A Phase 2 interventional study of Palovarotene dose level 1 and Palovarotene dose level 2 in Fibrodysplasia Ossificans Progressiva, sponsored by Clementia Pharmaceuticals Inc.. Completed at 8 sites in 5 countries. Open to participants aged 6 Years to 65 Years. Per ClinicalTrials.gov, last updated 2025-02-19.
Sponsored by Clementia Pharmaceuticals Inc. (part of Ipsen) · Phase 2, Interventional, and Treatment
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.
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.
24 studies on the registry are indexed under Myositis Ossificans; 5 are open to participants now.
This study's enrollment of 58 is above the median of 48 across 16 interventional studies indexed under Myositis Ossificans.
Browse Myositis Ossificans studies →Clementia Pharmaceuticals Inc. is the lead sponsor of 10 studies on the registry; none are open to participants now.
Of its 6 completed or terminated interventional studies of FDA-regulated products, 3 (50%) have results posted.
First submitted before Clementia Pharmaceuticals Inc. became part of Ipsen.
Counted across the registry records on this site, refreshed daily.
Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).
Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
The top of the normal range for a blood test, as set by the laboratory that runs it. Each lab prints its own range next to your result.
“≤ 2.5 × ULN” means the result can be up to two and a half times that top value.
Two enzymes measured in a routine blood test of the liver. Higher levels can mean the liver is under strain or damaged. SGPT and SGOT are older names for ALT and AST.
Criteria usually give a limit as a multiple of the upper limit of normal (ULN), often higher when cancer has spread to the liver.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Childbearing potential
Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).
Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraception
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ULN (upper limit of normal)
The top of the normal range for a blood test, as set by the laboratory that runs it. Each lab prints its own range next to your result.
“≤ 2.5 × ULN” means the result can be up to two and a half times that top value.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ALT and AST (liver enzymes)
Two enzymes measured in a routine blood test of the liver. Higher levels can mean the liver is under strain or damaged. SGPT and SGOT are older names for ALT and AST.
Criteria usually give a limit as a multiple of the upper limit of normal (ULN), often higher when cancer has spread to the liver.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
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).
Drug: Palovarotene dose level 1
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).
Drug: Palovarotene dose level 2
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).
Drug: Palovarotene dose level 3
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.
Drug: Palovarotene dose level 4
Palovarotene was taken orally once daily at approximately the same time each day.
Palovarotene will be taken orally once daily at approximately the same time each day.
Palovarotene will be taken orally once daily at approximately the same time each day.
Palovarotene will be taken orally once daily at approximately the same time each day.
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.
Time frame: 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.
Time frame: From Baseline (Day 1) up to end of 2 year follow-up period, approximately a maximum of 96 months
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.
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
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.
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
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.
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
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.
Time frame: 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.
Time frame: 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.
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
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.
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
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.
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
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.
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
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.
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
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.
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
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.
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
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.
Time frame: 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.
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
The bone formation was measured by PINP biomarker. Baseline was defined as flare-up screening/Day 1.
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
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.
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
The number of days of active symptomatic flare-up was the number of days the participant reported the presence of symptoms in the diary.
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
Whole body burden of HO was assessed by low-dose WBCT scan, excluding head. Baseline was Part B Screening.
Time frame: 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.
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
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.
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)
New HO was defined as total WBCT new HO volume \>0. Results for Month 72 are presented for overall ITT period.
Time frame: Months 12, 24, 36, 60, and 72 (last visit)
This Phase 2, open-label extension of study PVO-1A-201 was conducted in participants with FOP at 8 investigational sites in 5 countries. Participants enrolled in France were followed under a country-specific study PVO-1A-204 (as Part B of the study) as requested by French regulatory authorities. Overall, 58 participants were enrolled in this study.
| Milestone | All Participants |
|---|---|
| Started | 58 |
| Entered part a | 40 |
| Completed part a | 13 |
| Entered part b | 54 |
| Completed part b | 16 |
| Entered part c | 48 |
| Completed part c | 29 |
| Entered part d | 2 |
| Completed | 39 |
| Not completed | 19 |
| Withdrew: Non-compliance | 1 |
| Withdrew: Withdrawal by subject | 8 |
| Withdrew: Adverse event | 2 |
| Withdrew: Other | 7 |
| Withdrew: Lost to follow-up | 1 |
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.
