| ID | Type | Description | Link |
|---|---|---|---|
| 2014-002496-28 | EudraCT Number |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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). |
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| 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). |
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| 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). |
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| 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. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Palovarotene dose level 1 | Drug | Palovarotene was taken orally once daily at approximately the same time each day. |
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| Measure | Description | Time Frame |
|---|---|---|
| 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. | 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. | From Baseline (Day 1) up to end of 2 year follow-up period, approximately a maximum of 96 months |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Ipsen Medical Director | Ipsen | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of California San Francisco, Division of Endocrinology and Metabolism | San Francisco | California | 94143 | United States | ||
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 21460849 | Background | 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. | |
| 37957586 | Derived |
| Label | URL |
|---|---|
| Website for the International FOP Association | View source |
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Study divided into 4 parts: Part A (participants who completed PVO-1A-201 study were enrolled and followed for 3 years), Part B (participants from Part A and 18 new adult participants were followed for 2 years), Part C (participants from Part B were followed for 2 years) and Part D (treatment discontinued participants were followed for 2 years).
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.
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| ID | Title | Description |
|---|---|---|
| FG000 | All Participants | Participants who completed PVO-1A-201 study were followed for up to 36 months in Part A. Eligible participants with a flare-up received palovarotene 10 milligram (mg) capsule orally daily for 2 weeks followed by 5 mg daily for 4 weeks during the flare-up component of Part A. In Part B, eligible participants from Part A and participants from the new Adult Cohort received chronic treatment with palovarotene 5 mg daily for up to 24 months. Participants with flare-ups received palovarotene 20 mg daily for 4 weeks followed by 10 mg daily for 8 weeks. In Part C, eligible participants received chronic treatment of palovarotene 5mg daily for up to 36 months. Participants with flare-ups received palovarotene 20 mg daily for 4 weeks followed by 10 mg daily for 8 weeks. For skeletal immature participants, the exposure-equivalent dose was determined based on weight. In Part D, no study drug was administered. Participants in Part C/D were followed for up to an additional 48 months. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Dec 18, 2020 | Nov 10, 2023 |
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| Palovarotene dose level 2 | Drug | Palovarotene will be taken orally once daily at approximately the same time each day. |
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| Palovarotene dose level 3 | Drug | Palovarotene will be taken orally once daily at approximately the same time each day. |
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| Palovarotene dose level 4 | Drug | Palovarotene will be taken orally once daily at approximately the same time each day. |
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| 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | Months 12, 24, 36, 60, and 72 (last visit) |
| Mayo Clinic, Department of Medicine |
| Rochester |
| Minnesota |
| 55905 |
| United States |
| University of Pennsylvania, Center for FOP & Related Bone Disorders | Philadelphia | Pennsylvania | 19104 | United States |
| Hospital Italiano de Buenos Aires, Department of Pediatrics | Buenos Aires | Argentina |
| Royal North Shore Hospital | Saint Leonards | New South Wales | 2065 | Australia |
| Queensland University of Technology (QUT) Institute of Health and Biomedical Innovation (IHBI) | Woolloongabba | Queensland | 4102 | Australia |
| Hôpital Necker-Enfants Malades, Department of Genetics | Paris | France |
| The Royal National Orthopaedic Hospital, Brockley Hill | Stanmore | Middlesex | HA7 4LP | United Kingdom |
| Pignolo 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. |
| 36526263 | Derived | Pignolo 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 French FOP Association | View source |
| Entered Part A |
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| Completed Part A |
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| Entered Part B | New Adult Cohort into Part B |
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| Completed Part B |
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| Entered Part C |
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| Completed Part C |
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| Entered Part D |
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| COMPLETED |
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| NOT COMPLETED |
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The Enrolled Population included all participants enrolled in the study.
