, but a minimum of three data points in the terminal phase, excluding Cmax, was required to estimate λz.</description>
          <population>The PK population included all subjects who had sufficient blood samples collected for valid estimation of PK parameters.</population>
          <units>hr</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Week 2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="11"/>
                    <count group_id="O2" value="4"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.33" lower_limit="3.30" upper_limit="6.51"/>
                    <measurement group_id="O2" value="5.18" lower_limit="3.29" upper_limit="5.94"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 4/Week 6</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="16"/>
                    <count group_id="O2" value="4"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.39" lower_limit="3.11" upper_limit="6.38"/>
                    <measurement group_id="O2" value="4.40" lower_limit="4.13" upper_limit="5.11"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Area Under the Plasma Concentration Versus Time Curve Over the 24-hr Dosing Interval (AUC[0-24hr]) of Palovarotene</title>
        <description>The AUC(0-24hr) was calculated using linear trapezoid rule.</description>
        <time_frame>Pre-dose and 3, 6, 10, and 24 hrs post-dose at Week 2, and at Week 4 or 6</time_frame>
        <population>The PK population included all subjects who had sufficient blood samples collected for valid estimation of PK parameters.</population>
        <group_list>
          <group group_id="O1">
            <title>Palovarotene 10/5 mg</title>
            <description>Subjects received palovarotene 10 mg orally for 14 days followed by 5 mg orally 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.</description>
          </group>
          <group group_id="O2">
            <title>Palovarotene 5/2.5 mg</title>
            <description>Subjects received palovarotene 5 mg orally for 14 days followed by 2.5 mg orally 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.</description>
          </group>
        </group_list>
        <measure>
          <title>Area Under the Plasma Concentration Versus Time Curve Over the 24-hr Dosing Interval (AUC[0-24hr]) of Palovarotene</title>
          <description>The AUC(0-24hr) was calculated using linear trapezoid rule.</description>
          <population>The PK population included all subjects who had sufficient blood samples collected for valid estimation of PK parameters.</population>
          <units>hr*pg/mL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Week 2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="13"/>
                    <count group_id="O2" value="4"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="686308.92" spread="246797.81"/>
                    <measurement group_id="O2" value="350124.65" spread="181967.49"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 4/Week 6</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="17"/>
                    <count group_id="O2" value="7"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="311082.39" spread="128622.73"/>
                    <measurement group_id="O2" value="142748.47" spread="84838.75"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Apparent Clearance of Palovarotene (CL/F)</title>
        <description>The CL/F was defined as dose/AUC0-24hr.</description>
        <time_frame>Pre-dose and 3, 6, 10, and 24 hrs post-dose at Week 2, and at Week 4 or 6</time_frame>
        <population>The PK population included all subjects who had sufficient blood samples collected for valid estimation of PK parameters.</population>
        <group_list>
          <group group_id="O1">
            <title>Palovarotene 10/5 mg</title>
            <description>Subjects received palovarotene 10 mg orally for 14 days followed by 5 mg orally 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.</description>
          </group>
          <group group_id="O2">
            <title>Palovarotene 5/2.5 mg</title>
            <description>Subjects received palovarotene 5 mg orally for 14 days followed by 2.5 mg orally 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.</description>
          </group>
        </group_list>
        <measure>
          <title>Apparent Clearance of Palovarotene (CL/F)</title>
          <description>The CL/F was defined as dose/AUC0-24hr.</description>
          <population>The PK population included all subjects who had sufficient blood samples collected for valid estimation of PK parameters.</population>
          <units>L/hr</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Week 2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="13"/>
                    <count group_id="O2" value="4"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="15.55" spread="7.03"/>
                    <measurement group_id="O2" value="12.84" spread="4.07"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 4/Week 6</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="17"/>
                    <count group_id="O2" value="7"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="17.71" spread="7.44"/>
                    <measurement group_id="O2" value="19.51" spread="10.66"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>From first dose of study drug (Day 1) up to and including the Week 12 visit, approximately 85 days.</time_frame>
      <desc>Treatment-emergent adverse events were those with a start date/time after the first dose of study medication. The safety population included all subjects who received at least 1 dose of study drug (placebo or palovarotene).</desc>
      <group_list>
        <group group_id="E1">
          <title>Palovarotene 10/5 mg</title>
          <description>Subjects received palovarotene 10 mg orally for 14 days followed by 5 mg orally 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.</description>
        </group>
        <group group_id="E2">
          <title>Palovarotene 5/2.5 mg</title>
          <description>Subjects received palovarotene 5 mg orally for 14 days followed by 2.5 mg orally 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.</description>
        </group>
        <group group_id="E3">
          <title>Placebo</title>
          <description>Subjects received placebo (matching with palovarotene) 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.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA (17.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Condition aggravated</sub_title>
                <description>Any flare-ups reported during the 12-week duration of the study, which were not the flare-up that qualified the subject for the study, were recorded as adverse events.</description>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Myoclonus</sub_title>
                <counts group_id="E1" events="4" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Haemorrhagic ovarian cyst</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Asthmatic crisis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA (17.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="21" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="9"/>
                <counts group_id="E3" subjects_affected="10" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Leukocytosis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Thrombocytopenia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Iron deficiency anaemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Dry eye</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Eye pruritus</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Vision blurred</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Lip dry</sub_title>
                <counts group_id="E1" events="8" subjects_affected="7" subjects_at_risk="21"/>
