Fibrodysplasia Ossificans ProgressivaPhase 2NCT02279095
An Open-Label Extension Study of Palovarotene Treatment in Fibrodysplasia Ossificans Progressiva (FOP)
A Phase 2 study testing Palovarotene dose level 1, Palovarotene dose level 2 and Palovarotene dose level 3 in people with Fibrodysplasia Ossificans Progressiva, run by Clementia Pharmaceuticals Inc. at 8 sites in 5 countries.
Trial summary
Fibrodysplasia Ossificans Progressiva (FOP) is a rare, severely disabling disease characterized by heterotopic ossification (HO), i.e., abnormal bone formation, often associated with painful, recurrent episodes of soft tissue swelling (flare-ups). Read more about this study
- Who is it for?
- Ages 6 to 65 years
- Conditions the study is for
- Fibrodysplasia Ossificans Progressiva
- What is being tested?
- Palovarotene dose level 1, Palovarotene dose level 2 and Palovarotene dose level 3
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 58 participants
- Where
- 8 sitesin 5 countries
- Study dates
- 9 Oct 2014to 20 Sep 2022
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 6 to 65 years
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Completion of Study PVO-1A-202/Part B.
- Written, signed, and dated informed consent and, for participants who are minors, age-appropriate participant assent (performed according to local regulations).
- Accessible for treatment with palovarotene and follow-up (able and willing to travel to a site for the initial and all follow-up clinic visits).
- Able to undergo low-dose, WBCT scan, excluding head.
- Females of child-bearing potential must have a negative blood or urine pregnancy test (with sensitivity of at least 50 mIU/mL) prior to administration of palovarotene.
- Male and FOCBP participants must agree to remain abstinent from heterosexual sex during treatment and for 1 month after treatment or, if sexually active, to use two effective methods of birth control during and for 1 month after treatment. Additionally, sexually active females of childbearing potential (FOCBP) participants must already be using two effective methods of birth control 1 month before treatment is to start. Specific risk of the use of retinoids during pregnancy, and the agreement to remain abstinent or use two effective methods of birth control will be clearly defined in the informed consent and the participant or legally authorized representatives.
Who cannot join
- Any reason that, in the opinion of the Investigator, would lead to the inability of the participant and/or family to comply with the protocol.
- Amylase or lipase >2x above the upper limit of normal or with a history of pancreatitis.
- Elevated aspartate aminotransferase or alanine aminotransferase >2.5x the upper limit of normal.
- Fasting triglycerides >400 mg/dL with or without therapy.
- Currently using vitamin A or beta carotene, multivitamins containing vitamin A or beta carotene, herbal preparations containing vitamin A or beta carotene, or fish oil, and unable or unwilling to discontinue use of these products during palovarotene treatment.
- Participants experiencing suicidal ideation (type 4 or 5) or any suicidal behavior within the past month as defined by the Columbia Suicide Severity Rating Scale (C-SSRS).
Trial locations and contacts
8 sites in 5 countries.
8 sites in 5 countries
United States3 sites
University of Pennsylvania, Center for FOP & Related Bone Disorders
Philadelphia, Pennsylvania, 19104
Mayo Clinic, Department of Medicine
Rochester, Minnesota, 55905
University of California San Francisco, Division of Endocrinology and Metabolism
San Francisco, California, 94143
Australia2 sites
Royal North Shore Hospital
Saint Leonards, New South Wales, 2065
Queensland University of Technology (QUT) Institute of Health and Biomedical Innovation (IHBI)
Woolloongabba, Queensland, 4102
Argentina1 site
Hospital Italiano de Buenos Aires, Department of Pediatrics
Buenos Aires
United Kingdom1 site
The Royal National Orthopaedic Hospital, Brockley Hill
Stanmore, Middlesex, HA7 4LP
About this study
Official title: A Phase 2, Open-Label Extension, Efficacy and Safety Study of a Retinoic Acid Receptor Gamma (RARγ) Specific Agonist (Palovarotene) in the Treatment of Preosseous Flare-ups in Subjects With Fibrodysplasia Ossificans Progressiva (FOP)
Fibrodysplasia Ossificans Progressiva (FOP) is a rare, severely disabling disease characterized by heterotopic ossification (HO), i.e., abnormal bone formation, often associated with painful, recurrent episodes of soft tissue swelling (flare-ups). Lesions begin in early childhood and lead to progressive ankyloses of major joints with resultant loss of movement.
In this study, the ability of different palovarotene dosing regimens to prevent the formation of new HO will be evaluated in adult and pediatric participants with FOP.
Read the detailed description
The main objective of this Phase 2, multicenter, open-label study is to evaluate the safety and efficacy of different palovarotene dosing regimens in participants with FOP. Efficacy will be assessed based on the ability of palovarotene to prevent the formation of new heterotopic ossification (HO) as assessed by low-dose whole body computed tomography (WBCT) scan, excluding head.