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| ID | Title | Description |
|---|---|---|
| BG000 | All Participants | Participants who completed PVO-1A-201 study were followed for up to 36 months in Part A. Eligible participants with a flare-up received palovarotene 10 mg capsule orally daily for 2 weeks followed by 5 mg daily for 4 weeks during the flare-up component of Part A. In Part B, eligible participants from Part A and participants from the new Adult Cohort received chronic treatment with palovarotene 5 mg daily for up to 24 months. Participants with flare-ups received palovarotene 20 mg daily for 4 weeks followed by 10 mg daily for 8 weeks. In Part C, eligible participants received chronic treatment of palovarotene 5 mg daily for up to 36 months. Participants with flare-ups received palovarotene 20mg daily for 4 weeks followed by 10 mg daily for 8 weeks. For skeletal immature participants, the exposure-equivalent dose was determined based on weight. In Part D, no study drug was administered. Participants in Part C/D were followed for up to an additional 48 months. |
| Units | Counts |
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| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||
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| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants | No |
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| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||
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| Primary | 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. | Part A: Efficacy population included all participants in the treated population who had an evaluable Week 6 or Week 12 image [computed tomography (CT) scan or plain radiograph]. Part B: Flare-up population included all participants in the treated population who took at least 1 dose of palovarotene during flare-up based treatment in Part B. Only participants with flare-ups at baseline and Week 12 are reported. | Posted | Number | percentage of flare-ups | Baseline and Week 12 | Flare-ups | Flare-ups |
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| Primary | 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. | The Full Analysis Set (FAS) included all enrolled participants having a baseline HO volume measurement and at least 1 post-baseline HO volume measurement in the PVO-1A-202 study. | Posted | Mean | Standard Deviation | cubic millimeter (mm^3)/year | From Baseline (Day 1) up to end of 2 year follow-up period, approximately a maximum of 96 months |
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| Secondary | 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. | No participants were analyzed for this endpoint. | Posted | 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 |
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| Secondary | 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. | Part A: The Efficacy population included all participants in the treated population who had an evaluable Week 6 or Week 12 image (CT scan or plain radiograph). Part B: The Flare-up population included all participants in the treated population who took at least 1 dose of palovarotene during flare-up based treatment in Part B. Only participants with flare-ups at Week 12 are reported. | Posted | Mean | Standard Deviation | mm^3 | Month 12 | Number of flare-ups | Number of flare-ups |
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| Secondary | 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. | Part A: The Efficacy population. Part B: The Flare-up population. The data collected for flare-ups used each flare-up as the unit of analysis rather than each participant. Additionally, a study participant may have not had any flare-ups whereas another participant may have had multiple flare-ups (note, the number of flare-ups can be larger than the number of participants OR it can be smaller OR it can match, by chance). | Posted | Number | number of flare-ups | Part A and B: At Week 12 | Number of flare-ups | Number of flare-ups |
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| Secondary | 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. | Part A: Efficacy population included all participants in the treated population who had an evaluable Week 6 or Week 12 image (CT scan or plain radiograph). Part B: Flare-up population included all participants in the treated population who took at least 1 dose of palovarotene during flare-up based treatment in Part B. Only participants with flare-ups at baseline and Week 12 are reported. | Posted | Mean | Standard Deviation | percent of normal total arc of motion | Baseline and Week 12 | Number of flare-ups | Number of flare-ups |
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| Secondary | 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. | Flare-up population. The data collected for flare-ups used each flare-up as unit of analysis rather than each participant. Additionally, a study participant may have not had any flare-ups whereas another participant may have had multiple flare-ups (note, the number of flare-ups can be larger than the number of participants OR it can be smaller OR it can match, by chance). Only participants with flare-ups at baseline and at each time point are reported. | Posted | Mean | Standard Deviation | units on a scale | Baseline and Week 12 | Number of flare-ups | Number of flare-ups |
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| Secondary | 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. | The Safety analysis set included all enrolled participants who received at least 1 dose of palovarotene in the PVO-1A-202 study. Only participants analyzed at baseline and specific time point are reported. | Posted | Mean | Standard Deviation | units on a scale | Baseline and Months 6, 12, 18, 24, 30, 36, 42, and 48 |
