An Efficacy and Safety Study of Palovarotene for the Treatment of Fibrodysplasia Ossificans Progressiva.
An Efficacy and Safety Study of Palovarotene for the Treatment of Fibrodysplasia Ossificans Progressiva.
Fibrodysplasia Ossificans Progressiva (FOP) is a rare, severely disabling disease
 characterized by heterotopic ossification (HO) often associated with painful, recurrent
 episodes of soft tissue swelling (flare-ups) that lead to ankyloses of major joints with
 cumulative and irreversible loss of movement and disability.
One primary objective is to evaluate the efficacy of palovarotene in decreasing new HO in
 subjects with FOP as assessed by low-dose, whole body computed tomography (WBCT), excluding
 head, compared to untreated subjects from Clementia's FOP natural history study (Study
 PVO-1A-001, NHS). The other primary objective is to evaluate the safety of palovarotene in
 subjects with FOP.

 This is a Phase 3, multicenter, open-label study that will be conducted in two parts: Part A,
 the main part of the study; and Part B, the 24-month extension. Eligible subjects will
 receive a chronic/flare-up dosing regimen of palovarotene for 48 months as follows:

 -  Chronic treatment: orally administered 5 mg palovarotene once daily for 24 months.

 -  Flare-up treatment: orally administered 20 mg palovarotene once daily for 4 weeks (28
 days) followed by orally administered 10 mg palovarotene once daily for 8 weeks (56
 days). Flare-up treatment may be extended until the Investigator determines that the
 flare-up has resolved.

 Note that all dosing will be weight-adjusted in skeletally immature subjects (those under the
 age of 18 years with less than 90% skeletal maturity on hand/ wrist x-rays performed at
 Screening).
Key Inclusion Criteria:

 -  Written, signed, and dated informed subject/parent consent; and for subjects who are
 minors, age-appropriate assent (performed according to local regulations).

 -  Males or females at least 4 years of age.

 -  Previous participation in Clementia's natural history study (NCT02322255); clinically
 diagnosed with FOP, with the R206H ACVR1 mutation or other FOP variants reported to be
 associated with progressive HO (who have not participated in any Clementia-sponsored
 study); participants in Clementia's Phase 2 studies (NCT02279095 and NCT02979769) who
 cannot currently receive the chronic/flare-up regimen due to country of residence or
 those traveling long distances to participate in the Phase 2 studies.

 -  No flare-up symptoms within the past 4 weeks, including at the time of enrollment.

 -  Abstinent or using two highly effective forms of birth control.

 -  Accessible for treatment and follow-up; able to undergo all study procedures including
 low-dose WBCT (excluding head) without sedation.

 Key Exclusion Criteria:

 -  Weight <10 kg.

 -  Concomitant medications that are strong inhibitors or inducers of cytochrome P450
 (CYP450) 3A4 activity; or kinase inhibitors such as imatinib.

 -  Amylase or lipase >2x above the upper limit of normal (ULN) or with a history of
 chronic pancreatitis.

 -  Elevated aspartate aminotransferase or alanine aminotransferase >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.

 -  Simultaneous participation in another clinical research study (other than palovarotene
 studies) within 4 weeks prior to Screening; or within five half-lives of the
 investigational agent, whichever is longer.

 -  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.