An Open-Label Extension Study of Palovarotene Treatment in Fibrodysplasia Ossificans Progressiva (FOP)

Fibrodysplasia Ossificans Progressiva Clinical Trial

Official title:

A Phase 2, Open-Label Extension, Efficacy and Safety Study of a Retinoic Acid Receptor Gamma (RARγ) Specific Agonist (Palovarotene) in the Treatment of Preosseous Flare-ups in Subjects With Fibrodysplasia Ossificans Progressiva (FOP)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02279095
• Other study ID #: PVO-1A-202
• Secondary ID: 2014-002496-28
• Status: Completed
• Phase: Phase 2
• Start date: October 9, 2014
• Est. completion date: September 20, 2022

Study information

• Verified date: May 2024
• Source: Ipsen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Fibrodysplasia Ossificans Progressiva (FOP) is a rare, severely disabling disease characterized by heterotopic ossification (HO), i.e., abnormal bone formation, often associated with painful, recurrent episodes of soft tissue swelling (flare-ups). Lesions begin in early childhood and lead to progressive ankyloses of major joints with resultant loss of movement.

In this study, the ability of different palovarotene dosing regimens to prevent the formation of new HO will be evaluated in adult and pediatric participants with FOP.

Description:

The main objective of this Phase 2, multicenter, open-label study is to evaluate the safety and efficacy of different palovarotene dosing regimens in participants with FOP. Efficacy will be assessed based on the ability of palovarotene to prevent the formation of new heterotopic ossification (HO) as assessed by low-dose whole body computed tomography (WBCT) scan, excluding head.

The study was divided into four parts: Part A (completed on July 2017), Part B (completed on October 2018), Part C (completed) and Part D (completed). Each part was associated with revised palovarotene treatment regimens.

In Part A, all pediatric and adult participants who successfully completed Study PVO-1A-201 were enrolled and followed for up to 36 months. Participants who had an eligible flare-up received 10 mg palovarotene daily for 14 days, followed by 5 mg palovarotene daily for 28 days (or weight-based equivalent).

In Part B, participants who successfully completed Study PVO-1A-201 (including any participant who participated in Part A of Study PVO-1A-202) as well as up to 20 new adult participants were followed for up to 24 months. The Adult Cohort included all participants with at least 90% skeletal maturity, regardless of age. The Pediatric Cohort included all participants with less than 90% skeletal maturity. Any Pediatric Cohort participant who achieved ≥90% skeletal maturity during Part B was considered for enrollment into the Adult Cohort at the discretion of the Investigator. Part B added a 5 mg palovarotene daily chronic treatment regimen administered between flare-ups for participants in the Adult Cohort for up to 24 months. Part B also increased the flare-up dosing to 20 mg palovarotene daily for 28 days, followed by 10 mg palovarotene daily for 56 days (or weight-adjusted equivalents in the Pediatric Cohort). Treatment could be extended if the flare-up was still ongoing.

In Part C, participants from Part B are being followed for up to an additional 48 months. There will be no new participants in Part C. All eligible participants, including skeletally immature participants, are receiving 5 mg palovarotene daily chronic treatment regimen (weight-adjusted doses for skeletally immature participants).

In Part D, annual post last dose of study treatment assessments for up to 2 years will be obtained in participants who were skeletally immature at the time of study treatment discontinuation in order to obtain longer-term safety data. No new participants will be enrolled into Part D.

Part C plus Part D duration will not exceed 48 months.

All participants will undergo all study procedures as specified in the respective schedule of assessments and for as long as they are not 100% skeletally mature.

Other known NCT identifiers

• NCT02979769

Recruitment information / eligibility

• Status: Completed
• Enrollment: 58
• Est. completion date: September 20, 2022
• Est. primary completion date: September 20, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Years to 65 Years

Eligibility

Inclusion Criteria:

• Completion of Study PVO-1A-202/Part B.

• Written, signed, and dated informed consent and, for participants who are minors, age-appropriate participant assent (performed according to local regulations).

• Accessible for treatment with palovarotene and follow-up (able and willing to travel to a site for the initial and all follow-up clinic visits).

• Able to undergo low-dose, WBCT scan, excluding head.

