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

NCT02279095 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: PVO-1A-2022014-002496-28
• Study Type: interventional
• Target: 58
• Locations: 5 countries
• Sites: 8

Brief Summary

Fibrodysplasia Ossificans Progressiva (FOP) is a rare, severely disabling disease characterized by heterotopic ossification (HO), i.e., abnormal bone formation, often associated with painful, recurrent episodes of soft tissue swelling (flare-ups). Lesions begin in early childhood and lead to progressive ankyloses of major joints with resultant loss of movement. In this study, the ability of different palovarotene dosing regimens to prevent the formation of new HO will be evaluated in adult and pediatric participants with FOP.

Conditions

Fibrodysplasia Ossificans Progressiva

Keywords

Open-label extension study; Clinical trial Phase 2; Efficacy and safety; Heterotopic ossification; Fibrodysplasia Ossificans Progressiva; Flare-up; Palovarotene; Retinoic acid receptor agonist; Retinoic acid receptor gamma agonist; Clementia; Myositis Ossificans Progressiva; Munchmeyer's Disease; FOP; Ipsen

Outcome Measures

Primary Outcomes (2)

• Parts A and B: Percentage of Flare-ups With No New Heterotopic Ossification (HO) at Week 12

  A responder was defined as a participant with no or minimal new HO at original flare-up site compared with baseline (pre-dose data from PVO-1A-201 study). Minimal new HO was defined as new HO with an HO score \<=3 in both the anterior/posterior (AP) and lateral projections (or if 1 view is noninterpretable or non-evaluable, then remaining evaluable view was used). The HO score ranged from 0 to 6 where, 0 = no HO and 6 = single contiguous HO with longest dimension \>2 diameters of reference normotopic bone in any projection. Highest HO score from 2 projections was used.

  Baseline and Week 12

• Parts B and C: Annualized Change in New HO Volume

  The annualized change in new HO volume was assessed by low-dose whole body computed tomography (WBCT) scan, excluding head. Results are presented for overall intent to treat (ITT) period.

  From Baseline (Day 1) up to end of 2 year follow-up period, approximately a maximum of 96 months

Secondary Outcomes (21)

• Parts A and B: Percentage of Participants Across the 7 HO Scores at Month 12 of Part A; and Weeks 6 and 12 for Part B

  Part A: Baseline (pre-dose data from Study PVO-1A-201 for follow-up component and flare-up screening/Day 1 for flare-up component) and Month 12; Part B: Baseline (flare-up screening/baseline) and Weeks 6 and 12

• Parts A and B: Volume of New Heterotopic Bone Formed at Month 12

  Month 12

• Parts A and B: Number of Flare-ups With Significant Abnormalities in Cartilage, Bone, Angiogenesis, and Inflammation Biomarkers at Week 12

  Part A and B: At Week 12

• Parts A and B: Change From Baseline in Active Range of Motion (ROM) at Flare-up Site at Week 12

  Baseline and Week 12

• Part B: Change From Baseline in ROM at Week 12

  Baseline and Week 12

Study Arms (4)

Palovarotene dose level 1 (completed)

EXPERIMENTAL

Participants received 10 mg palovarotene for 14 days, followed by 5 mg palovarotene for 28 days (or weight-based equivalent) for eligible flare-ups (Part A).

Drug: Palovarotene dose level 1

Palovarotene dose level 2

EXPERIMENTAL

Participants with at least 90% skeletal maturity received 5 mg palovarotene for up to 24 months and 20 mg palovarotene for 28 days, followed by 10 mg for 56 days for eligible flare-ups (Part B).

Drug: Palovarotene dose level 2

Palovarotene dose level 3

EXPERIMENTAL

Participants with less than 90% skeletal maturity received weight-adjusted doses of 20 mg palovarotene for 28 days, followed by 10 mg for 56 days for eligible flare-ups (Part B).

