Fibrodysplasia Ossificans ProgressivaPhase 2NCT02190747
An Efficacy and Safety Study of Palovarotene to Treat Preosseous Flare-ups in FOP Subjects
A Phase 2 study testing Palovarotene in people with Fibrodysplasia Ossificans Progressiva, run by Clementia Pharmaceuticals Inc. at 4 sites in 3 countries.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 6 years and older
- Conditions the study is for
- Fibrodysplasia Ossificans Progressiva
- What is being tested?
- Palovarotene
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 40 participants
- Where
- 4 sitesin 3 countries
- Study dates
- 14 Jul 2014to 23 May 2016
- 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 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Written, signed, and dated informed subject/parent consent or age-appropriate assent.
- Subjects clinically diagnosed with classic Fibrodysplasia Ossificans Progressiva (FOP).
- Symptomatic onset of a distinct flare-up within 7 days of Study Day 1 (start of study drug) and defined by the presence of at least two of six of the following symptoms: pain, soft tissue swelling, decreased range of motion, stiffness, redness, and warmth. Flare-up must be confirmed by the physician at the Screening visit.
- Flare-up is at an appendicular area (upper or lower extremity), abdomen, or chest; and subject has received, is receiving, or is willing to receive treatment per standard of care, which may or may not include oral prednisone (2 mg/kg PO to a maximum dose of 100 mg daily) for 4 days.
- Abstinent or using two highly effective forms of birth control.
- Subjects must be accessible for treatment and follow-up. Subjects living at distant locations from the investigational site must be able and willing to travel to a site for the initial and all follow-up visits.
Who cannot join
- Weight <20 kg.
- Intercurrent non-healed fracture at any location.
- Complete immobilization of joint at site of flare-up.
- The inability of the subject to undergo imaging assessments using plain radiographs.
- If currently using vitamin A or beta carotene, multivitamins containing vitamin A or beta carotene, or herbal preparations, fish oil, and unable or unwilling to discontinue use of these products for the duration of the study.
- Exposure to synthetic oral retinoids in the past 30 days prior to Screening (signature of the informed consent).
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- Concurrent treatment with tetracycline due to the potential increased risk of pseudotumor cerebri.
- History of allergy or hypersensitivity to retinoids or lactose.
- Concomitant medications that are inhibitors or inducers of CYP450 3A4 activity.
- Amylase or lipase >1.5x above the upper limit of normal or with a history of chronic pancreatitis.
- Elevated aspartate aminotransferase or alanine aminotransferase >2.5x the upper limit of normal.
- Fasting triglycerides >400 mg/dL with or without therapy.
Trial locations and contacts
4 sites in 3 countries.
4 sites in 3 countries
United States2 sites
University of Pennsylvania, Center for Research in FOP & Related Disorders
Philadelphia, Pennsylvania, 19104
University of California San Francisco, Division of Endocrinology and Metabolism
San Francisco, California, 94143
United Kingdom1 site
The Royal National Orthopaedic Hospital, Brockley Hill
Stanmore, Middlesex, HA7 4LP
About this study
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)
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.
Read the detailed description
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:
- 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.
- A double-blind treatment period of 6 weeks (42 days) duration.
- 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.
- Conditions
- Fibrodysplasia Ossificans Progressiva
- Being tested
- Palovarotene, Placebo
- Keywords
- Intervention study, Clinical trial Phase 2, Efficacy and safety, Heterotopic ossification, Flare-up, Palovarotene, Retinoic acid receptor agonist, Retinoic acid receptor gamma agonist, Clementia, Myositis Ossificans Progressiva, Munchmeyer's Disease, FOP
- 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.
PalovaroteneDrug
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.
PlaceboDrug
| Study group | Role | What they receive |
|---|---|---|
| Palovarotene dose level 1 (Cohort 1) | Experimental | Doses of palovarotene in dose level 1 are 10 mg once daily for 14 days, followed by 5 mg once daily for 28 days. Receives: Drug: Palovarotene |
| Palovarotene dose level 2 (Cohort 2) | Experimental | Weight-adjusted doses of palovarotene in dose level 2 are 10 mg palovarotene once daily, followed by 5 mg once daily for 28 days. Receives: Drug: Palovarotene |
| Palovarotene dose level 3 (Cohort 2) | Experimental | 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. Receives: Drug: Palovarotene |
| Sugar pill | Placebo comparator | The placebo comparator will be taken once daily for the same duration as the palovarotene dose groups in both Cohorts 1 and 2. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Percentage of Responders at Week 6
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.
