Fibrodysplasia Ossificans Progressiva
Conditions
Keywords
Intervention study, Clinical trial Phase 2, Efficacy and safety, Heterotopic ossification, Flare-up, Palovarotene, Retinoic acid receptor agonist, Retinoic acid receptor gamma agonist, Clementia, Myositis Ossificans Progressiva, Munchmeyer's Disease, FOP
Brief summary
Fibrodysplasia ossificans progressiva (FOP) is a rare, severely disabling disease characterized by painful, recurrent episodes of soft tissue swelling (flare-ups) that result in abnormal bone formation in muscles, tendons, and ligaments. Flare-ups begin early in life and may occur spontaneously or after soft tissue trauma, vaccinations, or influenza infections. Recurrent flare-ups progressively restrict movement by locking joints leading to cumulative loss of function and disability. Mouse models of FOP have demonstrated the ability of retinoic acid receptor (RAR) gamma agonists to prevent heterotopic ossification (HO) following injury. The purpose of the study is to evaluate whether palovarotene, an RAR gamma agonist, will prevent HO during and following a flare-up in subjects with FOP.
Detailed description
The primary objective is to evaluate the ability of different doses of palovarotene to prevent HO at the flare-up site in subjects with FOP as assessed by plain radiographs. This is a Phase 2, multi-center, randomized, double-blind, sponsor-unblinded, placebo-controlled study. Two cohorts of subjects will be randomized into different dosing regimens of palovarotene for a 6-week (42 days) treatment period. The study will consist of three periods: 1. A Screening period to occur within 7 days of a distinct flare-up. The first dose of study drug will be taken within 7 days of the flare-up initiation. 2. A double-blind treatment period of 6 weeks (42 days) duration. 3. A follow-up period of 6 weeks (42 days) duration. An initial cohort (Cohort 1) of subjects will be randomly assigned 3:1 to either palovarotene or placebo daily for 42 days. Subjects randomized to palovarotene in Cohort 1 will receive an initial daily dose of 10 mg for 14 days followed by 5 mg daily for 28 days. In Cohort 2, new FOP subjects meeting all inclusion/exclusion criteria will be randomly assigned 3:3:2 to two dose regimens of palovarotene (10 mg for 14 days and 5 mg for 28 days; 5 mg for 14 days and 2.5 mg for 28 days) or placebo daily for 42 days. Doses will be weight-adjusted and subjects randomized within three weight-range categories (20 to \<40 kg, 40 to \<60 kg, and ≥60 kg). Subjects completing the study and still meeting eligibility requirements will be given the opportunity to enroll into an open-label extension study.
Interventions
DRUGPalovarotene
Palovarotene will be taken orally once daily at approximately the same time each day. Powder filled hard gelatin capsules will be opened and the contents added onto specific food.
DRUGPlacebo
Sponsors
Clementia Pharmaceuticals Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
6 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Written, signed, and dated informed subject/parent consent or age-appropriate assent. * Subjects clinically diagnosed with classic Fibrodysplasia Ossificans Progressiva (FOP). * Symptomatic onset of a distinct flare-up within 7 days of Study Day 1 (start of study drug) and defined by the presence of at least two of six of the following symptoms: pain, soft tissue swelling, decreased range of motion, stiffness, redness, and warmth. Flare-up must be confirmed by the physician at the Screening visit. * Flare-up is at an appendicular area (upper or lower extremity), abdomen, or chest; and subject has received, is receiving, or is willing to receive treatment per standard of care, which may or may not include oral prednisone (2 mg/kg PO to a maximum dose of 100 mg daily) for 4 days. * Abstinent or using two highly effective forms of birth control. * Subjects must be accessible for treatment and follow-up. Subjects living at distant locations from the investigational site must be able and willing to travel to a site for the initial and all follow-up visits.
Exclusion criteria
* Weight \<20 kg. * Intercurrent non-healed fracture at any location. * Complete immobilization of joint at site of flare-up. * The inability of the subject to undergo imaging assessments using plain radiographs. * If currently using vitamin A or beta carotene, multivitamins containing vitamin A or beta carotene, or herbal preparations, fish oil, and unable or unwilling to discontinue use of these products for the duration of the study. * Exposure to synthetic oral retinoids in the past 30 days prior to Screening (signature of the informed consent). * Concurrent treatment with tetracycline due to the potential increased risk of pseudotumor cerebri. * History of allergy or hypersensitivity to retinoids or lactose. * Concomitant medications that are inhibitors or inducers of CYP450 3A4 activity. * Amylase or lipase \>1.5x above the upper limit of normal or with a history of chronic pancreatitis. * Elevated aspartate aminotransferase or alanine aminotransferase \>2.5x the upper limit of normal. * Fasting triglycerides \>400 mg/dL with or without therapy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Responders at Week 6 | Baseline (Day 1) and Week 6 (Day 42) | A responder was defined as a subject with no or minimal new heterotopic ossification (HO) at flare-up site versus baseline as assessed by plain radiographs at Week 6. Minimal new HO is defined as new HO with an HO score \<=3 in both anterior/posterior (AP) and lateral projections (or if one view is non-interpretable or non-evaluable, then remaining evaluable view is used). The HO score ranges from 0 to 6 where, 0 = no HO and 6 = single contiguous HO with longest dimension \>2 diameters of reference normotopic bone in any projection. The highest HO score from the 2 projections was used. Results from Primary Read reviews are presented. The Primary Read process included a double-read radiology review paradigm with consensus adjudication. Radiography and CT scans were examined independently by scan type, flare-up region, and imaging time point in order to determine whether radiography would be sufficient to measure new HO formation. Only subjects with interpretable outcomes were evaluated. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Amount (Area) of New HO Formed at the Flare-up Site at Weeks 6 and 12 | Baseline, Weeks 6 and 12 | Interpretation of plain radiographs document the amount (area) of HO on both the AP and lateral radiograph views. The area for each view was a sum of all the new HO at the flare-up location (and thus if there are multiple HO lesions, the area of each lesion was determined and then the total across all lesions were summed to obtain a total new HO). This total new HO sum was used in the analysis of the area of new HO. Results from Primary Read reviews are presented. |
| Percentage of Responders at Week 12 | Baseline and Week 12 | A responder was defined as a subject with no or minimal new HO at the flare-up site versus baseline as assessed by plain radiographs at Week 12. Minimal new HO is defined as new HO with an HO score \<=3 in both the AP and lateral projections (or if one view is non-interpretable or non-evaluable, then the remaining evaluable view is used). The HO score ranges from 0 to 6 where, 0 = no HO and 6 = single contiguous HO with longest dimension \>2 diameters of the reference normotopic bone in any projection. The highest HO score from the 2 projections was used. Results from the Primary Read reviews are presented. The Primary Read process included a double-read radiology review paradigm with consensus adjudication. Radiography and CT scans were examined independently by scan type, flare-up region, and imaging time point in order to determine whether radiography would be sufficient to measure new HO formation. |
| Change From Baseline in Bone Specific Alkaline Phosphatase at Weeks 2, 4, 6 and 12 | Baseline, Weeks 2, 4, 6 and 12 | Blood and urine samples for analysis of cartilage, bone, angiogenesis, and inflammation biomarkers were collected. Bone specific alkaline phosphatase was analysed as a bone and cartilage biomarker. |
| Change From Baseline in C-Reactive Protein at Weeks 2, 4, 6 and 12 | Baseline, Weeks 2, 4, 6 and 12 | Blood and urine samples for analysis of cartilage, bone, angiogenesis, and inflammation biomarkers were collected. C-reactive protein was analysed as a inflammation biomarker. |
| Change From Baseline in C-Terminal Telopeptide at Weeks 2, 4, 6 and 12 | Baseline, Weeks 2, 4, 6 and 12 | Blood and urine samples for analysis of cartilage, bone, angiogenesis, and inflammation biomarkers were collected. C-terminal telopeptide was analysed as a bone and cartilage biomarker. |
| Change From Baseline in Procollagen Type 1 N-Terminal Propeptide at Weeks 2, 4, 6 and 12 | Baseline, Weeks 2, 4, 6 and 12 | Blood and urine samples for analysis of cartilage, bone, angiogenesis, and inflammation biomarkers were collected. Procollagen type 1 N-terminal propeptide was analysed as a bone and cartilage biomarker. |
| Change From Baseline in Procollagen Type 1 C-Terminal Propeptide Biomarker at Weeks 2, 4, 6 and 12 | Baseline, Weeks 2, 4, 6 and 12 | Blood and urine samples for analysis of cartilage, bone, angiogenesis, and inflammation biomarkers were collected. Procollagen type 1 C-terminal propeptide was analysed as a bone and cartilage biomarker. |
| Change From Baseline in Amount of Bone Formation (Volume) at Weeks 6 and 12 | Baseline, Weeks 6 and 12 | Low dose CT scan were used as a secondary imaging assessment of HO, and was performed at the same time points as plain radiographs. Interpretation of the CT scan documented the amount (volume) and grade of HO. The independent reviewer scored HO lesions according to the following scale for HO on CT. Grade 1 = fluid attenuation without evidence of calcification at CT, Grade 2 = calcification of soft tissues without evidence of bone formation, Grade 3 = immature bone formation, and Grade 4 = mature bone with cortical differentiation. Volume of new HO was determined according to the following steps: (1) calculate volume of new HO compared to baseline for each reviewer/HO ID, (2) sum the volume of new HO across HO IDs for each reviewer, and (3) average the volume of new HO across reviewers. Results from Primary Read reviews are presented. |
| Percentage of Subjects With Soft Tissue Swelling and Cartilage Formation Assessed by Magnetic Resonance Imaging (MRI) or Ultrasound (US) at Weeks 6 and 12 | Weeks 6 and 12 | The MRI was utilized to evaluate the presence of soft tissue swelling/edema (and volume of the swelling/edema) and presence of cartilage formation (yes or no). For subjects who could not have an MRI, US was used to assess edema severity for the sub-set of subjects enrolled after this opinion was introduced in a protocol amendment. Imaging film from MRI was assessed by two independent readers. When there was sufficient agreement between the independent readers on volume, both of the independent readings were used for analysis with the volume measurements averaged. When there was insufficient agreement between the independent readers, an adjudication reading was provided and used for analysis. The US was used for soft tissue swelling/edema but not cartilage formation. Percentage calculated as % = 100 x n/N' where N' is the number of subjects with interpretable outcomes. Results from Primary Read reviews are presented. |
| Change From Baseline in Percent of Normal Arc of Motion at the Primary Joint (Flare-up Site) at Weeks 6 and 12 | Baseline, Weeks 6 and 12 | Active range of motion, expressed as the percent of normal arc of motion, measurements at the primary joint associated with the flare-up and adjoining joints was assessed by goniometer. |
| Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Weeks 6 and 12 | Flare-up movement outcomes were independently assessed by both the subject (or parent of a subject under 8 years of age) and the Investigator at Weeks 6 and 12 by completing the global assessment of movement. The subject/parent completed the global assessment first. Prior to reviewing the subject's assessment, the Investigator completed his/her own assessment of the flare-up outcome. Subjects were assessed how the flare-up affected their movement on a scale ranging 1 to 5 where, 1 = severely worse movement and 5 = better movement compared with study Day 1 (day of first dose of study drug). Investigators were assessed how the flare-up affected the subject's movement on a scale ranging 1 to 5 where, 1 = severely worse movement and 5 = better movement compared with baseline (day of screening physical examination). |
