Clinical Trial: An Open-Label Extension Study of Palovarotene to Prevent Heterotopic Ossification in FOP Subjects in France

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

Official Title: A Phase 2, Open-Label, Efficacy and Safety Study of an RARγ Specific Agonist (Palovarotene) to Prevent Heterotopic Ossification in Subjects With Fibrodysplasia Ossificans Pr

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 (heterotopic ossification or HO) 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 gamma (RARγ) agonists such as palovarotene (PVO) to prevent HO following injury. This 24-month study will (1) continue to follow FOP subjects from France who completed Clementia Study PVO-1A-201; (2) enroll up to eight additional new French subjects who have achieved at least 90% skeletal maturity; and (3) evaluate the ability of different palovarotene dosing regimens to prevent HO in these subjects.

Detailed Summary:

The main objective of this Phase 2, open-label study is to evaluate the safety and efficacy of different palovarotene dosing regimens in subjects with FOP in France.

Adult Cohort subjects (those with at least 90% skeletal maturity) will be treated with 5 mg palovarotene daily for up to 24 months. Site visits will occur at baseline/screening and at Study Months 12 and 24; subjects will also be contacted by telephone every 3 months.

In the event of an eligible flare-up, Adult Cohort subjects will receive 20 mg palovarotene daily for 28 days, followed by 10 mg for 56 days. Dosing may be extended if the flare-up is not resolved by Flare-up Day 84 and continue until the flare-up resolves (at the end-of-treatment [EOT]). Dose reduction, as directed by the Investigator, may occur in the event of intolerable side effects.

The flare-up based dosing regimen for Pediatric Cohort subjects (those with less than 90% skeletal maturity) will be the same as for Adult Cohort subjects except doses will adjusted for weight. Pediatric subjects will not receive non-flare-up daily dosing until preliminary efficacy and safety data are obtained in the Adult Cohort. Site visits will occur at Flare-up Baseline and at Flare-up Day 84/EOT; subjects will also be contacted by telephone every 2 weeks.


Sponsor: Clementia Pharmaceuticals Inc.

Current Primary Outcome: Percentage of flare-ups with no new HO as assessed by low-dose CT scan [ Time Frame: Flare-up Day 84 ]

Original Primary Outcome: Same as current

Current Secondary Outcome:

  • Amount (volume) of new HO at the flare-up site as assessed by low-dose CT scan. [ Time Frame: baseline, Flare-up Day 84/end-of-treatment (EOT) ]
  • Amount (volume) of new HO overall as assessed by low-dose whole body CT scan, excluding head. [ Time Frame: baseline, Study Months 12 and 24 ]
  • Active range of motion measured by goniometer at the flare-up site. [ Time Frame: baseline, Flare-up Day 84/EOT ]
  • Range of motion as assessed by the Cumulative Analogue Joint Involvement Scale for FOP (CAJIS). [ Time Frame: baseline, Flare-up Day 84/EOT; Study Months 12 and 24 ]
  • Number of flare-ups per subject-month exposure. [ Time Frame: study start date to study end date (up to 24 months) ]
  • Subject and Investigator global assessment of movement. [ Time Frame: Flare-up Day 84/EOT ]
  • Age-appropriate patient-reported assessment of physical function. [ Time Frame: baseline, Flare-up days 28, 56, 84/EOT; Study Months 12 and 24 ]
  • Use of assistive devices and adaptations for daily living by FOP subjects. [ Time Frame: baseline, Flare-up Day 84/EOT; Study Months 12 and 24 ]
  • Plasma biomarker levels. [ Time Frame: baseline, Flare-up Days 28, 56, and 84/EOT; Study Months 12 and 24 ]
  • Presence of soft tissue swelling and/or cartilage by magnetic resonance imaging (or ultrasound). [ Time Frame: Flare-up Day 84/EOT ]
  • Pain at the flare-up site using a numeric rating scale for each symptom. [ Time Frame: baseline, Flare-up Days 14, 28, 42, 56, 70, and 84/EOT ]
  • Swelling at the flare-up site using a numeric rating scale for each symptom. [ Time Frame: baseline, Flare-up Days 14, 28, 42, 56, 70, and 84/EOT ]
  • Duration of active, symptomatic flare-up. [ Time Frame: subject-reported symptom start date to documented symptom end date assessed up to 84 days/EOT ]
  • Amount of new heterotopic bone formed at the original flare-up site as assessed by low-dose CT scan (or plain radiograph for those unable to undergo CT scan). [ Time Frame: baseline, Study Month 12 (Pediatric Cohort only) ]
  • Safety evaluation including adverse events and clinical safety laboratory parameters. [ Time Frame: Flare-up Days 1 (the first day of dosing), 7, 14, 28, 42, 56, 70, and 84/EOT; Study Months 3, 6, 9, 12, 15, 18, 21, and 24 ]


Original Secondary Outcome: Same as current

Information By: Clementia Pharmaceuticals Inc.

Dates:
Date Received: November 23, 2016
Date Started: November 2016
Date Completion: December 2018
Last Updated: February 10, 2017
Last Verified: November 2016