An Efficacy and Safety Study of Palovarotene to Treat Preosseous Flare-ups in FOP Subjects
Condition: Fibrodysplasia Ossificans Progressiva
MeSH terms: Myositis Ossificans
Intervention: Palovarotene; Placebo
Intervention description: 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.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 40.0
Sex: All
Minimum age: 6 Years
Healthy volunteers: No
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

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.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Written, signed, and dated informed subject/parent consent or age-appropriate assent.

          -  Subjects clinically diagnosed with classic Fibrodysplasia Ossificans Progressiva
             (FOP).

          -  Symptomatic onset of a distinct flare-up within 7 days of Study Day 1 (start of study
             drug) and defined by the presence of at least two of six of the following symptoms:
             pain, soft tissue swelling, decreased range of motion, stiffness, redness, and warmth.
             Flare-up must be confirmed by the physician at the Screening visit.

          -  Flare-up is at an appendicular area (upper or lower extremity), abdomen, or chest; and
             subject has received, is receiving, or is willing to receive treatment per standard of
             care, which may or may not include oral prednisone (2 mg/kg PO to a maximum dose of
             100 mg daily) for 4 days.

          -  Abstinent or using two highly effective forms of birth control.

          -  Subjects must be accessible for treatment and follow-up. Subjects living at distant
             locations from the investigational site must be able and willing to travel to a site
             for the initial and all follow-up visits.

        Exclusion Criteria:

          -  Weight <20 kg.

          -  Intercurrent non-healed fracture at any location.

          -  Complete immobilization of joint at site of flare-up.

          -  The inability of the subject to undergo imaging assessments using plain radiographs.

          -  If currently using vitamin A or beta carotene, multivitamins containing vitamin A or
             beta carotene, or herbal preparations, fish oil, and unable or unwilling to
             discontinue use of these products for the duration of the study.

          -  Exposure to synthetic oral retinoids in the past 30 days prior to Screening (signature
             of the informed consent).

          -  Concurrent treatment with tetracycline due to the potential increased risk of
             pseudotumor cerebri.

          -  History of allergy or hypersensitivity to retinoids or lactose.

          -  Concomitant medications that are inhibitors or inducers of CYP450 3A4 activity.

          -  Amylase or lipase >1.5x above the upper limit of normal or with a history of chronic
             pancreatitis.

          -  Elevated aspartate aminotransferase or alanine aminotransferase >2.5x the upper limit
             of normal.

          -  Fasting triglycerides >400 mg/dL with or without therapy.