• Females of child-bearing potential must have a negative blood or urine pregnancy test (with sensitivity of at least 50 mIU/mL) prior to administration of palovarotene.

• Male and FOCBP participants must agree to remain abstinent from heterosexual sex during treatment and for 1 month after treatment or, if sexually active, to use two effective methods of birth control during and for 1 month after treatment. Additionally, sexually active females of childbearing potential (FOCBP) participants must already be using two effective methods of birth control 1 month before treatment is to start. Specific risk of the use of retinoids during pregnancy, and the agreement to remain abstinent or use two effective methods of birth control will be clearly defined in the informed consent and the participant or legally authorized representatives.

Exclusion Criteria:

• Any reason that, in the opinion of the Investigator, would lead to the inability of the participant and/or family to comply with the protocol.

• Amylase or lipase >2x above the upper limit of normal or with a history of pancreatitis.

• Elevated aspartate aminotransferase or alanine aminotransferase >2.5x the upper limit of normal.

• Fasting triglycerides >400 mg/dL with or without therapy.

• Currently using vitamin A or beta carotene, multivitamins containing vitamin A or beta carotene, herbal preparations containing vitamin A or beta carotene, or fish oil, and unable or unwilling to discontinue use of these products during palovarotene treatment.

• Participants experiencing suicidal ideation (type 4 or 5) or any suicidal behavior within the past month as defined by the Columbia Suicide Severity Rating Scale (C-SSRS).

Related Conditions & MeSH terms

• Fibrodysplasia Ossificans Progressiva

Intervention

Drug:
• Palovarotene dose level 1
Palovarotene was taken orally once daily at approximately the same time each day.
• Palovarotene dose level 2
Palovarotene will be taken orally once daily at approximately the same time each day.
• Palovarotene dose level 3
Palovarotene will be taken orally once daily at approximately the same time each day.
• Palovarotene dose level 4
Palovarotene will be taken orally once daily at approximately the same time each day.

Locations

Country	Name	City	State
Argentina	Hospital Italiano de Buenos Aires, Department of Pediatrics	Buenos Aires
Australia	Royal North Shore Hospital	Saint Leonards	New South Wales
Australia	Queensland University of Technology (QUT) Institute of Health and Biomedical Innovation (IHBI)	Woolloongabba	Queensland
France	Hôpital Necker-Enfants Malades, Department of Genetics	Paris
United Kingdom	The Royal National Orthopaedic Hospital, Brockley Hill	Stanmore	Middlesex
United States	University of Pennsylvania, Center for FOP & Related Bone Disorders	Philadelphia	Pennsylvania
United States	Mayo Clinic, Department of Medicine	Rochester	Minnesota
United States	University of California San Francisco, Division of Endocrinology and Metabolism	San Francisco	California

Sponsors (1)

Lead Sponsor	Collaborator
Clementia Pharmaceuticals Inc.

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  France,  United Kingdom, 

References & Publications (1)