The study was divided into four parts: Part A (completed on July 2017), Part B (completed on October 2018), Part C (completed) and Part D (completed). Each part was associated with revised palovarotene treatment regimens.
In Part A, all pediatric and adult participants who successfully completed Study PVO-1A-201 were enrolled and followed for up to 36 months. Participants who had an eligible flare-up received 10 mg palovarotene daily for 14 days, followed by 5 mg palovarotene daily for 28 days (or weight-based equivalent).
In Part B, participants who successfully completed Study PVO-1A-201 (including any participant who participated in Part A of Study PVO-1A-202) as well as up to 20 new adult participants were followed for up to 24 months. The Adult Cohort included all participants with at least 90% skeletal maturity, regardless of age. The Pediatric Cohort included all participants with less than 90% skeletal maturity. Any Pediatric Cohort participant who achieved ≥90% skeletal maturity during Part B was considered for enrollment into the Adult Cohort at the discretion of the Investigator. Part B added a 5 mg palovarotene daily chronic treatment regimen administered between flare-ups for participants in the Adult Cohort for up to 24 months. Part B also increased the flare-up dosing to 20 mg palovarotene daily for 28 days, followed by 10 mg palovarotene daily for 56 days (or weight-adjusted equivalents in the Pediatric Cohort). Treatment could be extended if the flare-up was still ongoing.
In Part C, participants from Part B are being followed for up to an additional 48 months. There will be no new participants in Part C. All eligible participants, including skeletally immature participants, are receiving 5 mg palovarotene daily chronic treatment regimen (weight-adjusted doses for skeletally immature participants).
In Part D, annual post last dose of study treatment assessments for up to 2 years will be obtained in participants who were skeletally immature at the time of study treatment discontinuation in order to obtain longer-term safety data. No new participants will be enrolled into Part D.
Part C plus Part D duration will not exceed 48 months.
All participants will undergo all study procedures as specified in the respective schedule of assessments and for as long as they are not 100% skeletally mature.
- Conditions
- Fibrodysplasia Ossificans Progressiva
- Being tested
- Palovarotene dose level 1, Palovarotene dose level 2, Palovarotene dose level 3, Palovarotene dose level 4
- Keywords
- Open-label extension study, Clinical trial Phase 2, Efficacy and safety, Heterotopic ossification, Fibrodysplasia Ossificans Progressiva, Flare-up, Palovarotene, Retinoic acid receptor agonist, Retinoic acid receptor gamma agonist, Clementia, Myositis Ossificans Progressiva, Munchmeyer's Disease, FOP, Ipsen
- Medical subject headings
- Myositis Ossificans, Ossification, Heterotopic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Palovarotene dose level 1Drug
Palovarotene was taken orally once daily at approximately the same time each day.
Palovarotene dose level 2Drug
Palovarotene will be taken orally once daily at approximately the same time each day.
Palovarotene dose level 3Drug
Palovarotene will be taken orally once daily at approximately the same time each day.
Palovarotene dose level 4Drug
Palovarotene will be taken orally once daily at approximately the same time each day.
| Study group | Role | What they receive |
|---|---|---|
| Palovarotene dose level 1 (completed) | Experimental | Participants received 10 mg palovarotene for 14 days, followed by 5 mg palovarotene for 28 days (or weight-based equivalent) for eligible flare-ups (Part A). Receives: Drug: Palovarotene dose level 1 |
| Palovarotene dose level 2 | Experimental | Participants with at least 90% skeletal maturity received 5 mg palovarotene for up to 24 months and 20 mg palovarotene for 28 days, followed by 10 mg for 56 days for eligible flare-ups (Part B). Receives: Drug: Palovarotene dose level 2 |
| Palovarotene dose level 3 | Experimental | Participants with less than 90% skeletal maturity received weight-adjusted doses of 20 mg palovarotene for 28 days, followed by 10 mg for 56 days for eligible flare-ups (Part B). Receives: Drug: Palovarotene dose level 3 |
| Palovarotene dose level 4 | Experimental | All participants will receive 5 mg palovarotene for up to 48 months and 20 mg palovarotene for 28 days, followed by 10 mg for 56 days for eligible flare-ups (Part C). Skeletally immature participants will receive weight-adjusted doses. Receives: Drug: Palovarotene dose level 4 |
What is being measured
The primary outcome is the main question the study is designed to answer.
Parts A and B: Percentage of Flare-ups With No New Heterotopic Ossification (HO) at Week 12
A responder was defined as a participant with no or minimal new HO at original flare-up site compared with baseline (pre-dose data from PVO-1A-201 study). Minimal new HO was defined as new HO with an HO score <=3 in both the anterior/posterior (AP) and lateral projections (or if 1 view is noninterpretable or non-evaluable, then remaining evaluable view was used). The HO score ranged 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. Highest HO score from 2 projections was used.