| Percentage of Subjects With New HO at Weeks 6 and 12 | Weeks 6 and 12 (Day 84) | Low dose CT scan was used as a secondary imaging assessment of HO and was performed at the same time points as plain radiographs. The percentage of subjects with new HO (regardless of the amount of new HO) at the flare-up site as assessed by CT scan and/or plain radiographs at Weeks 6 and 12 were analysed. The results are from Global Read reviews. The holistic Global Read process allowed concurrent review of all modalities across all time points, and provided access to selected clinical data at the time of review. |
| Percentage of Subjects Who Used Any Assistive Devices and Adaptations for Daily Living at Weeks 6 and 12 | Weeks 6 and 12 | Subjects were given a list of FOP assistive devices and adaptations and asked to select those they use for daily living. The FOP assistive devices and adaptations included mobility aids, care attendants, eating tools, personal care tools/aids, bathroom aids and devices, bedroom aids and devices, home adaptations, work environment adaptations, technology adaptations, sports and recreation adaptations, school, and medical therapies for daily living. |
| Duration of Active Symptomatic Flare-up | From Day 1 to Day 84 | The duration of active symptomatic flare-up was defined as the number of days the subject reported the presence of symptoms in the diary ('Is your flare-up ongoing today?') from Day 1 to study completion at Day 84. The mean number of days of active, symptomatic flare-up is presented for subjects with evaluable diary data. |
| Change From Baseline in Percentage of Worst Total Score for FOP-Specific Physical Function Questionnaire (FOP-PFQ) at Weeks 2, 4, 6, 9 and 12 | Baseline, Weeks 2, 4, 6, 9 and 12 | The FOP-PFQ consists of 28 questions rated on scales from 1 to 5, with lower scores denoting more difficulty. The adult form of the FOP-PFQ was administered to subjects 15 years of age and older. There are two Pediatric FOP-PFQ (FOP-PFQ-P) forms: a self-completed form for 8 to 14 year-olds and a parent proxy-completed form for 5 to 14 year-olds. For subjects between 8 to 14 years of age, both the self-completed (for 8 to 14 year-olds) and the proxy-completed (for 5 to 14 year olds) forms of the FOP-PFQ-P were administered. However, only the proxy-completed form was used for analysis. Percentage of worst scores ranges from 0% to 100% with 0% = best possible function and 100% = worst possible function. Change from baseline for each time point is presented. |
| Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12 | Baseline, Weeks 2, 4, 6, 9 and 12 | The PROMIS Global Health contains 10 questions which are rated on scales from 1 to 5 or 0 to 10. Global physical health scores were calculated as the sum of scores from parameters 3, 6, 7, and 8 and ranges from 4 to 20 where, 4 = worse health and 20 = better health. Global mental health scores were calculated as the sum of scores from parameters 2, 4, 5, and 10 and ranges from 4 to 20 where, 4 = worse health and 20 = better health. For paediatric subjects, the PROMIS was administered as per the adult version. However, there is a single total score for the paediatric PROMIS (as opposed to global physical and global mental health scores as are in the adult version). The total score were converted to a T-score. A T-score of 50 is normal and increments of 10 are +/- 1 standard deviation away from the norm. A T-score \<50 indicates worse health, while a T-score \>50 indicates better health. The higher values (positive changes) indicate better health. |
| Maximum Measured Plasma Concentration (Cmax) of Palovarotene | Pre-dose and 3, 6, 10, and 24 hours (hrs) post-dose at Week 2, and at Week 4 or 6 | The Cmax of palovarotene was determined. |
| Minimum Measured Plasma Concentration (Cmin) of Palovarotene | Pre-dose and 3, 6, 10, and 24 hrs post-dose at Week 2, and at Week 4 or 6 | The Cmin of palovarotene was determined. |
| Time of Maximum Measured Plasma Concentration (Tmax) of Palovarotene | Pre-dose and 3, 6, 10, and 24 hrs post-dose at Week 2, and at Week 4 or 6 | The Tmax obtained by inspection of palovarotene was determined. |
| Apparent Terminal Elimination Half-life (t1/2) of Palovarotene | Pre-dose and 3, 6, 10, and 24 hrs post-dose at Week 2, and at Week 4 or 6 | The t1/2 was calculated as ln(2)/ λz. The number of data points included in the regression was determined by visual inspection, but a minimum of three data points in the terminal phase, excluding Cmax, was required to estimate λz. |
| Area Under the Plasma Concentration Versus Time Curve Over the 24-hr Dosing Interval (AUC[0-24hr]) of Palovarotene | Pre-dose and 3, 6, 10, and 24 hrs post-dose at Week 2, and at Week 4 or 6 | The AUC(0-24hr) was calculated using linear trapezoid rule. |
| Apparent Clearance of Palovarotene (CL/F) | Pre-dose and 3, 6, 10, and 24 hrs post-dose at Week 2, and at Week 4 or 6 | The CL/F was defined as dose/AUC0-24hr. |
| Change From Baseline in Flare-Up Pain and Swelling at Weeks 2, 4, 6, 9 and 12 | Baseline, Weeks 2, 4, 6, 9 and 12 | The pain and swelling associated with flare-ups was evaluated using 2 separate numeric rating scales, one for pain and one for swelling. The pain scale ranges from 0 to 10 where, 0 = no pain and 10 = worst pain ever experienced. The swelling scale ranges from 0 to 10 where, 0 = no swelling and 10 = worst swelling ever experienced. The Faces Pain Scale - Revised (FPS-R) was used for children less than 8 years old. The FPS-R ranges from 0 to 10 where, 0 = no pain and 10 = very much pain in two-point increments. |
Countries
France, United Kingdom, United States
Participant flow
Recruitment details
Eight subjects were randomized 3:1 to either palovarotene or placebo in Cohort 1; 8 additional subjects were randomized 3:1 in an interim period between Cohorts 1 and 2. In Cohort 2, 24 additional fibrodysplasia ossificans progressiva (FOP) subjects were randomized 3:3:2 across 2 weight-based regimens of palovarotene or placebo.
Pre-assignment details
The study included clinically diagnosed FOP subjects at least 6 years of age (Cohort 2) or 15 years of age and older (Cohort 1) with symptomatic onset of a flare-up within 7 days of treatment start and accessible for treatment and follow-up.
Participants by arm
| Arm | Count |
|---|---|
| Palovarotene 10/5 mg Subjects received palovarotene 10 mg orally for 14 days followed by 5 mg orally for 28 days during flare-ups (10/5 mg regimen). The subjects were followed for an additional 42 days without treatment. Subjects in Cohort 1 and Cohort 2 contributed to this arm. | 21 |
| Palovarotene 5/2.5 mg Subjects received palovarotene 5 mg orally for 14 days followed by 2.5 mg orally for 28 days during flare-ups (5/2.5 mg regimen). The subjects were followed for an additional 42 days without treatment. Only subjects in Cohort 2 contributed to this arm. | 9 |
| Placebo Subjects received placebo (matching with palovarotene) for 42 days during flare-ups. Subjects were followed for an additional 42 days without treatment. Subjects in Cohort 1 and Cohort 2 contributed to this arm. | 10 |
| Total | 40 |
Baseline characteristics
| Characteristic | Palovarotene 10/5 mg | Palovarotene 5/2.5 mg | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 22.8 years STANDARD_DEVIATION 10.3 | 17.9 years STANDARD_DEVIATION 8.6 | 21.2 years STANDARD_DEVIATION 13.7 | 21.3 years STANDARD_DEVIATION 10.8 |
| Age, Customized Adolescents (12-17 years) | 5 Participants | 0 Participants | 4 Participants | 9 Participants |
| Age, Customized Adults (18-64 years) | 13 Participants | 5 Participants | 4 Participants | 22 Participants |
| Age, Customized Children (2-11 years) | 3 Participants | 4 Participants | 2 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 1 Participants | 1 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants | 8 Participants | 6 Participants | 27 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 6 Participants | 0 Participants | 3 Participants | 9 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Multiple | 2 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Not available | 6 Participants | 0 Participants | 3 Participants | 9 Participants |
| Race/Ethnicity, Customized White | 12 Participants | 7 Participants | 6 Participants | 25 Participants |
| Sex: Female, Male Female | 9 Participants | 6 Participants | 7 Participants | 22 Participants |
| Sex: Female, Male Male | 12 Participants | 3 Participants | 3 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 21 | 0 / 9 | 0 / 10 |
| other Total, other adverse events | 21 / 21 | 9 / 9 | 10 / 10 |
| serious Total, serious adverse events | 2 / 21 | 1 / 9 | 1 / 10 |
Outcome results
Primary
Percentage of Responders at Week 6
A responder was defined as a subject with no or minimal new heterotopic ossification (HO) at flare-up site versus baseline as assessed by plain radiographs at Week 6. Minimal new HO is defined as new HO with an HO score \<=3 in both anterior/posterior (AP) and lateral projections (or if one view is non-interpretable or non-evaluable, then remaining evaluable view is used). The HO score ranges from 0 to 6 where, 0 = no HO and 6 = single contiguous HO with longest dimension \>2 diameters of reference normotopic bone in any projection. The highest HO score from the 2 projections was used. Results from Primary Read reviews are presented. The Primary Read process included a double-read radiology review paradigm with consensus adjudication. Radiography and CT scans were examined independently by scan type, flare-up region, and imaging time point in order to determine whether radiography would be sufficient to measure new HO formation. Only subjects with interpretable outcomes were evaluated.
Time frame: Baseline (Day 1) and Week 6 (Day 42)
Population: The Per Protocol (PP) population included all subjects who were eligible for full analysis set (FAS) population, completed Week 6 study visit with no major protocol deviations with at least 80% compliance with study drug, and had an evaluable radiograph or computed tomography (CT) at Week 6 sufficient to allow determination of HO at flare-up site.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Palovarotene 10/5 mg | Percentage of Responders at Week 6 | 100 percentage of subjects |
| Palovarotene 5/2.5 mg | Percentage of Responders at Week 6 | 88.9 percentage of subjects |
| Placebo | Percentage of Responders at Week 6 | 88.9 percentage of subjects |
Comparison: Cochran-Armitage test of trend (one-sided). The Cochran-Armitage test of trend assessed the overall trend of response across the dose groups (from the lowest dose \[or placebo\], to the highest dose).p-value: 0.1664Cochran-Armitage test of trend
Secondary
Apparent Clearance of Palovarotene (CL/F)
The CL/F was defined as dose/AUC0-24hr.
Time frame: Pre-dose and 3, 6, 10, and 24 hrs post-dose at Week 2, and at Week 4 or 6
Population: The PK population included all subjects who had sufficient blood samples collected for valid estimation of PK parameters.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Palovarotene 10/5 mg | Apparent Clearance of Palovarotene (CL/F) | Week 2 | 15.55 L/hr | Standard Deviation 7.03 |
| Palovarotene 10/5 mg | Apparent Clearance of Palovarotene (CL/F) | Week 4/Week 6 | 17.71 L/hr | Standard Deviation 7.44 |
| Palovarotene 5/2.5 mg | Apparent Clearance of Palovarotene (CL/F) | Week 2 | 12.84 L/hr | Standard Deviation 4.07 |
| Palovarotene 5/2.5 mg | Apparent Clearance of Palovarotene (CL/F) | Week 4/Week 6 | 19.51 L/hr | Standard Deviation 10.66 |
Secondary
Apparent Terminal Elimination Half-life (t1/2) of Palovarotene
The t1/2 was calculated as ln(2)/ λz. The number of data points included in the regression was determined by visual inspection, but a minimum of three data points in the terminal phase, excluding Cmax, was required to estimate λz.
