In-Home Evaluation of Episodic Administration of Palovarotene in Fibrodysplasia Ossificans Progressiva (FOP) Subjects
Condition: Fibrodysplasia Ossificans Progressiva
MeSH terms: Myositis Ossificans
Intervention: Palovarotene
Intervention description: Palovarotene will be taken orally once daily at approximately the same time each day. Powder filled hard gelatin capsules may be opened and the contents added onto specific food.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 6.0
Sex: All
Minimum age: 6 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: Open-label 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

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 (heterotopic ossification or HO) 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 gamma (RARγ) agonists
      such as palovarotene to prevent HO following injury. This 36-month study will evaluate the
      long-term safety and efficacy of episodic treatment with palovarotene for flare-ups in FOP
      subjects who successfully complete two flare-up treatment periods (6 weeks duration) and two
      follow-up periods (6 weeks duration) in Study PVO-1A-202.
    

Eligibility criteria:

        Inclusion Criteria:

        For study enrollment

          -  Completed Study PVO-1A-202 having been treated with palovarotene (ie, 6 weeks
             on-treatment and 6-weeks follow-up) for two flare-ups.

          -  Written, signed, and dated informed consent or age-appropriate subject/parent assent
             (this must be performed according to local regulations).

        For treatment with palovarotene for subsequent flare-ups

          -  Symptomatic onset of a new, distinct flare-up within 10 days of the first dose of
             study drug. Symptoms must be reported by the subject, be consistent with their
             previous flare-ups, and include a subject-reported onset date. The flare-up must be
             confirmed by the physician at screening via telephone contact and/or
             video-conferencing.

          -  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 subjects must agree to remain abstinent during treatment
             and for 1 month after treatment or, if sexually active, to use two highly effective
             methods of birth control during and for 1 month after treatment. Additionally,
             sexually active FOCBP subjects must already be using two highly 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 highly
             effective methods of birth control will be clearly defined in the informed consent,
             and the subject or legally authorized representatives (eg, parents, caregivers, or
             legal guardians) must specifically sign this section.

          -  Subjects must be accessible for treatment with palovarotene and follow-up.

        Exclusion Criteria:

        For study enrollment

          -  Any reason that, in the opinion of the Investigator, would lead to the inability of
             the subject and/or family to comply with the protocol.

        For treatment with palovarotene for subsequent flare-ups:

          -  Weight <20 kg.

          -  The flare-up is at a completely ankylosed joint.

          -  Intercurrent non-healed fracture at any location.

          -  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 during palovarotene treatment.

          -  Exposure to synthetic oral retinoids in the past 30 days prior to screening (signature
             of the informed consent or age-appropriate subject assent).

          -  Concurrent treatment with tetracycline or any tetracycline derivatives due to the
             potential increased risk of pseudotumor cerebri

          -  History of allergy or hypersensitivity to retinoids or lactose.

          -  Female subjects who are breastfeeding.

          -  Subjects with uncontrolled cardiovascular, hepatic, pulmonary, gastrointestinal,
             endocrine, metabolic, ophthalmologic, immunologic, psychiatric, clinically significant
             abnormal laboratory findings, or other significant disease.

          -  Simultaneous participation in another interventional clinical research study within
             the past 4 weeks (except for Study PVO-1A-202).

          -  Subjects experiencing suicidal ideation (type 4 or 5) or any suicidal behavior within
             the past month prior to Screening as defined by the Columbia Suicide Severity Rating
             Scale.

          -  Any reason that, in the opinion of the Investigator, would lead to the inability of
             the subject and/or family to comply with the protocol.