                <counts group_id="E2" events="5" subjects_affected="5" subjects_at_risk="9"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="7" subjects_affected="6" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Chapped lips</sub_title>
                <counts group_id="E1" events="6" subjects_affected="5" subjects_at_risk="21"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="21"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Dry mouth</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Flatulence</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Frequent bowel movements</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Abdominal pain upper</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Condition aggravated</sub_title>
                <description>Any flare-ups reported during the 12-week duration of the study, which were not the flare-up that qualified the subject for the study, were recorded as adverse events.</description>
                <counts group_id="E1" events="27" subjects_affected="13" subjects_at_risk="21"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="9"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" events="4" subjects_affected="3" subjects_at_risk="9"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Application site erythema</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Feeling cold</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Vessel puncture site bruise</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Chest pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Influenza</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Pharyngitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Nasopharyngitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Oral candidiasis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Contusion</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Excoriation</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Post-traumatic pain</sub_title>
                <counts group_id="E1" events="4" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Haemoglobin decreased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Lipase increased</sub_title>
                <counts group_id="E1" events="5" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" events="5" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Blood alkaline phosphatase increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Blood bilirubin increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Blood thyroid stimulating hormone decreased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Gamma-glutamyltransferase increased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Amylase increased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" events="3" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Blood potassium increased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Thyroxine free increased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Thyroxine increased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hypercholesterolaemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Increased appetite</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hyperglycaemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" events="13" subjects_affected="10" subjects_at_risk="21"/>
                <counts group_id="E2" events="4" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E3" events="14" subjects_affected="6" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" events="4" subjects_affected="3" subjects_at_risk="9"/>
                <counts group_id="E3" events="3" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Joint swelling</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Joint stiffness</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Musculoskeletal stiffness</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Neck pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Groin pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Bone pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Muscle spasms</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="9" subjects_affected="8" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E3" events="5" subjects_affected="3" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hypoaesthesia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="3" subjects_affected="2" subjects_at_risk="9"/>
                <counts group_id="E3" events="5" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Migraine</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Irritability</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Pollakiuria</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Haematuria</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Polyuria</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Glycosuria</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Nasal congestion</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Rhinorrhoea</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Dry skin</sub_title>
                <counts group_id="E1" events="38" subjects_affected="17" subjects_at_risk="21"/>
                <counts group_id="E2" events="5" subjects_affected="5" subjects_at_risk="9"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Erythema</sub_title>
                <counts group_id="E1" events="6" subjects_affected="3" subjects_at_risk="21"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Pruritus generalised</sub_title>
                <counts group_id="E1" events="5" subjects_affected="4" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Dermatitis acneiform</sub_title>
                <counts group_id="E1" events="5" subjects_affected="4" subjects_at_risk="21"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" events="5" subjects_affected="4" subjects_at_risk="21"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Eczema</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Rash maculo-papular</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Skin exfoliation</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Dandruff</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Dermatitis contact</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Ecchymosis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Macule</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Pain of skin</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Skin hypopigmentation</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Pallor</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>Radiography was less sensitive than CT for detecting new HO. Thus, Global Read data are presented where available using more sensitive CT scans at Week 12 in the PP population.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Medical Director</name_or_title>
      <organization>Ipsen</organization>
      <phone>see email</phone>
      <email>clinical.trials@ipsen.com</email>
    </point_of_contact>
  </clinical_results>
</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/NCT02190747
org study id: PVO-1A-201
secondary id: 2014-001453-17
nct id: NCT02190747
lead sponsor: 
has dmc: Yes
Fibrodysplasia ossificans progressiva (FOP) is a rare, severely disabling disease
      characterized by painful, recurrent episodes of soft tissue swelling (flare-ups) that result
      in abnormal bone formation in muscles, tendons, and ligaments. Flare-ups begin early in life
      and may occur spontaneously or after soft tissue trauma, vaccinations, or influenza
      infections. Recurrent flare-ups progressively restrict movement by locking joints leading to
      cumulative loss of function and disability. Mouse models of FOP have demonstrated the ability
      of retinoic acid receptor (RAR) gamma agonists to prevent heterotopic ossification (HO)
      following injury. The purpose of the study is to evaluate whether palovarotene, an RAR gamma
      agonist, will prevent HO during and following a flare-up in subjects with FOP.