Shimono K, Tung WE, Macolino C, Chi AH, Didizian JH, Mundy C, Chandraratna RA, Mishina Y, Enomoto-Iwamoto M, Pacifici M, Iwamoto M. Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-gamma agonists. Nat Med. 2011 Apr;17(4):454-60. doi: 10.1038/nm.2334. Epub 2011 Apr 3. Erratum In: Nat Med. 2012 Oct;18(10):1592. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Parts A and B: Percentage of Flare-ups With No New Heterotopic Ossification (HO) at Week 12	A responder was defined as a participant with no or minimal new HO at original flare-up site compared with baseline (pre-dose data from PVO-1A-201 study). Minimal new HO was defined as new HO with an HO score <=3 in both the anterior/posterior (AP) and lateral projections (or if 1 view is noninterpretable or non-evaluable, then remaining evaluable view was used). The HO score ranged from 0 to 6 where, 0 = no HO and 6 = single contiguous HO with longest dimension >2 diameters of reference normotopic bone in any projection. Highest HO score from 2 projections was used.	Baseline and Week 12
Primary	Parts B and C: Annualized Change in New HO Volume	The annualized change in new HO volume was assessed by low-dose whole body computed tomography (WBCT) scan, excluding head. Results are presented for overall intent to treat (ITT) period.	From Baseline (Day 1) up to end of 2 year follow-up period, approximately a maximum of 96 months
Secondary	Parts A and B: Percentage of Participants Across the 7 HO Scores at Month 12 of Part A; and Weeks 6 and 12 for Part B	The HO score ranged from 0 to 6 where, 0 = no HO and 6 = single contiguous HO with longest dimension >2 diameters of the reference normotopic bone in any projection. Highest HO score from 2 projections was used.	Part A: Baseline (pre-dose data from Study PVO-1A-201 for follow-up component and flare-up screening/Day 1 for flare-up component) and Month 12; Part B: Baseline (flare-up screening/baseline) and Weeks 6 and 12
Secondary	Parts A and B: Volume of New Heterotopic Bone Formed at Month 12	Plain radiographs were utilized in Part A of the study. The interpretation of radiographs was to have documented the absence or presence of new HO at the flare-up site compared with the baseline assessment, and the volume of new HO if present. Low-dose CT scans were utilized in Part B of the study. Low-dose, flare-up site-specific CT scan was used as the primary imaging assessment of HO for flare-ups and low-dose, WBCT scans were used as the primary imaging assessment for total body HO in those participants receiving chronic treatment.	Month 12
Secondary	Parts A and B: Number of Flare-ups With Significant Abnormalities in Cartilage, Bone, Angiogenesis, and Inflammation Biomarkers at Week 12	Blood and urine samples for cartilage, bone, angiogenesis, and inflammation biomarkers were evaluated during Part A and Part B of the study. Bone and cartilage biomarkers included: osteocalcin, bone-specific alkaline phosphatase (ALP), procollagen type 1-N-terminal pro-peptide (PINP), cartilage-derived (CD) retinoic acid protein, procollagen type 1-C-terminal pro-peptide (PICP), and C-terminal telopeptide. Angiogenesis included urinary basic fibroblast growth factor. Inflammation included erythrocyte sedimentation rate, C-reactive protein, Interleukin(IL)-6, IL-1 beta, tumor necrosis factor (TNF)-alpha, creatine phosphokinase, and lactate dehydrogenase. Based on emerging data from studies PVO-1A-001, PVO-1A-201, and Parts A and B of PVO-1A-202, biomarkers were removed from the evaluation during Part C.	Part A and B: At Week 12
Secondary	Parts A and B: Change From Baseline in Active Range of Motion (ROM) at Flare-up Site at Week 12	Active ROM was assessed by goniometer in Parts A and B of the study. Measurements were performed by trained and qualified study personnel (eg, physiotherapist) in order to standardize the performance of procedures and minimize variability. Flare-ups at the primary joint was expressed as percent of normal arc of motion. Based on the change in the schedule for flare-up based assessments. Baseline was defined as pre-dose data from Study PVO-1A-201 for follow-up component and flare-up screening/Day 1 for flare-up component for Part A and flare-up screening/baseline for Part B.	Baseline and Week 12
Secondary	Part B: Change From Baseline in ROM at Week 12	The ROM was assessed by the Investigator using Cumulative Analogue Joint Involvement Scale (CAJIS) for participants in Part B. It includes 12 joints (shoulder, elbow, wrist, hip, knee, and ankle on both the right and left sides), and 3 body regions (jaw, cervical spine [neck], and thoracic/lumbar spine). Each joint/region was assessed as: 0=uninvolved; 1=partially involved; and 2=completely ankylosed. The total score range is 0 (no involvement) to 30 (maximally involved). Baseline was flare-up screening.	Baseline and Week 12
