Fibrodysplasia Ossificans Progressiva
Conditions
Keywords
Open-label extension study, Clinical trial Phase 2, Efficacy and safety, Heterotopic ossification, Fibrodysplasia Ossificans Progressiva, Flare-up, Palovarotene, Retinoic acid receptor agonist, Retinoic acid receptor gamma agonist, Clementia, Myositis Ossificans Progressiva, Munchmeyer's Disease, FOP, Ipsen
Brief summary
Fibrodysplasia Ossificans Progressiva (FOP) is a rare, severely disabling disease characterized by heterotopic ossification (HO), i.e., abnormal bone formation, often associated with painful, recurrent episodes of soft tissue swelling (flare-ups). Lesions begin in early childhood and lead to progressive ankyloses of major joints with resultant loss of movement. In this study, the ability of different palovarotene dosing regimens to prevent the formation of new HO will be evaluated in adult and pediatric participants with FOP.
Detailed description
The main objective of this Phase 2, multicenter, open-label study is to evaluate the safety and efficacy of different palovarotene dosing regimens in participants with FOP. Efficacy will be assessed based on the ability of palovarotene to prevent the formation of new heterotopic ossification (HO) as assessed by low-dose whole body computed tomography (WBCT) scan, excluding head. The study was divided into four parts: Part A (completed on July 2017), Part B (completed on October 2018), Part C (completed) and Part D (completed). Each part was associated with revised palovarotene treatment regimens. In Part A, all pediatric and adult participants who successfully completed Study PVO-1A-201 were enrolled and followed for up to 36 months. Participants who had an eligible flare-up received 10 mg palovarotene daily for 14 days, followed by 5 mg palovarotene daily for 28 days (or weight-based equivalent). In Part B, participants who successfully completed Study PVO-1A-201 (including any participant who participated in Part A of Study PVO-1A-202) as well as up to 20 new adult participants were followed for up to 24 months. The Adult Cohort included all participants with at least 90% skeletal maturity, regardless of age. The Pediatric Cohort included all participants with less than 90% skeletal maturity. Any Pediatric Cohort participant who achieved ≥90% skeletal maturity during Part B was considered for enrollment into the Adult Cohort at the discretion of the Investigator. Part B added a 5 mg palovarotene daily chronic treatment regimen administered between flare-ups for participants in the Adult Cohort for up to 24 months. Part B also increased the flare-up dosing to 20 mg palovarotene daily for 28 days, followed by 10 mg palovarotene daily for 56 days (or weight-adjusted equivalents in the Pediatric Cohort). Treatment could be extended if the flare-up was still ongoing. In Part C, participants from Part B are being followed for up to an additional 48 months. There will be no new participants in Part C. All eligible participants, including skeletally immature participants, are receiving 5 mg palovarotene daily chronic treatment regimen (weight-adjusted doses for skeletally immature participants). In Part D, annual post last dose of study treatment assessments for up to 2 years will be obtained in participants who were skeletally immature at the time of study treatment discontinuation in order to obtain longer-term safety data. No new participants will be enrolled into Part D. Part C plus Part D duration will not exceed 48 months. All participants will undergo all study procedures as specified in the respective schedule of assessments and for as long as they are not 100% skeletally mature.
Interventions
DRUGPalovarotene dose level 1
Palovarotene was taken orally once daily at approximately the same time each day.
DRUGPalovarotene dose level 2
Palovarotene will be taken orally once daily at approximately the same time each day.
DRUGPalovarotene dose level 3
Palovarotene will be taken orally once daily at approximately the same time each day.
DRUGPalovarotene dose level 4
Palovarotene will be taken orally once daily at approximately the same time each day.
Sponsors
Clementia Pharmaceuticals Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Completion of Study PVO-1A-202/Part B. * Written, signed, and dated informed consent and, for participants who are minors, age-appropriate participant assent (performed according to local regulations). * Accessible for treatment with palovarotene and follow-up (able and willing to travel to a site for the initial and all follow-up clinic visits). * Able to undergo low-dose, WBCT scan, excluding head. * Females of child-bearing potential must have a negative blood or urine pregnancy test (with sensitivity of at least 50 mIU/mL) prior to administration of palovarotene. * Male and FOCBP participants must agree to remain abstinent from heterosexual sex during treatment and for 1 month after treatment or, if sexually active, to use two effective methods of birth control during and for 1 month after treatment. Additionally, sexually active females of childbearing potential (FOCBP) participants must already be using two effective methods of birth control 1 month before treatment is to start. Specific risk of the use of retinoids during pregnancy, and the agreement to remain abstinent or use two effective methods of birth control will be clearly defined in the informed consent and the participant or legally authorized representatives.