Drug: Palovarotene dose level 3

Palovarotene dose level 4

EXPERIMENTAL

All participants will receive 5 mg palovarotene for up to 48 months and 20 mg palovarotene for 28 days, followed by 10 mg for 56 days for eligible flare-ups (Part C). Skeletally immature participants will receive weight-adjusted doses.

Drug: Palovarotene dose level 4

Interventions

Palovarotene dose level 1 DRUG

Palovarotene was taken orally once daily at approximately the same time each day.

Palovarotene dose level 1 (completed)

Palovarotene dose level 2 DRUG

Palovarotene will be taken orally once daily at approximately the same time each day.

Palovarotene dose level 2

Palovarotene dose level 3 DRUG

Palovarotene will be taken orally once daily at approximately the same time each day.

Palovarotene dose level 3

Palovarotene dose level 4 DRUG

Palovarotene will be taken orally once daily at approximately the same time each day.

Palovarotene dose level 4

Eligibility Criteria

• Age: 6 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• Clementia Pharmaceuticals Inc.: lead

Study Sites (8)

University of California San Francisco, Division of Endocrinology and Metabolism

San Francisco, California, 94143, United States

Location

Mayo Clinic, Department of Medicine

Rochester, Minnesota, 55905, United States

Location

University of Pennsylvania, Center for FOP & Related Bone Disorders

Philadelphia, Pennsylvania, 19104, United States

Location

Hospital Italiano de Buenos Aires, Department of Pediatrics

Buenos Aires, Argentina

Location

Royal North Shore Hospital

Saint Leonards, New South Wales, 2065, Australia

Location

Queensland University of Technology (QUT) Institute of Health and Biomedical Innovation (IHBI)

Woolloongabba, Queensland, 4102, Australia

Location

Hôpital Necker-Enfants Malades, Department of Genetics

Paris, France

Location

The Royal National Orthopaedic Hospital, Brockley Hill

Stanmore, Middlesex, HA7 4LP, United Kingdom

Location

Related Publications (3)

• 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.

  PMID: 21460849 BACKGROUND

• Pignolo RJ, Al Mukaddam M, Baujat G, Brown MA, De Cunto C, Hsiao EC, Keen R, Le Quan Sang KH, Grogan DR, Marino R, Strahs AR, Kaplan FS. Study methodology and insights from the palovarotene clinical development program in fibrodysplasia ossificans progressiva. BMC Med Res Methodol. 2023 Nov 13;23(1):269. doi: 10.1186/s12874-023-02080-7.

  PMID: 37957586 DERIVED

• Pignolo RJ, Kimel M, Whalen J, Kawata AK, Artyomenko A, Kaplan FS. The Fibrodysplasia Ossificans Progressiva Physical Function Questionnaire (FOP-PFQ): A patient-reported, disease-specific measure. Bone. 2023 Mar;168:116642. doi: 10.1016/j.bone.2022.116642. Epub 2022 Dec 13.

  PMID: 36526263 DERIVED

Related Links

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

MeSH Terms

Conditions

Myositis Ossificans; Ossification, Heterotopic

Condition Hierarchy (Ancestors)

Myositis; Muscular Diseases; Musculoskeletal Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Limitations and Caveats

On 04-Dec-2019, participants \<14 years were required to interrupt treatment due to partial clinical hold placed on palovarotene clinical development program by the FDA. On 24-Jan-2020, treatment was temporarily halted in participants 14 years and older in palovarotene FOP trials when futility boundary was crossed at an interim analysis in PVO-1A-301 study. After post-hoc analyses, dosing was re-initiated only in participants 14 years and above who were able and willing to re-start treatment.

Results Point of Contact

• Title: Medical Director
• Organization: Ipsen

clinical.trials@ipsen.com

see email

Study Officials

• Ipsen Medical Director

  Ipsen

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 26, 2014
• First Posted: October 30, 2014
• Study Start: October 9, 2014
• Primary Completion: September 20, 2022
• Study Completion: September 20, 2022
• Last Updated: February 19, 2025
• Results First Posted: May 17, 2024

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (3); AR (1); AU (2); FR (1); GB (1)