Measured: Baseline and Week 12
Parts B and C: Annualized Change in New HO Volume
The annualized change in new HO volume was assessed by low-dose whole body computed tomography (WBCT) scan, excluding head. Results are presented for overall intent to treat (ITT) period.
Measured: From Baseline (Day 1) up to end of 2 year follow-up period, approximately a maximum of 96 months
Secondary outcomes (21)
Parts A and B: Percentage of Participants Across the 7 HO Scores at Month 12 of Part A; and Weeks 6 and 12 for Part B
The HO score ranged 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. Highest HO score from 2 projections was used.
Measured: Part A: Baseline (pre-dose data from Study PVO-1A-201 for follow-up component and flare-up screening/Day 1 for flare-up component) and Month 12; Part B: Baseline (flare-up screening/baseline) and Weeks 6 and 12
Parts A and B: Volume of New Heterotopic Bone Formed at Month 12
Plain radiographs were utilized in Part A of the study. The interpretation of radiographs was to have documented the absence or presence of new HO at the flare-up site compared with the baseline assessment, and the volume of new HO if present. Low-dose CT scans were utilized in Part B of the study. Low-dose, flare-up site-specific CT scan was used as the primary imaging assessment of HO for flare-ups and low-dose, WBCT scans were used as the primary imaging assessment for total body HO in those participants receiving chronic treatment.
Measured: Month 12
Parts A and B: Number of Flare-ups With Significant Abnormalities in Cartilage, Bone, Angiogenesis, and Inflammation Biomarkers at Week 12
Blood and urine samples for cartilage, bone, angiogenesis, and inflammation biomarkers were evaluated during Part A and Part B of the study. Bone and cartilage biomarkers included: osteocalcin, bone-specific alkaline phosphatase (ALP), procollagen type 1-N-terminal pro-peptide (PINP), cartilage-derived (CD) retinoic acid protein, procollagen type 1-C-terminal pro-peptide (PICP), and C-terminal telopeptide. Angiogenesis included urinary basic fibroblast growth factor. Inflammation included erythrocyte sedimentation rate, C-reactive protein, Interleukin(IL)-6, IL-1 beta, tumor necrosis factor (TNF)-alpha, creatine phosphokinase, and lactate dehydrogenase. Based on emerging data from studies PVO-1A-001, PVO-1A-201, and Parts A and B of PVO-1A-202, biomarkers were removed from the evaluation during Part C.
Measured: Part A and B: At Week 12
Parts A and B: Change From Baseline in Active Range of Motion (ROM) at Flare-up Site at Week 12
Active ROM was assessed by goniometer in Parts A and B of the study. Measurements were performed by trained and qualified study personnel (eg, physiotherapist) in order to standardize the performance of procedures and minimize variability. Flare-ups at the primary joint was expressed as percent of normal arc of motion. Based on the change in the schedule for flare-up based assessments. Baseline was defined as pre-dose data from Study PVO-1A-201 for follow-up component and flare-up screening/Day 1 for flare-up component for Part A and flare-up screening/baseline for Part B.
Measured: Baseline and Week 12
Part B: Change From Baseline in ROM at Week 12
The ROM was assessed by the Investigator using Cumulative Analogue Joint Involvement Scale (CAJIS) for participants in Part B. It includes 12 joints (shoulder, elbow, wrist, hip, knee, and ankle on both the right and left sides), and 3 body regions (jaw, cervical spine [neck], and thoracic/lumbar spine). Each joint/region was assessed as: 0=uninvolved; 1=partially involved; and 2=completely ankylosed. The total score range is 0 (no involvement) to 30 (maximally involved). Baseline was flare-up screening.
Measured: Baseline and Week 12
Part C: Change From Baseline in ROM at Months 6, 12, 18, 24, 30, 36, 42, and 48
The ROM was assessed by the Investigator using CAJIS for participants in Part C. It includes 12 joints (shoulder, elbow, wrist, hip, knee, and ankle on both the right and left sides), and 3 body regions (jaw, cervical spine [neck], and thoracic/lumbar spine). Each joint/region was assessed as: 0=uninvolved; 1=partially involved; and 2=completely ankylosed. The total score range is 0 (no involvement) to 30 (maximally involved). Baseline was chronic Day 1.
Measured: Baseline and Months 6, 12, 18, 24, 30, 36, 42, and 48
Part B: Participant and Investigator Global Assessment of Movement at Week 12
Participants/Investigators assessed how the flare-up was affecting movement (better, same, slightly worse, moderately worse, or severely worse movement) compared with baseline. Based on the change in the schedule for flare-up based assessments. PA = Participant assessment and IA = Investigator assessment.