Exclusion criteria
* Any reason that, in the opinion of the Investigator, would lead to the inability of the participant and/or family to comply with the protocol. * Amylase or lipase \>2x above the upper limit of normal or with a history of pancreatitis. * Elevated aspartate aminotransferase or alanine aminotransferase \>2.5x the upper limit of normal. * Fasting triglycerides \>400 mg/dL with or without therapy. * Currently using vitamin A or beta carotene, multivitamins containing vitamin A or beta carotene, herbal preparations containing vitamin A or beta carotene, or fish oil, and unable or unwilling to discontinue use of these products during palovarotene treatment. * Participants experiencing suicidal ideation (type 4 or 5) or any suicidal behavior within the past month as defined by the Columbia Suicide Severity Rating Scale (C-SSRS).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Parts A and B: Percentage of Flare-ups With No New Heterotopic Ossification (HO) at Week 12 | Baseline and Week 12 | A responder was defined as a participant with no or minimal new HO at original flare-up site compared with baseline (pre-dose data from PVO-1A-201 study). Minimal new HO was defined as new HO with an HO score \<=3 in both the anterior/posterior (AP) and lateral projections (or if 1 view is noninterpretable or non-evaluable, then remaining evaluable view was used). The HO score ranged from 0 to 6 where, 0 = no HO and 6 = single contiguous HO with longest dimension \>2 diameters of reference normotopic bone in any projection. Highest HO score from 2 projections was used. |
| Parts B and C: Annualized Change in New HO Volume | From Baseline (Day 1) up to end of 2 year follow-up period, approximately a maximum of 96 months | The annualized change in new HO volume was assessed by low-dose whole body computed tomography (WBCT) scan, excluding head. Results are presented for overall intent to treat (ITT) period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Parts A and B: Number of Flare-ups With Significant Abnormalities in Cartilage, Bone, Angiogenesis, and Inflammation Biomarkers at Week 12 | Part A and B: 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. |
| Parts A and B: Change From Baseline in Active Range of Motion (ROM) at Flare-up Site at Week 12 | Baseline and 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 B: Change From Baseline in ROM at Week 12 | Baseline and 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. |
| Part C: Change From Baseline in ROM at Months 6, 12, 18, 24, 30, 36, 42, and 48 | Baseline and 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. |
| Part B: Participant and Investigator Global Assessment of Movement at Week 12 | 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. |
| 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 | Baseline and 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. |
| 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 | Part A: Baseline and Weeks 2, 4, 6, 9, and 12; and Part B: Baseline and Weeks 4, 8, and 12 | 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 C: Change From Baseline in Physical Function at Months 6, 12, 18, 24, 30, 36, 42, and 48 | Baseline and 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. |
| 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 | Part A: Baseline and Weeks 2, 4, 6, 9, and 12; and Part B: Baseline and Weeks 4, 8, and 12 | 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. |
| 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 | 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 | 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. |
| 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 | Part A: Weeks 6 and 12; and Part B: Week 12 | 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: Percentage of Responders at Week 12 | 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. |
| 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 | Part A: Baseline and Weeks 6 and 12; and Part B: Baseline and Week 12 | The bone formation was measured by PINP biomarker. Baseline was defined as flare-up screening/Day 1. |
| 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 | Part A: Baseline and Weeks 6 and 12; and Part B: Baseline and Week 12 | 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. |
| Parts A and B: Duration of Active Symptomatic Flare-up | Part A: From Baseline up to 36 months; and Part B: From Baseline up to 24 months | 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 B: Change From Baseline in Whole Body Burden of HO at Months 12 and 24 | Baseline and Months 12 and 24 | Whole body burden of HO was assessed by low-dose WBCT scan, excluding head. Baseline was Part B Screening. |
| Part B: Mean Percentage of Flare-ups Per Participant-Month Overall | From Baseline (Day 1) up to end of 2 year follow-up period, approximately a maximum of 96 months | 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. |
| Part C: Mean Percentage of Flare-ups Per Participant-Month Overall | From Baseline (Day 1) up to end of 2 year follow-up period, approximately a maximum of 96 months | 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. |
| Part C: Percentage of Participants With New HO at Months 12, 24, 36, 60, and 72 (Last Visit) | 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. |
| Part C: Change From Baseline in Physical and Mental Health at Months 6, 12, 18, 24, 30, 36, 42, and 48 | Baseline and 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. |
| Parts A and B: Volume of New Heterotopic Bone Formed at Month 12 | 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. |
Countries
Argentina, Australia, France, United Kingdom, United States
Participant flow
Recruitment details
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.
Pre-assignment details
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).
Participants by arm
| Arm | Count |
|---|---|
| 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. | 58 |
| Total | 58 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 2 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Non-Compliance | 1 |
| Overall Study | Other | 7 |
| Overall Study | Withdrawal by Subject | 8 |
Baseline characteristics
| Characteristic | All Participants | — |
|---|---|---|
| Age, Continuous | 21.0 years STANDARD_DEVIATION 9.27 | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Sex: Female, Male Female | 32 Participants | — |
| Sex: Female, Male Male | 26 Participants | — |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 52 | 0 / 46 | 0 / 1 |
| other Total, other adverse events | 20 / 20 | 52 / 52 | 46 / 46 | 0 / 1 |
| serious Total, serious adverse events | 2 / 20 | 9 / 52 | 25 / 46 | 0 / 1 |
Outcome results
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.
Time frame: Baseline and Week 12
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: Palovarotene 10/5 mg - Flare-up | Parts A and B: Percentage of Flare-ups With No New Heterotopic Ossification (HO) at Week 12 | 64.3 percentage of flare-ups |
| Part B: Flare-up Combined | Parts A and B: Percentage of Flare-ups With No New Heterotopic Ossification (HO) at Week 12 | 72.5 percentage of flare-ups |
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.
Time frame: From Baseline (Day 1) up to end of 2 year follow-up period, approximately a maximum of 96 months
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Palovarotene 10/5 mg - Flare-up | Parts B and C: Annualized Change in New HO Volume | -3464.0 cubic millimeter (mm^3)/year | Standard Deviation 5081.5 |
| Part B: Flare-up Combined | Parts B and C: Annualized Change in New HO Volume | 29522.8 cubic millimeter (mm^3)/year | Standard Deviation 89408.15 |
| Part B: No Flare-ups | Parts B and C: Annualized Change in New HO Volume | 25041.1 cubic millimeter (mm^3)/year | Standard Deviation 58529.79 |
| Part B: All Treated and No Flare-ups Combined | Parts B and C: Annualized Change in New HO Volume | 16270.3 cubic millimeter (mm^3)/year | Standard Deviation 49777.4 |
| Part C: Palovarotene - All Treated Flare-ups | Parts B and C: Annualized Change in New HO Volume | -10343.4 cubic millimeter (mm^3)/year | Standard Deviation 18007.89 |
| Part C: Untreated/Undertreated Flare-ups | Parts B and C: Annualized Change in New HO Volume | 52291.4 cubic millimeter (mm^3)/year | Standard Deviation 86019.62 |
| Part C: No Flare-ups | Parts B and C: Annualized Change in New HO Volume | 30530.9 cubic millimeter (mm^3)/year | Standard Deviation 51800.47 |
| Part C: All Treated and No Flare-ups Combined | Parts B and C: Annualized Change in New HO Volume | 8731.3 cubic millimeter (mm^3)/year | Standard Deviation 41924.3 |
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.
