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: 19.0 Level: PT Classification code 10068715 Term: Fibrodysplasia os
Conditions
Interventions
Product Name: Palovarotene
Product Code: Palovarotene
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Palovarotene
CAS Number: 410528-02-8
Other descriptive name: Palovarotene
Concentration un
Sponsors
Clementia Pharmaceuticals Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Study Population (Adult and Pediatric Cohorts) 1.Completion of Study PVO-1A-201 (through Study Day 84) including any subject from Study PVO-1A-202; 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) 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 Cohort) 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 m
Exclusion criteria
Exclusion criteria: Study Population (Adult and Pediatric Cohorts) 1.Simultaneous participation in another clinical research study (except for Studies PVO-1A-201, PVO-1A-202 , PVO-1A-203 or PVO-1A-001) within 4 weeks prior to 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) 1.Weight 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) 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 Appendix 4). 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: •To evaluate the safety and efficacy of different palovarotene dosing regimens to prevent heterotopic ossification following a flare-up in subjects with FOP. Efficacy will be based on the ability of palovarotene to prevent heterotopic ossification (HO) as assessed by low dose computed tomography (CT) scan (or plain radiographs for subjects unable to undergo CT scan).;Secondary Objective: •To evaluate the effect of palovarotene at the flare up site: on active range of motion (ROM) , on physical function, on physical and mental health, on pain and swelling associated with the flare up ; on the use of assistive devices and adaptations for daily living, on soft tissue swelling and cartilage formation. •To evaluate the effect of palovarotene by the subject and Investigator on global assessment of movement at the flare up sites. •To evaluate bone, cartilage, angiogenesis, and inflammation biomarkers (section 7.5) and explore correlations between changes from baseline in biomarkers and clinical efficacy. •To evaluate the pharmacokinetics of palovarotene during the first treated flare up. •To evaluate the ability of different dosing regimens of palovarotene to prevent new flare ups. •To evaluate the long-term safety and efficacy of prior palovarotene treatment at the original flare-up site in Study PVO-1A-201. ;Primary end point(s): Primary Efficacy Endpoint 1.Proportion of flare-ups with no new HO (“responders”). | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary Efficacy Endpoints for Flare-up Based Treatment (baseline is Flare-up Screening/Baseline): 1.Change from baseline in amount of bone formation (volume) as assessed by low-dose CT scan (or area by plain radiographs for subjects unable to undergo CT scan) at Flare-up Day 84/EOT. 2.Change from baseline in active ROM measured by goniometer at the flare up site at Flare-up Day 84/EOT. 3.Change from baseline in ROM as assessed by CAJIS at Flare-Up Day 84/EOT. 4.Subject and Investigator global assessment of movement at the flare-up site at Flare-Up Day 84/EOT. 5.Change from baseline in physical function using age-appropriate forms of the FOP-PFQ at Flare-up Days 28, 56, and 84/EOT. 6.Change from baseline in physical and mental health using age-appropriate forms of the PROMIS Global Health Scale at Flare-up Days 28, 56, and 84/EOT. 7.Change from baseline in the use of assistive devices and adaptations for daily living by FOP subjects at Flare-Up Day 84/EOT. 8.Presence of soft tissue swelling and/or cartilage by MRI at Flare-up Day 84/EOT; or presence of soft tissue swelling by US at Flare up Day 84/EOT in subjects unable to undergo MRI. 9.Change from baseline in cartilage, bone, angiogenesis, and inflammation biomarkers at Flare-up Days 28, 56, and 84/EOT. 10.Duration of active, symptomatic flare-up (start date and end date), as assessed by the subject and the Investigator. Secondary Endpoints for Non-Flare-up Based Treatment (baseline is Screening): 1.Change from baseline in whole body burden of HO as assessed by low dose whole body CT scan, excluding head, at Study Months 12 and 24. 2.Change from baseline in ROM as assessed by CAJIS at Study Months 12 and 24. 3.Number of flare-ups per subject-month overall, and by edema severity. Secondary Endpoints for Follow-up of Original Flare-up in Study PVO-1A-201 (baseline is pre-dose from Study PVO-1A-201): 1.Change from baseline in amount of new HO formed at the original flare u | — |
Countries
France
Contacts
Public ContactClinical Trials Information
Medpace France
Outcome results
None listed