Time frame: Pre-dose and 3, 6, 10, and 24 hrs post-dose at Week 2, and at Week 4 or 6
Population: The PK population included all subjects who had sufficient blood samples collected for valid estimation of PK parameters.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Palovarotene 10/5 mg | Apparent Terminal Elimination Half-life (t1/2) of Palovarotene | Week 2 | 4.33 hr |
| Palovarotene 10/5 mg | Apparent Terminal Elimination Half-life (t1/2) of Palovarotene | Week 4/Week 6 | 4.39 hr |
| Palovarotene 5/2.5 mg | Apparent Terminal Elimination Half-life (t1/2) of Palovarotene | Week 2 | 5.18 hr |
| Palovarotene 5/2.5 mg | Apparent Terminal Elimination Half-life (t1/2) of Palovarotene | Week 4/Week 6 | 4.40 hr |
Secondary
Area Under the Plasma Concentration Versus Time Curve Over the 24-hr Dosing Interval (AUC[0-24hr]) of Palovarotene
The AUC(0-24hr) was calculated using linear trapezoid rule.
Time frame: Pre-dose and 3, 6, 10, and 24 hrs post-dose at Week 2, and at Week 4 or 6
Population: The PK population included all subjects who had sufficient blood samples collected for valid estimation of PK parameters.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Palovarotene 10/5 mg | Area Under the Plasma Concentration Versus Time Curve Over the 24-hr Dosing Interval (AUC[0-24hr]) of Palovarotene | Week 2 | 686308.92 hr*pg/mL | Standard Deviation 246797.81 |
| Palovarotene 10/5 mg | Area Under the Plasma Concentration Versus Time Curve Over the 24-hr Dosing Interval (AUC[0-24hr]) of Palovarotene | Week 4/Week 6 | 311082.39 hr*pg/mL | Standard Deviation 128622.73 |
| Palovarotene 5/2.5 mg | Area Under the Plasma Concentration Versus Time Curve Over the 24-hr Dosing Interval (AUC[0-24hr]) of Palovarotene | Week 4/Week 6 | 142748.47 hr*pg/mL | Standard Deviation 84838.75 |
| Palovarotene 5/2.5 mg | Area Under the Plasma Concentration Versus Time Curve Over the 24-hr Dosing Interval (AUC[0-24hr]) of Palovarotene | Week 2 | 350124.65 hr*pg/mL | Standard Deviation 181967.49 |
Secondary
Change From Baseline in Amount (Area) of New HO Formed at the Flare-up Site at Weeks 6 and 12
Interpretation of plain radiographs document the amount (area) of HO on both the AP and lateral radiograph views. The area for each view was a sum of all the new HO at the flare-up location (and thus if there are multiple HO lesions, the area of each lesion was determined and then the total across all lesions were summed to obtain a total new HO). This total new HO sum was used in the analysis of the area of new HO. Results from Primary Read reviews are presented.
Time frame: Baseline, Weeks 6 and 12
Population: The PP population included all subjects who were eligible for the FAS population, completed Week 6 study visit with no major protocol deviations with at least 80% compliance with study drug, and had an evaluable radiograph or CT at Week 6 sufficient to allow determination of HO at flare-up site.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Palovarotene 10/5 mg | Change From Baseline in Amount (Area) of New HO Formed at the Flare-up Site at Weeks 6 and 12 | Week 6 | 0.00 square millimeters (mm) | Standard Deviation 0 |
| Palovarotene 10/5 mg | Change From Baseline in Amount (Area) of New HO Formed at the Flare-up Site at Weeks 6 and 12 | Week 12 | 19.00 square millimeters (mm) | Standard Deviation 84.955 |
| Palovarotene 5/2.5 mg | Change From Baseline in Amount (Area) of New HO Formed at the Flare-up Site at Weeks 6 and 12 | Week 6 | 38.85 square millimeters (mm) | Standard Deviation 116.542 |
| Palovarotene 5/2.5 mg | Change From Baseline in Amount (Area) of New HO Formed at the Flare-up Site at Weeks 6 and 12 | Week 12 | 71.22 square millimeters (mm) | Standard Deviation 213.65 |
| Placebo | Change From Baseline in Amount (Area) of New HO Formed at the Flare-up Site at Weeks 6 and 12 | Week 6 | 75.89 square millimeters (mm) | Standard Deviation 176.744 |
| Placebo | Change From Baseline in Amount (Area) of New HO Formed at the Flare-up Site at Weeks 6 and 12 | Week 12 | 621.71 square millimeters (mm) | Standard Deviation 1287.519 |
Comparison: Week 6: Analysis of area of new HOp-value: 0.6984Pairwise test
Comparison: Week 6: Analysis of area of new HOp-value: 0.8811Pairwise test
Comparison: Week 12: Analysis of area of new HOp-value: 0.0017Pairwise test
Comparison: Week 12: Analysis of area of new HOp-value: 0.0094Pairwise test
Secondary
Change From Baseline in Amount of Bone Formation (Volume) at Weeks 6 and 12
Low dose CT scan were used as a secondary imaging assessment of HO, and was performed at the same time points as plain radiographs. Interpretation of the CT scan documented the amount (volume) and grade of HO. The independent reviewer scored HO lesions according to the following scale for HO on CT. Grade 1 = fluid attenuation without evidence of calcification at CT, Grade 2 = calcification of soft tissues without evidence of bone formation, Grade 3 = immature bone formation, and Grade 4 = mature bone with cortical differentiation. Volume of new HO was determined according to the following steps: (1) calculate volume of new HO compared to baseline for each reviewer/HO ID, (2) sum the volume of new HO across HO IDs for each reviewer, and (3) average the volume of new HO across reviewers. Results from Primary Read reviews are presented.
Time frame: Baseline, Weeks 6 and 12
Population: The PP population included all subjects who were eligible for the FAS population, completed Week 6 study visit with no major protocol deviations with at least 80% compliance with study drug, and had an evaluable radiograph or CT at Week 6 sufficient to allow determination of HO at flare-up site.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Palovarotene 10/5 mg | Change From Baseline in Amount of Bone Formation (Volume) at Weeks 6 and 12 | Week 6 | 2820.53 cubic mm | Standard Deviation 11078.233 |
| Palovarotene 10/5 mg | Change From Baseline in Amount of Bone Formation (Volume) at Weeks 6 and 12 | Week 12 | 3857.95 cubic mm | Standard Deviation 11860.978 |
| Palovarotene 5/2.5 mg | Change From Baseline in Amount of Bone Formation (Volume) at Weeks 6 and 12 | Week 6 | 326.58 cubic mm | Standard Deviation 979.733 |
| Palovarotene 5/2.5 mg | Change From Baseline in Amount of Bone Formation (Volume) at Weeks 6 and 12 | Week 12 | 1184.99 cubic mm | Standard Deviation 3188.02 |
| Placebo | Change From Baseline in Amount of Bone Formation (Volume) at Weeks 6 and 12 | Week 6 | 11459.42 cubic mm | Standard Deviation 29759.691 |
| Placebo | Change From Baseline in Amount of Bone Formation (Volume) at Weeks 6 and 12 | Week 12 | 16181.64 cubic mm | Standard Deviation 41643.976 |
Secondary
Change From Baseline in Bone Specific Alkaline Phosphatase at Weeks 2, 4, 6 and 12
Blood and urine samples for analysis of cartilage, bone, angiogenesis, and inflammation biomarkers were collected. Bone specific alkaline phosphatase was analysed as a bone and cartilage biomarker.
Time frame: Baseline, Weeks 2, 4, 6 and 12
Population: The FAS population included all subjects who received at least 1 dose of study drug and had at least 1 evaluable post-baseline radiograph or CT sufficient to allow determination of HO at the flare-up site.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Palovarotene 10/5 mg | Change From Baseline in Bone Specific Alkaline Phosphatase at Weeks 2, 4, 6 and 12 | Week 2 | -1.33 microgram per liter (mcg/L) | Standard Deviation 13.267 |
| Palovarotene 10/5 mg | Change From Baseline in Bone Specific Alkaline Phosphatase at Weeks 2, 4, 6 and 12 | Week 4 | -1.41 microgram per liter (mcg/L) | Standard Deviation 8.328 |
| Palovarotene 10/5 mg | Change From Baseline in Bone Specific Alkaline Phosphatase at Weeks 2, 4, 6 and 12 | Week 6 | -2.53 microgram per liter (mcg/L) | Standard Deviation 8.157 |
| Palovarotene 10/5 mg | Change From Baseline in Bone Specific Alkaline Phosphatase at Weeks 2, 4, 6 and 12 | Week 12 | 2.49 microgram per liter (mcg/L) | Standard Deviation 5.506 |
| Palovarotene 5/2.5 mg | Change From Baseline in Bone Specific Alkaline Phosphatase at Weeks 2, 4, 6 and 12 | Week 12 | 0.89 microgram per liter (mcg/L) | Standard Deviation 6.738 |
| Palovarotene 5/2.5 mg | Change From Baseline in Bone Specific Alkaline Phosphatase at Weeks 2, 4, 6 and 12 | Week 2 | -3.18 microgram per liter (mcg/L) | Standard Deviation 4.619 |
| Palovarotene 5/2.5 mg | Change From Baseline in Bone Specific Alkaline Phosphatase at Weeks 2, 4, 6 and 12 | Week 6 | 0.74 microgram per liter (mcg/L) | Standard Deviation 3.316 |
| Palovarotene 5/2.5 mg | Change From Baseline in Bone Specific Alkaline Phosphatase at Weeks 2, 4, 6 and 12 | Week 4 | 3.80 microgram per liter (mcg/L) | Standard Deviation 12.072 |
| Placebo | Change From Baseline in Bone Specific Alkaline Phosphatase at Weeks 2, 4, 6 and 12 | Week 12 | 10.00 microgram per liter (mcg/L) | Standard Deviation 10.091 |
| Placebo | Change From Baseline in Bone Specific Alkaline Phosphatase at Weeks 2, 4, 6 and 12 | Week 4 | 7.53 microgram per liter (mcg/L) | Standard Deviation 10.208 |
| Placebo | Change From Baseline in Bone Specific Alkaline Phosphatase at Weeks 2, 4, 6 and 12 | Week 6 | 6.23 microgram per liter (mcg/L) | Standard Deviation 6.851 |
| Placebo | Change From Baseline in Bone Specific Alkaline Phosphatase at Weeks 2, 4, 6 and 12 | Week 2 | 12.02 microgram per liter (mcg/L) | Standard Deviation 35.263 |
Secondary
Change From Baseline in C-Reactive Protein at Weeks 2, 4, 6 and 12
Blood and urine samples for analysis of cartilage, bone, angiogenesis, and inflammation biomarkers were collected. C-reactive protein was analysed as a inflammation biomarker.
