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

Sponsor

Clementia Pharmaceuticals Inc. (Industry)

Overall Status

Completed

CT.gov ID

NCT02979769

Collaborator

(none)

Enrollment

Location

Arm

Actual Duration (Months)

0.1

Patients Per Site Per Month

Study Details

Study Description

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 in France.

Condition or Disease	Intervention/Treatment	Phase
Fibrodysplasia Ossificans Progressiva	Drug: Palovarotene	Phase 2

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 Design

Study Type:

Interventional

Actual Enrollment :

9 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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)

Actual Study Start Date :

Nov 28, 2016

Actual Primary Completion Date :

Jun 28, 2022

Actual Study Completion Date :

Jun 28, 2022

Arms and Interventions

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.

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.

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

6 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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).