The primary objective is to evaluate the ability of different doses of palovarotene to
      prevent HO at the flare-up site in subjects with FOP as assessed by plain radiographs.

      This is a Phase 2, multi-center, randomized, double-blind, sponsor-unblinded,
      placebo-controlled study. Two cohorts of subjects will be randomized into different dosing
      regimens of palovarotene for a 6-week (42 days) treatment period. The study will consist of
      three periods:

        1. A Screening period to occur within 7 days of a distinct flare-up. The first dose of
           study drug will be taken within 7 days of the flare-up initiation.

        2. A double-blind treatment period of 6 weeks (42 days) duration.

        3. A follow-up period of 6 weeks (42 days) duration.

      An initial cohort (Cohort 1) of subjects will be randomly assigned 3:1 to either palovarotene
      or placebo daily for 42 days. Subjects randomized to palovarotene in Cohort 1 will receive an
      initial daily dose of 10 mg for 14 days followed by 5 mg daily for 28 days.

      In Cohort 2, new FOP subjects meeting all inclusion/exclusion criteria will be randomly
      assigned 3:3:2 to two dose regimens of palovarotene (10 mg for 14 days and 5 mg for 28 days;
      5 mg for 14 days and 2.5 mg for 28 days) or placebo daily for 42 days. Doses will be
      weight-adjusted and subjects randomized within three weight-range categories (20 to <40 kg,
      40 to <60 kg, and ≥60 kg).

      Subjects completing the study and still meeting eligibility requirements will be given the
      opportunity to enroll into an open-label extension study.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
measure: Percentage of Responders at Week 6
time frame: Baseline (Day 1) and Week 6 (Day 42)
description: A responder was defined as a subject with no or minimal new heterotopic ossification (HO) at flare-up site versus baseline as assessed by plain radiographs at Week 6. Minimal new HO is defined as new HO with an HO score <=3 in both anterior/posterior (AP) and lateral projections (or if one view is non-interpretable or non-evaluable, then remaining evaluable view is used). The HO score ranges from 0 to 6 where, 0 = no HO and 6 = single contiguous HO with longest dimension >2 diameters of reference normotopic bone in any projection. The highest HO score from the 2 projections was used. Results from Primary Read reviews are presented. The Primary Read process included a double-read radiology review paradigm with consensus adjudication. Radiography and CT scans were examined independently by scan type, flare-up region, and imaging time point in order to determine whether radiography would be sufficient to measure new HO formation. Only subjects with interpretable outcomes were evaluated.
measure: Percentage of Subjects With New HO at Weeks 6 and 12
time frame: Weeks 6 and 12 (Day 84)
description: Low dose CT scan was used as a secondary imaging assessment of HO and was performed at the same time points as plain radiographs. The percentage of subjects with new HO (regardless of the amount of new HO) at the flare-up site as assessed by CT scan and/or plain radiographs at Weeks 6 and 12 were analysed. The results are from Global Read reviews. The holistic Global Read process allowed concurrent review of all modalities across all time points, and provided access to selected clinical data at the time of review.
measure: Change From Baseline in Amount (Area) of New HO Formed at the Flare-up Site at Weeks 6 and 12
time frame: Baseline, Weeks 6 and 12
description: Interpretation of plain radiographs document the amount (area) of HO on both the AP and lateral radiograph views. The area for each view was a sum of all the new HO at the flare-up location (and thus if there are multiple HO lesions, the area of each lesion was determined and then the total across all lesions were summed to obtain a total new HO). This total new HO sum was used in the analysis of the area of new HO. Results from Primary Read reviews are presented.