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| Secondary | 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. | The Flare-up population. The data collected for flare-ups used each flare-up as the unit of analysis rather than each participant. Additionally, a study participant may have not had any flare-ups whereas another participant may have had multiple flare-ups (note, the number of flare-ups can be larger than the number of participants OR it can be smaller OR it can match, by chance). Only participants with flare-ups at baseline and Week 12 are reported. | Posted | Number | number of flare-ups | Week 12 | Flare-ups | Flare-ups |
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| Secondary | 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. | The Efficacy population. The data collected for flare-ups used each flare-up as unit of analysis rather than each participant. Additionally, a study participant may have not had any flare-ups whereas another participant may have had multiple flare-ups (note, number of flare-ups can be larger than the number of participants OR it can be smaller OR it can match, by chance). Only participants with flare-ups at baseline and at each time point are reported. | Posted | Mean | Standard Deviation | units on a scale | Baseline and Weeks 2, 4, 6, 9, and 12 | Number of flare-ups | Number of flare-ups |
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| Secondary | 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. | Part A: Efficacy population. Part B: Flare-up population. Data collected for flare-ups used each flare-up as unit of analysis rather than each participant. A study participant may have not had any flare-ups whereas another participant may have had multiple flare-ups (number of flare-ups can be larger than number of participants OR it can be smaller OR it can match, by chance). Only participants with flare-ups at baseline and at each time point are reported. | Posted | Mean | Standard Deviation | units on a scale | Part A: Baseline and Weeks 2, 4, 6, 9, and 12; and Part B: Baseline and Weeks 4, 8, and 12 | Number of flare-ups | Number of flare-ups |
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| Secondary | 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. | The Safety analysis set included all enrolled participants who received at least 1 dose of palovarotene in the PVO-1A-202 study. Only participants analyzed at baseline and specific time point are reported. | Posted | Mean | Standard Deviation | units on a scale | Baseline and Months 6, 12, 18, 24, 30, 36, 42, and 48 |
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| Secondary | 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. | Part A: Efficacy population. Part B: Flare-up population. Data collected for flare-ups used each flare-up as unit of analysis rather than each participant. A study participant may have not had any flare-ups whereas another participant may have had multiple flare-ups (number of flare-ups can be larger than number of participants OR it can be smaller OR it can match, by chance). Only participants with flare-ups at baseline and at each time point are reported. | Posted | Mean | Standard Deviation | units on a scale | Part A: Baseline and Weeks 2, 4, 6, 9, and 12; and Part B: Baseline and Weeks 4, 8, and 12 | Number of flare-ups | Number of flare-ups |
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| Secondary | 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. | The Safety analysis set included all enrolled participants who received at least 1 dose of palovarotene in the PVO-1A-202 study. Only participants analyzed at baseline and specific time point are reported. | Posted | Mean | Standard Deviation | units on a scale | Baseline and Months 6, 12, 18, 24, 30, 36, 42, and 48 |
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| Secondary | 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. | Part A: The Efficacy population. Part B: The Flare-up population. Only participants with flare-ups at baseline and at each time point are reported. | Posted | Mean | Standard Deviation | devices adaptations | Part A: Weeks 6 and 12; and Part B: Week 12 | Number of flare-ups | Number of flare-ups |
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| Secondary | 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. | The Efficacy population included all participants in the treated population who had an evaluable Week 6 or Week 12 image (CT scan or plain radiograph). Only participants with flare-ups at baseline and Week 12 are reported. | Posted | Number | percentage of participants | Week 12 | Number of flare-ups | Number of flare-ups |
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| Secondary | 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. | Part A: The Efficacy population. Part B: The Flare-up population. The data collected for flare-ups used each flare-up as unit of analysis rather than each participant. Additionally, a study participant may have not had any flare-ups whereas another participant may have had multiple flare-ups (note, number of flare-ups can be larger than the number of participants OR it can be smaller OR it can match, by chance). Only participants with flare-ups at baseline and at each time point are reported. | Posted | Mean | Standard Deviation | microgram per liter | Part A: Baseline and Weeks 6 and 12; and Part B: Baseline and Week 12 | Number of flare-ups | Number of flare-ups |
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| Secondary | 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. | Part A: The Efficacy population. Part B: The Flare-up population. The data collected for flare-ups used each flare-up as unit of analysis rather than each participant. Additionally, a study participant may have not had any flare-ups whereas another participant may have had multiple flare-ups (note, number of flare-ups can be larger than the number of participants OR it can be smaller OR it can match, by chance). Only participants with flare-ups at baseline and at each time point are reported. | Posted | Number | flare-up | Part A: Baseline and Weeks 6 and 12; and Part B: Baseline and Week 12 | Number of flare-ups | Number of flare-ups |
