An Open-Label Extension Study of Palovarotene to Treat Preosseous Flare-ups in FOP Subjects


About this study

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 24-month study will (1) continue to follow the 40 FOP subjects who completed Clementia Study PVO-1A-201; (2) enroll up to 20 additional new subjects who have achieved at least 90% skeletal maturity; and (3) evaluate the ability of different palovarotene dosing regimens to prevent HO in these subjects.

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

Study Population (Adult and Pediatric Cohorts – Part B)

Inclusion Criteria:

  • Completion of Study PVO-1A-201 (through Study Day 84) or Adult Cohort subjects not enrolled in Study PVO-1A-201.
  • Have the confirmed R206H genetic mutation consistent with FOP.
  • Have had at least two acute symptomatic flare-ups in the past 2 years but no flare-up symptoms within the past 4 weeks, including at the time of enrollment.
  • Have a CAJIS score of 6 to 16, inclusive, and must be able to receive non-flare-up based dosing.
  • For the Adult Cohort, subjects under the age of 18 must have knee and hand/wrist radiographs confirming ≥ 90% skeletal maturity.
  • Written, signed, and dated subject/parent informed consent; and, for subjects who are minors, age-appropriate assent (this must be performed acording to local regulations).

Exclusion Criteria:

  • Simultaneous participation in another clinical research study (except for Studies PVO-1A-201, PVO-1A-203, or PVO-1A-001) within 4 weeks prior to Part B Screening.
  • 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.

Study Population for Non-Flare-up Based Treatment (Adult Cohort - Part B)

Inclusion Criteria:

  • 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 (e.g., parents, caregivers, or legal guardians) must specifically sign this section.
  • Subjects must be accessible for treatment with palovarotene 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 on-site follow-up visits.

Exclusion Criteria:

  • Weight < 20 kg.
  • Intercurrent known or suspected 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 other than palovarotene in the past 30 days prior to Part B Screening (signature of the informed consent).
  • 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.
  • Concomitant medications that are inhibitors or inducers of cytochrome P450 (CYP450) 3A4 activity.
  • Amylase or lipase > 2x above the upper limit of normal (ULN) or with a history of chronic pancreatitis.
  • Elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5x ULN.
  • Fasting triglycerides > 400 mg/dL with or without therapy.
  • Female subjects who are breastfeeding.
  • Subjects with uncontrolled cardiovascular, hepatic, pulmonary, gastrointestinal, endocrine, metabolic, ophthalmologic, immunologic, psychiatric, or other significant disease.
  • Subjects experiencing suicidal ideation (type 4 or 5) or any suicidal behavior within the past month as defined by the C-SSRS.



Participating Mayo Clinic locations

Study statuses change often. Please contact the study team for the most up-to-date information regarding possible participation.

Mayo Clinic Location Status Contact

Rochester, Minn.

Mayo Clinic principal investigator

Robert Pignolo, M.D., Ph.D.

Closed for enrollment

Contact information:

Kerry Crawley CCRP

(507) 255-8724

More information


  • Heterotopic ossification consists of ectopic bone formation within soft tissues after surgery or trauma. It can have debilitating consequences, but there is no definitive cure. Here we show that heterotopic ossification was essentially prevented in mice receiving a nuclear retinoic acid receptor-γ (RAR-γ) agonist. Side effects were minimal, and there was no significant rebound effect. To uncover the mechanisms of these responses, we treated mouse mesenchymal stem cells with an RAR-γ agonist and transplanted them into nude mice. Whereas control cells formed ectopic bone masses, cells that had been pretreated with the RAR-γ agonist did not, suggesting that they had lost their skeletogenic potential. The cells became unresponsive to rBMP-2 treatment in vitro and showed decreases in phosphorylation of Smad1, Smad5 and Smad8 and in overall levels of Smad proteins. In addition, an RAR-γ agonist blocked heterotopic ossification in transgenic mice expressing activin receptor-like kinase-2 (ALK2) Q207D, a constitutively active form of the receptor that is related to ALK2 R206H found in individuals with fibrodysplasia ossificans progressiva. The data indicate that RAR-γ agonists are potent inhibitors of heterotopic ossification in mouse models and, thus, may also be effective against injury-induced and congenital heterotopic ossification in humans. Read More on PubMed

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