Secondary	Part C: Change From Baseline in ROM at Months 6, 12, 18, 24, 30, 36, 42, and 48	The ROM was assessed by the Investigator using CAJIS for participants in Part C. It includes 12 joints (shoulder, elbow, wrist, hip, knee, and ankle on both the right and left sides), and 3 body regions (jaw, cervical spine [neck], and thoracic/lumbar spine). Each joint/region was assessed as: 0=uninvolved; 1=partially involved; and 2=completely ankylosed. The total score range is 0 (no involvement) to 30 (maximally involved). Baseline was chronic Day 1.	Baseline and Months 6, 12, 18, 24, 30, 36, 42, and 48
Secondary	Part B: Participant and Investigator Global Assessment of Movement at Week 12	Participants/Investigators assessed how the flare-up was affecting movement (better, same, slightly worse, moderately worse, or severely worse movement) compared with baseline. Based on the change in the schedule for flare-up based assessments. PA = Participant assessment and IA = Investigator assessment.	Week 12
Secondary	Part A: Change From Baseline in Numeric Rating Scale (NRS) Pain and Swelling or Faces Pain Scale-Revised (FPS-R) at Weeks 2, 4, 6, 9, and 12	The NRSs for pain and swelling were used in Part A of the study to evaluate the effect of palovarotene on pain and swelling at the flare-up site. Flare-up pain was rated on a scale ranging from 0 (no pain or swelling) to 10 (worst pain or swelling ever experienced). For children less than 8 years old, pain was rated using the FPS-R, which ranging from 0 to 10 in 2-point increments where 0 = no pain and 10 = very much pain. Flare-up swelling was rated on a scale from 0 to 10 where 0 = no swelling and 10 = worst swelling ever experienced. Higher scores indicate worst quality of life for all scales. Baseline was predose data from PVO-1A-201 study/flare-up screening/Day 1.	Baseline and Weeks 2, 4, 6, 9, and 12
Secondary	Parts A and B: Change From Baseline in Physical Function at Weeks 2, 4, 6, 9, and 12 of Part A; and Weeks 4, 8, and 12 of Part B	The effect of palovarotene on physical function was determined using Fibrodysplasia Ossificans Progressiva-Physical Function Questionnaire (FOP-PFQ). The questionnaire consisted of 28 items ranging from 1 (not able to do) to 5 (with no trouble; without help or assistive device). Total score range from 28 to 140. Lower scores denoted more difficulty, with items categorized into upper extremity and mobility sections.	Part A: Baseline and Weeks 2, 4, 6, 9, and 12; and Part B: Baseline and Weeks 4, 8, and 12
Secondary	Part C: Change From Baseline in Physical Function at Months 6, 12, 18, 24, 30, 36, 42, and 48	The effect of palovarotene on physical function was determined using FOP-PFQ. The questionnaire consisted of 28 items ranging from 1 (not able to do) to 5 (with no trouble; without help or assistive device). Total score range from 28 to 140. Lower scores denoted more difficulty, with items categorized into upper extremity and mobility sections.	Baseline and Months 6, 12, 18, 24, 30, 36, 42, and 48
Secondary	Parts A and B: Change From Baseline in Physical and Mental Health at Weeks 2, 4, 6, 9, and 12 of Part A; and Weeks 4, 8, and 12 of Part B	The patient reported outcomes measurement information system (PROMIS) global health scale was administered to evaluate the effect of palovarotene on physical and mental health in participants =15 years of age and mental health in participants <15 years of age, age-appropriate forms of the PROMIS global health scales were administered. A T-score of 50 is normal and increments of 10 are +/- standard deviation away from the norm. A T-score <50 indicates worse health, while a T-score >50 indicates better health. Higher values (positive changes) indicate better health. AFPH = Adult Form, Physical Health; AFMH = Adult Form, Mental Health; PFH = Paediatric Form, Health.	Part A: Baseline and Weeks 2, 4, 6, 9, and 12; and Part B: Baseline and Weeks 4, 8, and 12
Secondary	Part C: Change From Baseline in Physical and Mental Health at Months 6, 12, 18, 24, 30, 36, 42, and 48	The PROMIS global health scale was administered to evaluate the effect of palovarotene on physical and mental health in participants =15 years of age and mental health in participants <15 years of age, age-appropriate forms of the PROMIS global health scales were administered. A T-score of 50 is normal and increments of 10 are +/- standard deviation away from the norm. A T-score <50 indicates worse health, while a T-score >50 indicates better health. Higher values (positive changes) indicate better health. AFPH = Adult Form, Physical Health; AFMH = Adult Form, Mental Health; PFH = Paediatric Form, Health.	Baseline and Months 6, 12, 18, 24, 30, 36, 42, and 48
