an open-label extension study of palovarotene treatment in fibrodysplasia ossificans progressiva (fop)

Conditions: Fibrodysplasia Ossificans Progressiva

Summary: fibrodysplasia ossificans progressiva (fop) is a rare, severely disabling disease characterized by heterotopic ossification (ho), i.e., abnormal bone formation, often associated with painful, recurrent episodes of soft tissue swelling (flare-ups). lesions begin in early childhood and lead to progressive ankyloses of major joints with resultant loss of movement. in this study, the ability of different palovarotene dosing regimens to prevent the formation of new ho will be evaluated in adult and pediatric participants with fop.

the main objective of this phase 2, multicenter, open-label study is to evaluate the safety and efficacy of different palovarotene dosing regimens in participants with fop. efficacy will be assessed based on the ability of palovarotene to prevent the formation of new heterotopic ossification (ho) as assessed by low-dose whole body computed tomography (wbct) scan, excluding head. the study was divided into four parts: part a (completed on july 2017), part b (completed on october 2018), part c (completed) and part d (completed). each part was associated with revised palovarotene treatment regimens. in part a, all pediatric and adult participants who successfully completed study pvo-1a-201 were enrolled and followed for up to 36 months. participants who had an eligible flare-up received 10 mg palovarotene daily for 14 days, followed by 5 mg palovarotene daily for 28 days (or weight-based equivalent). in part b, participants who successfully completed study pvo-1a-201 (including any participant who participated in part a of study pvo-1a-202) as well as up to 20 new adult participants were followed for up to 24 months. the adult cohort included all participants with at least 90% skeletal maturity, regardless of age. the pediatric cohort included all participants with less than 90% skeletal maturity. any pediatric cohort participant who achieved ≥90% skeletal maturity during part b was considered for enrollment into the adult cohort at the discretion of the investigator. part b added a 5 mg palovarotene daily chronic treatment regimen administered between flare-ups for participants in the adult cohort for up to 24 months. part b also increased the flare-up dosing to 20 mg palovarotene daily for 28 days, followed by 10 mg palovarotene daily for 56 days (or weight-adjusted equivalents in the pediatric cohort). treatment could be extended if the flare-up was still ongoing. in part c, participants from part b are being followed for up to an additional 48 months. there will be no new participants in part c. all eligible participants, including skeletally immature participants, are receiving 5 mg palovarotene daily chronic treatment regimen (weight-adjusted doses for skeletally immature participants). in part d, annual post last dose of study treatment assessments for up to 2 years will be obtained in participants who were skeletally immature at the time of study treatment discontinuation in order to obtain longer-term safety data. no new participants will be enrolled into part d. part c plus part d duration will not exceed 48 months. all participants will undergo all study procedures as specified in the respective schedule of assessments and for as long as they are not 100% skeletally mature.

Eligibility criteria:
inclusion criteria: * completion of study pvo-1a-202/part b. * written, signed, and dated informed consent and, for participants who are minors, age-appropriate participant assent (performed according to local regulations). * accessible for treatment with palovarotene and follow-up (able and willing to travel to a site for the initial and all follow-up clinic visits). * able to undergo low-dose, wbct scan, excluding head. * females of child-bearing potential 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 participants must agree to remain abstinent from heterosexual sex during treatment and for 1 month after treatment or, if sexually active, to use two effective methods of birth control during and for 1 month after treatment. additionally, sexually active females of childbearing potential (focbp) participants must already be using two 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 effective methods of birth control will be clearly defined in the informed consent and the participant or legally authorized representatives. exclusion criteria: * any reason that, in the opinion of the investigator, would lead to the inability of the participant and/or family to comply with the protocol. * amylase or lipase \>2x above the upper limit of normal or with a history of pancreatitis. * elevated aspartate aminotransferase or alanine aminotransferase \>2.5x the upper limit of normal. * fasting triglycerides \>400 mg/dl with or without therapy. * currently using vitamin a or beta carotene, multivitamins containing vitamin a or beta carotene, herbal preparations containing vitamin a or beta carotene, or fish oil, and unable or unwilling to discontinue use of these products during palovarotene treatment. * participants experiencing suicidal ideation (type 4 or 5) or any suicidal behavior within the past month as defined by the columbia suicide severity rating scale (c-ssrs).

Keywords: open-label extension 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 ipsen