Measured: Week 12
Part A: Change From Baseline in Numeric Rating Scale (NRS) Pain and Swelling or Faces Pain Scale-Revised (FPS-R) at Weeks 2, 4, 6, 9, and 12
The NRSs for pain and swelling were used in Part A of the study to evaluate the effect of palovarotene on pain and swelling at the flare-up site. Flare-up pain was rated on a scale ranging from 0 (no pain or swelling) to 10 (worst pain or swelling ever experienced). For children less than 8 years old, pain was rated using the FPS-R, which ranging from 0 to 10 in 2-point increments where 0 = no pain and 10 = very much pain. Flare-up swelling was rated on a scale from 0 to 10 where 0 = no swelling and 10 = worst swelling ever experienced. Higher scores indicate worst quality of life for all scales. Baseline was predose data from PVO-1A-201 study/flare-up screening/Day 1.
Measured: Baseline and Weeks 2, 4, 6, 9, and 12
Parts A and B: Change From Baseline in Physical Function at Weeks 2, 4, 6, 9, and 12 of Part A; and Weeks 4, 8, and 12 of Part B
The effect of palovarotene on physical function was determined using Fibrodysplasia Ossificans Progressiva-Physical Function Questionnaire (FOP-PFQ). The questionnaire consisted of 28 items ranging from 1 (not able to do) to 5 (with no trouble; without help or assistive device). Total score range from 28 to 140. Lower scores denoted more difficulty, with items categorized into upper extremity and mobility sections.
Measured: Part A: Baseline and Weeks 2, 4, 6, 9, and 12; and Part B: Baseline and Weeks 4, 8, and 12
Part C: Change From Baseline in Physical Function at Months 6, 12, 18, 24, 30, 36, 42, and 48
The effect of palovarotene on physical function was determined using FOP-PFQ. The questionnaire consisted of 28 items ranging from 1 (not able to do) to 5 (with no trouble; without help or assistive device). Total score range from 28 to 140. Lower scores denoted more difficulty, with items categorized into upper extremity and mobility sections.
Measured: Baseline and Months 6, 12, 18, 24, 30, 36, 42, and 48
Parts A and B: Change From Baseline in Physical and Mental Health at Weeks 2, 4, 6, 9, and 12 of Part A; and Weeks 4, 8, and 12 of Part B
The patient reported outcomes measurement information system (PROMIS) global health scale was administered to evaluate the effect of palovarotene on physical and mental health in participants ≥15 years of age and mental health in participants <15 years of age, age-appropriate forms of the PROMIS global health scales were administered. A T-score of 50 is normal and increments of 10 are +/- standard deviation away from the norm. A T-score <50 indicates worse health, while a T-score >50 indicates better health. Higher values (positive changes) indicate better health. AFPH = Adult Form, Physical Health; AFMH = Adult Form, Mental Health; PFH = Paediatric Form, Health.
Measured: Part A: Baseline and Weeks 2, 4, 6, 9, and 12; and Part B: Baseline and Weeks 4, 8, and 12
Part C: Change From Baseline in Physical and Mental Health at Months 6, 12, 18, 24, 30, 36, 42, and 48
The PROMIS global health scale was administered to evaluate the effect of palovarotene on physical and mental health in participants ≥15 years of age and mental health in participants <15 years of age, age-appropriate forms of the PROMIS global health scales were administered. A T-score of 50 is normal and increments of 10 are +/- standard deviation away from the norm. A T-score <50 indicates worse health, while a T-score >50 indicates better health. Higher values (positive changes) indicate better health. AFPH = Adult Form, Physical Health; AFMH = Adult Form, Mental Health; PFH = Paediatric Form, Health.
Measured: Baseline and Months 6, 12, 18, 24, 30, 36, 42, and 48
Parts A and B: Number of Any Assistive Devices and Adaptations by FOP Participants at Weeks 6 and 12 of Part A; and Week 12 of Part B
The FOP assistive devices and adaptations questionnaire was used in Part A and Part B of the study. Assistive devices and adaptations were grouped into the following categories: 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. When a flare-up did not use an assistive device or adaptation or considered the assistive device or adaptation not applicable, 0 was imputed for analysis.
Measured: Part A: Weeks 6 and 12; and Part B: Week 12
Part A: Percentage of Responders at Week 12
A responder was defined as a participant with no or minimal new HO at original flare-up site compared with baseline (flare-up screening/Day 1). Minimal new HO was defined as new HO with an HO score <=3 in both the AP and lateral projections (or if 1 view is non-interpretable or non-evaluable, then remaining evaluable view was used). The HO score ranged 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. Highest HO score from 2 projections was used. Results from the Primary Read reviews are presented.
Measured: Week 12
Parts A and B: Change From Baseline in Amount of Bone Formation Biomarker at Weeks 6 and 12 of Part A; and Week 12 of Part B
The bone formation was measured by PINP biomarker. Baseline was defined as flare-up screening/Day 1.