Measured: Baseline (Day 1) and Week 6 (Day 42)
Secondary outcomes (23)
Percentage of Subjects With New HO at Weeks 6 and 12
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.
Measured: Weeks 6 and 12 (Day 84)
Change From Baseline in Amount (Area) of New HO Formed at the Flare-up Site at Weeks 6 and 12
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.
Measured: Baseline, Weeks 6 and 12
Percentage of Responders at Week 12
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.
Measured: Baseline and Week 12
Change From Baseline in Bone Specific Alkaline Phosphatase at Weeks 2, 4, 6 and 12
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.
Measured: Baseline, Weeks 2, 4, 6 and 12
Change From Baseline in C-Reactive Protein at Weeks 2, 4, 6 and 12
Blood and urine samples for analysis of cartilage, bone, angiogenesis, and inflammation biomarkers were collected. C-reactive protein was analysed as a inflammation biomarker.
Measured: Baseline, Weeks 2, 4, 6 and 12
Change From Baseline in C-Terminal Telopeptide at Weeks 2, 4, 6 and 12
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.
Measured: Baseline, Weeks 2, 4, 6 and 12
Change From Baseline in Procollagen Type 1 N-Terminal Propeptide at Weeks 2, 4, 6 and 12
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.
Measured: Baseline, Weeks 2, 4, 6 and 12
Change From Baseline in Procollagen Type 1 C-Terminal Propeptide Biomarker at Weeks 2, 4, 6 and 12
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.
Measured: Baseline, Weeks 2, 4, 6 and 12
Change From Baseline in Amount of Bone Formation (Volume) at Weeks 6 and 12
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.
Measured: Baseline, Weeks 6 and 12
Percentage of Subjects With Soft Tissue Swelling and Cartilage Formation Assessed by Magnetic Resonance Imaging (MRI) or Ultrasound (US) at Weeks 6 and 12
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.
Measured: Weeks 6 and 12
Change From Baseline in Percent of Normal Arc of Motion at the Primary Joint (Flare-up Site) at Weeks 6 and 12
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.
Measured: Baseline, Weeks 6 and 12
Subject and Investigator Global Assessment of Movement at Weeks 6 and 12
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).
Measured: Weeks 6 and 12
Change From Baseline in Flare-Up Pain and Swelling at Weeks 2, 4, 6, 9 and 12
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.
Measured: Baseline, Weeks 2, 4, 6, 9 and 12
Percentage of Subjects Who Used Any Assistive Devices and Adaptations for Daily Living at Weeks 6 and 12
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.
Measured: Weeks 6 and 12
Duration of Active Symptomatic Flare-up
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.
Measured: From Day 1 to Day 84
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
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.
Measured: Baseline, Weeks 2, 4, 6, 9 and 12
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
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.
Measured: Baseline, Weeks 2, 4, 6, 9 and 12
Maximum Measured Plasma Concentration (Cmax) of Palovarotene
The Cmax of palovarotene was determined.
Measured: Pre-dose and 3, 6, 10, and 24 hours (hrs) post-dose at Week 2, and at Week 4 or 6
Minimum Measured Plasma Concentration (Cmin) of Palovarotene
The Cmin of palovarotene was determined.
Measured: Pre-dose and 3, 6, 10, and 24 hrs post-dose at Week 2, and at Week 4 or 6
Time of Maximum Measured Plasma Concentration (Tmax) of Palovarotene
The Tmax obtained by inspection of palovarotene was determined.
Measured: Pre-dose and 3, 6, 10, and 24 hrs post-dose at Week 2, and at Week 4 or 6
Apparent Terminal Elimination Half-life (t1/2) of Palovarotene
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.
Measured: Pre-dose and 3, 6, 10, and 24 hrs post-dose at Week 2, and at Week 4 or 6
Area Under the Plasma Concentration Versus Time Curve Over the 24-hr Dosing Interval (AUC[0-24hr]) of Palovarotene
The AUC(0-24hr) was calculated using linear trapezoid rule.