| percentage of flare-ups | Part A: Palovarotene 10/5 mg - Flare-up | Part B: Flare-up Combined |
|---|---|---|
| Parts A and B: Percentage of Flare-ups With No New Heterotopic Ossification (HO) at Week 12 | 64.3 | 72.5 |
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.
| cubic millimeter (mm^3)/year | Part B: Palovarotene - All Treated Flare-ups | Part B: Untreated/Undertreated Flare-ups | Part B: No Flare-ups | Part B: All Treated and No Flare-ups Combined | Part C: Palovarotene - All Treated Flare-ups | Part C: Untreated/Undertreated Flare-ups | Part C: No Flare-ups | Part C: All Treated and No Flare-ups Combined |
|---|---|---|---|---|---|---|---|---|
| Parts B and C: Annualized Change in New HO Volume | -3464.0 ± 5081.50 | 29522.8 ± 89408.15 | 25041.1 ± 58529.79 | 16270.3 ± 49777.40 | -10343.4 ± 18007.89 | 52291.4 ± 86019.62 | 30530.9 ± 51800.47 | 8731.3 ± 41924.30 |
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.
No measurements were reported for this outcome.
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.
| mm^3 | Part A: Palovarotene 10/5 mg - Flare-up | Part B: Flare-up Combined |
|---|---|---|
| Parts A and B: Volume of New Heterotopic Bone Formed at Month 12 | 2310 ± 4739 | 4818 ± 17349 |
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.
| number of flare-ups | Part A: Palovarotene 10/5 mg - Flare-up | Part B: Flare-up Combined |
|---|---|---|
| Parts A and B: Osteocalcin | 10 | 6 |
| Parts A and B: Bone-specific ALP | 2 | 2 |
| Parts A and B: P1NP | 10 | 2 |
| Parts A and B: CD retinoic acid protein | 4 | 6 |
| Parts A and B: P1CP | 3 | 2 |
| Parts A and B: C-terminal telopeptide | 0 | 1 |
| Parts A and B: Urinary basic FGF | 6 | 5 |
| Parts A and B: ESR | 4 | 0 |
| Parts A and B: C-reactive protein | 6 | 5 |
| Parts A and B: IL-6 | 0 | 3 |
| Parts A and B: IL-1 beta | 5 | 5 |
| Parts A and B: TNF-alpha | 3 | 1 |
| Parts A and B: Creatine kinase | 1 | 3 |
| Parts A and B: Lactate dehydrogenase | 4 | 1 |
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.
| percent of normal total arc of motion | Part A: Palovarotene 10/5 mg - Flare-up | Part B: Flare-up Combined |
|---|---|---|
| Parts A and B: Change From Baseline in Active Range of Motion (ROM) at Flare-up Site at Week 12 | -6.16 ± 14.362 | -0.49 ± 18.096 |
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.
| units on a scale | Part B: Flare-up Combined |
|---|---|
| Part B: Change From Baseline in ROM at Week 12 | 0.3 ± 1.80 |
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.
| units on a scale | Part C: Palovarotene - All Treated Flare-ups |
|---|---|
| Month 6 | 0.2 ± 1.58 |
| Month 12 | 0.6 ± 1.76 |
| Month 18 | 0.9 ± 1.73 |
| Month 24 | 1.3 ± 2.74 |
| Month 30 | 1.5 ± 2.79 |
| Month 36 | 1.6 ± 3.38 |
| Month 42 | 1.6 ± 3.03 |
| Month 48 | 3.0 ± 2.55 |
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.