Measured: Part A: Baseline and Weeks 6 and 12; and Part B: Baseline and Week 12
Parts A and B: Number of Flare-ups With Soft Tissue Swelling and/or Cartilage Formation at Weeks 6 and 12 of Part A; and Week 12 of Part B
Magnetic resonance imaging (MRI) was utilized as an imaging modality to evaluate for the presence of soft tissue swelling/edema and cartilage formation for participants who received flare-up based treatment. Ultrasound (US) was utilized to evaluate for the presence of soft tissue swelling in participants unable to undergo MRI. Both MRI and US were interpreted centrally. When US was used, cartilage formation was not assessed.
Measured: Part A: Baseline and Weeks 6 and 12; and Part B: Baseline and Week 12
Parts A and B: Duration of Active Symptomatic Flare-up
The number of days of active symptomatic flare-up was the number of days the participant reported the presence of symptoms in the diary.
Measured: Part A: From Baseline up to 36 months; and Part B: From Baseline up to 24 months
Part B: Change From Baseline in Whole Body Burden of HO at Months 12 and 24
Whole body burden of HO was assessed by low-dose WBCT scan, excluding head. Baseline was Part B Screening.
Measured: Baseline and Months 12 and 24
Part B: Mean Percentage of Flare-ups Per Participant-Month Overall
Flare-ups were counted using the number of participant/Investigator-reported flare-ups. Percentage was calculated by dividing the total number of flare-ups by the total participant months of follow-up. Results are presented for overall ITT period.
Measured: From Baseline (Day 1) up to end of 2 year follow-up period, approximately a maximum of 96 months
Part C: Mean Percentage of Flare-ups Per Participant-Month Overall
Flare-ups were counted using the number of participant/Investigator-reported flare-ups. Percentage was calculated by dividing the total number of flare-ups by the total participant months of follow-up. Results are presented for overall ITT period.
Measured: From Baseline (Day 1) up to end of 2 year follow-up period, approximately a maximum of 96 months
Part C: Percentage of Participants With New HO at Months 12, 24, 36, 60, and 72 (Last Visit)
New HO was defined as total WBCT new HO volume >0. Results for Month 72 are presented for overall ITT period.
Measured: Months 12, 24, 36, 60, and 72 (last visit)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Oct 2014 (estimated)
- Study start9 Oct 2014
- Primary completion20 Sep 2022
- Study completion20 Sep 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Fibrodysplasia Ossificans ProgressivaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 58 participants (actual)
Sponsor and investigators
- Lead sponsor
- Clementia Pharmaceuticals Inc.
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Ipsen Medical Director, Study director, Ipsen
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02279095
- Sponsor's protocol ID
- PVO-1A-202
- Other IDs
- 2014-002496-28, 2014
- Status last verified
- Feb 2025
- First submitted
- 26 Oct 2014
- Last updated
- 19 Feb 2025
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 21460849Pignolo RJ, Hsiao EC, Al Mukaddam M, Baujat G, Berglund SK, Cheung AM, De Cunto C, Delai P, Haga N, Kannu P, Mancilla EE, Marino R, Shih F, Strahs A, Kaplan FS. Palovarotene impact on fibrodysplasia ossificans progressiva (FOP): data from month 48 of the phase III MOVE trial. JBMR Plus. 2026 Aug 29;10(10):ziag141. doi: 10.1093/jbmrpl/ziag141. eCollection 2026 Oct.
PubMed 42770123Pignolo RJ, Al Mukaddam M, Baujat G, Brown MA, De Cunto C, Hsiao EC, Keen R, Le Quan Sang KH, Grogan DR, Marino R, Strahs AR, Kaplan FS. Study methodology and insights from the palovarotene clinical development program in fibrodysplasia ossificans progressiva. BMC Med Res Methodol. 2023 Nov 13;23(1):269. doi: 10.1186/s12874-023-02080-7.
PubMed 37957586Pignolo RJ, Kimel M, Whalen J, Kawata AK, Artyomenko A, Kaplan FS. The Fibrodysplasia Ossificans Progressiva Physical Function Questionnaire (FOP-PFQ): A patient-reported, disease-specific measure. Bone. 2023 Mar;168:116642. doi: 10.1016/j.bone.2022.116642. Epub 2022 Dec 13.