Time frame: Baseline and Weeks 2, 4, 6, 9, and 12
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Palovarotene 10/5 mg - Flare-up | 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 | Week 2: Pain | -1.4 units on a scale | Standard Deviation 2.22 |
| Part A: Palovarotene 10/5 mg - Flare-up | 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 | Week 4: Pain | -2.1 units on a scale | Standard Deviation 2.27 |
| Part A: Palovarotene 10/5 mg - Flare-up | 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 | Week 6: Pain | -2.6 units on a scale | Standard Deviation 2.71 |
| Part A: Palovarotene 10/5 mg - Flare-up | 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 | Week 9: Pain | -2.9 units on a scale | Standard Deviation 2.97 |
| Part A: Palovarotene 10/5 mg - Flare-up | 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 | Week 12: Pain | -2.6 units on a scale | Standard Deviation 2.85 |
| Part A: Palovarotene 10/5 mg - Flare-up | 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 | Week 2: Swelling | -1.7 units on a scale | Standard Deviation 1.83 |
| Part A: Palovarotene 10/5 mg - Flare-up | 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 | Week 4: Swelling | -2.3 units on a scale | Standard Deviation 2.31 |
| Part A: Palovarotene 10/5 mg - Flare-up | 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 | Week 6: Swelling | -2.4 units on a scale | Standard Deviation 2.38 |
| Part A: Palovarotene 10/5 mg - Flare-up | 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 | Week 9: Swelling | -2.7 units on a scale | Standard Deviation 2.47 |
| Part A: Palovarotene 10/5 mg - Flare-up | 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 | Week 12: Swelling | -2.9 units on a scale | Standard Deviation 2.46 |
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.
Time frame: Week 12
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: Palovarotene 10/5 mg - Flare-up | Part A: Percentage of Responders at Week 12 | 64.3 percentage of participants |
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.
Time frame: Baseline and Week 12
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Palovarotene 10/5 mg - Flare-up | Part B: Change From Baseline in ROM at Week 12 | 0.3 units on a scale | Standard Deviation 1.8 |
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.
Time frame: Baseline and Months 12 and 24
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Palovarotene 10/5 mg - Flare-up | Part B: Change From Baseline in Whole Body Burden of HO at Months 12 and 24 | Month 12 | 28386 mm^3 | Standard Deviation 89918 |
| Part A: Palovarotene 10/5 mg - Flare-up | Part B: Change From Baseline in Whole Body Burden of HO at Months 12 and 24 | Month 24 | 193150 mm^3 | Standard Deviation 9999 |
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.
Time frame: From Baseline (Day 1) up to end of 2 year follow-up period, approximately a maximum of 96 months
Population: The Safety analysis set included all enrolled participants who received at least 1 dose of palovarotene in the PVO-1A-202 study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Palovarotene 10/5 mg - Flare-up | Part B: Mean Percentage of Flare-ups Per Participant-Month Overall | 0.12 percentage of flare-up/participant-month | Standard Deviation 0.124 |
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.
Time frame: Week 12
Population: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A: Palovarotene 10/5 mg - Flare-up | Part B: Participant and Investigator Global Assessment of Movement at Week 12 | PA: New HO - Severely worse movement | 2 number of flare-ups |
| Part A: Palovarotene 10/5 mg - Flare-up | Part B: Participant and Investigator Global Assessment of Movement at Week 12 | PA: New HO - Better movement | 5 number of flare-ups |
| Part A: Palovarotene 10/5 mg - Flare-up | Part B: Participant and Investigator Global Assessment of Movement at Week 12 | PA: New HO - Same movement | 3 number of flare-ups |
| Part A: Palovarotene 10/5 mg - Flare-up | Part B: Participant and Investigator Global Assessment of Movement at Week 12 | PA: New HO - Slightly worse movement | 2 number of flare-ups |
| Part A: Palovarotene 10/5 mg - Flare-up | Part B: Participant and Investigator Global Assessment of Movement at Week 12 | PA: New HO - Moderately worse movement | 2 number of flare-ups |
| Part A: Palovarotene 10/5 mg - Flare-up | Part B: Participant and Investigator Global Assessment of Movement at Week 12 | PA: No new HO - Better movement | 11 number of flare-ups |
| Part A: Palovarotene 10/5 mg - Flare-up | Part B: Participant and Investigator Global Assessment of Movement at Week 12 | PA: No new HO - Same movement | 20 number of flare-ups |
| Part A: Palovarotene 10/5 mg - Flare-up | Part B: Participant and Investigator Global Assessment of Movement at Week 12 | PA: No new HO - Slightly worse movement | 5 number of flare-ups |
| Part A: Palovarotene 10/5 mg - Flare-up | Part B: Participant and Investigator Global Assessment of Movement at Week 12 | PA: No new HO - Moderately worse movement | 1 number of flare-ups |
| Part A: Palovarotene 10/5 mg - Flare-up | Part B: Participant and Investigator Global Assessment of Movement at Week 12 | PA: No new HO - Severely worse movement | 0 number of flare-ups |
| Part A: Palovarotene 10/5 mg - Flare-up | Part B: Participant and Investigator Global Assessment of Movement at Week 12 | IA: New HO - Better movement | 5 number of flare-ups |
| Part A: Palovarotene 10/5 mg - Flare-up | Part B: Participant and Investigator Global Assessment of Movement at Week 12 | IA: New HO - Same movement | 3 number of flare-ups |
| Part A: Palovarotene 10/5 mg - Flare-up | Part B: Participant and Investigator Global Assessment of Movement at Week 12 | IA: New HO - Slightly worse movement | 2 number of flare-ups |
| Part A: Palovarotene 10/5 mg - Flare-up | Part B: Participant and Investigator Global Assessment of Movement at Week 12 | IA: New HO - Moderately worse movement | 3 number of flare-ups |
| Part A: Palovarotene 10/5 mg - Flare-up | Part B: Participant and Investigator Global Assessment of Movement at Week 12 | IA: New HO - Severely worse movement | 1 number of flare-ups |
| Part A: Palovarotene 10/5 mg - Flare-up | Part B: Participant and Investigator Global Assessment of Movement at Week 12 | IA: No new HO - Better movement | 1 number of flare-ups |
| Part A: Palovarotene 10/5 mg - Flare-up | Part B: Participant and Investigator Global Assessment of Movement at Week 12 | IA: No new HO - Same movement | 29 number of flare-ups |
| Part A: Palovarotene 10/5 mg - Flare-up | Part B: Participant and Investigator Global Assessment of Movement at Week 12 | IA: No new HO - Slightly worse movement | 6 number of flare-ups |
| Part A: Palovarotene 10/5 mg - Flare-up | Part B: Participant and Investigator Global Assessment of Movement at Week 12 | IA: No new HO - Moderately worse movement | 1 number of flare-ups |
| Part A: Palovarotene 10/5 mg - Flare-up | Part B: Participant and Investigator Global Assessment of Movement at Week 12 | IA: No new HO - Severely worse movement | 0 number of flare-ups |
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.