| number of flare-ups | Part B: Flare-up Combined |
|---|---|
| PA: New HO - Better movement | 5 |
| PA: New HO - Same movement | 3 |
| PA: New HO - Slightly worse movement | 2 |
| PA: New HO - Moderately worse movement | 2 |
| PA: New HO - Severely worse movement | 2 |
| PA: No new HO - Better movement | 11 |
| PA: No new HO - Same movement | 20 |
| PA: No new HO - Slightly worse movement | 5 |
| PA: No new HO - Moderately worse movement | 1 |
| PA: No new HO - Severely worse movement | 0 |
| IA: New HO - Better movement | 5 |
| IA: New HO - Same movement | 3 |
| IA: New HO - Slightly worse movement | 2 |
| IA: New HO - Moderately worse movement | 3 |
| IA: New HO - Severely worse movement | 1 |
| IA: No new HO - Better movement | 1 |
| IA: No new HO - Same movement | 29 |
| IA: No new HO - Slightly worse movement | 6 |
| IA: No new HO - Moderately worse movement | 1 |
| IA: No new HO - Severely worse movement | 0 |
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.
| units on a scale | Part A: Palovarotene 10/5 mg - Flare-up |
|---|---|
| Week 2: Pain | -1.4 ± 2.22 |
| Week 4: Pain | -2.1 ± 2.27 |
| Week 6: Pain | -2.6 ± 2.71 |
| Week 9: Pain | -2.9 ± 2.97 |
| Week 12: Pain | -2.6 ± 2.85 |
| Week 2: Swelling | -1.7 ± 1.83 |
| Week 4: Swelling | -2.3 ± 2.31 |
| Week 6: Swelling | -2.4 ± 2.38 |
| Week 9: Swelling | -2.7 ± 2.47 |
| Week 12: Swelling | -2.9 ± 2.46 |
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.
| units on a scale | Part A: Palovarotene 10/5 mg - Flare-up | Part B: Flare-up Combined |
|---|---|---|
| Parts A and B: Week 2 | -0.97 ± 4.939 | — |
| Parts A and B: Week 4 | 0.38 ± 4.746 | -1.23 ± 4.453 |
| Parts A and B: Week 6 | 0.21 ± 6.501 | — |
| Parts A and B: Week 8 | — | 0.88 ± 9.357 |
| Parts A and B: Week 9 | 0.76 ± 6.054 | — |
| Parts A and B: Week 12 | 0.69 ± 6.604 | 0.17 ± 6.893 |
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.
| units on a scale | Part C: Palovarotene - All Treated Flare-ups |
|---|---|
| Month 6 | 1.8 ± 6.36 |
| Month 12 | 1.8 ± 9.81 |
| Month 18 | 4.0 ± 9.49 |
| Month 24 | 7.5 ± 14.00 |
| Month 30 | 8.2 ± 13.45 |
| Month 36 | 9.8 ± 14.11 |
| Month 42 | 7.0 ± 13.14 |
| Month 48 | 8.3 ± 7.76 |
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.
| units on a scale | Part A: Palovarotene 10/5 mg - Flare-up | Part B: Flare-up Combined |
|---|---|---|
| Parts A and B: AFPH - Week 2 | 3.26 ± 4.819 | — |
| Parts A and B: AFPH - Week 4 | 2.14 ± 3.976 | 0.2 ± 3.17 |
| Parts A and B: AFPH - Week 6 | 1.78 ± 3.735 | — |
| Parts A and B: AFPH - Week 8 | — | 0.3 ± 3.33 |
| Parts A and B: AFPH - Week 9 | 2.87 ± 5.352 | — |
| Parts A and B: AFPH - Week 12 | 3.22 ± 4.855 | 0.6 ± 3.79 |
| Parts A and B: AFMH - Week 2 | 1.00 ± 4.667 | — |
| Parts A and B: AFMH - Week 4 | 0.39 ± 3.264 | 1.0 ± 8.05 |
| Parts A and B: AFMH - Week 6 | 1.03 ± 3.122 | — |
| Parts A and B: AFMH - Week 8 | — | -0.3 ± 7.47 |
| Parts A and B: AFMH - Week 9 | -0.16 ± 4.422 | — |
| Parts A and B: AFMH - Week 12 | 0.99 ± 2.915 | 0.2 ± 7.63 |
| Parts A and B: PFH - Week 2 | -0.05 ± 2.475 | — |
| Parts A and B: PFH - Week 4 | 1.70 ± 4.950 | 0.7 ± 4.77 |
| Parts A and B: PFH - Week 6 | 5.25 ± 4.596 | — |
| Parts A and B: PFH - Week 8 | — | -2.5 ± 6.32 |
| Parts A and B: PFH - Week 9 | 0.85 ± 1.202 | — |
| Parts A and B: PFH - Week 12 | 0.85 ± 3.748 | 0.4 ± 5.65 |
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.
