An Open-Label Extension Study of Palovarotene to Prevent Heterotopic Ossification in People With Fibrodysplasia Ossificans Progressiva (FOP) in France

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)

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 in France.

Study Overview

• Status: Completed
• Conditions: Fibrodysplasia Ossificans Progressiva
• Intervention / Treatment: Drug: Palovarotene

Detailed Description

The main objective of this Phase 2, open-label study is to evaluate the safety and efficacy of different palovarotene dosing regimens in participants with FOP in France. 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.

Participants who successfully completed study PVO-1A-201 as well as up to two new adult participants were followed for up to 24 months. Participants under Amendment 1 will be followed for up to an additional 48 months. No new participants will be enrolled.

The Adult Cohort will include all participants with at least 90% skeletal maturity, regardless of age. The Pediatric Cohort will include all participants with less than 90% skeletal maturity. Any Pediatric Cohort participants who achieves ≥90% skeletal maturity during the study can be considered for enrollment into the Adult Cohort at the discretion of then Investigator.

Participants that were skeletally immature at their last assessment will be invited back to participate in a safety follow-up (Part D) that includes yearly visits for up to a 2-year follow-up period following last dose. No dosing will occur in Part D.

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Paris, France
    • Hôpital Necker-Enfants Malades, Department of Genetics

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 61 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Prior participation in Amendment 1 of the current study (PVO-1A-204).
• 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 (FOCBP) 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 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.
• If 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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Palovarotene; All participants will receive non-flare-up based treatment of 5 mg palovarotene once daily for 24 months. Participants who continued non-flare-up based treatment under Amendment 1 will receive non-flare-up based treatment for up to an additional 48 months (therefore 72 months over the entire study). Participants who start non-flare-up based treatment under Amendment 1 will receive non-flare-up based treatment for up to 48 months. Participants that are skeletally immature will receive weight-adjusted doses. In the event of an eligible flare-up all participants will receive 20 mg palovarotene for 28 days, followed by 10 mg palovarotene for 56 days. Participants under the age of 18 years will receive weight-adjusted doses.

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Annualized change in new HO volume	Assessed by low-dose whole body computed tomography (WBCT) (excluding head)	Every 12 months until the end of the study (up to 72 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent of participants with new HO		Every 12 months for up to 72 months
Change from baseline in range of motion (ROM)	Assessed by Cumulative Analogue Joint Involvement Scale (CAJIS)	Every 6 months for up to 72 months
Change from baseline in physical function	Assessed by age-appropriate forms of the FOP-Physical Function Questionnaire (FOP-PFQ)	Every 6 months for up to 72 months
Change from baseline in physical and mental function for participants ≥15 years old and mental function for participants <15 years old	Assessed by age-appropriate forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale	Every 6 months for up to 72 months

Collaborators and Investigators

• Sponsor: Clementia Pharmaceuticals Inc.

Publications and helpful links

General Publications

• 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.

Helpful 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)

Study record dates

Study Major Dates

• Study Start (Actual): November 28, 2016
• Primary Completion (Actual): June 28, 2022
• Study Completion (Actual): June 28, 2022

Study Registration Dates

• First Submitted: November 23, 2016
• First Submitted That Met QC Criteria: November 29, 2016
• First Posted (Estimate): December 2, 2016

Study Record Updates

• Last Update Posted (Actual): July 29, 2022
• Last Update Submitted That Met QC Criteria: July 28, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: Efficacy and safety; Clinical trial Phase 2; Heterotopic ossification; Flare-up; Palovarotene; Clementia; Munchmeyer's Disease; FOP; Open-label extension study; Ipsen; Retinoic acide receptor agonist; Retinoic acide receptor gamma agonist; Myositis Ossificans
• Additional Relevant MeSH Terms: Musculoskeletal Diseases; Muscular Diseases; Myositis; Myositis Ossificans
• Other Study ID Numbers: PVO-1A-204; 2016-002526-36 (EudraCT Number)