Measured: Pre-dose and 3, 6, 10, and 24 hrs post-dose at Week 2, and at Week 4 or 6
Apparent Clearance of Palovarotene (CL/F)
The CL/F was defined as dose/AUC0-24hr.
Measured: Pre-dose and 3, 6, 10, and 24 hrs post-dose at Week 2, and at Week 4 or 6
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Jul 2014 (estimated)
- Study start14 Jul 2014
- Primary completion23 May 2016
- Study completion23 May 2016
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 (5)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
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 40 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
- NCT02190747
- Sponsor's protocol ID
- PVO-1A-201
- Other IDs
- 2014-001453-17, 2014
- Status last verified
- Jan 2021
- First submitted
- 13 Jul 2014
- Last updated
- 16 Feb 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
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, 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 37957586Lindborg CM, Al Mukaddam M, Baujat G, Cho TJ, De Cunto CL, Delai PLR, Eekhoff EMW, Haga N, Hsiao EC, Morhart R, de Ruiter R, Scott C, Seemann P, Szczepanek M, Tabarkiewicz J, Pignolo RJ, Kaplan FS. Most Fractures Treated Nonoperatively in Individuals With Fibrodysplasia Ossificans Progressiva Heal With a Paucity of Flareups, Heterotopic Ossification, and Loss of Mobility. Clin Orthop Relat Res. 2023 Dec 1;481(12):2447-2458. doi: 10.1097/CORR.0000000000002672. Epub 2023 May 8.
PubMed 37156007Pignolo 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 36526263Pignolo RJ, Baujat G, Hsiao EC, Keen R, Wilson A, Packman J, Strahs AL, Grogan DR, Kaplan FS. Palovarotene for Fibrodysplasia Ossificans Progressiva (FOP): Results of a Randomized, Placebo-Controlled, Double-Blind Phase 2 Trial. J Bone Miner Res. 2022 Oct;37(10):1891-1902. doi: 10.1002/jbmr.4655. Epub 2022 Aug 17.
PubMed 35854638
Study at a glance
From the registry record, last updated by the sponsor on 16 Feb 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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)
- ClinicalTrials.gov ID
- NCT02190747
- Acronym / sponsor ID
- PVO-1A-201
- Conditions
- Fibrodysplasia Ossificans Progressiva
- Keywords
- Intervention study, Clinical trial Phase 2, Efficacy and safety, Heterotopic ossification, Flare-up, Palovarotene, Retinoic acid receptor agonist, Retinoic acid receptor gamma agonist
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 40 participants (actual)
- Lead sponsor
- Clementia Pharmaceuticals Inc.Industry (pharma, biotech, devices)
- Study start
- 14 Jul 2014 (actual)
- Primary completion
- 23 May 2016 (actual)
- Study completion
- 23 May 2016 (actual)
- First posted
- 15 Jul 2014 (estimated)
- Results
- Posted 24 Jun 2020
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 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.
Detailed description
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:
- 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.
- A double-blind treatment period of 6 weeks (42 days) duration.
- 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Palovarotene dose level 1 (Cohort 1) | Experimental | Drug: PalovaroteneDoses of palovarotene in dose level 1 are 10 mg once daily for 14 days, followed by 5 mg once daily for 28 days. |
| Palovarotene dose level 2 (Cohort 2) | Experimental | Drug: PalovaroteneWeight-adjusted doses of palovarotene in dose level 2 are 10 mg palovarotene once daily, followed by 5 mg once daily for 28 days. |
| Palovarotene dose level 3 (Cohort 2) | Experimental | Drug: PalovaroteneWeight-adjusted doses of palovarotene in dose level 3 are 5 mg palovarotene once daily, followed by 2.5 mg once daily for 28 days. |
| Sugar pill | Placebo comparator | Drug: PlaceboThe placebo comparator will be taken once daily for the same duration as the palovarotene dose groups in both Cohorts 1 and 2. |
Who may qualify
- Ages
- 6 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (6 listed)
- Written, signed, and dated informed subject/parent consent or age-appropriate assent.
- Subjects clinically diagnosed with classic Fibrodysplasia Ossificans Progressiva (FOP).
- Symptomatic onset of a distinct flare-up within 7 days of Study Day 1 (start of study drug) and defined by the presence of at least two of six of the following symptoms: pain, soft tissue swelling, decreased range of motion, stiffness, redness, and warmth. Flare-up must be confirmed by the physician at the Screening visit.