| units on a scale | Part C: Palovarotene - All Treated Flare-ups |
|---|---|
| AFPH - Month 6 | -0.2 ± 5.59 |
| AFPH - Month 12 | 0.6 ± 6.04 |
| AFPH - Month 18 | -0.1 ± 5.30 |
| AFPH - Month 24 | -1.1 ± 7.10 |
| AFPH - Month 30 | 0.1 ± 4.46 |
| AFPH - Month 36 | -1.1 ± 5.97 |
| AFPH - Month 42 | -1.8 ± 6.55 |
| AFPH - Month 48 | -1.6 ± 3.02 |
| AFMH - Month 6 | -2.2 ± 6.49 |
| AFMH - Month 12 | -0.0 ± 3.96 |
| AFMH - Month 18 | -0.8 ± 5.04 |
| AFMH - Month 24 | -2.5 ± 5.96 |
| AFMH - Month 30 | -3.0 ± 5.30 |
| AFMH - Month 36 | -1.5 ± 4.95 |
| AFMH - Month 42 | -2.9 ± 6.24 |
| AFMH - Month 48 | -5.2 ± 7.83 |
| PFH - Month 6 | 3.8 ± 2.91 |
| PFH - Month 12 | 1.7 ± 1.65 |
| PFH - Month 18 | 4.7 ± 1.93 |
| PFH - Month 24 | 3.4 ± 4.63 |
| PFH - Month 30 | 4.6 ± 2.52 |
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.
| devices adaptations | Part A: Palovarotene 10/5 mg - Flare-up | Part B: Flare-up Combined |
|---|---|---|
| Part A: Week 6 | 12.9 ± 11.52 | — |
| Parts A and B: Week 12 | 14.3 ± 12.39 | 13.2 ± 10.50 |
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.
| percentage of participants | Part A: Palovarotene 10/5 mg - Flare-up |
|---|---|
| Part A: Percentage of Responders at Week 12 | 64.3 |
The bone formation was measured by PINP biomarker. Baseline was defined as flare-up screening/Day 1.
| microgram per liter | Part A: Palovarotene 10/5 mg - Flare-up | Part B: Flare-up Combined |
|---|---|---|
| Part A: Week 6 | 38.755 ± 50.547 | — |
| Parts A and B: Week 12 | 54.592 ± 140.540 | 70.916 ± 130.608 |
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.
| flare-up | Part A: Palovarotene 10/5 mg - Flare-up | Part B: Flare-up Combined |
|---|---|---|
| Part A: Edema - Week 6 | 7 | — |
| Part A: Cartilage Formation - Week 6 | 0 | — |
| Parts A and B: Edema - Week 12 | 9 | 36 |
| Parts A and B: Cartilage Formation - Week 12 | 0 | 1 |
The number of days of active symptomatic flare-up was the number of days the participant reported the presence of symptoms in the diary.
| day | Part A: Palovarotene 10/5 mg - Flare-up | Part B: Flare-up Combined |
|---|---|---|
| Parts A and B: Duration of Active Symptomatic Flare-up | 27.1 ± 29.9 | 39.5 ± 36.1 |
Whole body burden of HO was assessed by low-dose WBCT scan, excluding head. Baseline was Part B Screening.
| mm^3 | Part B: Whole Body Computed Tomography (WBCT) Population |
|---|---|
| Month 12 | 28386 ± 89918 |
| Month 24 | 193150 ± 9999 |
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.
| percentage of flare-up/participant-month | Part B: Flare-up Combined |
|---|---|
| Part B: Mean Percentage of Flare-ups Per Participant-Month Overall | 0.12 ± 0.124 |
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.