Time frame: Baseline and Months 6, 12, 18, 24, 30, 36, 42, and 48
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Palovarotene 10/5 mg - Flare-up | Part C: Change From Baseline in Physical and Mental Health at Months 6, 12, 18, 24, 30, 36, 42, and 48 | AFPH - Month 6 | -0.2 units on a scale | Standard Deviation 5.59 |
| Part A: Palovarotene 10/5 mg - Flare-up | Part C: Change From Baseline in Physical and Mental Health at Months 6, 12, 18, 24, 30, 36, 42, and 48 | AFPH - Month 12 | 0.6 units on a scale | Standard Deviation 6.04 |
| Part A: Palovarotene 10/5 mg - Flare-up | Part C: Change From Baseline in Physical and Mental Health at Months 6, 12, 18, 24, 30, 36, 42, and 48 | AFPH - Month 18 | -0.1 units on a scale | Standard Deviation 5.3 |
| Part A: Palovarotene 10/5 mg - Flare-up | Part C: Change From Baseline in Physical and Mental Health at Months 6, 12, 18, 24, 30, 36, 42, and 48 | AFPH - Month 24 | -1.1 units on a scale | Standard Deviation 7.1 |
| Part A: Palovarotene 10/5 mg - Flare-up | Part C: Change From Baseline in Physical and Mental Health at Months 6, 12, 18, 24, 30, 36, 42, and 48 | AFPH - Month 30 | 0.1 units on a scale | Standard Deviation 4.46 |
| Part A: Palovarotene 10/5 mg - Flare-up | Part C: Change From Baseline in Physical and Mental Health at Months 6, 12, 18, 24, 30, 36, 42, and 48 | AFPH - Month 36 | -1.1 units on a scale | Standard Deviation 5.97 |
| Part A: Palovarotene 10/5 mg - Flare-up | Part C: Change From Baseline in Physical and Mental Health at Months 6, 12, 18, 24, 30, 36, 42, and 48 | AFPH - Month 42 | -1.8 units on a scale | Standard Deviation 6.55 |
| Part A: Palovarotene 10/5 mg - Flare-up | Part C: Change From Baseline in Physical and Mental Health at Months 6, 12, 18, 24, 30, 36, 42, and 48 | AFPH - Month 48 | -1.6 units on a scale | Standard Deviation 3.02 |
| Part A: Palovarotene 10/5 mg - Flare-up | Part C: Change From Baseline in Physical and Mental Health at Months 6, 12, 18, 24, 30, 36, 42, and 48 | AFMH - Month 6 | -2.2 units on a scale | Standard Deviation 6.49 |
| Part A: Palovarotene 10/5 mg - Flare-up | Part C: Change From Baseline in Physical and Mental Health at Months 6, 12, 18, 24, 30, 36, 42, and 48 | AFMH - Month 12 | -0.0 units on a scale | Standard Deviation 3.96 |
| Part A: Palovarotene 10/5 mg - Flare-up | Part C: Change From Baseline in Physical and Mental Health at Months 6, 12, 18, 24, 30, 36, 42, and 48 | AFMH - Month 18 | -0.8 units on a scale | Standard Deviation 5.04 |
| Part A: Palovarotene 10/5 mg - Flare-up | Part C: Change From Baseline in Physical and Mental Health at Months 6, 12, 18, 24, 30, 36, 42, and 48 | AFMH - Month 24 | -2.5 units on a scale | Standard Deviation 5.96 |
| Part A: Palovarotene 10/5 mg - Flare-up | Part C: Change From Baseline in Physical and Mental Health at Months 6, 12, 18, 24, 30, 36, 42, and 48 | AFMH - Month 30 | -3.0 units on a scale | Standard Deviation 5.3 |
| Part A: Palovarotene 10/5 mg - Flare-up | Part C: Change From Baseline in Physical and Mental Health at Months 6, 12, 18, 24, 30, 36, 42, and 48 | AFMH - Month 36 | -1.5 units on a scale | Standard Deviation 4.95 |
| Part A: Palovarotene 10/5 mg - Flare-up | Part C: Change From Baseline in Physical and Mental Health at Months 6, 12, 18, 24, 30, 36, 42, and 48 | AFMH - Month 42 | -2.9 units on a scale | Standard Deviation 6.24 |
| Part A: Palovarotene 10/5 mg - Flare-up | Part C: Change From Baseline in Physical and Mental Health at Months 6, 12, 18, 24, 30, 36, 42, and 48 | AFMH - Month 48 | -5.2 units on a scale | Standard Deviation 7.83 |
| Part A: Palovarotene 10/5 mg - Flare-up | Part C: Change From Baseline in Physical and Mental Health at Months 6, 12, 18, 24, 30, 36, 42, and 48 | PFH - Month 6 | 3.8 units on a scale | Standard Deviation 2.91 |
| Part A: Palovarotene 10/5 mg - Flare-up | Part C: Change From Baseline in Physical and Mental Health at Months 6, 12, 18, 24, 30, 36, 42, and 48 | PFH - Month 12 | 1.7 units on a scale | Standard Deviation 1.65 |
| Part A: Palovarotene 10/5 mg - Flare-up | Part C: Change From Baseline in Physical and Mental Health at Months 6, 12, 18, 24, 30, 36, 42, and 48 | PFH - Month 18 | 4.7 units on a scale | Standard Deviation 1.93 |
| Part A: Palovarotene 10/5 mg - Flare-up | Part C: Change From Baseline in Physical and Mental Health at Months 6, 12, 18, 24, 30, 36, 42, and 48 | PFH - Month 24 | 3.4 units on a scale | Standard Deviation 4.63 |
| Part A: Palovarotene 10/5 mg - Flare-up | Part C: Change From Baseline in Physical and Mental Health at Months 6, 12, 18, 24, 30, 36, 42, and 48 | PFH - Month 30 | 4.6 units on a scale | Standard Deviation 2.52 |
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.