PubMed 36526263
Study at a glance
From the registry record, last updated by the sponsor on 19 Feb 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 2, Open-Label Extension, Efficacy and Safety Study of a Retinoic Acid Receptor Gamma (RARγ) Specific Agonist (Palovarotene) in the Treatment of Preosseous Flare-ups in Subjects With Fibrodysplasia Ossificans Progressiva (FOP)
- ClinicalTrials.gov ID
- NCT02279095
- Acronym / sponsor ID
- PVO-1A-202
- Conditions
- Fibrodysplasia Ossificans Progressiva
- Keywords
- Open-label extension study, Clinical trial Phase 2, Efficacy and safety, Heterotopic ossification, Fibrodysplasia Ossificans Progressiva, Flare-up, Palovarotene, Retinoic acid receptor agonist
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 58 participants (actual)
- Lead sponsor
- Clementia Pharmaceuticals Inc.Industry (pharma, biotech, devices)
- Study start
- 9 Oct 2014 (actual)
- Primary completion
- 20 Sep 2022 (actual)
- Study completion
- 20 Sep 2022 (actual)
- First posted
- 30 Oct 2014 (estimated)
- Results
- Posted 17 May 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Fibrodysplasia Ossificans Progressiva (FOP) is a rare, severely disabling disease characterized by heterotopic ossification (HO), i.e., abnormal bone formation, often associated with painful, recurrent episodes of soft tissue swelling (flare-ups). Lesions begin in early childhood and lead to progressive ankyloses of major joints with resultant loss of movement.
In this study, the ability of different palovarotene dosing regimens to prevent the formation of new HO will be evaluated in adult and pediatric participants with FOP.
Detailed description
The main objective of this Phase 2, multicenter, open-label study is to evaluate the safety and efficacy of different palovarotene dosing regimens in participants with FOP. Efficacy will be assessed based on the ability of palovarotene to prevent the formation of new heterotopic ossification (HO) as assessed by low-dose whole body computed tomography (WBCT) scan, excluding head.
The study was divided into four parts: Part A (completed on July 2017), Part B (completed on October 2018), Part C (completed) and Part D (completed). Each part was associated with revised palovarotene treatment regimens.
In Part A, all pediatric and adult participants who successfully completed Study PVO-1A-201 were enrolled and followed for up to 36 months. Participants who had an eligible flare-up received 10 mg palovarotene daily for 14 days, followed by 5 mg palovarotene daily for 28 days (or weight-based equivalent).
In Part B, participants who successfully completed Study PVO-1A-201 (including any participant who participated in Part A of Study PVO-1A-202) as well as up to 20 new adult participants were followed for up to 24 months. The Adult Cohort included all participants with at least 90% skeletal maturity, regardless of age. The Pediatric Cohort included all participants with less than 90% skeletal maturity. Any Pediatric Cohort participant who achieved ≥90% skeletal maturity during Part B was considered for enrollment into the Adult Cohort at the discretion of the Investigator. Part B added a 5 mg palovarotene daily chronic treatment regimen administered between flare-ups for participants in the Adult Cohort for up to 24 months. Part B also increased the flare-up dosing to 20 mg palovarotene daily for 28 days, followed by 10 mg palovarotene daily for 56 days (or weight-adjusted equivalents in the Pediatric Cohort). Treatment could be extended if the flare-up was still ongoing.
In Part C, participants from Part B are being followed for up to an additional 48 months. There will be no new participants in Part C. All eligible participants, including skeletally immature participants, are receiving 5 mg palovarotene daily chronic treatment regimen (weight-adjusted doses for skeletally immature participants).
In Part D, annual post last dose of study treatment assessments for up to 2 years will be obtained in participants who were skeletally immature at the time of study treatment discontinuation in order to obtain longer-term safety data. No new participants will be enrolled into Part D.
Part C plus Part D duration will not exceed 48 months.
All participants will undergo all study procedures as specified in the respective schedule of assessments and for as long as they are not 100% skeletally mature.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Palovarotene dose level 1 (completed) | Experimental | Drug: Palovarotene dose level 1Participants received 10 mg palovarotene for 14 days, followed by 5 mg palovarotene for 28 days (or weight-based equivalent) for eligible flare-ups (Part A). |
| Palovarotene dose level 2 | Experimental | Drug: Palovarotene dose level 2Participants with at least 90% skeletal maturity received 5 mg palovarotene for up to 24 months and 20 mg palovarotene for 28 days, followed by 10 mg for 56 days for eligible flare-ups (Part B). |
| Palovarotene dose level 3 | Experimental | Drug: Palovarotene dose level 3Participants with less than 90% skeletal maturity received weight-adjusted doses of 20 mg palovarotene for 28 days, followed by 10 mg for 56 days for eligible flare-ups (Part B). |
| Palovarotene dose level 4 | Experimental | Drug: Palovarotene dose level 4All participants will receive 5 mg palovarotene for up to 48 months and 20 mg palovarotene for 28 days, followed by 10 mg for 56 days for eligible flare-ups (Part C). Skeletally immature participants will receive weight-adjusted doses. |
Who may qualify
- Ages
- 6 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (6 listed)
- Completion of Study PVO-1A-202/Part B.
- Written, signed, and dated informed consent and, for participants who are minors, age-appropriate participant assent (performed according to local regulations).
- Accessible for treatment with palovarotene and follow-up (able and willing to travel to a site for the initial and all follow-up clinic visits).
- Able to undergo low-dose, WBCT scan, excluding head.
- Females of child-bearing potential must have a negative blood or urine pregnancy test (with sensitivity of at least 50 mIU/mL) prior to administration of palovarotene.
