Clinical Trial: An Open-Label Extension 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, Open-Label Extension, 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 (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 to prevent HO following injury. This 24-month study will (1) continue to follow the 40 FOP subjects who completed Clementia Study PVO-1A-201; (2) enroll up to 20 additional new 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, multicenter, open-label study is to evaluate the safety and efficacy of different palovarotene dosing regimens in subjects with FOP.

In Part A, all subjects who completed Study PVO-1A-201 and enrolled into the current study received daily treatment with open-label palovarotene at a dose of 10 mg for 14 days, followed by 5 mg for 28 days (or the weight-based equivalent). This part of the study is completed.

In Part B, 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:

  • Percentage of subject responders at the original flare-up site, as assessed by plain radiographs (Follow-up Component). [ Time Frame: Study Month 6 ]
  • Percentage of subject responders at the original flare-up site, as assessed by plain radiographs (Follow-up Component). [ Time Frame: Study Month 12 ]
  • Percentage of subject responders at subsequent distinct flare-up site(s), as assessed by plain radiographs (Flare-up Component). [ Time Frame: Flare-up Day 42 ]


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/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 ]
  • 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, and 84 (EOT) ]
  • Use of assistive devices and adaptations for daily living by FOP subjects. [ Time Frame: baseline, Flare-up Day 84/EOT ]
  • Plasma biomarker levels. [ Time Frame: baseline, Flare-up Days 28, 56, and 84/EOT ]
  • Presence of soft tissue swelling and/or cartilage by magnetic resonance imaging (or ultrasound). [ Time Frame: Flare-up Day 84/EOT ]
  • Pain and 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: symptom start date to symptom end date ]
  • 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), 14, 28, 42, 56, 70, and 84/EOT; Study Months 3, 6, 9, 12, 15, 18, 21, and 24 ]


Original Secondary Outcome:

  • Numeric heterotopic ossification scores at the flare-up site as assessed by plain radiograph. [ Time Frame: Study Months 6 and 12 (Follow-up Component); and Flare-up Days 42 and 84 (Flare-up Component). ]
  • Amount (area) of new heterotopic bone formed at the flare-up site assessed by plain radiographs. [ Time Frame: Study Months 6 and 12 (Follow-up Component); and baseline, Flare-up Days 42 and 84 (Flare-up Component). ]
  • Plasma biomarker levels. [ Time Frame: Study Months 6 and 12 (Follow-up Component); and baseline, Flare-up Days 14, 28, 42, 63, and 84 (Flare-up Component). ]
  • Pain and swelling at the flare-up site using a numeric rating scale for each symptom. [ Time Frame: Study Months 6 and 12 (Follow-up Component); and baseline, Flare-up Days 14, 28, 42, 63, and 84 (Flare-up Component). ]
  • Patient-reported assessment of physical function. [ Time Frame: Study Months 6 and 12 (Follow-up Component); and baseline, Flare-up Days 14, 28, 42, 63, and 84 (Flare-up Component). ]
  • Safety evaluation including adverse events and clinical safety laboratory parameters. [ Time Frame: Study Months 6 and 12 (Follow-up Component); and Flare-up Days 1 (the first day of dosing), 14, 28, 42, 63, and 84 (Flare-up Component). ]
  • Percentage of subject responders as assessed by plain radiographs. [ Time Frame: Flare-up Day 84 (Flare-up Component) ]
  • Amount of bone formation (volume) as assessed by low-dose CT scan. [ Time Frame: baseline, Flare-up Days 42 and 84 (Flare-up Component). ]
  • Presence of soft tissue swelling and/or cartilage as assessed by MRI. [ Time Frame: baseline, Flare-up Days 42 and 84 (Flare-up Component). ]
  • Active range of motion measured by goniometer of the relevant joint. [ Time Frame: baseline, Flare-up Days 42 and 84 (Flare-up Component). ]
  • Duration of active, symptomatic flare-up. [ Time Frame: Symptom start date to symptom end date (Flare-up Component). ]


Information By: Clementia Pharmaceuticals Inc.

Dates:
Date Received: October 26, 2014
Date Started: October 2014
Date Completion: December 2018
Last Updated: April 20, 2017
Last Verified: December 2016