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| Secondary | 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. | Part A: The Efficacy population included all participants in the treated population who had an evaluable Week 6 or Week 12 image (CT scan or plain radiograph). Part B: The Flare-up population included all participants in the treated population who took at least 1 dose of palovarotene during flare-up based treatment in Part B. Only participants analyzed at baseline and specific time point are reported. | Posted | Mean | Standard Deviation | day | Part A: From Baseline up to 36 months; and Part B: From Baseline up to 24 months | Number of flare-ups | Number of flare-ups |
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| Secondary | 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. | The WBCT Population included participants who received chronic dosing and had baseline and Month 12 WBCT scans. Only participants analyzed at baseline and specific time point are reported. | Posted | Mean | Standard Deviation | mm^3 | Baseline and Months 12 and 24 |
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| Secondary | 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. | The Safety analysis set included all enrolled participants who received at least 1 dose of palovarotene in the PVO-1A-202 study. | Posted | Mean | Standard Deviation | percentage of flare-up/participant-month | From Baseline (Day 1) up to end of 2 year follow-up period, approximately a maximum of 96 months | Number of flare-ups | Number of flare-ups |
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| Secondary | 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. | The Safety analysis set included all enrolled participants who received at least 1 dose of palovarotene in the PVO-1A-202 study. | Posted | Mean | Standard Deviation | percentage of flare-up/participant-month | From Baseline (Day 1) up to end of 2 year follow-up period, approximately a maximum of 96 months |
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| Secondary | 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. | The FAS included all enrolled participants having a baseline HO volume measurement and at least 1 post-baseline HO volume measurement in the PVO-1A-202 study. | Posted | Number | percentage of participants | Months 12, 24, 36, 60, and 72 (last visit) |
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Treatment-emergent adverse events were recorded from the time informed consent was signed through end of the study (a maximum of 96 months).
The Safety analysis set included all enrolled participants who received at least 1 dose of palovarotene in the PVO-1A-202 study.
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Part A | Participants who completed PVO-1A-201 study were followed for up to 36 months in Part A. Eligible participants with a flare-up received palovarotene 10 mg capsule orally daily for 2 weeks followed by 5 mg daily for 4 weeks during the flare-up component of Part A. | 0 | 20 | 2 | 20 | 20 | 20 |
| EG001 | Part B | Eligible participants from Part A and participants from the new Adult Cohort received chronic treatment with palovarotene 5 mg daily for up to 24 months. Participants with flare-ups received palovarotene 20 mg daily for 4 weeks followed by 10 mg daily for 8 weeks. | 0 | 52 | 9 | 52 | 52 | 52 |
| EG002 | Part C | Eligible participants received chronic treatment of palovarotene 5 mg daily for up to 36 months. Participants with flare-ups received palovarotene 20mg daily for 4 weeks followed by 10 mg daily for 8 weeks. For skeletal immature participants, the exposure-equivalent dose was determined based on weight. | 0 | 46 | 25 | 46 | 46 | 46 |
| EG003 | Part D | Eligible participants were followed for up to an additional 48 months. No study drug was administered. | 0 | 1 | 0 | 1 | 0 | 1 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Adrenal insufficiency | Endocrine disorders | MedDRA 17.0 | Systematic Assessment |
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| Abdominal pain | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
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| Diarrhoea | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
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| Dysphagia | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
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| Gastritis | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
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| Haematemesis | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Oesophageal stenosis | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Small intestinal obstruction | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
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| Tooth impacted | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
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| Vomiting | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
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| Condition aggravated | General disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Local swelling | General disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Oedema peripheral | General disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Bronchitis | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
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| Cellulitis | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
| |
| Corona virus infection | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
| |
| Gastroenteritis | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
| |
| Influenza | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
| |
| Osteomyelitis | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
| |
| Parainfluenzae virus infection | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
| |
| Pneumonia | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