measure: Percentage of Responders at Week 12
time frame: Baseline and Week 12
description: A responder was defined as a subject with no or minimal new HO at the flare-up site versus baseline as assessed by plain radiographs at Week 12. Minimal new HO is defined as new HO with an HO score <=3 in both the AP and lateral projections (or if one view is non-interpretable or non-evaluable, then the remaining evaluable view is used). The HO score ranges from 0 to 6 where, 0 = no HO and 6 = single contiguous HO with longest dimension >2 diameters of the reference normotopic bone in any projection. The highest HO score from the 2 projections was used. Results from the Primary Read reviews are presented. The Primary Read process included a double-read radiology review paradigm with consensus adjudication. Radiography and CT scans were examined independently by scan type, flare-up region, and imaging time point in order to determine whether radiography would be sufficient to measure new HO formation.
measure: Change From Baseline in Bone Specific Alkaline Phosphatase at Weeks 2, 4, 6 and 12
time frame: Baseline, Weeks 2, 4, 6 and 12
description: Blood and urine samples for analysis of cartilage, bone, angiogenesis, and inflammation biomarkers were collected. Bone specific alkaline phosphatase was analysed as a bone and cartilage biomarker.
measure: Change From Baseline in C-Reactive Protein at Weeks 2, 4, 6 and 12
time frame: Baseline, Weeks 2, 4, 6 and 12
description: Blood and urine samples for analysis of cartilage, bone, angiogenesis, and inflammation biomarkers were collected. C-reactive protein was analysed as a inflammation biomarker.
measure: Change From Baseline in C-Terminal Telopeptide at Weeks 2, 4, 6 and 12
time frame: Baseline, Weeks 2, 4, 6 and 12
description: Blood and urine samples for analysis of cartilage, bone, angiogenesis, and inflammation biomarkers were collected. C-terminal telopeptide was analysed as a bone and cartilage biomarker.
measure: Change From Baseline in Procollagen Type 1 N-Terminal Propeptide at Weeks 2, 4, 6 and 12
time frame: Baseline, Weeks 2, 4, 6 and 12
description: Blood and urine samples for analysis of cartilage, bone, angiogenesis, and inflammation biomarkers were collected. Procollagen type 1 N-terminal propeptide was analysed as a bone and cartilage biomarker.
measure: Change From Baseline in Procollagen Type 1 C-Terminal Propeptide Biomarker at Weeks 2, 4, 6 and 12
time frame: Baseline, Weeks 2, 4, 6 and 12
description: Blood and urine samples for analysis of cartilage, bone, angiogenesis, and inflammation biomarkers were collected. Procollagen type 1 C-terminal propeptide was analysed as a bone and cartilage biomarker.
measure: Change From Baseline in Amount of Bone Formation (Volume) at Weeks 6 and 12
time frame: Baseline, Weeks 6 and 12
description: Low dose CT scan were used as a secondary imaging assessment of HO, and was performed at the same time points as plain radiographs. Interpretation of the CT scan documented the amount (volume) and grade of HO. The independent reviewer scored HO lesions according to the following scale for HO on CT. Grade 1 = fluid attenuation without evidence of calcification at CT, Grade 2 = calcification of soft tissues without evidence of bone formation, Grade 3 = immature bone formation, and Grade 4 = mature bone with cortical differentiation. Volume of new HO was determined according to the following steps: (1) calculate volume of new HO compared to baseline for each reviewer/HO ID, (2) sum the volume of new HO across HO IDs for each reviewer, and (3) average the volume of new HO across reviewers. Results from Primary Read reviews are presented.
measure: Percentage of Subjects With Soft Tissue Swelling and Cartilage Formation Assessed by Magnetic Resonance Imaging (MRI) or Ultrasound (US) at Weeks 6 and 12
time frame: Weeks 6 and 12
description: The MRI was utilized to evaluate the presence of soft tissue swelling/edema (and volume of the swelling/edema) and presence of cartilage formation (yes or no). For subjects who could not have an MRI, US was used to assess edema severity for the sub-set of subjects enrolled after this opinion was introduced in a protocol amendment. Imaging film from MRI was assessed by two independent readers. When there was sufficient agreement between the independent readers on volume, both of the independent readings were used for analysis with the volume measurements averaged. When there was insufficient agreement between the independent readers, an adjudication reading was provided and used for analysis. The US was used for soft tissue swelling/edema but not cartilage formation. Percentage calculated as % = 100 x n/N' where N' is the number of subjects with interpretable outcomes. Results from Primary Read reviews are presented.