Time frame: Baseline and Months 6, 12, 18, 24, 30, 36, 42, and 48
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Palovarotene 10/5 mg - Flare-up | Part C: Change From Baseline in Physical Function at Months 6, 12, 18, 24, 30, 36, 42, and 48 | Month 6 | 1.8 units on a scale | Standard Deviation 6.36 |
| Part A: Palovarotene 10/5 mg - Flare-up | Part C: Change From Baseline in Physical Function at Months 6, 12, 18, 24, 30, 36, 42, and 48 | Month 12 | 1.8 units on a scale | Standard Deviation 9.81 |
| Part A: Palovarotene 10/5 mg - Flare-up | Part C: Change From Baseline in Physical Function at Months 6, 12, 18, 24, 30, 36, 42, and 48 | Month 18 | 4.0 units on a scale | Standard Deviation 9.49 |
| Part A: Palovarotene 10/5 mg - Flare-up | Part C: Change From Baseline in Physical Function at Months 6, 12, 18, 24, 30, 36, 42, and 48 | Month 24 | 7.5 units on a scale | Standard Deviation 14 |
| Part A: Palovarotene 10/5 mg - Flare-up | Part C: Change From Baseline in Physical Function at Months 6, 12, 18, 24, 30, 36, 42, and 48 | Month 30 | 8.2 units on a scale | Standard Deviation 13.45 |
| Part A: Palovarotene 10/5 mg - Flare-up | Part C: Change From Baseline in Physical Function at Months 6, 12, 18, 24, 30, 36, 42, and 48 | Month 36 | 9.8 units on a scale | Standard Deviation 14.11 |
| Part A: Palovarotene 10/5 mg - Flare-up | Part C: Change From Baseline in Physical Function at Months 6, 12, 18, 24, 30, 36, 42, and 48 | Month 42 | 7.0 units on a scale | Standard Deviation 13.14 |
| Part A: Palovarotene 10/5 mg - Flare-up | Part C: Change From Baseline in Physical Function at Months 6, 12, 18, 24, 30, 36, 42, and 48 | Month 48 | 8.3 units on a scale | Standard Deviation 7.76 |
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.
Time frame: Baseline and Months 6, 12, 18, 24, 30, 36, 42, and 48
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Palovarotene 10/5 mg - Flare-up | Part C: Change From Baseline in ROM at Months 6, 12, 18, 24, 30, 36, 42, and 48 | Month 6 | 0.2 units on a scale | Standard Deviation 1.58 |
| Part A: Palovarotene 10/5 mg - Flare-up | Part C: Change From Baseline in ROM at Months 6, 12, 18, 24, 30, 36, 42, and 48 | Month 12 | 0.6 units on a scale | Standard Deviation 1.76 |
| Part A: Palovarotene 10/5 mg - Flare-up | Part C: Change From Baseline in ROM at Months 6, 12, 18, 24, 30, 36, 42, and 48 | Month 18 | 0.9 units on a scale | Standard Deviation 1.73 |
| Part A: Palovarotene 10/5 mg - Flare-up | Part C: Change From Baseline in ROM at Months 6, 12, 18, 24, 30, 36, 42, and 48 | Month 24 | 1.3 units on a scale | Standard Deviation 2.74 |
| Part A: Palovarotene 10/5 mg - Flare-up | Part C: Change From Baseline in ROM at Months 6, 12, 18, 24, 30, 36, 42, and 48 | Month 30 | 1.5 units on a scale | Standard Deviation 2.79 |
| Part A: Palovarotene 10/5 mg - Flare-up | Part C: Change From Baseline in ROM at Months 6, 12, 18, 24, 30, 36, 42, and 48 | Month 36 | 1.6 units on a scale | Standard Deviation 3.38 |
| Part A: Palovarotene 10/5 mg - Flare-up | Part C: Change From Baseline in ROM at Months 6, 12, 18, 24, 30, 36, 42, and 48 | Month 42 | 1.6 units on a scale | Standard Deviation 3.03 |
| Part A: Palovarotene 10/5 mg - Flare-up | Part C: Change From Baseline in ROM at Months 6, 12, 18, 24, 30, 36, 42, and 48 | Month 48 | 3.0 units on a scale | Standard Deviation 2.55 |
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.
Time frame: From Baseline (Day 1) up to end of 2 year follow-up period, approximately a maximum of 96 months
Population: The Safety analysis set included all enrolled participants who received at least 1 dose of palovarotene in the PVO-1A-202 study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Palovarotene 10/5 mg - Flare-up | Part C: Mean Percentage of Flare-ups Per Participant-Month Overall | 0.14 percentage of flare-up/participant-month | Standard Deviation 0.15 |
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.