- Flare-up is at an appendicular area (upper or lower extremity), abdomen, or chest; and subject has received, is receiving, or is willing to receive treatment per standard of care, which may or may not include oral prednisone (2 mg/kg PO to a maximum dose of 100 mg daily) for 4 days.
- Abstinent or using two highly effective forms of birth control.
Key exclusion criteria (12 listed)
- Weight <20 kg.
- Intercurrent non-healed fracture at any location.
- Complete immobilization of joint at site of flare-up.
- The inability of the subject to undergo imaging assessments using plain radiographs.
- If currently using vitamin A or beta carotene, multivitamins containing vitamin A or beta carotene, or herbal preparations, fish oil, and unable or unwilling to discontinue use of these products for the duration of the study.
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 |
|---|---|---|
| PalovarotenePalovarotene 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. | Drug | Palovarotene dose level 1 (Cohort 1), Palovarotene dose level 2 (Cohort 2), Palovarotene dose level 3 (Cohort 2) |
| Placebo | Drug | Sugar pill |
Primary outcome
Percentage of Responders at Week 6
Time frame: Baseline (Day 1) and Week 6 (Day 42)
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.
23 secondary outcomes
Percentage of Subjects With New HO at Weeks 6 and 12
Time frame: Weeks 6 and 12 (Day 84)
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
Percentage of Responders at Week 12
Time frame: Baseline and Week 12
Change From Baseline in Bone Specific Alkaline Phosphatase at Weeks 2, 4, 6 and 12
Time frame: Baseline, Weeks 2, 4, 6 and 12
Change From Baseline in C-Reactive Protein at Weeks 2, 4, 6 and 12
Time frame: Baseline, Weeks 2, 4, 6 and 12
Change From Baseline in C-Terminal Telopeptide at Weeks 2, 4, 6 and 12
Time frame: Baseline, Weeks 2, 4, 6 and 12
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
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
Change From Baseline in Amount of Bone Formation (Volume) at Weeks 6 and 12
Time frame: Baseline, Weeks 6 and 12
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
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
Subject and Investigator Global Assessment of Movement at Weeks 6 and 12
Time frame: Weeks 6 and 12
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
Percentage of Subjects Who Used Any Assistive Devices and Adaptations for Daily Living at Weeks 6 and 12
Time frame: Weeks 6 and 12
Duration of Active Symptomatic Flare-up
Time frame: From Day 1 to Day 84
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
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
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
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
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
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
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
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
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 Feb 2021.
- 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 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 37156007Lindborg CM, Al Mukaddam M, Baujat G, Cho TJ, De Cunto CL, Delai PLR, Eekhoff EMW, Haga N, Hsiao EC, Morhart R, de Ruiter R, Scott C, Seemann P, Szczepanek M, Tabarkiewicz J, Pignolo RJ, Kaplan FS. Most Fractures Treated Nonoperatively in Individuals With Fibrodysplasia Ossificans Progressiva Heal With a Paucity of Flareups, Heterotopic Ossification, and Loss of Mobility. Clin Orthop Relat Res. 2023 Dec 1;481(12):2447-2458. doi: 10.1097/CORR.0000000000002672. Epub 2023 May 8.
- 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.
- Derived from this study: PubMed 35854638Pignolo RJ, Baujat G, Hsiao EC, Keen R, Wilson A, Packman J, Strahs AL, Grogan DR, Kaplan FS. Palovarotene for Fibrodysplasia Ossificans Progressiva (FOP): Results of a Randomized, Placebo-Controlled, Double-Blind Phase 2 Trial. J Bone Miner Res. 2022 Oct;37(10):1891-1902. doi: 10.1002/jbmr.4655. Epub 2022 Aug 17.
- Website for the International FOP AssociationLink provided by the sponsor.
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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
4 sites in 3 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Palovarotene in people with Fibrodysplasia Ossificans Progressiva, run by Clementia Pharmaceuticals Inc. at 4 sites in 3 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 12 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 16 Feb 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in United States, 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. Some participants in this study may receive a placebo. 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 24 Jun 2020). 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?
Percentage of Responders at Week 6 (time frame: Baseline (Day 1) and Week 6 (Day 42)). 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 NCT02190747, which also lists 5 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 16 Feb 2021.