Overview

This trial is active, not recruiting.

Condition fibrodysplasia ossificans progressiva
Treatments palovarotene, placebo
Phase phase 2
Sponsor Clementia Pharmaceuticals Inc.
Start date July 2014
End date June 2017
Trial size 40 participants
Trial identifier NCT02190747, PVO-1A-201

Summary

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 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 (RAR) gamma agonists to prevent heterotopic ossification (HO) following injury. The purpose of the study is to evaluate whether palovarotene, an RAR gamma agonist, will prevent HO during and following a flare-up in subjects with FOP.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Allocation randomized
Endpoint classification safety/efficacy study
Intervention model parallel assignment
Masking double blind (subject, caregiver, investigator)
Primary purpose treatment
Arm
(Experimental)
Doses of palovarotene in dose level 1 are 10 mg once daily for 14 days, followed by 5 mg once daily for 28 days.
palovarotene
Palovarotene will be taken orally once daily at approximately the same time each day. Powder filled hard gelatin capsules will be opened and the contents added onto specific food.
(Experimental)
Weight-adjusted doses of palovarotene in dose level 2 are 10 mg palovarotene once daily, followed by 5 mg once daily for 28 days.
palovarotene
Palovarotene will be taken orally once daily at approximately the same time each day. Powder filled hard gelatin capsules will be opened and the contents added onto specific food.
(Experimental)
Weight-adjusted doses of palovarotene in dose level 3 are 5 mg palovarotene once daily, followed by 2.5 mg once daily for 28 days.
palovarotene
Palovarotene will be taken orally once daily at approximately the same time each day. Powder filled hard gelatin capsules will be opened and the contents added onto specific food.
(Placebo Comparator)
The placebo comparator will be taken once daily for the same duration as the palovarotene dose groups in both Cohorts 1 and 2.
placebo

Primary Outcomes

Measure
Percentage of subject responders as assessed by plain radiographs.
time frame: Study Day 42

Secondary Outcomes

Measure
Numeric heterotopic ossification scores at the flare-up site as assessed by plain radiograph.
time frame: Study Days 42 and 84
Amount (area) of new heterotopic bone formed at the flare-up site assessed by plain radiographs.
time frame: Baseline, Study Days 42 and 84
Percentage of subject responders as assessed by plain radiographs.
time frame: Study Day 84
Plasma biomarker levels.
time frame: Baseline, Study Days 14, 28, 42, and 84
Amount of bone formation (volume) as assessed by low dose CT scan.
time frame: Baseline, Study Days 42 and 84
Presence of soft tissue swelling and/or cartilage as assessed by MRI (or soft tissue swelling by ultrasound in subjects unable to undergo MRI).
time frame: Baseline, Study Days 42 and 84
Active range of motion measured by goniometer of the relevant joint.
time frame: Baseline, Study Days 42 and 84
Subject and Investigator global assessment of movement.
time frame: Baseline, Study Days 42 and 84
Pain and swelling at the flare-up site using a numeric rating scale for each symptom (or the Faces Pain Scale-Revised for subjects under 8 years of age).
time frame: Baseline, Study Days 14, 28, 42, 63, and 84
Use of assistive devices and adaptations for daily living by FOP subjects.
time frame: Baseline, Study Days 42 and 84
Duration of active, symptomatic flare-up.
time frame: Symptom start date to symptom end date
Age-appropriate patient-reported assessment of physical function.
time frame: Baseline, Study Days 14, 28, 42, 63, and 84
Safety evaluation including adverse events, clinical safety laboratory parameters, and assessment of epiphyseal growth plate and linear growth in subjects under the age of 18 years.
time frame: Study Days 1 (the first day of dosing), 14, 28, 42, 63, and 84

Eligibility Criteria

Male or female participants at least 6 years old.

Inclusion Criteria: - Written, signed, and dated informed subject/parent consent or age-appropriate assent. - Subjects clinically diagnosed with classic Fibrodysplasia Ossificans Progressiva (FOP). - Symptomatic onset of a distinct flare-up within 7 days of Study Day 1 (start of study drug) and defined by the presence of at least two of six of the following symptoms: pain, soft tissue swelling, decreased range of motion, stiffness, redness, and warmth. Flare-up must be confirmed by the physician at the Screening visit. - Flare-up is at an appendicular area (upper or lower extremity), abdomen, or chest; and subject has received, is receiving, or is willing to receive treatment per standard of care, which may or may not include oral prednisone (2 mg/kg PO to a maximum dose of 100 mg daily) for 4 days. - Abstinent or using two highly effective forms of birth control. - Subjects must be accessible for treatment 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 follow-up visits. Exclusion Criteria: - Weight <20 kg. - Intercurrent non-healed fracture at any location. - Complete immobilization of joint at site of flare-up. - The inability of the subject to undergo imaging assessments using plain radiographs. - 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 for the duration of the study. - Exposure to synthetic oral retinoids in the past 30 days prior to Screening (signature of the informed consent). - Concurrent treatment with tetracycline 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 CYP450 3A4 activity. - Amylase or lipase >1.5x above the upper limit of normal or with a history of chronic pancreatitis. - Elevated aspartate aminotransferase or alanine aminotransferase >2.5x the upper limit of normal. - Fasting triglycerides >400 mg/dL with or without therapy.

Additional Information

Official title A Phase 2 Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of a RARγ-Specific Agonist (Palovarotene) in the Treatment of Preosseous Flare-ups in Subjects With Fibrodysplasia Ossificans Progressiva (FOP)
Principal investigator Robert J Pignolo, MD, PhD
Description The primary objective is to evaluate the ability of different doses of palovarotene to prevent HO at the flare-up site in subjects with FOP as assessed by plain radiographs. This is a Phase 2, multi-center, randomized, double-blind, sponsor-unblinded, placebo-controlled study. Two cohorts of subjects will be randomized into different dosing regimens of palovarotene for a 6-week (42 days) treatment period. The study will consist of three periods: 1. A Screening period to occur within 7 days of a distinct flare-up. The first dose of study drug will be taken within 7 days of the flare-up initiation. 2. A double-blind treatment period of 6 weeks (42 days) duration. 3. A follow-up period of 6 weeks (42 days) duration. An initial cohort (Cohort 1) of subjects will be randomly assigned 3:1 to either palovarotene or placebo daily for 42 days. Subjects randomized to palovarotene in Cohort 1 will receive an initial daily dose of 10 mg for 14 days followed by 5 mg daily for 28 days. In Cohort 2, new FOP subjects meeting all inclusion/exclusion criteria will be randomly assigned 3:3:2 to two dose regimens of palovarotene (10 mg for 14 days and 5 mg for 28 days; 5 mg for 14 days and 2.5 mg for 28 days) or placebo daily for 42 days. Doses will be weight-adjusted and subjects randomized within three weight-range categories (20 to <40 kg, 40 to <60 kg, and ≥60 kg). Subjects completing the study and still meeting eligibility requirements will be given the opportunity to enroll into an open-label extension study.
Trial information was received from ClinicalTrials.gov and was last updated in July 2016.
Information provided to ClinicalTrials.gov by Clementia Pharmaceuticals Inc..