Time frame: Baseline, Weeks 2, 4, 6 and 12
Population: The FAS population included all subjects who received at least 1 dose of study drug and had at least 1 evaluable post-baseline radiograph or CT sufficient to allow determination of HO at the flare-up site.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Palovarotene 10/5 mg | Change From Baseline in C-Reactive Protein at Weeks 2, 4, 6 and 12 | Week 12 | 2.82 mg/L | Standard Deviation 11.762 |
| Palovarotene 10/5 mg | Change From Baseline in C-Reactive Protein at Weeks 2, 4, 6 and 12 | Week 4 | 1.48 mg/L | Standard Deviation 4.924 |
| Palovarotene 10/5 mg | Change From Baseline in C-Reactive Protein at Weeks 2, 4, 6 and 12 | Week 6 | 0.14 mg/L | Standard Deviation 3.419 |
| Palovarotene 10/5 mg | Change From Baseline in C-Reactive Protein at Weeks 2, 4, 6 and 12 | Week 2 | 8.62 mg/L | Standard Deviation 28.085 |
| Palovarotene 5/2.5 mg | Change From Baseline in C-Reactive Protein at Weeks 2, 4, 6 and 12 | Week 6 | 2.70 mg/L | Standard Deviation 7.984 |
| Palovarotene 5/2.5 mg | Change From Baseline in C-Reactive Protein at Weeks 2, 4, 6 and 12 | Week 12 | 1.27 mg/L | Standard Deviation 1.789 |
| Palovarotene 5/2.5 mg | Change From Baseline in C-Reactive Protein at Weeks 2, 4, 6 and 12 | Week 2 | 0.09 mg/L | Standard Deviation 2.37 |
| Palovarotene 5/2.5 mg | Change From Baseline in C-Reactive Protein at Weeks 2, 4, 6 and 12 | Week 4 | 23.26 mg/L | Standard Deviation 38.311 |
| Placebo | Change From Baseline in C-Reactive Protein at Weeks 2, 4, 6 and 12 | Week 12 | -0.30 mg/L | Standard Deviation 2.951 |
| Placebo | Change From Baseline in C-Reactive Protein at Weeks 2, 4, 6 and 12 | Week 2 | -1.59 mg/L | Standard Deviation 1.909 |
| Placebo | Change From Baseline in C-Reactive Protein at Weeks 2, 4, 6 and 12 | Week 6 | 1.20 mg/L | Standard Deviation 1.319 |
| Placebo | Change From Baseline in C-Reactive Protein at Weeks 2, 4, 6 and 12 | Week 4 | 2.34 mg/L | Standard Deviation 3.704 |
Secondary
Change From Baseline in C-Terminal Telopeptide at Weeks 2, 4, 6 and 12
Blood and urine samples for analysis of cartilage, bone, angiogenesis, and inflammation biomarkers were collected. C-terminal telopeptide was analysed as a bone and cartilage biomarker.
Time frame: Baseline, Weeks 2, 4, 6 and 12
Population: The FAS population included all subjects who received at least 1 dose of study drug and had at least 1 evaluable post-baseline radiograph or CT sufficient to allow determination of HO at the flare-up site.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Palovarotene 10/5 mg | Change From Baseline in C-Terminal Telopeptide at Weeks 2, 4, 6 and 12 | Week 6 | 0.105 mcg/L | Standard Deviation 0.304 |
| Palovarotene 10/5 mg | Change From Baseline in C-Terminal Telopeptide at Weeks 2, 4, 6 and 12 | Week 2 | -0.020 mcg/L | Standard Deviation 0.29 |
| Palovarotene 10/5 mg | Change From Baseline in C-Terminal Telopeptide at Weeks 2, 4, 6 and 12 | Week 12 | 0.116 mcg/L | Standard Deviation 0.241 |
| Palovarotene 10/5 mg | Change From Baseline in C-Terminal Telopeptide at Weeks 2, 4, 6 and 12 | Week 4 | 0.015 mcg/L | Standard Deviation 0.337 |
| Palovarotene 5/2.5 mg | Change From Baseline in C-Terminal Telopeptide at Weeks 2, 4, 6 and 12 | Week 6 | 0.078 mcg/L | Standard Deviation 0.293 |
| Palovarotene 5/2.5 mg | Change From Baseline in C-Terminal Telopeptide at Weeks 2, 4, 6 and 12 | Week 4 | 0.095 mcg/L | Standard Deviation 0.38 |
| Palovarotene 5/2.5 mg | Change From Baseline in C-Terminal Telopeptide at Weeks 2, 4, 6 and 12 | Week 2 | 0.118 mcg/L | Standard Deviation 0.359 |
| Palovarotene 5/2.5 mg | Change From Baseline in C-Terminal Telopeptide at Weeks 2, 4, 6 and 12 | Week 12 | 0.054 mcg/L | Standard Deviation 0.285 |
| Placebo | Change From Baseline in C-Terminal Telopeptide at Weeks 2, 4, 6 and 12 | Week 12 | 0.126 mcg/L | Standard Deviation 0.197 |
| Placebo | Change From Baseline in C-Terminal Telopeptide at Weeks 2, 4, 6 and 12 | Week 2 | 0.071 mcg/L | Standard Deviation 0.342 |
| Placebo | Change From Baseline in C-Terminal Telopeptide at Weeks 2, 4, 6 and 12 | Week 4 | 0.188 mcg/L | Standard Deviation 0.219 |
| Placebo | Change From Baseline in C-Terminal Telopeptide at Weeks 2, 4, 6 and 12 | Week 6 | 0.125 mcg/L | Standard Deviation 0.351 |
Secondary
Change From Baseline in Flare-Up Pain and Swelling at Weeks 2, 4, 6, 9 and 12
The pain and swelling associated with flare-ups was evaluated using 2 separate numeric rating scales, one for pain and one for swelling. The pain scale ranges from 0 to 10 where, 0 = no pain and 10 = worst pain ever experienced. The swelling scale ranges from 0 to 10 where, 0 = no swelling and 10 = worst swelling ever experienced. The Faces Pain Scale - Revised (FPS-R) was used for children less than 8 years old. The FPS-R ranges from 0 to 10 where, 0 = no pain and 10 = very much pain in two-point increments.
Time frame: Baseline, Weeks 2, 4, 6, 9 and 12
Population: The PP population included all subjects who were eligible for the FAS population, completed Week 6 study visit with no major protocol deviations with at least 80% compliance with study drug, and had an evaluable radiograph or CT at Week 6 sufficient to allow determination of HO at flare-up site.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Palovarotene 10/5 mg | Change From Baseline in Flare-Up Pain and Swelling at Weeks 2, 4, 6, 9 and 12 | Flare-up pain: Week 2 | -2.5 units on a scale | Standard Deviation 2.5 |
| Palovarotene 10/5 mg | Change From Baseline in Flare-Up Pain and Swelling at Weeks 2, 4, 6, 9 and 12 | Flare-up pain: Week 4 | -3.2 units on a scale | Standard Deviation 2.46 |
| Palovarotene 10/5 mg | Change From Baseline in Flare-Up Pain and Swelling at Weeks 2, 4, 6, 9 and 12 | Flare-up pain: Week 6 | -3.5 units on a scale | Standard Deviation 2.78 |
| Palovarotene 10/5 mg | Change From Baseline in Flare-Up Pain and Swelling at Weeks 2, 4, 6, 9 and 12 | Flare-up pain: Week 9 | -3.8 units on a scale | Standard Deviation 2.62 |
| Palovarotene 10/5 mg | Change From Baseline in Flare-Up Pain and Swelling at Weeks 2, 4, 6, 9 and 12 | Flare-up pain: Week 12 | -3.6 units on a scale | Standard Deviation 2.72 |
| Palovarotene 10/5 mg | Change From Baseline in Flare-Up Pain and Swelling at Weeks 2, 4, 6, 9 and 12 | Flare-up swelling: Week 2 | -1.4 units on a scale | Standard Deviation 2.76 |
| Palovarotene 10/5 mg | Change From Baseline in Flare-Up Pain and Swelling at Weeks 2, 4, 6, 9 and 12 | Flare-up swelling: Week 4 | -1.7 units on a scale | Standard Deviation 3.3 |
| Palovarotene 10/5 mg | Change From Baseline in Flare-Up Pain and Swelling at Weeks 2, 4, 6, 9 and 12 | Flare-up swelling: Week 6 | -2.2 units on a scale | Standard Deviation 3.32 |
| Palovarotene 10/5 mg | Change From Baseline in Flare-Up Pain and Swelling at Weeks 2, 4, 6, 9 and 12 | Flare-up swelling: Week 9 | -2.7 units on a scale | Standard Deviation 3.32 |
| Palovarotene 10/5 mg | Change From Baseline in Flare-Up Pain and Swelling at Weeks 2, 4, 6, 9 and 12 | Flare-up swelling: Week 12 | -2.1 units on a scale | Standard Deviation 3.73 |
| Palovarotene 5/2.5 mg | Change From Baseline in Flare-Up Pain and Swelling at Weeks 2, 4, 6, 9 and 12 | Flare-up swelling: Week 9 | -2.3 units on a scale | Standard Deviation 2.43 |
| Palovarotene 5/2.5 mg | Change From Baseline in Flare-Up Pain and Swelling at Weeks 2, 4, 6, 9 and 12 | Flare-up pain: Week 2 | 0.0 units on a scale | Standard Deviation 2.4 |
| Palovarotene 5/2.5 mg | Change From Baseline in Flare-Up Pain and Swelling at Weeks 2, 4, 6, 9 and 12 | Flare-up swelling: Week 2 | -1.3 units on a scale | Standard Deviation 2.93 |
| Palovarotene 5/2.5 mg | Change From Baseline in Flare-Up Pain and Swelling at Weeks 2, 4, 6, 9 and 12 | Flare-up pain: Week 12 | -1.9 units on a scale | Standard Deviation 2.42 |
| Palovarotene 5/2.5 mg | Change From Baseline in Flare-Up Pain and Swelling at Weeks 2, 4, 6, 9 and 12 | Flare-up pain: Week 4 | -1.3 units on a scale | Standard Deviation 1.58 |
| Palovarotene 5/2.5 mg | Change From Baseline in Flare-Up Pain and Swelling at Weeks 2, 4, 6, 9 and 12 | Flare-up swelling: Week 12 | -2.5 units on a scale | Standard Deviation 2.2 |
| Palovarotene 5/2.5 mg | Change From Baseline in Flare-Up Pain and Swelling at Weeks 2, 4, 6, 9 and 12 | Flare-up swelling: Week 6 | -2.0 units on a scale | Standard Deviation 2.45 |
| Palovarotene 5/2.5 mg | Change From Baseline in Flare-Up Pain and Swelling at Weeks 2, 4, 6, 9 and 12 | Flare-up pain: Week 6 | -1.3 units on a scale | Standard Deviation 1.58 |
| Palovarotene 5/2.5 mg | Change From Baseline in Flare-Up Pain and Swelling at Weeks 2, 4, 6, 9 and 12 | Flare-up swelling: Week 4 | -1.9 units on a scale | Standard Deviation 1.81 |
| Palovarotene 5/2.5 mg | Change From Baseline in Flare-Up Pain and Swelling at Weeks 2, 4, 6, 9 and 12 | Flare-up pain: Week 9 | -1.1 units on a scale | Standard Deviation 1.64 |
| Placebo | Change From Baseline in Flare-Up Pain and Swelling at Weeks 2, 4, 6, 9 and 12 | Flare-up swelling: Week 6 | -2.6 units on a scale | Standard Deviation 3.5 |
| Placebo | Change From Baseline in Flare-Up Pain and Swelling at Weeks 2, 4, 6, 9 and 12 | Flare-up pain: Week 9 | -2.1 units on a scale | Standard Deviation 1.85 |
| Placebo | Change From Baseline in Flare-Up Pain and Swelling at Weeks 2, 4, 6, 9 and 12 | Flare-up pain: Week 12 | -2.2 units on a scale | Standard Deviation 2.53 |
| Placebo | Change From Baseline in Flare-Up Pain and Swelling at Weeks 2, 4, 6, 9 and 12 | Flare-up swelling: Week 2 | -2.3 units on a scale | Standard Deviation 2.79 |
| Placebo | Change From Baseline in Flare-Up Pain and Swelling at Weeks 2, 4, 6, 9 and 12 | Flare-up swelling: Week 9 | -1.9 units on a scale | Standard Deviation 4.41 |
| Placebo | Change From Baseline in Flare-Up Pain and Swelling at Weeks 2, 4, 6, 9 and 12 | Flare-up swelling: Week 4 | -2.0 units on a scale | Standard Deviation 3.3 |
| Placebo | Change From Baseline in Flare-Up Pain and Swelling at Weeks 2, 4, 6, 9 and 12 | Flare-up pain: Week 2 | -2.0 units on a scale | Standard Deviation 1.76 |
| Placebo | Change From Baseline in Flare-Up Pain and Swelling at Weeks 2, 4, 6, 9 and 12 | Flare-up swelling: Week 12 | -2.3 units on a scale | Standard Deviation 3.16 |
| Placebo | Change From Baseline in Flare-Up Pain and Swelling at Weeks 2, 4, 6, 9 and 12 | Flare-up pain: Week 4 | -1.9 units on a scale | Standard Deviation 3.14 |
| Placebo | Change From Baseline in Flare-Up Pain and Swelling at Weeks 2, 4, 6, 9 and 12 | Flare-up pain: Week 6 | -2.4 units on a scale | Standard Deviation 2.91 |
Secondary
Change From Baseline in Percentage of Worst Total Score for FOP-Specific Physical Function Questionnaire (FOP-PFQ) at Weeks 2, 4, 6, 9 and 12
The FOP-PFQ consists of 28 questions rated on scales from 1 to 5, with lower scores denoting more difficulty. The adult form of the FOP-PFQ was administered to subjects 15 years of age and older. There are two Pediatric FOP-PFQ (FOP-PFQ-P) forms: a self-completed form for 8 to 14 year-olds and a parent proxy-completed form for 5 to 14 year-olds. For subjects between 8 to 14 years of age, both the self-completed (for 8 to 14 year-olds) and the proxy-completed (for 5 to 14 year olds) forms of the FOP-PFQ-P were administered. However, only the proxy-completed form was used for analysis. Percentage of worst scores ranges from 0% to 100% with 0% = best possible function and 100% = worst possible function. Change from baseline for each time point is presented.
