Clinical Trial: An Efficacy and Safety Study of Palovarotene to Treat Preosseous Flare-ups in FOP Subjects

Study Status: Active, not recruiting
Recruit Status: Active, not recruiting
Study Type: Interventional

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

Brief 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.

Detailed Summary:

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.


Sponsor: Clementia Pharmaceuticals Inc.

Current Primary Outcome: Percentage of subject responders as assessed by plain radiographs. [ Time Frame: Study Day 42 ]

Original Primary Outcome: Same as current

Current Secondary Outcome:

  • 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 ]


Original Secondary Outcome:

  • 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. [ 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 ]
  • Pain and swelling at the flare-up site using a numeric rating scale for each symptom. [ 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 ]
  • Patient-reported assessment of physical function. [ Time Frame: Baseline, Study Days 14, 28, 42, 63, and 84 ]
  • Safety evaluation including adverse events and clinical safety laboratory parameters. [ Time Frame: Study Days 1 (the first day of dosing), 14, 28, 42, 63, and 84 ]


Information By: Clementia Pharmaceuticals Inc.

Dates:
Date Received: July 13, 2014
Date Started: July 2014
Date Completion:
Last Updated: July 22, 2016
Last Verified: February 2016