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Eligibility
for people ages 6 years to 65 years
Location
at San Francisco, California and other locations
Dates
study started
estimated completion:
Principal Investigator

Description

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.

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 Ossificans Progressiva (FOP)

Details

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.

Keywords

Fibrodysplasia Ossificans Progressiva Open-label extension study Clinical trial Phase 2 Efficacy and safety Heterotopic ossification Flare-up Palovarotene Retinoic acid receptor agonist Retinoic acid receptor gamma agonist Clementia Myositis Ossificans Progressiva Munchmeyer's Disease FOP

Eligibility

You can join if…

Open to people ages 6 years to 65 years

  • Completion of Study PVO-1A-201; or new Adult Cohort subjects with confirmed R206H mutation who (1) have had at least two symptomatic flare-ups in the past 2 years, but no flare-up symptoms within the past 4 weeks; (2) have a Cumulative Analogue Joint Involvement for FOP (CAJIS) score of 6-16 (inclusive); and (3) are able to receive 5 mg palovarotene daily.
  • Adult Cohort subjects under the age of 18 years must have knee and hand/wrist radiographs confirming at least 90% skeletal maturity.
  • Abstinent or using two highly effective forms of birth control.
  • 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.
  • Written, signed, and dated informed consent and, for subjects who are minors,age-appropriate subject assent (performed according to local regulations).

You CAN'T join if...

  • Weight <20 kg.
  • Intercurrent non-healed fracture.
  • 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 Part B 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 of CYP450 3A4 activity.
  • Amylase or lipase>2x above the upper limit of normal or with a history of pancreatitis.
  • Elevated aspartate aminotransferase or alanine aminotransferase>2.5x the upper limit of normal.
  • Fasting triglycerides>400 mg/dL with or without therapy.
  • 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.

Locations

  • Mayo Clinic, Department of Medicine
    Rochester, Minnesota, 55905, USA
  • University of Pennsylvania, Center for FOP & Related Bone Disorders
    Philadelphia, Pennsylvania, 19104, USA
  • Hospital Italiano de Buenos Aires, Department of Pediatrics
    Buenos Aires, Argentina
  • Queensland University of Technology (QUT) Institute of Health and Biomedical Innovation (IHBI)
    Woolloongabba, Queensland, 4102, Australia
  • Hôpital Necker-Enfants Malades, Department of Genetics
    Paris, France
  • The Royal National Orthopaedic Hospital, Brockley Hill
    Stanmore, Middlesex, HA7 4LP, United Kingdom

Details

Status
in progress, not accepting new patients
Start Date
Completion Date
(estimated)
Sponsor
Clementia Pharmaceuticals Inc.
Links
Website for the International FOP Association
Website for the French FOP Association
Click here for more information about this study: 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 Ossificans Progressiva (FOP)
ID
NCT02279095
Phase
Phase 2
Lead Scientist
Edward Hsiao
Study Type
Interventional
Last Updated
December 2016