Time frame: Months 12, 24, 36, 60, and 72 (last visit)
Population: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A: Palovarotene 10/5 mg - Flare-up | Part C: Percentage of Participants With New HO at Months 12, 24, 36, 60, and 72 (Last Visit) | Month 12 | 60.0 percentage of participants |
| Part A: Palovarotene 10/5 mg - Flare-up | Part C: Percentage of Participants With New HO at Months 12, 24, 36, 60, and 72 (Last Visit) | Month 24 | 54.5 percentage of participants |
| Part A: Palovarotene 10/5 mg - Flare-up | Part C: Percentage of Participants With New HO at Months 12, 24, 36, 60, and 72 (Last Visit) | Month 36 | 61.5 percentage of participants |
| Part A: Palovarotene 10/5 mg - Flare-up | Part C: Percentage of Participants With New HO at Months 12, 24, 36, 60, and 72 (Last Visit) | Month 60 | 100.0 percentage of participants |
| Part A: Palovarotene 10/5 mg - Flare-up | Part C: Percentage of Participants With New HO at Months 12, 24, 36, 60, and 72 (Last Visit) | Month 72 | 86.2 percentage of participants |
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.
Time frame: Baseline and Week 12
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Palovarotene 10/5 mg - Flare-up | Parts A and B: Change From Baseline in Active Range of Motion (ROM) at Flare-up Site at Week 12 | -6.16 percent of normal total arc of motion | Standard Deviation 14.362 |
| 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 | -0.49 percent of normal total arc of motion | Standard Deviation 18.096 |
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.
Time frame: Part A: Baseline and Weeks 6 and 12; and Part B: Baseline and Week 12
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Palovarotene 10/5 mg - Flare-up | 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 | Part A: Week 6 | 38.755 microgram per liter | Standard Deviation 50.547 |
| Part A: Palovarotene 10/5 mg - Flare-up | 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 | Parts A and B: Week 12 | 54.592 microgram per liter | Standard Deviation 140.54 |
| Part B: Flare-up Combined | 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 | Parts A and B: Week 12 | 70.916 microgram per liter | Standard Deviation 130.608 |
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.
Time frame: Part A: Baseline and Weeks 2, 4, 6, 9, and 12; and Part B: Baseline and Weeks 4, 8, and 12
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Palovarotene 10/5 mg - Flare-up | 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 | Parts A and B: AFMH - Week 9 | -0.16 units on a scale | Standard Deviation 4.422 |
| Part A: Palovarotene 10/5 mg - Flare-up | 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 | Parts A and B: AFMH - Week 12 | 0.99 units on a scale | Standard Deviation 2.915 |
| Part A: Palovarotene 10/5 mg - Flare-up | 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 | Parts A and B: PFH - Week 12 | 0.85 units on a scale | Standard Deviation 3.748 |
| Part A: Palovarotene 10/5 mg - Flare-up | 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 | Parts A and B: AFPH - Week 2 | 3.26 units on a scale | Standard Deviation 4.819 |
| Part A: Palovarotene 10/5 mg - Flare-up | 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 | Parts A and B: AFPH - Week 4 | 2.14 units on a scale | Standard Deviation 3.976 |
| Part A: Palovarotene 10/5 mg - Flare-up | 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 | Parts A and B: AFPH - Week 6 | 1.78 units on a scale | Standard Deviation 3.735 |
| Part A: Palovarotene 10/5 mg - Flare-up | 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 | Parts A and B: AFPH - Week 9 | 2.87 units on a scale | Standard Deviation 5.352 |
| Part A: Palovarotene 10/5 mg - Flare-up | 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 | Parts A and B: AFPH - Week 12 | 3.22 units on a scale | Standard Deviation 4.855 |
| Part A: Palovarotene 10/5 mg - Flare-up | 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 | Parts A and B: AFMH - Week 2 | 1.00 units on a scale | Standard Deviation 4.667 |
| Part A: Palovarotene 10/5 mg - Flare-up | 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 | Parts A and B: AFMH - Week 4 | 0.39 units on a scale | Standard Deviation 3.264 |
| Part A: Palovarotene 10/5 mg - Flare-up | 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 | Parts A and B: AFMH - Week 6 | 1.03 units on a scale | Standard Deviation 3.122 |
| Part A: Palovarotene 10/5 mg - Flare-up | 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 | Parts A and B: PFH - Week 2 | -0.05 units on a scale | Standard Deviation 2.475 |
| Part A: Palovarotene 10/5 mg - Flare-up | 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 | Parts A and B: PFH - Week 4 | 1.70 units on a scale | Standard Deviation 4.95 |
| Part A: Palovarotene 10/5 mg - Flare-up | 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 | Parts A and B: PFH - Week 6 | 5.25 units on a scale | Standard Deviation 4.596 |
| Part A: Palovarotene 10/5 mg - Flare-up | 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 | Parts A and B: PFH - Week 9 | 0.85 units on a scale | Standard Deviation 1.202 |
| Part B: Flare-up Combined | 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 | Parts A and B: AFMH - Week 12 | 0.2 units on a scale | Standard Deviation 7.63 |
| Part B: Flare-up Combined | 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 | Parts A and B: AFMH - Week 4 | 1.0 units on a scale | Standard Deviation 8.05 |
| Part B: Flare-up Combined | 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 | Parts A and B: AFMH - Week 8 | -0.3 units on a scale | Standard Deviation 7.47 |
| Part B: Flare-up Combined | 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 | Parts A and B: PFH - Week 4 | 0.7 units on a scale | Standard Deviation 4.77 |
| Part B: Flare-up Combined | 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 | Parts A and B: AFPH - Week 4 | 0.2 units on a scale | Standard Deviation 3.17 |
| Part B: Flare-up Combined | 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 | Parts A and B: PFH - Week 8 | -2.5 units on a scale | Standard Deviation 6.32 |
| Part B: Flare-up Combined | 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 | Parts A and B: AFPH - Week 12 | 0.6 units on a scale | Standard Deviation 3.79 |
| Part B: Flare-up Combined | 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 | Parts A and B: AFPH - Week 8 | 0.3 units on a scale | Standard Deviation 3.33 |
| Part B: Flare-up Combined | 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 | Parts A and B: PFH - Week 12 | 0.4 units on a scale | Standard Deviation 5.65 |
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.