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| Pneumonia bacterial | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
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| Staphylococcal sepsis | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
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| Ankle fracture | Injury, poisoning and procedural complications | MedDRA 17.0 | Systematic Assessment |
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| Exposure to communicable disease | Injury, poisoning and procedural complications | MedDRA 17.0 | Systematic Assessment |
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| Fall | Injury, poisoning and procedural complications | MedDRA 17.0 | Systematic Assessment |
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| Femur fracture | Injury, poisoning and procedural complications | MedDRA 17.0 | Systematic Assessment |
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| Fracture | Injury, poisoning and procedural complications | MedDRA 17.0 | Systematic Assessment |
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| Hip fracture | Injury, poisoning and procedural complications | MedDRA 17.0 | Systematic Assessment |
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| Humerus fracture | Injury, poisoning and procedural complications | MedDRA 17.0 | Systematic Assessment |
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| Post-traumatic pain | Injury, poisoning and procedural complications | MedDRA 17.0 | Systematic Assessment |
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| Skull fracture | Injury, poisoning and procedural complications | MedDRA 17.0 | Systematic Assessment |
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| Subdural haemorrhage | Injury, poisoning and procedural complications | MedDRA 17.0 | Systematic Assessment |
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| Coronavirus test positive | Investigations | MedDRA 17.0 | Systematic Assessment |
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| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Epiphyses premature fusion | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Extraskeletal ossification | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
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| Muscle tightness | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
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| Convulsion | Nervous system disorders | MedDRA 17.0 | Systematic Assessment |
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| Epilepsy | Nervous system disorders | MedDRA 17.0 | Systematic Assessment |
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| Grand mal convulsion | Nervous system disorders | MedDRA 17.0 | Systematic Assessment |
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| Myoclonus | Nervous system disorders | MedDRA 17.0 | Systematic Assessment |
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| Syncope | Nervous system disorders | MedDRA 17.0 | Systematic Assessment |
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| Drug dependence | Psychiatric disorders | MedDRA 17.0 | Systematic Assessment |
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| Haematuria | Renal and urinary disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Nephrolithiasis | Renal and urinary disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Urinary retention | Renal and urinary disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Aspiration | Respiratory, thoracic and mediastinal disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Asthma | Respiratory, thoracic and mediastinal disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Hypercapnia | Respiratory, thoracic and mediastinal disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Hypoxia | Respiratory, thoracic and mediastinal disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Pneumonia aspiration | Respiratory, thoracic and mediastinal disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Respiratory distress | Respiratory, thoracic and mediastinal disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Respiratory failure | Respiratory, thoracic and mediastinal disorders | MedDRA 17.0 | Systematic Assessment |
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| Decubitus ulcer | Skin and subcutaneous tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Erythema | Skin and subcutaneous tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Tooth extraction | Surgical and medical procedures | MedDRA 17.0 | Systematic Assessment |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Thrombocytopenia | Blood and lymphatic system disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Tachycardia | Cardiac disorders | MedDRA 17.0 | Systematic Assessment |
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| Ear congestion | Ear and labyrinth disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Ear pain | Ear and labyrinth disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Dry eye | Eye disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Eye irritation | Eye disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Eyelid skin dryness | Eye disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Ocular hyperaemia | Eye disorders | MedDRA 17.0 | Systematic Assessment |
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| Vision blurred | Eye disorders | MedDRA 17.0 | Systematic Assessment |
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| Abdominal discomfort | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Abdominal distension | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Abdominal pain | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Abdominal pain upper | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
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| Chapped lips | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Cheilitis | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
