Extension Study of an Investigational Drug, Palovarotene, in the Treatment of Preosseous Flare-ups in Subjects with Fibrodysplasia Ossificans Progressiva (FOP)
- Conditions
- Fibrodysplasia Ossificans Progressiva (FOP) is a rare, severely disabling disease characterized by painful, recurrent episodes of soft tissue swelling (flare-ups) and abnormal heterotopic ossification (HO) in muscles, tendons, and ligaments. Lesions begin in early childhood and lead to progressive ankyloses of major joints with resultant loss of movement. Prognosis is poor and median life expectancy is 40 years.MedDRA version: 20.0Level: PTClassification code 10068715Term: Fibrodysplasia ossificans progressivaSystem Organ Class: 10010331 - Congenital, familial and genetic disordersTherapeutic area: Diseases [C] - Musculoskeletal Diseases [C05]
- Registration Number
- EUCTR2014-002496-28-GB
- Lead Sponsor
- Clementia Pharmaceuticals Inc.
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Authorised-recruitment may be ongoing or finished
- Sex
- All
- Target Recruitment
- 60
Study Population (Adult and Pediatric Cohorts -Part B)
1.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.
2.For the Adult Cohort, subjects under the age of 18 must have knee and hand/wrist radiographs confirming = 90% skeletal maturity.
3.Written, signed, and dated subject/parent informed consent; and, for subjects who are minors, age appropriate assent (this must be performed according to local regulations).
Study Population for Non Flare-Up Based Treatment
(Adult Cohort-Part B)
1.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.
2.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.
Study Population for Flare Up Based Treatment
(Adult and Pediatric Cohorts-Part B)
1.Symptomatic onset of a flare-up within 7 days before the first dose of study drug and defined by the presence of at least two of the following symptoms: pain, soft tissue swelling, decreased ROM, stiffness, redness, and warmth. Symptoms must be reported by the subject, be consistent with their previous flare-ups, and include a subject reported onset date, and flare-up must be confirmed by the Investigator.
2.Flare-up is at an appendicular area (upper or lower extremity), abdomen, chest, neck, or lower back; and subject has received, is receiving, or is willing to receive treatment per standard of care, which may or may not include prednisone (2 mg/kg PO to a maximum dose of 100 mg daily) for 4 days.
3.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 cl
Study Population
(Adult and Pediatric Cohorts-Part B)
1.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.
2.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)
1.Weight <20 kg.
2.Intercurrent known or suspected non-healed fracture at any location.
3.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.
4.Exposure to synthetic oral retinoids other than palovarotene in the past 30 days prior to Part B Screening (signature of the informed consent).
5.Concurrent treatment with tetracycline or any tetracycline derivatives due to the potential increased risk of pseudotumor cerebri.
6.History of allergy or hypersensitivity to retinoids or lactose.
7.Concomitant medications that are inhibitors or inducers of cytochrome P450 (CYP450) 3A4 activity (see Section 5.4).
8.Amylase or lipase >2x above the upper limit of normal (ULN) or with a history of chronic pancreatitis.
9.Elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5x ULN.
10.Fasting triglycerides >400 mg/dL with or without therapy.
11.Female subjects who are breastfeeding.
12.Subjects with uncontrolled cardiovascular, hepatic, pulmonary, gastrointestinal, endocrine, metabolic, ophthalmologic, immunologic, psychiatric, or other significant disease.
13.Subjects 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).
Study Population for Flare Up Based Treatment
(Adult and Pediatric Cohorts-Part B)
1.Weight <20 kg.
2.Intercurrent known or suspected non-healed fracture at any location.
3.Complete immobilization of joint at site of flare-up.
4.Inability of the subject to undergo imaging assessments using plain radiographs.
5.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.
6.Exposure to synthetic oral retinoids other than palovarotene in the past 30 days prior to Flare-up Screening (signature of the informed consent).
7.Concurrent treatment with tetracycline or any tetracycline derivatives due to the potential increased risk of pseudotumor cerebri.
8.History of allergy or hypersensitivity to retinoids or lactose.
9.Concomitant medications that are inhibitors or inducers of CYP450 3A4 activity (see Section 5.4.1).
10.Any subject with clinically significant elevations in amylase, lipase, AST, ALT, or fasting triglycerides during the most recent clinical laboratory assessment will require re-test prior to immediate flare-up based dosing with palovarotene per the Investigator. If upon re-test, the laboratory value in question remains clinically significantly abnormal, then the subject will not receive flare-up based treatment for this flare-up.
11.Female subjects who are breastfeeding.
12.Subjects with uncontrolled cardiovascular, hepatic, pulmonary, gastrointestinal, endocrine, metabolic, ophthalmologic, immunologic, psychiatric, or other significant diseas
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method