measure: Change From Baseline in Percent of Normal Arc of Motion at the Primary Joint (Flare-up Site) at Weeks 6 and 12
time frame: Baseline, Weeks 6 and 12
description: Active range of motion, expressed as the percent of normal arc of motion, measurements at the primary joint associated with the flare-up and adjoining joints was assessed by goniometer.
measure: Subject and Investigator Global Assessment of Movement at Weeks 6 and 12
time frame: Weeks 6 and 12
description: Flare-up movement outcomes were independently assessed by both the subject (or parent of a subject under 8 years of age) and the Investigator at Weeks 6 and 12 by completing the global assessment of movement. The subject/parent completed the global assessment first. Prior to reviewing the subject's assessment, the Investigator completed his/her own assessment of the flare-up outcome. Subjects were assessed how the flare-up affected their movement on a scale ranging 1 to 5 where, 1 = severely worse movement and 5 = better movement compared with study Day 1 (day of first dose of study drug). Investigators were assessed how the flare-up affected the subject's movement on a scale ranging 1 to 5 where, 1 = severely worse movement and 5 = better movement compared with baseline (day of screening physical examination).
measure: Change From Baseline in Flare-Up Pain and Swelling at Weeks 2, 4, 6, 9 and 12
time frame: Baseline, Weeks 2, 4, 6, 9 and 12
description: The pain and swelling associated with flare-ups was evaluated using 2 separate numeric rating scales, one for pain and one for swelling. The pain scale ranges from 0 to 10 where, 0 = no pain and 10 = worst pain ever experienced. The swelling scale ranges from 0 to 10 where, 0 = no swelling and 10 = worst swelling ever experienced. The Faces Pain Scale - Revised (FPS-R) was used for children less than 8 years old. The FPS-R ranges from 0 to 10 where, 0 = no pain and 10 = very much pain in two-point increments.
measure: Percentage of Subjects Who Used Any Assistive Devices and Adaptations for Daily Living at Weeks 6 and 12
time frame: Weeks 6 and 12
description: Subjects were given a list of FOP assistive devices and adaptations and asked to select those they use for daily living. The FOP assistive devices and adaptations included mobility aids, care attendants, eating tools, personal care tools/aids, bathroom aids and devices, bedroom aids and devices, home adaptations, work environment adaptations, technology adaptations, sports and recreation adaptations, school, and medical therapies for daily living.
measure: Duration of Active Symptomatic Flare-up
time frame: From Day 1 to Day 84
description: The duration of active symptomatic flare-up was defined as the number of days the subject reported the presence of symptoms in the diary ('Is your flare-up ongoing today?') from Day 1 to study completion at Day 84. The mean number of days of active, symptomatic flare-up is presented for subjects with evaluable diary data.
measure: Change From Baseline in Percentage of Worst Total Score for FOP-Specific Physical Function Questionnaire (FOP-PFQ) at Weeks 2, 4, 6, 9 and 12
time frame: Baseline, Weeks 2, 4, 6, 9 and 12
description: The FOP-PFQ consists of 28 questions rated on scales from 1 to 5, with lower scores denoting more difficulty. The adult form of the FOP-PFQ was administered to subjects 15 years of age and older. There are two Pediatric FOP-PFQ (FOP-PFQ-P) forms: a self-completed form for 8 to 14 year-olds and a parent proxy-completed form for 5 to 14 year-olds. For subjects between 8 to 14 years of age, both the self-completed (for 8 to 14 year-olds) and the proxy-completed (for 5 to 14 year olds) forms of the FOP-PFQ-P were administered. However, only the proxy-completed form was used for analysis. Percentage of worst scores ranges from 0% to 100% with 0% = best possible function and 100% = worst possible function. Change from baseline for each time point is presented.