Key exclusion criteria (6 listed)
- Any reason that, in the opinion of the Investigator, would lead to the inability of the participant and/or family to comply with the protocol.
- Amylase or lipase >2x above the upper limit of normal or with a history of pancreatitis.
- Elevated aspartate aminotransferase or alanine aminotransferase >2.5x the upper limit of normal.
- Fasting triglycerides >400 mg/dL with or without therapy.
- Currently using vitamin A or beta carotene, multivitamins containing vitamin A or beta carotene, herbal preparations containing vitamin A or beta carotene, or fish oil, and unable or unwilling to discontinue use of these products during palovarotene treatment.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Palovarotene dose level 1Palovarotene was taken orally once daily at approximately the same time each day. | Drug | Palovarotene dose level 1 (completed) |
| Palovarotene dose level 2Palovarotene will be taken orally once daily at approximately the same time each day. | Drug | Palovarotene dose level 2 |
| Palovarotene dose level 3Palovarotene will be taken orally once daily at approximately the same time each day. | Drug | Palovarotene dose level 3 |
| Palovarotene dose level 4Palovarotene will be taken orally once daily at approximately the same time each day. | Drug | Palovarotene dose level 4 |
Primary outcome
Parts A and B: Percentage of Flare-ups With No New Heterotopic Ossification (HO) at Week 12
Time frame: Baseline and Week 12
A responder was defined as a participant with no or minimal new HO at original flare-up site compared with baseline (pre-dose data from PVO-1A-201 study). Minimal new HO was defined as new HO with an HO score <=3 in both the anterior/posterior (AP) and lateral projections (or if 1 view is noninterpretable or non-evaluable, then remaining evaluable view was used). The HO score ranged 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. Highest HO score from 2 projections was used.
Parts B and C: Annualized Change in New HO Volume
Time frame: From Baseline (Day 1) up to end of 2 year follow-up period, approximately a maximum of 96 months
The annualized change in new HO volume was assessed by low-dose whole body computed tomography (WBCT) scan, excluding head. Results are presented for overall intent to treat (ITT) period.
21 secondary outcomes
Parts A and B: Percentage of Participants Across the 7 HO Scores at Month 12 of Part A; and Weeks 6 and 12 for Part B
Time frame: Part A: Baseline (pre-dose data from Study PVO-1A-201 for follow-up component and flare-up screening/Day 1 for flare-up component) and Month 12; Part B: Baseline (flare-up screening/baseline) and Weeks 6 and 12
Parts A and B: Volume of New Heterotopic Bone Formed at Month 12
Time frame: Month 12
Parts A and B: Number of Flare-ups With Significant Abnormalities in Cartilage, Bone, Angiogenesis, and Inflammation Biomarkers at Week 12
Time frame: Part A and B: At Week 12
Parts A and B: Change From Baseline in Active Range of Motion (ROM) at Flare-up Site at Week 12
Time frame: Baseline and Week 12
Part B: Change From Baseline in ROM at Week 12
Time frame: Baseline and Week 12
Part C: Change From Baseline in ROM at Months 6, 12, 18, 24, 30, 36, 42, and 48
Time frame: Baseline and Months 6, 12, 18, 24, 30, 36, 42, and 48
Part B: Participant and Investigator Global Assessment of Movement at Week 12
Time frame: Week 12
Part A: Change From Baseline in Numeric Rating Scale (NRS) Pain and Swelling or Faces Pain Scale-Revised (FPS-R) at Weeks 2, 4, 6, 9, and 12
Time frame: Baseline and Weeks 2, 4, 6, 9, and 12
Parts A and B: Change From Baseline in Physical Function at Weeks 2, 4, 6, 9, and 12 of Part A; and Weeks 4, 8, and 12 of Part B
Time frame: Part A: Baseline and Weeks 2, 4, 6, 9, and 12; and Part B: Baseline and Weeks 4, 8, and 12
Part C: Change From Baseline in Physical Function at Months 6, 12, 18, 24, 30, 36, 42, and 48
Time frame: Baseline and Months 6, 12, 18, 24, 30, 36, 42, and 48
Parts A and B: Change From Baseline in Physical and Mental Health at Weeks 2, 4, 6, 9, and 12 of Part A; and Weeks 4, 8, and 12 of Part B
Time frame: Part A: Baseline and Weeks 2, 4, 6, 9, and 12; and Part B: Baseline and Weeks 4, 8, and 12
Part C: Change From Baseline in Physical and Mental Health at Months 6, 12, 18, 24, 30, 36, 42, and 48
Time frame: Baseline and Months 6, 12, 18, 24, 30, 36, 42, and 48
Parts A and B: Number of Any Assistive Devices and Adaptations by FOP Participants at Weeks 6 and 12 of Part A; and Week 12 of Part B
Time frame: Part A: Weeks 6 and 12; and Part B: Week 12