Time frame: Baseline, Weeks 2, 4, 6, 9 and 12
Population: The FAS population included all subjects who received at least 1 dose of study drug and had at least 1 evaluable post-baseline radiograph or CT sufficient to allow determination of HO at the flare-up site.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Palovarotene 10/5 mg | Change From Baseline in Percentage of Worst Total Score for FOP-Specific Physical Function Questionnaire (FOP-PFQ) at Weeks 2, 4, 6, 9 and 12 | Week 9 | 1.89 units on a scale | Standard Deviation 5.432 |
| Palovarotene 10/5 mg | Change From Baseline in Percentage of Worst Total Score for FOP-Specific Physical Function Questionnaire (FOP-PFQ) at Weeks 2, 4, 6, 9 and 12 | Week 12 | 4.22 units on a scale | Standard Deviation 7.915 |
| Palovarotene 10/5 mg | Change From Baseline in Percentage of Worst Total Score for FOP-Specific Physical Function Questionnaire (FOP-PFQ) at Weeks 2, 4, 6, 9 and 12 | Week 4 | 3.42 units on a scale | Standard Deviation 7.932 |
| Palovarotene 10/5 mg | Change From Baseline in Percentage of Worst Total Score for FOP-Specific Physical Function Questionnaire (FOP-PFQ) at Weeks 2, 4, 6, 9 and 12 | Week 6 | 3.79 units on a scale | Standard Deviation 7.787 |
| Palovarotene 10/5 mg | Change From Baseline in Percentage of Worst Total Score for FOP-Specific Physical Function Questionnaire (FOP-PFQ) at Weeks 2, 4, 6, 9 and 12 | Week 2 | 0.95 units on a scale | Standard Deviation 5.484 |
| Palovarotene 5/2.5 mg | Change From Baseline in Percentage of Worst Total Score for FOP-Specific Physical Function Questionnaire (FOP-PFQ) at Weeks 2, 4, 6, 9 and 12 | Week 4 | 2.67 units on a scale | Standard Deviation 7.2 |
| Palovarotene 5/2.5 mg | Change From Baseline in Percentage of Worst Total Score for FOP-Specific Physical Function Questionnaire (FOP-PFQ) at Weeks 2, 4, 6, 9 and 12 | Week 9 | -0.52 units on a scale | Standard Deviation 7.881 |
| Palovarotene 5/2.5 mg | Change From Baseline in Percentage of Worst Total Score for FOP-Specific Physical Function Questionnaire (FOP-PFQ) at Weeks 2, 4, 6, 9 and 12 | Week 2 | 0.31 units on a scale | Standard Deviation 3.818 |
| Palovarotene 5/2.5 mg | Change From Baseline in Percentage of Worst Total Score for FOP-Specific Physical Function Questionnaire (FOP-PFQ) at Weeks 2, 4, 6, 9 and 12 | Week 12 | 1.08 units on a scale | Standard Deviation 8.724 |
| Palovarotene 5/2.5 mg | Change From Baseline in Percentage of Worst Total Score for FOP-Specific Physical Function Questionnaire (FOP-PFQ) at Weeks 2, 4, 6, 9 and 12 | Week 6 | 2.88 units on a scale | Standard Deviation 7.55 |
| Placebo | Change From Baseline in Percentage of Worst Total Score for FOP-Specific Physical Function Questionnaire (FOP-PFQ) at Weeks 2, 4, 6, 9 and 12 | Week 12 | 3.02 units on a scale | Standard Deviation 9.587 |
| Placebo | Change From Baseline in Percentage of Worst Total Score for FOP-Specific Physical Function Questionnaire (FOP-PFQ) at Weeks 2, 4, 6, 9 and 12 | Week 2 | 2.11 units on a scale | Standard Deviation 6.659 |
| Placebo | Change From Baseline in Percentage of Worst Total Score for FOP-Specific Physical Function Questionnaire (FOP-PFQ) at Weeks 2, 4, 6, 9 and 12 | Week 4 | 2.91 units on a scale | Standard Deviation 8.427 |
| Placebo | Change From Baseline in Percentage of Worst Total Score for FOP-Specific Physical Function Questionnaire (FOP-PFQ) at Weeks 2, 4, 6, 9 and 12 | Week 6 | 1.75 units on a scale | Standard Deviation 5.98 |
| Placebo | Change From Baseline in Percentage of Worst Total Score for FOP-Specific Physical Function Questionnaire (FOP-PFQ) at Weeks 2, 4, 6, 9 and 12 | Week 9 | 4.91 units on a scale | Standard Deviation 13.185 |
Secondary
Change From Baseline in Percent of Normal Arc of Motion at the Primary Joint (Flare-up Site) at Weeks 6 and 12
Active range of motion, expressed as the percent of normal arc of motion, measurements at the primary joint associated with the flare-up and adjoining joints was assessed by goniometer.
Time frame: Baseline, Weeks 6 and 12
Population: The FAS population included all subjects who received at least 1 dose of study drug and had at least 1 evaluable post-baseline radiograph or CT sufficient to allow determination of HO at the flare-up site.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Palovarotene 10/5 mg | Change From Baseline in Percent of Normal Arc of Motion at the Primary Joint (Flare-up Site) at Weeks 6 and 12 | Week 6 | -0.40 percent of normal arc of motion | Standard Deviation 9.574 |
| Palovarotene 10/5 mg | Change From Baseline in Percent of Normal Arc of Motion at the Primary Joint (Flare-up Site) at Weeks 6 and 12 | Week 12 | 0.58 percent of normal arc of motion | Standard Deviation 15.079 |
| Palovarotene 5/2.5 mg | Change From Baseline in Percent of Normal Arc of Motion at the Primary Joint (Flare-up Site) at Weeks 6 and 12 | Week 6 | -1.36 percent of normal arc of motion | Standard Deviation 21.336 |
| Palovarotene 5/2.5 mg | Change From Baseline in Percent of Normal Arc of Motion at the Primary Joint (Flare-up Site) at Weeks 6 and 12 | Week 12 | -4.23 percent of normal arc of motion | Standard Deviation 26.791 |
| Placebo | Change From Baseline in Percent of Normal Arc of Motion at the Primary Joint (Flare-up Site) at Weeks 6 and 12 | Week 12 | -2.31 percent of normal arc of motion | Standard Deviation 18.963 |
| Placebo | Change From Baseline in Percent of Normal Arc of Motion at the Primary Joint (Flare-up Site) at Weeks 6 and 12 | Week 6 | -0.99 percent of normal arc of motion | Standard Deviation 18.951 |
Secondary
Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12
The PROMIS Global Health contains 10 questions which are rated on scales from 1 to 5 or 0 to 10. Global physical health scores were calculated as the sum of scores from parameters 3, 6, 7, and 8 and ranges from 4 to 20 where, 4 = worse health and 20 = better health. Global mental health scores were calculated as the sum of scores from parameters 2, 4, 5, and 10 and ranges from 4 to 20 where, 4 = worse health and 20 = better health. For paediatric subjects, the PROMIS was administered as per the adult version. However, there is a single total score for the paediatric PROMIS (as opposed to global physical and global mental health scores as are in the adult version). The total score were converted to a T-score. A T-score of 50 is normal and increments of 10 are +/- 1 standard deviation away from the norm. A T-score \<50 indicates worse health, while a T-score \>50 indicates better health. The higher values (positive changes) indicate better health.