Time frame: Part A: Baseline and Weeks 2, 4, 6, 9, and 12; and Part B: Baseline and Weeks 4, 8, and 12
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Palovarotene 10/5 mg - Flare-up | 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 | Parts A and B: Week 9 | 0.76 units on a scale | Standard Deviation 6.054 |
| Part A: Palovarotene 10/5 mg - Flare-up | 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 | Parts A and B: Week 12 | 0.69 units on a scale | Standard Deviation 6.604 |
| Part A: Palovarotene 10/5 mg - Flare-up | 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 | Parts A and B: Week 2 | -0.97 units on a scale | Standard Deviation 4.939 |
| Part A: Palovarotene 10/5 mg - Flare-up | 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 | Parts A and B: Week 6 | 0.21 units on a scale | Standard Deviation 6.501 |
| Part A: Palovarotene 10/5 mg - Flare-up | 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 | Parts A and B: Week 4 | 0.38 units on a scale | Standard Deviation 4.746 |
| Part B: Flare-up Combined | 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 | Parts A and B: Week 12 | 0.17 units on a scale | Standard Deviation 6.893 |
| Part B: Flare-up Combined | 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 | Parts A and B: Week 4 | -1.23 units on a scale | Standard Deviation 4.453 |
| Part B: Flare-up Combined | 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 | Parts A and B: Week 8 | 0.88 units on a scale | Standard Deviation 9.357 |
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.
Time frame: Part A: From Baseline up to 36 months; and Part B: From Baseline up to 24 months
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Palovarotene 10/5 mg - Flare-up | Parts A and B: Duration of Active Symptomatic Flare-up | 27.1 day | Standard Deviation 29.9 |
| Part B: Flare-up Combined | Parts A and B: Duration of Active Symptomatic Flare-up | 39.5 day | Standard Deviation 36.1 |
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.
Time frame: Part A: Weeks 6 and 12; and Part B: Week 12
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Palovarotene 10/5 mg - Flare-up | 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 | Part A: Week 6 | 12.9 devices adaptations | Standard Deviation 11.52 |
| Part A: Palovarotene 10/5 mg - Flare-up | 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 | Parts A and B: Week 12 | 14.3 devices adaptations | Standard Deviation 12.39 |
| Part B: Flare-up Combined | 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 | Parts A and B: Week 12 | 13.2 devices adaptations | Standard Deviation 10.5 |
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.
Time frame: Part A and B: At Week 12
Population: 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).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A: Palovarotene 10/5 mg - Flare-up | Parts A and B: Number of Flare-ups With Significant Abnormalities in Cartilage, Bone, Angiogenesis, and Inflammation Biomarkers at Week 12 | Parts A and B: Osteocalcin | 10 number of flare-ups |
| Part A: Palovarotene 10/5 mg - Flare-up | Parts A and B: Number of Flare-ups With Significant Abnormalities in Cartilage, Bone, Angiogenesis, and Inflammation Biomarkers at Week 12 | Parts A and B: Bone-specific ALP | 2 number of flare-ups |
| Part A: Palovarotene 10/5 mg - Flare-up | Parts A and B: Number of Flare-ups With Significant Abnormalities in Cartilage, Bone, Angiogenesis, and Inflammation Biomarkers at Week 12 | Parts A and B: P1NP | 10 number of flare-ups |
| Part A: Palovarotene 10/5 mg - Flare-up | Parts A and B: Number of Flare-ups With Significant Abnormalities in Cartilage, Bone, Angiogenesis, and Inflammation Biomarkers at Week 12 | Parts A and B: CD retinoic acid protein | 4 number of flare-ups |
| Part A: Palovarotene 10/5 mg - Flare-up | Parts A and B: Number of Flare-ups With Significant Abnormalities in Cartilage, Bone, Angiogenesis, and Inflammation Biomarkers at Week 12 | Parts A and B: P1CP | 3 number of flare-ups |
| Part A: Palovarotene 10/5 mg - Flare-up | Parts A and B: Number of Flare-ups With Significant Abnormalities in Cartilage, Bone, Angiogenesis, and Inflammation Biomarkers at Week 12 | Parts A and B: C-terminal telopeptide | 0 number of flare-ups |
| Part A: Palovarotene 10/5 mg - Flare-up | Parts A and B: Number of Flare-ups With Significant Abnormalities in Cartilage, Bone, Angiogenesis, and Inflammation Biomarkers at Week 12 | Parts A and B: Urinary basic FGF | 6 number of flare-ups |
| Part A: Palovarotene 10/5 mg - Flare-up | Parts A and B: Number of Flare-ups With Significant Abnormalities in Cartilage, Bone, Angiogenesis, and Inflammation Biomarkers at Week 12 | Parts A and B: ESR | 4 number of flare-ups |
| Part A: Palovarotene 10/5 mg - Flare-up | Parts A and B: Number of Flare-ups With Significant Abnormalities in Cartilage, Bone, Angiogenesis, and Inflammation Biomarkers at Week 12 | Parts A and B: C-reactive protein | 6 number of flare-ups |
| Part A: Palovarotene 10/5 mg - Flare-up | Parts A and B: Number of Flare-ups With Significant Abnormalities in Cartilage, Bone, Angiogenesis, and Inflammation Biomarkers at Week 12 | Parts A and B: IL-6 | 0 number of flare-ups |
| Part A: Palovarotene 10/5 mg - Flare-up | Parts A and B: Number of Flare-ups With Significant Abnormalities in Cartilage, Bone, Angiogenesis, and Inflammation Biomarkers at Week 12 | Parts A and B: IL-1 beta | 5 number of flare-ups |