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| Constipation | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Dental caries | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Diarrhoea | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Dry mouth | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Dyspepsia | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Dysphagia | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Gastrooesophageal reflux disease | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Haematochezia | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Lip dry | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Nausea | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Toothache | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Vomiting | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Asthenia | General disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Chills | General disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Condition aggravated | General disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Fatigue | General disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Feeling cold | General disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Gait disturbance | General disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Influenza like illness | General disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Local swelling | General disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Oedema peripheral | General disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Pyrexia | General disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Vessel puncture site bruise | General disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Cellulitis | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
| |
| Conjunctivitis | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
| |
| Ear infection | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
| |
| Folliculitis | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
| |
| Fungal skin infection | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
| |
| Gastroenteritis | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
| |
| Hordeolum | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
| |
| Impetigo | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
| |
| Influenza | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
| |
| Lower respiratory tract infection | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
| |
| Nasopharyngitis | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
| |
| Onychomycosis | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
| |
| Oral herpes | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
| |
| Paronychia | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
| |
| Pharyngitis | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
| |
| Pneumonia | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
| |
| Sinusitis | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
| |
| Skin infection | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
| |
| Subcutaneous abscess | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
| |
| Upper respiratory tract infection | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
| |
| Urinary tract infection | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
| |
| Vulvovaginal mycotic infection | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
| |
| Arthropod bite | Injury, poisoning and procedural complications | MedDRA 17.0 | Systematic Assessment |
| |
| Contusion | Injury, poisoning and procedural complications | MedDRA 17.0 | Systematic Assessment |
| |
| Excoriation | Injury, poisoning and procedural complications | MedDRA 17.0 | Systematic Assessment |
| |
| Fall | Injury, poisoning and procedural complications | MedDRA 17.0 | Systematic Assessment |
| |
| Head injury | Injury, poisoning and procedural complications | MedDRA 17.0 | Systematic Assessment |
| |
| Joint injury | Injury, poisoning and procedural complications | MedDRA 17.0 | Systematic Assessment |
| |
| Laceration | Injury, poisoning and procedural complications | MedDRA 17.0 | Systematic Assessment |
| |
| Post-traumatic pain | Injury, poisoning and procedural complications | MedDRA 17.0 | Systematic Assessment |
| |
| Sunburn | Injury, poisoning and procedural complications | MedDRA 17.0 | Systematic Assessment |
| |
| Amylase increased | Investigations | MedDRA 17.0 | Systematic Assessment |
| |
| Blood alkaline phosphatase increased | Investigations | MedDRA 17.0 | Systematic Assessment |
| |
| Blood bilirubin increased | Investigations | MedDRA 17.0 | Systematic Assessment |
| |
| Blood thyroid stimulating hormone increased | Investigations | MedDRA 17.0 | Systematic Assessment |
| |
| Bone density decreased | Investigations | MedDRA 17.0 | Systematic Assessment |
| |
| Gamma-glutamyltransferase increased | Investigations | MedDRA 17.0 | Systematic Assessment |
| |
| Lipase increased | Investigations | MedDRA 17.0 | Systematic Assessment |
| |
| Urine analysis abnormal | Investigations | MedDRA 17.0 | Systematic Assessment |
| |
| Urobilinogen urine increased | Investigations | MedDRA 17.0 | Systematic Assessment |
| |
| Weight decreased | Investigations | MedDRA 17.0 | Systematic Assessment |
| |