Time frame: Baseline, Weeks 2, 4, 6, 9 and 12
Population: The FAS population included all subjects who received at least 1 dose of study drug and had at least 1 evaluable post-baseline radiograph or CT sufficient to allow determination of HO at the flare-up site.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Palovarotene 10/5 mg | Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12 | Adult-only: Global Mental Health T-Score: Week 2 | 3.66 t-score | Standard Deviation 5.216 |
| Palovarotene 10/5 mg | Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12 | Adult-only: Global Physical Health T-Score: Week 6 | 4.69 t-score | Standard Deviation 5.585 |
| Palovarotene 10/5 mg | Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12 | Paediatric-only: Global Health T-Score: Week 2 | -2.27 t-score | Standard Deviation 4.278 |
| Palovarotene 10/5 mg | Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12 | Adult-only: Global Mental Health T-Score: Week 4 | 3.32 t-score | Standard Deviation 5.066 |
| Palovarotene 10/5 mg | Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12 | Adult-only: Global Physical Health T-Score: Week 4 | 4.66 t-score | Standard Deviation 6.59 |
| Palovarotene 10/5 mg | Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12 | Adult-only: Global Mental Health T-Score: Week 12 | 4.33 t-score | Standard Deviation 7.527 |
| Palovarotene 10/5 mg | Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12 | Adult-only: Global Mental Health T-Score: Week 6 | 4.15 t-score | Standard Deviation 6.878 |
| Palovarotene 10/5 mg | Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12 | Paediatric-only: Global Health T-Score: Week 6 | -2.23 t-score | Standard Deviation 3.499 |
| Palovarotene 10/5 mg | Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12 | Adult-only: Global Mental Health T-Score: Week 9 | 4.62 t-score | Standard Deviation 7.684 |
| Palovarotene 10/5 mg | Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12 | Adult-only: Global Physical Health T-Score: Week 9 | 4.96 t-score | Standard Deviation 5.489 |
| Palovarotene 10/5 mg | Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12 | Paediatric-only: Global Health T-Score: Week 12 | 0.17 t-score | Standard Deviation 7.572 |
| Palovarotene 10/5 mg | Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12 | Adult-only: Global Physical Health T-Score: Week 2 | 2.76 t-score | Standard Deviation 5.308 |
| Palovarotene 10/5 mg | Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12 | Adult-only:Global Physical Health T-Score: Week 12 | 3.97 t-score | Standard Deviation 6.764 |
| Palovarotene 10/5 mg | Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12 | Paediatric-only: Global Health T-Score: Week 9 | 1.17 t-score | Standard Deviation 2.021 |
| Palovarotene 10/5 mg | Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12 | Paediatric-only: Global Health T-Score: Week 4 | -0.57 t-score | Standard Deviation 2.499 |
| Palovarotene 5/2.5 mg | Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12 | Paediatric-only: Global Health T-Score: Week 4 | 1.43 t-score | Standard Deviation 6.352 |
| Palovarotene 5/2.5 mg | Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12 | Adult-only: Global Physical Health T-Score: Week 2 | 0.00 t-score | Standard Deviation 1.768 |
| Palovarotene 5/2.5 mg | Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12 | Adult-only: Global Physical Health T-Score: Week 4 | 2.66 t-score | Standard Deviation 4.345 |
| Palovarotene 5/2.5 mg | Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12 | Adult-only: Global Physical Health T-Score: Week 6 | 7.08 t-score | Standard Deviation 6.591 |
| Palovarotene 5/2.5 mg | Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12 | Adult-only: Global Physical Health T-Score: Week 9 | 5.58 t-score | Standard Deviation 3.381 |
| Palovarotene 5/2.5 mg | Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12 | Adult-only:Global Physical Health T-Score: Week 12 | 4.98 t-score | Standard Deviation 6.246 |
| Palovarotene 5/2.5 mg | Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12 | Adult-only: Global Mental Health T-Score: Week 2 | 3.20 t-score | Standard Deviation 2.024 |
| Palovarotene 5/2.5 mg | Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12 | Adult-only: Global Mental Health T-Score: Week 4 | 2.28 t-score | Standard Deviation 2.7 |
| Palovarotene 5/2.5 mg | Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12 | Adult-only: Global Mental Health T-Score: Week 6 | 2.54 t-score | Standard Deviation 4.98 |
| Palovarotene 5/2.5 mg | Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12 | Adult-only: Global Mental Health T-Score: Week 9 | 1.68 t-score | Standard Deviation 3.641 |
| Palovarotene 5/2.5 mg | Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12 | Adult-only: Global Mental Health T-Score: Week 12 | 3.10 t-score | Standard Deviation 4.127 |
| Palovarotene 5/2.5 mg | Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12 | Paediatric-only: Global Health T-Score: Week 2 | 1.05 t-score | Standard Deviation 2.352 |
| Palovarotene 5/2.5 mg | Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12 | Paediatric-only: Global Health T-Score: Week 6 | 2.80 t-score | Standard Deviation 4.955 |
| Palovarotene 5/2.5 mg | Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12 | Paediatric-only: Global Health T-Score: Week 9 | 1.83 t-score | Standard Deviation 1.434 |
| Palovarotene 5/2.5 mg | Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12 | Paediatric-only: Global Health T-Score: Week 12 | -2.13 t-score | Standard Deviation 2.964 |
| Placebo | Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12 | Adult-only: Global Mental Health T-Score: Week 2 | 1.98 t-score | Standard Deviation 3.124 |
| Placebo | Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12 | Paediatric-only: Global Health T-Score: Week 9 | -3.50 t-score | Standard Deviation 4.668 |
| Placebo | Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12 | Paediatric-only: Global Health T-Score: Week 2 | -1.80 t-score | Standard Deviation 4.668 |
| Placebo | Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12 | Adult-only:Global Physical Health T-Score: Week 12 | 3.78 t-score | Standard Deviation 3.883 |
| Placebo | Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12 | Adult-only: Global Physical Health T-Score: Week 9 | 4.94 t-score | Standard Deviation 3.135 |
| Placebo | Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12 | Paediatric-only: Global Health T-Score: Week 4 | -6.40 t-score | Standard Deviation 4.314 |
| Placebo | Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12 | Adult-only: Global Physical Health T-Score: Week 6 | 5.73 t-score | Standard Deviation 2.75 |
| Placebo | Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12 | Adult-only: Global Physical Health T-Score: Week 2 | 5.90 t-score | Standard Deviation 2.087 |
| Placebo | Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12 | Paediatric-only: Global Health T-Score: Week 6 | -3.30 t-score | Standard Deviation 7.826 |
| Placebo | Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12 | Adult-only: Global Mental Health T-Score: Week 6 | 4.34 t-score | Standard Deviation 5.85 |
| Placebo | Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12 | Adult-only: Global Physical Health T-Score: Week 4 | 5.56 t-score | Standard Deviation 2.904 |
| Placebo | Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12 | Adult-only: Global Mental Health T-Score: Week 9 | 5.38 t-score | Standard Deviation 5.438 |
| Placebo | Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12 | Adult-only: Global Mental Health T-Score: Week 4 | 7.30 t-score | Standard Deviation 5.609 |
| Placebo | Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12 | Paediatric-only: Global Health T-Score: Week 12 | -6.57 t-score | Standard Deviation 1.95 |
| Placebo | Change From Baseline in Physical and Mental Health Using Age-Appropriate Forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Weeks 2, 4, 6, 9 and 12 | Adult-only: Global Mental Health T-Score: Week 12 | 1.04 t-score | Standard Deviation 3.664 |
Secondary
Change From Baseline in Procollagen Type 1 C-Terminal Propeptide Biomarker at Weeks 2, 4, 6 and 12
Blood and urine samples for analysis of cartilage, bone, angiogenesis, and inflammation biomarkers were collected. Procollagen type 1 C-terminal propeptide was analysed as a bone and cartilage biomarker.
Time frame: Baseline, Weeks 2, 4, 6 and 12
Population: The FAS population included all subjects who received at least 1 dose of study drug and had at least 1 evaluable post-baseline radiograph or CT sufficient to allow determination of HO at the flare-up site.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Palovarotene 10/5 mg | Change From Baseline in Procollagen Type 1 C-Terminal Propeptide Biomarker at Weeks 2, 4, 6 and 12 | Week 2 | 22.12 mcg/L | Standard Deviation 61.976 |
| Palovarotene 10/5 mg | Change From Baseline in Procollagen Type 1 C-Terminal Propeptide Biomarker at Weeks 2, 4, 6 and 12 | Week 4 | 72.16 mcg/L | Standard Deviation 98.697 |
| Palovarotene 10/5 mg | Change From Baseline in Procollagen Type 1 C-Terminal Propeptide Biomarker at Weeks 2, 4, 6 and 12 | Week 6 | 73.36 mcg/L | Standard Deviation 130.437 |
| Palovarotene 10/5 mg | Change From Baseline in Procollagen Type 1 C-Terminal Propeptide Biomarker at Weeks 2, 4, 6 and 12 | Week 12 | 51.21 mcg/L | Standard Deviation 82.901 |
| Palovarotene 5/2.5 mg | Change From Baseline in Procollagen Type 1 C-Terminal Propeptide Biomarker at Weeks 2, 4, 6 and 12 | Week 12 | 47.30 mcg/L | Standard Deviation 112.113 |
| Palovarotene 5/2.5 mg | Change From Baseline in Procollagen Type 1 C-Terminal Propeptide Biomarker at Weeks 2, 4, 6 and 12 | Week 2 | 23.26 mcg/L | Standard Deviation 11.585 |
| Palovarotene 5/2.5 mg | Change From Baseline in Procollagen Type 1 C-Terminal Propeptide Biomarker at Weeks 2, 4, 6 and 12 | Week 6 | 87.19 mcg/L | Standard Deviation 96.451 |
| Palovarotene 5/2.5 mg | Change From Baseline in Procollagen Type 1 C-Terminal Propeptide Biomarker at Weeks 2, 4, 6 and 12 | Week 4 | 76.10 mcg/L | Standard Deviation 110.041 |
| Placebo | Change From Baseline in Procollagen Type 1 C-Terminal Propeptide Biomarker at Weeks 2, 4, 6 and 12 | Week 12 | 96.49 mcg/L | Standard Deviation 92.215 |
| Placebo | Change From Baseline in Procollagen Type 1 C-Terminal Propeptide Biomarker at Weeks 2, 4, 6 and 12 | Week 4 | 140.26 mcg/L | Standard Deviation 155.036 |
| Placebo | Change From Baseline in Procollagen Type 1 C-Terminal Propeptide Biomarker at Weeks 2, 4, 6 and 12 | Week 6 | 125.31 mcg/L | Standard Deviation 110.389 |
| Placebo | Change From Baseline in Procollagen Type 1 C-Terminal Propeptide Biomarker at Weeks 2, 4, 6 and 12 | Week 2 | 82.93 mcg/L | Standard Deviation 109.01 |
Secondary
Change From Baseline in Procollagen Type 1 N-Terminal Propeptide at Weeks 2, 4, 6 and 12
Blood and urine samples for analysis of cartilage, bone, angiogenesis, and inflammation biomarkers were collected. Procollagen type 1 N-terminal propeptide was analysed as a bone and cartilage biomarker.
Time frame: Baseline, Weeks 2, 4, 6 and 12
Population: The FAS population included all subjects who received at least 1 dose of study drug and had at least 1 evaluable post-baseline radiograph or CT sufficient to allow determination of HO at the flare-up site.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Palovarotene 10/5 mg | Change From Baseline in Procollagen Type 1 N-Terminal Propeptide at Weeks 2, 4, 6 and 12 | Week 2 | 53.022 mcg/L | Standard Deviation 72.091 |
| Palovarotene 10/5 mg | Change From Baseline in Procollagen Type 1 N-Terminal Propeptide at Weeks 2, 4, 6 and 12 | Week 4 | 123.986 mcg/L | Standard Deviation 207.513 |
| Palovarotene 10/5 mg | Change From Baseline in Procollagen Type 1 N-Terminal Propeptide at Weeks 2, 4, 6 and 12 | Week 6 | 141.304 mcg/L | Standard Deviation 206.163 |
| Palovarotene 10/5 mg | Change From Baseline in Procollagen Type 1 N-Terminal Propeptide at Weeks 2, 4, 6 and 12 | Week 12 | 120.489 mcg/L | Standard Deviation 211.565 |
| Palovarotene 5/2.5 mg | Change From Baseline in Procollagen Type 1 N-Terminal Propeptide at Weeks 2, 4, 6 and 12 | Week 12 | 25.766 mcg/L | Standard Deviation 233.86 |
| Palovarotene 5/2.5 mg | Change From Baseline in Procollagen Type 1 N-Terminal Propeptide at Weeks 2, 4, 6 and 12 | Week 2 | 78.930 mcg/L | Standard Deviation 113.443 |
| Palovarotene 5/2.5 mg | Change From Baseline in Procollagen Type 1 N-Terminal Propeptide at Weeks 2, 4, 6 and 12 | Week 6 | 147.409 mcg/L | Standard Deviation 246.219 |
| Palovarotene 5/2.5 mg | Change From Baseline in Procollagen Type 1 N-Terminal Propeptide at Weeks 2, 4, 6 and 12 | Week 4 | 117.476 mcg/L | Standard Deviation 169.238 |
| Placebo | Change From Baseline in Procollagen Type 1 N-Terminal Propeptide at Weeks 2, 4, 6 and 12 | Week 12 | 141.367 mcg/L | Standard Deviation 213.926 |
| Placebo | Change From Baseline in Procollagen Type 1 N-Terminal Propeptide at Weeks 2, 4, 6 and 12 | Week 4 | 194.193 mcg/L | Standard Deviation 318.92 |
| Placebo | Change From Baseline in Procollagen Type 1 N-Terminal Propeptide at Weeks 2, 4, 6 and 12 | Week 6 | 252.328 mcg/L | Standard Deviation 389.359 |
| Placebo | Change From Baseline in Procollagen Type 1 N-Terminal Propeptide at Weeks 2, 4, 6 and 12 | Week 2 | 42.058 mcg/L | Standard Deviation 77.358 |
Secondary
Duration of Active Symptomatic Flare-up
The duration of active symptomatic flare-up was defined as the number of days the subject reported the presence of symptoms in the diary ('Is your flare-up ongoing today?') from Day 1 to study completion at Day 84. The mean number of days of active, symptomatic flare-up is presented for subjects with evaluable diary data.
