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Trial record 5 of 29 for:    fop

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

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT02190747
First Posted: July 15, 2014
Last Update Posted: October 23, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Clementia Pharmaceuticals Inc.
  Purpose
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.

Condition Intervention Phase
Fibrodysplasia Ossificans Progressiva Drug: Palovarotene Drug: Placebo Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
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)

Resource links provided by NLM:


Further study details as provided by Clementia Pharmaceuticals Inc.:

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

Secondary Outcome Measures:
  • 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 ]

Enrollment: 40
Study Start Date: July 2014
Study Completion Date: May 23, 2016
Primary Completion Date: May 23, 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Palovarotene dose level 1 (Cohort 1)
Doses of palovarotene in dose level 1 are 10 mg once daily for 14 days, followed by 5 mg once daily for 28 days.
Drug: 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: Palovarotene dose level 2 (Cohort 2)
Weight-adjusted doses of palovarotene in dose level 2 are 10 mg palovarotene once daily, followed by 5 mg once daily for 28 days.
Drug: 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: Palovarotene dose level 3 (Cohort 2)
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.
Drug: 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: Sugar pill
The placebo comparator will be taken once daily for the same duration as the palovarotene dose groups in both Cohorts 1 and 2.
Drug: Placebo

Detailed 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.

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   6 Years and older   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02190747


Locations
United States, California
University of California San Francisco, Division of Endocrinology and Metabolism
San Francisco, California, United States, 94143
United States, Pennsylvania
University of Pennsylvania, Center for Research in FOP & Related Disorders
Philadelphia, Pennsylvania, United States, 19104
France
Hôpital Necker-Enfants Malades, Department of Genetics
Paris, France
United Kingdom
The Royal National Orthopaedic Hospital, Brockley Hill
Stanmore, Middlesex, United Kingdom, HA7 4LP
Sponsors and Collaborators
Clementia Pharmaceuticals Inc.
Investigators
Principal Investigator: Robert J Pignolo, MD, PhD University of Pennsylvania, Center for Research in FOP & Related Disorders
Principal Investigator: Edward Hsiao, MD, PhD University of California San Francisco, Division of Endocrinology and Metabolism
Principal Investigator: Genevieve Baujat, MD Hôpital Necker-Enfants Malades, Department of Genetics
Principal Investigator: Richard Keen, BSc, PhD The Royal National Orthopaedic Hospital, Brockley Hill
  More Information

Additional Information:
Publications:
Responsible Party: Clementia Pharmaceuticals Inc.
ClinicalTrials.gov Identifier: NCT02190747     History of Changes
Other Study ID Numbers: PVO-1A-201
First Submitted: July 13, 2014
First Posted: July 15, 2014
Last Update Posted: October 23, 2017
Last Verified: October 2017

Keywords provided by Clementia Pharmaceuticals Inc.:
Myositis Ossificans Progressiva
FOP
Intervention study
Clinical trial Phase 2
Efficacy and safety
Heterotopic ossification
Flare-up
Palovarotene
Retinoic acid receptor agonist
Retinoic acid receptor gamma agonist
Clementia
Munchmeyer's Disease

Additional relevant MeSH terms:
Myositis Ossificans
Myositis
Muscular Diseases
Musculoskeletal Diseases