| percentage of flare-up/participant-month | Part C: Palovarotene - All Treated Flare-ups |
|---|---|
| Part C: Mean Percentage of Flare-ups Per Participant-Month Overall | 0.14 ± 0.150 |
New HO was defined as total WBCT new HO volume \>0. Results for Month 72 are presented for overall ITT period.
| percentage of participants | Part C: Palovarotene - All Treated Flare-ups |
|---|---|
| Month 12 | 60.0 |
| Month 24 | 54.5 |
| Month 36 | 61.5 |
| Month 60 | 100.0 |
| Month 72 | 86.2 |
Collected over Treatment-emergent adverse events were recorded from the time informed consent was signed through end of the study (a maximum of 96 months).. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Part A | 0/20 (0%) | 2/20 (10%) | 20/20 (100%) |
| Part B | 0/52 (0%) | 9/52 (17.3%) | 52/52 (100%) |
| Part C | 0/46 (0%) | 25/46 (54.3%) | 46/46 (100%) |
| Part D | 0/1 (0%) | 0/1 (0%) | 0/1 (0%) |
| Event | Part A | Part B | Part C | Part D |
|---|---|---|---|---|
| Corona virus infectionInfections and infestations | 0/20 | 0/52 | 6/46 | 0/1 |
| Coronavirus test positiveInvestigations | 0/20 | 0/52 | 5/46 | 0/1 |
| PneumoniaInfections and infestations | 1/20 | 1/52 | 4/46 | 0/1 |
| Exposure to communicable diseaseInjury, poisoning and procedural complications | 0/20 | 0/52 | 4/46 | 0/1 |
| Pain in extremityMusculoskeletal and connective tissue disorders | 0/20 | 0/52 | 3/46 | 0/1 |
| Condition aggravatedGeneral disorders | 1/20 | 2/52 | 2/46 | 0/1 |
| Post-traumatic painInjury, poisoning and procedural complications | 1/20 | 0/52 | 1/46 | 0/1 |
| MyoclonusNervous system disorders | 1/20 | 1/52 | 0/46 | 0/1 |
| Drug dependencePsychiatric disorders | 1/20 | 0/52 | 0/46 | 0/1 |
| Tooth impactedGastrointestinal disorders | 0/20 | 0/52 | 2/46 | 0/1 |
| Event | Part A | Part B | Part C | Part D |
|---|---|---|---|---|
| Dry skinSkin and subcutaneous tissue disorders | 15/20 | 44/52 | 38/46 | 0/1 |
| Lip dryGastrointestinal disorders | 13/20 | 32/52 | 26/46 | 0/1 |
| ArthralgiaMusculoskeletal and connective tissue disorders | 11/20 | 25/52 | 27/46 | 0/1 |
| Condition aggravatedGeneral disorders | 9/20 | 29/52 | 6/46 | 0/1 |
| PruritusSkin and subcutaneous tissue disorders | 7/20 | 28/52 | 18/46 | 0/1 |
| Pain in extremityMusculoskeletal and connective tissue disorders | 10/20 | 26/52 | 23/46 | 0/1 |
| AlopeciaSkin and subcutaneous tissue disorders | 0/20 | 26/52 | 20/46 | 0/1 |
| RashSkin and subcutaneous tissue disorders | 3/20 | 24/52 | 16/46 | 0/1 |
| ProteinuriaRenal and urinary disorders | 9/20 | 6/52 | 0/46 | 0/1 |
| ErythemaSkin and subcutaneous tissue disorders | 5/20 | 23/52 | 16/46 | 0/1 |
The Enrolled Population included all participants enrolled in the study.
| Age, Continuous(years) | All Participants |
|---|---|
| Mean | 21.0 ± 9.27 |
| Sex: Female, Male(Participants) | All Participants |
|---|---|
| Female | 32 |
| Male | 26 |
| Race and Ethnicity Not Collected(Participants) | All Participants |
|---|
PDFs hosted by the registry, ClinicalTrials.gov.
Plan to share: No
Ran from Oct 2014 to primary completion in Sep 2022, 95 months.
Results were first posted in May 2024, 1 year 7 months after primary completion.
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