Time frame: From Day 1 to Day 84
Population: The PP population included all subjects who were eligible for the FAS population, completed Week 6 study visit with no major protocol deviations with at least 80% compliance with study drug, and had an evaluable radiograph or CT at Week 6 sufficient to allow determination of HO at flare-up site.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Palovarotene 10/5 mg | Duration of Active Symptomatic Flare-up | 22.1 days | Standard Deviation 20.53 |
| Palovarotene 5/2.5 mg | Duration of Active Symptomatic Flare-up | 44.1 days | Standard Deviation 38.36 |
| Placebo | Duration of Active Symptomatic Flare-up | 34.4 days | Standard Deviation 34.15 |
Secondary
Maximum Measured Plasma Concentration (Cmax) of Palovarotene
The Cmax of palovarotene was determined.
Time frame: Pre-dose and 3, 6, 10, and 24 hours (hrs) post-dose at Week 2, and at Week 4 or 6
Population: The Pharmacokinetic (PK) population included all subjects who had sufficient blood samples collected for valid estimation of PK parameters.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Palovarotene 10/5 mg | Maximum Measured Plasma Concentration (Cmax) of Palovarotene | Week 2 | 95620.00 picograms per milliliter (pg/mL) | Standard Deviation 30296.77 |
| Palovarotene 10/5 mg | Maximum Measured Plasma Concentration (Cmax) of Palovarotene | Week 4/Week 6 | 45505.88 picograms per milliliter (pg/mL) | Standard Deviation 17061.05 |
| Palovarotene 5/2.5 mg | Maximum Measured Plasma Concentration (Cmax) of Palovarotene | Week 2 | 35620.00 picograms per milliliter (pg/mL) | Standard Deviation 19882.08 |
| Palovarotene 5/2.5 mg | Maximum Measured Plasma Concentration (Cmax) of Palovarotene | Week 4/Week 6 | 18958.57 picograms per milliliter (pg/mL) | Standard Deviation 9238.62 |
Secondary
Minimum Measured Plasma Concentration (Cmin) of Palovarotene
The Cmin of palovarotene was determined.
Time frame: Pre-dose and 3, 6, 10, and 24 hrs post-dose at Week 2, and at Week 4 or 6
Population: The PK population included all subjects who had sufficient blood samples collected for valid estimation of PK parameters.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Palovarotene 10/5 mg | Minimum Measured Plasma Concentration (Cmin) of Palovarotene | Week 2 | 3128.53 pg/mL | Standard Deviation 2358.88 |
| Palovarotene 10/5 mg | Minimum Measured Plasma Concentration (Cmin) of Palovarotene | Week 4/Week 6 | 3879.00 pg/mL | Standard Deviation 7042.29 |
| Palovarotene 5/2.5 mg | Minimum Measured Plasma Concentration (Cmin) of Palovarotene | Week 2 | 1739.40 pg/mL | Standard Deviation 963.68 |
| Palovarotene 5/2.5 mg | Minimum Measured Plasma Concentration (Cmin) of Palovarotene | Week 4/Week 6 | 614.14 pg/mL | Standard Deviation 289.72 |
Secondary
Percentage of Responders at Week 12
A responder was defined as a subject with no or minimal new HO at the flare-up site versus baseline as assessed by plain radiographs at Week 12. Minimal new HO is defined as new HO with an HO score \<=3 in both the AP and lateral projections (or if one view is non-interpretable or non-evaluable, then the remaining evaluable view is used). The HO score ranges from 0 to 6 where, 0 = no HO and 6 = single contiguous HO with longest dimension \>2 diameters of the reference normotopic bone in any projection. The highest HO score from the 2 projections was used. Results from the Primary Read reviews are presented. The Primary Read process included a double-read radiology review paradigm with consensus adjudication. Radiography and CT scans were examined independently by scan type, flare-up region, and imaging time point in order to determine whether radiography would be sufficient to measure new HO formation.
Time frame: Baseline and Week 12
Population: The PP population included all subjects who were eligible for FAS population, completed Week 6 study visit with no major protocol deviations with at least 80% compliance with study drug, and had an evaluable radiograph or CT at Week 6 sufficient to allow determination of HO at flare-up site. Only subjects with interpretable outcomes were evaluated.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Palovarotene 10/5 mg | Percentage of Responders at Week 12 | 95.0 percentage of subjects |
| Palovarotene 5/2.5 mg | Percentage of Responders at Week 12 | 88.9 percentage of subjects |
| Placebo | Percentage of Responders at Week 12 | 77.8 percentage of subjects |
Comparison: Cochran-Armitage test of trend (one-sided). The Cochran-Armitage test of trend assessed the overall trend of response across the dose groups (from the lowest dose \[or placebo\], to the highest dose).p-value: 0.1503Cochran-Armitage test of trend
Secondary
Percentage of Subjects Who Used Any Assistive Devices and Adaptations for Daily Living at Weeks 6 and 12
Subjects were given a list of FOP assistive devices and adaptations and asked to select those they use for daily living. The FOP assistive devices and adaptations included mobility aids, care attendants, eating tools, personal care tools/aids, bathroom aids and devices, bedroom aids and devices, home adaptations, work environment adaptations, technology adaptations, sports and recreation adaptations, school, and medical therapies for daily living.
Time frame: Weeks 6 and 12
Population: The FAS population included all subjects who received at least 1 dose of study drug and had at least 1 evaluable post-baseline radiograph or CT sufficient to allow determination of HO at the flare-up site.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Palovarotene 10/5 mg | Percentage of Subjects Who Used Any Assistive Devices and Adaptations for Daily Living at Weeks 6 and 12 | Week 12 | 90.5 percentage of subjects |
| Palovarotene 10/5 mg | Percentage of Subjects Who Used Any Assistive Devices and Adaptations for Daily Living at Weeks 6 and 12 | Week 6 | 85.0 percentage of subjects |
| Palovarotene 5/2.5 mg | Percentage of Subjects Who Used Any Assistive Devices and Adaptations for Daily Living at Weeks 6 and 12 | Week 6 | 100.0 percentage of subjects |
| Palovarotene 5/2.5 mg | Percentage of Subjects Who Used Any Assistive Devices and Adaptations for Daily Living at Weeks 6 and 12 | Week 12 | 100.0 percentage of subjects |
| Placebo | Percentage of Subjects Who Used Any Assistive Devices and Adaptations for Daily Living at Weeks 6 and 12 | Week 6 | 100.0 percentage of subjects |
| Placebo | Percentage of Subjects Who Used Any Assistive Devices and Adaptations for Daily Living at Weeks 6 and 12 | Week 12 | 100.0 percentage of subjects |
Secondary
Percentage of Subjects With New HO at Weeks 6 and 12
Low dose CT scan was used as a secondary imaging assessment of HO and was performed at the same time points as plain radiographs. The percentage of subjects with new HO (regardless of the amount of new HO) at the flare-up site as assessed by CT scan and/or plain radiographs at Weeks 6 and 12 were analysed. The results are from Global Read reviews. The holistic Global Read process allowed concurrent review of all modalities across all time points, and provided access to selected clinical data at the time of review.
Time frame: Weeks 6 and 12 (Day 84)
Population: The PP population included all subjects who were eligible for the FAS population, completed Week 6 study visit with no major protocol deviations with at least 80% compliance with study drug, and had an evaluable radiograph or CT at Week 6 sufficient to allow determination of HO at flare-up site.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Palovarotene 10/5 mg | Percentage of Subjects With New HO at Weeks 6 and 12 | Week 6 | 15.0 percentage of subjects |
| Palovarotene 10/5 mg | Percentage of Subjects With New HO at Weeks 6 and 12 | Week 12 | 15.0 percentage of subjects |
| Palovarotene 5/2.5 mg | Percentage of Subjects With New HO at Weeks 6 and 12 | Week 6 | 22.2 percentage of subjects |
| Palovarotene 5/2.5 mg | Percentage of Subjects With New HO at Weeks 6 and 12 | Week 12 | 44.4 percentage of subjects |
| Placebo | Percentage of Subjects With New HO at Weeks 6 and 12 | Week 6 | 30.0 percentage of subjects |
| Placebo | Percentage of Subjects With New HO at Weeks 6 and 12 | Week 12 | 40.0 percentage of subjects |
Comparison: Week 6: Cochran-Armitage test of trend (one-sided). The Cochran-Armitage test of trend assessed the overall trend of response across the dose groups (from the lowest dose \[or placebo\], to the highest dose).p-value: 0.2335Cochran-Armitage test of trend
Comparison: Week 12: Cochran-Armitage test of trend (one-sided). The Cochran-Armitage test of trend assessed the overall trend of response across the dose groups (from the lowest dose \[or placebo\], to the highest dose).p-value: 0.0837Cochran-Armitage test of trend
Secondary
Percentage of Subjects With Soft Tissue Swelling and Cartilage Formation Assessed by Magnetic Resonance Imaging (MRI) or Ultrasound (US) at Weeks 6 and 12
The MRI was utilized to evaluate the presence of soft tissue swelling/edema (and volume of the swelling/edema) and presence of cartilage formation (yes or no). For subjects who could not have an MRI, US was used to assess edema severity for the sub-set of subjects enrolled after this opinion was introduced in a protocol amendment. Imaging film from MRI was assessed by two independent readers. When there was sufficient agreement between the independent readers on volume, both of the independent readings were used for analysis with the volume measurements averaged. When there was insufficient agreement between the independent readers, an adjudication reading was provided and used for analysis. The US was used for soft tissue swelling/edema but not cartilage formation. Percentage calculated as % = 100 x n/N' where N' is the number of subjects with interpretable outcomes. Results from Primary Read reviews are presented.