| Part A: Palovarotene 10/5 mg - Flare-up | Parts A and B: Number of Flare-ups With Significant Abnormalities in Cartilage, Bone, Angiogenesis, and Inflammation Biomarkers at Week 12 | Parts A and B: TNF-alpha | 3 number of flare-ups |
| Part A: Palovarotene 10/5 mg - Flare-up | Parts A and B: Number of Flare-ups With Significant Abnormalities in Cartilage, Bone, Angiogenesis, and Inflammation Biomarkers at Week 12 | Parts A and B: Creatine kinase | 1 number of flare-ups |
| Part A: Palovarotene 10/5 mg - Flare-up | Parts A and B: Number of Flare-ups With Significant Abnormalities in Cartilage, Bone, Angiogenesis, and Inflammation Biomarkers at Week 12 | Parts A and B: Lactate dehydrogenase | 4 number of flare-ups |
| Part B: Flare-up Combined | Parts A and B: Number of Flare-ups With Significant Abnormalities in Cartilage, Bone, Angiogenesis, and Inflammation Biomarkers at Week 12 | Parts A and B: IL-1 beta | 5 number of flare-ups |
| Part B: Flare-up Combined | Parts A and B: Number of Flare-ups With Significant Abnormalities in Cartilage, Bone, Angiogenesis, and Inflammation Biomarkers at Week 12 | Parts A and B: Osteocalcin | 6 number of flare-ups |
| Part B: Flare-up Combined | Parts A and B: Number of Flare-ups With Significant Abnormalities in Cartilage, Bone, Angiogenesis, and Inflammation Biomarkers at Week 12 | Parts A and B: ESR | 0 number of flare-ups |
| Part B: Flare-up Combined | Parts A and B: Number of Flare-ups With Significant Abnormalities in Cartilage, Bone, Angiogenesis, and Inflammation Biomarkers at Week 12 | Parts A and B: Bone-specific ALP | 2 number of flare-ups |
| Part B: Flare-up Combined | Parts A and B: Number of Flare-ups With Significant Abnormalities in Cartilage, Bone, Angiogenesis, and Inflammation Biomarkers at Week 12 | Parts A and B: Creatine kinase | 3 number of flare-ups |
| Part B: Flare-up Combined | Parts A and B: Number of Flare-ups With Significant Abnormalities in Cartilage, Bone, Angiogenesis, and Inflammation Biomarkers at Week 12 | Parts A and B: P1NP | 2 number of flare-ups |
| Part B: Flare-up Combined | Parts A and B: Number of Flare-ups With Significant Abnormalities in Cartilage, Bone, Angiogenesis, and Inflammation Biomarkers at Week 12 | Parts A and B: C-reactive protein | 5 number of flare-ups |
| Part B: Flare-up Combined | Parts A and B: Number of Flare-ups With Significant Abnormalities in Cartilage, Bone, Angiogenesis, and Inflammation Biomarkers at Week 12 | Parts A and B: CD retinoic acid protein | 6 number of flare-ups |
| Part B: Flare-up Combined | Parts A and B: Number of Flare-ups With Significant Abnormalities in Cartilage, Bone, Angiogenesis, and Inflammation Biomarkers at Week 12 | Parts A and B: TNF-alpha | 1 number of flare-ups |
| Part B: Flare-up Combined | Parts A and B: Number of Flare-ups With Significant Abnormalities in Cartilage, Bone, Angiogenesis, and Inflammation Biomarkers at Week 12 | Parts A and B: P1CP | 2 number of flare-ups |
| Part B: Flare-up Combined | Parts A and B: Number of Flare-ups With Significant Abnormalities in Cartilage, Bone, Angiogenesis, and Inflammation Biomarkers at Week 12 | Parts A and B: IL-6 | 3 number of flare-ups |
| Part B: Flare-up Combined | Parts A and B: Number of Flare-ups With Significant Abnormalities in Cartilage, Bone, Angiogenesis, and Inflammation Biomarkers at Week 12 | Parts A and B: C-terminal telopeptide | 1 number of flare-ups |
| Part B: Flare-up Combined | Parts A and B: Number of Flare-ups With Significant Abnormalities in Cartilage, Bone, Angiogenesis, and Inflammation Biomarkers at Week 12 | Parts A and B: Lactate dehydrogenase | 1 number of flare-ups |
| Part B: Flare-up Combined | Parts A and B: Number of Flare-ups With Significant Abnormalities in Cartilage, Bone, Angiogenesis, and Inflammation Biomarkers at Week 12 | Parts A and B: Urinary basic FGF | 5 number of flare-ups |
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.
Time frame: Part A: Baseline and Weeks 6 and 12; and Part B: Baseline and Week 12
Population: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A: Palovarotene 10/5 mg - Flare-up | 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 | Part A: Edema - Week 6 | 7 flare-up |
| Part A: Palovarotene 10/5 mg - Flare-up | 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 | Part A: Cartilage Formation - Week 6 | 0 flare-up |
| Part A: Palovarotene 10/5 mg - Flare-up | 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 | Parts A and B: Edema - Week 12 | 9 flare-up |
| Part A: Palovarotene 10/5 mg - Flare-up | 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 | Parts A and B: Cartilage Formation - Week 12 | 0 flare-up |
| Part B: Flare-up Combined | 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 | Parts A and B: Edema - Week 12 | 36 flare-up |
| Part B: Flare-up Combined | 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 | Parts A and B: Cartilage Formation - Week 12 | 1 flare-up |
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.
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
Population: No participants were analyzed for this endpoint.
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.
Time frame: Month 12
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Palovarotene 10/5 mg - Flare-up | Parts A and B: Volume of New Heterotopic Bone Formed at Month 12 | 2310 mm^3 | Standard Deviation 4739 |
| Part B: Flare-up Combined | Parts A and B: Volume of New Heterotopic Bone Formed at Month 12 | 4818 mm^3 | Standard Deviation 17349 |