Part A: Percentage of Responders at Week 12
Time frame: Week 12
Parts A and B: Change From Baseline in Amount of Bone Formation Biomarker at Weeks 6 and 12 of Part A; and Week 12 of Part B
Time frame: Part A: Baseline and Weeks 6 and 12; and Part B: Baseline and Week 12
Parts A and B: Number of Flare-ups With Soft Tissue Swelling and/or Cartilage Formation at Weeks 6 and 12 of Part A; and Week 12 of Part B
Time frame: Part A: Baseline and Weeks 6 and 12; and Part B: Baseline and Week 12
Parts A and B: Duration of Active Symptomatic Flare-up
Time frame: Part A: From Baseline up to 36 months; and Part B: From Baseline up to 24 months
Part B: Change From Baseline in Whole Body Burden of HO at Months 12 and 24
Time frame: Baseline and Months 12 and 24
Part B: Mean Percentage of Flare-ups Per Participant-Month Overall
Time frame: From Baseline (Day 1) up to end of 2 year follow-up period, approximately a maximum of 96 months
Part C: Mean Percentage of Flare-ups Per Participant-Month Overall
Time frame: From Baseline (Day 1) up to end of 2 year follow-up period, approximately a maximum of 96 months
Part C: Percentage of Participants With New HO at Months 12, 24, 36, 60, and 72 (Last Visit)
Time frame: Months 12, 24, 36, 60, and 72 (last visit)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Feb 2025.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 21460849Shimono 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.
- Derived from this study: PubMed 42770123Pignolo RJ, Hsiao EC, Al Mukaddam M, Baujat G, Berglund SK, Cheung AM, De Cunto C, Delai P, Haga N, Kannu P, Mancilla EE, Marino R, Shih F, Strahs A, Kaplan FS. Palovarotene impact on fibrodysplasia ossificans progressiva (FOP): data from month 48 of the phase III MOVE trial. JBMR Plus. 2026 Aug 29;10(10):ziag141. doi: 10.1093/jbmrpl/ziag141. eCollection 2026 Oct.
- Derived from this study: PubMed 37957586Pignolo RJ, Al Mukaddam M, Baujat G, Brown MA, De Cunto C, Hsiao EC, Keen R, Le Quan Sang KH, Grogan DR, Marino R, Strahs AR, Kaplan FS. Study methodology and insights from the palovarotene clinical development program in fibrodysplasia ossificans progressiva. BMC Med Res Methodol. 2023 Nov 13;23(1):269. doi: 10.1186/s12874-023-02080-7.
- Derived from this study: PubMed 36526263Pignolo RJ, Kimel M, Whalen J, Kawata AK, Artyomenko A, Kaplan FS. The Fibrodysplasia Ossificans Progressiva Physical Function Questionnaire (FOP-PFQ): A patient-reported, disease-specific measure. Bone. 2023 Mar;168:116642. doi: 10.1016/j.bone.2022.116642. Epub 2022 Dec 13.
- Website for the International FOP AssociationLink provided by the sponsor.
- Website for the French FOP AssociationLink provided by the sponsor.
- Individual participant dataSharing planned: No
Related trials for Fibrodysplasia Ossificans Progressiva
Active, not recruitingPhase 2/3
A Study of Andecaliximab in Participants With Fibrodysplasia Ossificans Progressiva (FOP)
Fibrodysplasia Ossificans Progressiva
RecruitingObservational study
A Study to Document and to Further Describe Long-term Safety and Effectiveness of Palovarotene in Participants With Fibrodysplasia Ossificans Progressiva (FOP)
Fibrodysplasia Ossificans Progressiva
RecruitingPhase 2
To Assess the Efficacy, Safety, and Tolerability of INCB000928 in Participants With Fibrodysplasia Ossificans Progressiva
Fibrodysplasia Ossificans Progressiva (FOP)
Not yet recruitingPhase 3
A Study to Investigate the Safety, Pharmacokinetics (PK), and Efficacy of Garetosmab in Children and Adolescents With Fibrodysplasia Ossificans Progressiva (FOP)
Fibrodysplasia Ossificans Progressiva, FOP
Active, not recruitingPhase 2
Saracatinib Trial TO Prevent FOP
Fibrodysplasia Ossificans Progressiva
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ipsen Medical Director study director
Ipsen
8 sites in 5 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Palovarotene dose level 1, Palovarotene dose level 2 and Palovarotene dose level 3 in people with Fibrodysplasia Ossificans Progressiva, run by Clementia Pharmaceuticals Inc. at 8 sites in 5 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 19 Feb 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 8 sites in United States, Australia, Argentina, France, United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 17 May 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Parts A and B: Percentage of Flare-ups With No New Heterotopic Ossification (HO) at Week 12 (time frame: Baseline and Week 12). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02279095, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Feb 2025.