Secondary	Parts A and B: Number of Any Assistive Devices and Adaptations by FOP Participants at Weeks 6 and 12 of Part A; and Week 12 of Part B	The FOP assistive devices and adaptations questionnaire was used in Part A and Part B of the study. Assistive devices and adaptations were grouped into the following categories: mobility aids, care attendants, eating tools, personal care tools/aids, bathroom aids and devices, bedroom aids and devices, home adaptations, work environment adaptations, technology adaptations, sports and recreation adaptations, school, and medical therapies for daily living. When a flare-up did not use an assistive device or adaptation or considered the assistive device or adaptation not applicable, 0 was imputed for analysis.	Part A: Weeks 6 and 12; and Part B: Week 12
Secondary	Part A: Percentage of Responders at Week 12	A responder was defined as a participant with no or minimal new HO at original flare-up site compared with baseline (flare-up screening/Day 1). Minimal new HO was defined as new HO with an HO score <=3 in both the AP and lateral projections (or if 1 view is non-interpretable or non-evaluable, then remaining evaluable view was used). The HO score ranged from 0 to 6 where, 0 = no HO and 6 = single contiguous HO with longest dimension >2 diameters of the reference normotopic bone in any projection. Highest HO score from 2 projections was used. Results from the Primary Read reviews are presented.	Week 12
Secondary	Parts A and B: Change From Baseline in Amount of Bone Formation Biomarker at Weeks 6 and 12 of Part A; and Week 12 of Part B	The bone formation was measured by PINP biomarker. Baseline was defined as flare-up screening/Day 1.	Part A: Baseline and Weeks 6 and 12; and Part B: Baseline and Week 12
Secondary	Parts A and B: Number of Flare-ups With Soft Tissue Swelling and/or Cartilage Formation at Weeks 6 and 12 of Part A; and Week 12 of Part B	Magnetic resonance imaging (MRI) was utilized as an imaging modality to evaluate for the presence of soft tissue swelling/edema and cartilage formation for participants who received flare-up based treatment. Ultrasound (US) was utilized to evaluate for the presence of soft tissue swelling in participants unable to undergo MRI. Both MRI and US were interpreted centrally. When US was used, cartilage formation was not assessed.	Part A: Baseline and Weeks 6 and 12; and Part B: Baseline and Week 12
Secondary	Parts A and B: Duration of Active Symptomatic Flare-up	The number of days of active symptomatic flare-up was the number of days the participant reported the presence of symptoms in the diary.	Part A: From Baseline up to 36 months; and Part B: From Baseline up to 24 months
Secondary	Part B: Change From Baseline in Whole Body Burden of HO at Months 12 and 24	Whole body burden of HO was assessed by low-dose WBCT scan, excluding head. Baseline was Part B Screening.	Baseline and Months 12 and 24
Secondary	Part B: Mean Percentage of Flare-ups Per Participant-Month Overall	Flare-ups were counted using the number of participant/Investigator-reported flare-ups. Percentage was calculated by dividing the total number of flare-ups by the total participant months of follow-up. Results are presented for overall ITT period.	From Baseline (Day 1) up to end of 2 year follow-up period, approximately a maximum of 96 months
Secondary	Part C: Mean Percentage of Flare-ups Per Participant-Month Overall	Flare-ups were counted using the number of participant/Investigator-reported flare-ups. Percentage was calculated by dividing the total number of flare-ups by the total participant months of follow-up. Results are presented for overall ITT period.	From Baseline (Day 1) up to end of 2 year follow-up period, approximately a maximum of 96 months
Secondary	Part C: Percentage of Participants With New HO at Months 12, 24, 36, 60, and 72 (Last Visit)	New HO was defined as total WBCT new HO volume >0. Results for Month 72 are presented for overall ITT period.	Months 12, 24, 36, 60, and 72 (last visit)

External Links

•   Click here for more information about this study: A Phase 2, Open-Label Extension, Efficacy and Safety Study of a RAR?-Specific Agonist (Palovarotene) in the Treatment of Preosseous Flare-ups in Subjects with Fibrodysplasia Ossificans Progressiva (FOP)
•   Website for the French FOP Association
•   Website for the International FOP Association