| Decreased appetite | Metabolism and nutrition disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Hypercholesterolaemia | Metabolism and nutrition disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Hyperglycaemia | Metabolism and nutrition disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Hypertriglyceridaemia | Metabolism and nutrition disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Vitamin D deficiency | Metabolism and nutrition disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Extraskeletal ossification | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Groin pain | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Joint range of motion decreased | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Joint stiffness | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Joint swelling | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Muscle fatigue | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Muscle spasms | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Muscular weakness | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Musculoskeletal chest pain | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Musculoskeletal discomfort | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Musculoskeletal pain | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Musculoskeletal stiffness | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Myalgia | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Neck pain | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Osteoporosis | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Pain in jaw | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Tendonitis | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Dizziness | Nervous system disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Headache | Nervous system disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Hypoaesthesia | Nervous system disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Migraine | Nervous system disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Paraesthesia | Nervous system disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Presyncope | Nervous system disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Sciatica | Nervous system disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Anxiety | Psychiatric disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Depressed mood | Psychiatric disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Depression | Psychiatric disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Insomnia | Psychiatric disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Irritability | Psychiatric disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Sleep disorder | Psychiatric disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Glycosuria | Renal and urinary disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Haematuria | Renal and urinary disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Nephrolithiasis | Renal and urinary disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Pollakiuria | Renal and urinary disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Proteinuria | Renal and urinary disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Dysmenorrhoea | Reproductive system and breast disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Epistaxis | Respiratory, thoracic and mediastinal disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Nasal congestion | Respiratory, thoracic and mediastinal disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Nasal dryness | Respiratory, thoracic and mediastinal disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Rhinorrhoea | Respiratory, thoracic and mediastinal disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Acne | Skin and subcutaneous tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Alopecia | Skin and subcutaneous tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Blister | Skin and subcutaneous tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Cold sweat | Skin and subcutaneous tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Decubitus ulcer | Skin and subcutaneous tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Drug eruption | Skin and subcutaneous tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Dry skin | Skin and subcutaneous tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Eczema | Skin and subcutaneous tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Erythema | Skin and subcutaneous tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Hyperhidrosis | Skin and subcutaneous tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Ingrowing nail | Skin and subcutaneous tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Madarosis | Skin and subcutaneous tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Onychoclasis | Skin and subcutaneous tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Pain of skin | Skin and subcutaneous tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Pruritus | Skin and subcutaneous tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Pruritus generalised | Skin and subcutaneous tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Rash | Skin and subcutaneous tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Rash erythematous | Skin and subcutaneous tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Seborrhoea | Skin and subcutaneous tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Skin burning sensation | Skin and subcutaneous tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Skin discolouration | Skin and subcutaneous tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Skin disorder | Skin and subcutaneous tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Skin exfoliation | Skin and subcutaneous tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Skin fissures | Skin and subcutaneous tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Skin irritation | Skin and subcutaneous tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Skin lesion | Skin and subcutaneous tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Swelling face | Skin and subcutaneous tissue disorders | MedDRA 17.0 | Systematic Assessment |
| |
| Flushing | Vascular disorders | MedDRA 17.0 | Systematic Assessment |
|
On 04-Dec-2019, participants <14 years were required to interrupt treatment due to partial clinical hold placed on palovarotene clinical development program by the FDA. On 24-Jan-2020, treatment was temporarily halted in participants 14 years and older in palovarotene FOP trials when futility boundary was crossed at an interim analysis in PVO-1A-301 study. After post-hoc analyses, dosing was re-initiated only in participants 14 years and above who were able and willing to re-start treatment.