Time frame: Weeks 6 and 12
Population: The FAS population included all subjects who received at least 1 dose of study drug and had at least 1 evaluable post-baseline radiograph or CT sufficient to allow determination of HO at the flare-up site.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Palovarotene 10/5 mg | Percentage of Subjects With Soft Tissue Swelling and Cartilage Formation Assessed by Magnetic Resonance Imaging (MRI) or Ultrasound (US) at Weeks 6 and 12 | Soft tissue swelling: Week 6 | 50.0 percentage of subjects |
| Palovarotene 10/5 mg | Percentage of Subjects With Soft Tissue Swelling and Cartilage Formation Assessed by Magnetic Resonance Imaging (MRI) or Ultrasound (US) at Weeks 6 and 12 | Soft tissue swelling: Week 12 | 60.0 percentage of subjects |
| Palovarotene 10/5 mg | Percentage of Subjects With Soft Tissue Swelling and Cartilage Formation Assessed by Magnetic Resonance Imaging (MRI) or Ultrasound (US) at Weeks 6 and 12 | Cartilage formation: Week 6 | 15.4 percentage of subjects |
| Palovarotene 10/5 mg | Percentage of Subjects With Soft Tissue Swelling and Cartilage Formation Assessed by Magnetic Resonance Imaging (MRI) or Ultrasound (US) at Weeks 6 and 12 | Cartilage formation: Week 12 | 8.3 percentage of subjects |
| Palovarotene 5/2.5 mg | Percentage of Subjects With Soft Tissue Swelling and Cartilage Formation Assessed by Magnetic Resonance Imaging (MRI) or Ultrasound (US) at Weeks 6 and 12 | Cartilage formation: Week 12 | 0.0 percentage of subjects |
| Palovarotene 5/2.5 mg | Percentage of Subjects With Soft Tissue Swelling and Cartilage Formation Assessed by Magnetic Resonance Imaging (MRI) or Ultrasound (US) at Weeks 6 and 12 | Soft tissue swelling: Week 6 | 50.0 percentage of subjects |
| Palovarotene 5/2.5 mg | Percentage of Subjects With Soft Tissue Swelling and Cartilage Formation Assessed by Magnetic Resonance Imaging (MRI) or Ultrasound (US) at Weeks 6 and 12 | Cartilage formation: Week 6 | 0.0 percentage of subjects |
| Palovarotene 5/2.5 mg | Percentage of Subjects With Soft Tissue Swelling and Cartilage Formation Assessed by Magnetic Resonance Imaging (MRI) or Ultrasound (US) at Weeks 6 and 12 | Soft tissue swelling: Week 12 | 66.7 percentage of subjects |
| Placebo | Percentage of Subjects With Soft Tissue Swelling and Cartilage Formation Assessed by Magnetic Resonance Imaging (MRI) or Ultrasound (US) at Weeks 6 and 12 | Cartilage formation: Week 12 | 0.0 percentage of subjects |
| Placebo | Percentage of Subjects With Soft Tissue Swelling and Cartilage Formation Assessed by Magnetic Resonance Imaging (MRI) or Ultrasound (US) at Weeks 6 and 12 | Soft tissue swelling: Week 12 | 66.7 percentage of subjects |
| Placebo | Percentage of Subjects With Soft Tissue Swelling and Cartilage Formation Assessed by Magnetic Resonance Imaging (MRI) or Ultrasound (US) at Weeks 6 and 12 | Cartilage formation: Week 6 | 0.0 percentage of subjects |
| Placebo | Percentage of Subjects With Soft Tissue Swelling and Cartilage Formation Assessed by Magnetic Resonance Imaging (MRI) or Ultrasound (US) at Weeks 6 and 12 | Soft tissue swelling: Week 6 | 66.7 percentage of subjects |
Secondary
Subject and Investigator Global Assessment of Movement at Weeks 6 and 12
Flare-up movement outcomes were independently assessed by both the subject (or parent of a subject under 8 years of age) and the Investigator at Weeks 6 and 12 by completing the global assessment of movement. The subject/parent completed the global assessment first. Prior to reviewing the subject's assessment, the Investigator completed his/her own assessment of the flare-up outcome. Subjects were assessed how the flare-up affected their movement on a scale ranging 1 to 5 where, 1 = severely worse movement and 5 = better movement compared with study Day 1 (day of first dose of study drug). Investigators were assessed how the flare-up affected the subject's movement on a scale ranging 1 to 5 where, 1 = severely worse movement and 5 = better movement compared with baseline (day of screening physical examination).
Time frame: Weeks 6 and 12
Population: The FAS population included all subjects who received at least 1 dose of study drug and had at least 1 evaluable post-baseline radiograph or CT sufficient to allow determination of HO at the flare-up site. Only subjects with non-missing values were presented.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Palovarotene 10/5 mg | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Subject Global Assessment: Week 6 | Score 3 | 0 Participants |
| Palovarotene 10/5 mg | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Investigator Global Assessment: Week 6 | Score 4 | 3 Participants |
| Palovarotene 10/5 mg | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Subject Global Assessment: Week 12 | Score 3 | 1 Participants |
| Palovarotene 10/5 mg | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Investigator Global Assessment: Week 12 | Score 5 | 4 Participants |
| Palovarotene 10/5 mg | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Investigator Global Assessment: Week 6 | Score 3 | 0 Participants |
| Palovarotene 10/5 mg | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Subject Global Assessment: Week 12 | Score 4 | 6 Participants |
| Palovarotene 10/5 mg | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Investigator Global Assessment: Week 12 | Score 3 | 0 Participants |
| Palovarotene 10/5 mg | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Investigator Global Assessment: Week 6 | Score 2 | 0 Participants |
| Palovarotene 10/5 mg | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Subject Global Assessment: Week 12 | Score 5 | 6 Participants |
| Palovarotene 10/5 mg | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Subject Global Assessment: Week 6 | Score 4 | 2 Participants |
| Palovarotene 10/5 mg | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Investigator Global Assessment: Week 6 | Score 1 | 1 Participants |
| Palovarotene 10/5 mg | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Subject Global Assessment: Week 6 | Score 2 | 1 Participants |
| Palovarotene 10/5 mg | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Investigator Global Assessment: Week 12 | Score 2 | 0 Participants |
| Palovarotene 10/5 mg | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Subject Global Assessment: Week 6 | Score 5 | 6 Participants |
| Palovarotene 10/5 mg | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Subject Global Assessment: Week 6 | Score 1 | 0 Participants |
| Palovarotene 10/5 mg | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Investigator Global Assessment: Week 12 | Score 1 | 1 Participants |
| Palovarotene 10/5 mg | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Subject Global Assessment: Week 12 | Score 1 | 0 Participants |
| Palovarotene 10/5 mg | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Investigator Global Assessment: Week 12 | Score 4 | 8 Participants |
| Palovarotene 10/5 mg | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Investigator Global Assessment: Week 6 | Score 5 | 5 Participants |
| Palovarotene 10/5 mg | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Subject Global Assessment: Week 12 | Score 2 | 0 Participants |
| Palovarotene 5/2.5 mg | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Subject Global Assessment: Week 6 | Score 5 | 4 Participants |
| Palovarotene 5/2.5 mg | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Subject Global Assessment: Week 6 | Score 1 | 1 Participants |
| Palovarotene 5/2.5 mg | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Subject Global Assessment: Week 6 | Score 2 | 0 Participants |
| Palovarotene 5/2.5 mg | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Subject Global Assessment: Week 6 | Score 3 | 0 Participants |
| Palovarotene 5/2.5 mg | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Subject Global Assessment: Week 6 | Score 4 | 3 Participants |
| Palovarotene 5/2.5 mg | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Investigator Global Assessment: Week 12 | Score 1 | 1 Participants |
| Palovarotene 5/2.5 mg | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Subject Global Assessment: Week 12 | Score 1 | 1 Participants |
| Palovarotene 5/2.5 mg | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Subject Global Assessment: Week 12 | Score 2 | 1 Participants |
| Palovarotene 5/2.5 mg | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Subject Global Assessment: Week 12 | Score 3 | 0 Participants |
| Palovarotene 5/2.5 mg | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Subject Global Assessment: Week 12 | Score 4 | 2 Participants |
| Palovarotene 5/2.5 mg | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Subject Global Assessment: Week 12 | Score 5 | 5 Participants |
| Palovarotene 5/2.5 mg | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Investigator Global Assessment: Week 6 | Score 1 | 1 Participants |
| Palovarotene 5/2.5 mg | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Investigator Global Assessment: Week 6 | Score 2 | 0 Participants |
| Palovarotene 5/2.5 mg | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Investigator Global Assessment: Week 6 | Score 3 | 0 Participants |
| Palovarotene 5/2.5 mg | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Investigator Global Assessment: Week 6 | Score 4 | 2 Participants |
| Palovarotene 5/2.5 mg | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Investigator Global Assessment: Week 6 | Score 5 | 5 Participants |
| Palovarotene 5/2.5 mg | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Investigator Global Assessment: Week 12 | Score 2 | 1 Participants |
| Palovarotene 5/2.5 mg | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Investigator Global Assessment: Week 12 | Score 3 | 1 Participants |
| Palovarotene 5/2.5 mg | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Investigator Global Assessment: Week 12 | Score 4 | 2 Participants |
| Palovarotene 5/2.5 mg | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Investigator Global Assessment: Week 12 | Score 5 | 4 Participants |
| Placebo | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Subject Global Assessment: Week 12 | Score 2 | 1 Participants |
| Placebo | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Subject Global Assessment: Week 6 | Score 2 | 0 Participants |
| Placebo | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Investigator Global Assessment: Week 6 | Score 4 | 3 Participants |
| Placebo | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Subject Global Assessment: Week 12 | Score 1 | 0 Participants |
| Placebo | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Investigator Global Assessment: Week 12 | Score 5 | 2 Participants |
| Placebo | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Investigator Global Assessment: Week 6 | Score 5 | 1 Participants |
| Placebo | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Subject Global Assessment: Week 6 | Score 5 | 3 Participants |
| Placebo | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Investigator Global Assessment: Week 12 | Score 1 | 1 Participants |
| Placebo | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Subject Global Assessment: Week 6 | Score 4 | 2 Participants |
| Placebo | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Investigator Global Assessment: Week 12 | Score 4 | 4 Participants |
| Placebo | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Investigator Global Assessment: Week 12 | Score 2 | 0 Participants |
| Placebo | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Subject Global Assessment: Week 12 | Score 5 | 1 Participants |
| Placebo | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Subject Global Assessment: Week 6 | Score 3 | 1 Participants |
| Placebo | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Investigator Global Assessment: Week 6 | Score 1 | 0 Participants |
| Placebo | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Subject Global Assessment: Week 12 | Score 4 | 4 Participants |
| Placebo | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Subject Global Assessment: Week 6 | Score 1 | 0 Participants |
| Placebo | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Investigator Global Assessment: Week 6 | Score 2 | 1 Participants |
| Placebo | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Subject Global Assessment: Week 12 | Score 3 | 1 Participants |
| Placebo | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Investigator Global Assessment: Week 12 | Score 3 | 0 Participants |
| Placebo | Subject and Investigator Global Assessment of Movement at Weeks 6 and 12 | Investigator Global Assessment: Week 6 | Score 3 | 1 Participants |
Secondary
Time of Maximum Measured Plasma Concentration (Tmax) of Palovarotene
The Tmax obtained by inspection of palovarotene was determined.
Time frame: Pre-dose and 3, 6, 10, and 24 hrs post-dose at Week 2, and at Week 4 or 6
Population: The PK population included all subjects who had sufficient blood samples collected for valid estimation of PK parameters.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Palovarotene 10/5 mg | Time of Maximum Measured Plasma Concentration (Tmax) of Palovarotene | Week 2 | 3.00 hr |
| Palovarotene 10/5 mg | Time of Maximum Measured Plasma Concentration (Tmax) of Palovarotene | Week 4/Week 6 | 3.00 hr |
| Palovarotene 5/2.5 mg | Time of Maximum Measured Plasma Concentration (Tmax) of Palovarotene | Week 2 | 2.77 hr |
| Palovarotene 5/2.5 mg | Time of Maximum Measured Plasma Concentration (Tmax) of Palovarotene | Week 4/Week 6 | 3.00 hr |