measure: Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12
time frame: Baseline, Weeks 2, 4, 6, 9 and 12
description: The PROMIS Global Health contains 10 questions which are rated on scales from 1 to 5 or 0 to 10. Global physical health scores were calculated as the sum of scores from parameters 3, 6, 7, and 8 and ranges from 4 to 20 where, 4 = worse health and 20 = better health. Global mental health scores were calculated as the sum of scores from parameters 2, 4, 5, and 10 and ranges from 4 to 20 where, 4 = worse health and 20 = better health. For paediatric subjects, the PROMIS was administered as per the adult version. However, there is a single total score for the paediatric PROMIS (as opposed to global physical and global mental health scores as are in the adult version). The total score were converted to a T-score. A T-score of 50 is normal and increments of 10 are +/- 1 standard deviation away from the norm. A T-score <50 indicates worse health, while a T-score >50 indicates better health. The higher values (positive changes) indicate better health.
measure: Maximum Measured Plasma Concentration (Cmax) of Palovarotene
time frame: Pre-dose and 3, 6, 10, and 24 hours (hrs) post-dose at Week 2, and at Week 4 or 6
description: The Cmax of palovarotene was determined.
measure: Minimum Measured Plasma Concentration (Cmin) of Palovarotene
time frame: Pre-dose and 3, 6, 10, and 24 hrs post-dose at Week 2, and at Week 4 or 6
description: The Cmin of palovarotene was determined.
measure: Time of Maximum Measured Plasma Concentration (Tmax) of Palovarotene
time frame: Pre-dose and 3, 6, 10, and 24 hrs post-dose at Week 2, and at Week 4 or 6
description: The Tmax obtained by inspection of palovarotene was determined.
measure: Apparent Terminal Elimination Half-life (t1/2) of Palovarotene
time frame: Pre-dose and 3, 6, 10, and 24 hrs post-dose at Week 2, and at Week 4 or 6
description: The t1/2 was calculated as ln(2)/ λz. The number of data points included in the regression was determined by visual inspection, but a minimum of three data points in the terminal phase, excluding Cmax, was required to estimate λz.
measure: Area Under the Plasma Concentration Versus Time Curve Over the 24-hr Dosing Interval (AUC[0-24hr]) of Palovarotene
time frame: Pre-dose and 3, 6, 10, and 24 hrs post-dose at Week 2, and at Week 4 or 6
description: The AUC(0-24hr) was calculated using linear trapezoid rule.
measure: Apparent Clearance of Palovarotene (CL/F)
time frame: Pre-dose and 3, 6, 10, and 24 hrs post-dose at Week 2, and at Week 4 or 6
description: The CL/F was defined as dose/AUC0-24hr.
arm group label: Palovarotene dose level 1 (Cohort 1)
arm group type: Experimental
description: Doses of palovarotene in dose level 1 are 10 mg once daily for 14 days, followed by 5 mg once daily for 28 days.
arm group label: Palovarotene dose level 2 (Cohort 2)
arm group type: Experimental
description: Weight-adjusted doses of palovarotene in dose level 2 are 10 mg palovarotene once daily, followed by 5 mg once daily for 28 days.
arm group label: Palovarotene dose level 3 (Cohort 2)
arm group type: Experimental
description: Weight-adjusted doses of palovarotene in dose level 3 are 5 mg palovarotene once daily, followed by 2.5 mg once daily for 28 days.
arm group label: Sugar pill
arm group type: Placebo Comparator
description: The placebo comparator will be taken once daily for the same duration as the palovarotene dose groups in both Cohorts 1 and 2.
intervention type: Drug
intervention name: Palovarotene
description: Palovarotene will be taken orally once daily at approximately the same time each day. Powder filled hard gelatin capsules will be opened and the contents added onto specific food.
arm group label: Palovarotene dose level 1 (Cohort 1)
arm group label: Palovarotene dose level 2 (Cohort 2)
arm group label: Palovarotene dose level 3 (Cohort 2)
intervention type: Drug
intervention name: Placebo
arm group label: Sugar pill
criteria: 
gender: All
minimum age: 6 Years
maximum age: N/A
healthy volunteers: No
last name: Ipsen Medical Director
role: Study Director
affiliation: Ipsen
facility: 
facility: 
facility: 
facility: 
country: France
country: United Kingdom
country: United States
url: http://ifopa.org
description: Website for the International FOP Association
url: http://clementiapharma.com/
description: Click here for more information about this study: 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 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
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: Radiography was less sensitive than CT for detecting new HO. Thus, Global Read data are presented where available using more sensitive CT scans at Week 12 in the PP population.
point of contact: 