Not provided
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Medical Director | Ipsen | see email | clinical.trials@ipsen.com |
| Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Dec 16, 2022 | Aug 24, 2023 | SAP_001.pdf |
| ID | Term |
|---|---|
| D009221 | Myositis Ossificans |
| D009999 | Ossification, Heterotopic |
| ID | Term |
|---|---|
| D009220 | Myositis |
| D009135 | Muscular Diseases |
| D009140 | Musculoskeletal Diseases |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
Not provided
Not provided
| OG002 | Part B: No Flare-ups | Participants received palovarotene 5 mg daily. No flare-ups were reported. The change in new HO total volume was compared to baseline where the baseline value was performed prior to the initiation of non-flare-up based dosing (in Part B). |
| OG003 | Part B: All Treated and No Flare-ups Combined | Participants received palovarotene 20 mg for 28 days followed by 10 mg for 56 days during flare-ups and with 5 mg daily when not taking flare-up dosing for skeletally mature participants. This group pools data from all participants irrespective of treatment. The change in new HO total volume was compared to baseline where the baseline value was performed prior to the initiation of non-flare-up based dosing (in Part B). |
| OG004 | Part C: Palovarotene - All Treated Flare-ups | Participants received palovarotene 5 mg daily and 20 mg for 28 days followed by 10 mg for 56 days during flare-ups. Participants were treated for all flare-ups. The change in new HO total volume was compared to baseline where the baseline value was performed prior to the initiation of non-flare-up based dosing (in Part B or Part C). |
| OG005 | Part C: Untreated/Undertreated Flare-ups | At least 1 flare-up was untreated/undertreated. The change in new HO total volume was compared to baseline where the baseline value was performed prior to the initiation of non-flare-up based dosing (in Part B or Part C). |
| OG006 | Part C: No Flare-ups | No flare-ups were reported. The change in new HO total volume was compared to baseline where the baseline value was performed prior to the initiation of non-flare-up based dosing (in Part B or Part C). |
| OG007 | Part C: All Treated and No Flare-ups Combined | This group pools data from all participants irrespective of treatment. The change in new HO total volume was compared to baseline where the baseline value was performed prior to the initiation of non-flare-up based dosing (in Part B or Part C). |
|
|
| Units | Counts |
|---|---|
| Participants |
|
|
|
| OG001 | Part B: Flare-up Combined | Participants received palovarotene 20 mg for 28 days followed by 10 mg for 56 days during flare-ups (20/10-mg regimen) and with 5 mg daily when not taking flare-up dosing for skeletally mature participants. Treatment may have been extended if the flare-up was ongoing and continued until the flare-up resolved. Dosing was extended in 4-week intervals and was based on clinical signs and symptoms as assessed by the Investigator. |
|
|
Participants received palovarotene 20 mg for 28 days followed by 10 mg for 56 days during flare-ups (20/10-mg regimen) and with 5 mg daily when not taking flare-up dosing for skeletally mature participants. Treatment may have been extended if the flare-up was ongoing and continued until the flare-up resolved. Dosing was extended in 4-week intervals and was based on clinical signs and symptoms as assessed by the Investigator.
|
|
| Units | Counts |
|---|---|
| Participants |
|
| Number of flare-ups |
|
|
|
| Participants |
|
| Flare-ups |
|
|
|
|
Participants received palovarotene 20 mg for 28 days followed by 10 mg for 56 days during flare-ups (20/10-mg regimen) and with 5 mg daily when not taking flare-up dosing for skeletally mature participants. Treatment may have been extended if the flare-up was ongoing and continued until the flare-up resolved. Dosing was extended in 4-week intervals and was based on clinical signs and symptoms as assessed by the Investigator.
|
|
|
| OG001 | Part B: Flare-up Combined | Participants received palovarotene 20 mg for 28 days followed by 10 mg for 56 days during flare-ups (20/10-mg regimen) and with 5 mg daily when not taking flare-up dosing for skeletally mature participants. Treatment may have been extended if the flare-up was ongoing and continued until the flare-up resolved. Dosing was extended in 4-week intervals and was based on clinical signs and symptoms as assessed by the Investigator. |
|
|
| Counts |
|---|
| Participants |
|
|
|
|
| Number of flare-ups |
|
|
|
|
Participants received palovarotene 20 mg for 28 days followed by 10 mg for 56 days during flare-ups (20/10-mg regimen) and with 5 mg daily when not taking flare-up dosing for skeletally mature participants. Treatment may have been extended if the flare-up was ongoing and continued until the flare-up resolved. Dosing was extended in 4-week intervals and was based on clinical signs and symptoms as assessed by the Investigator.
|
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| Number of flare-ups |
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