Conditions: Fibrodysplasia Ossificans Progressiva
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
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 40
Healthy volunteers: no

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.

Arms:
arm 1: Doses of palovarotene in dose level 1 are 10 mg once daily for 14 days, followed by 5 mg once daily for 28 days. arm 2: Weight-adjusted doses of palovarotene in dose level 2 are 10 mg palovarotene once daily, followed by 5 mg once daily for 28 days. arm 3: Weight-adjusted doses of palovarotene in dose level 3 are 5 mg palovarotene once daily, followed by 2.5 mg once daily for 28 days. arm 4: The placebo comparator will be taken once daily for the same duration as the palovarotene dose groups in both Cohorts 1 and 2.

Interventions: intervention 1: Palovarotene intervention 2: Placebo
Intervention descriptions: intervention 1: 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. intervention 2: None

Protocol document: