This site became the new ClinicalTrials.gov on June 19th. Learn more.
Show more
ClinicalTrials.gov Menu IMPORTANT: Listing of a study on this site does not reflect endorsement by the National Institutes of Health. Talk with a trusted healthcare professional before volunteering for a study. Read more...
ClinicalTrials.gov Menu IMPORTANT: Talk with a trusted healthcare professional before volunteering for a study. Read more...
ClinicalTrials.gov Menu
Give us feedback

An Open-Label Extension Study of Palovarotene to Treat Preosseous Flare-ups in FOP Subjects

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Clementia Pharmaceuticals Inc.
ClinicalTrials.gov Identifier:
NCT02279095
First received: October 26, 2014
Last updated: April 20, 2017
Last verified: December 2016
  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 (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.

Condition Intervention Phase
Fibrodysplasia Ossificans Progressiva Drug: Palovarotene dose level 1 Drug: Palovarotene dose level 2 Drug: Palovarotene dose level 3 Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
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)

Resource links provided by NLM:


Further study details as provided by Clementia Pharmaceuticals Inc.:

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

Secondary Outcome Measures:
  • 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 ]

Estimated Enrollment: 58
Study Start Date: October 2014
Estimated Study Completion Date: December 2018
Estimated Primary Completion Date: December 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Palovarotene dose level 1 (completed)
Subjects received weight-adjusted doses of palovarotene equivalent to 10 mg once daily for 14 days, followed by 5 mg once daily for 28 days (Part A).
Drug: Palovarotene dose level 1
Palovarotene was taken orally once daily at approximately the same time each day.
Experimental: Palovarotene dose level 2
Adult Cohort subjects (those with at least 90% skeletal maturity) will receive 5 mg palovarotene once daily for up to 24 months; and 20 mg palovarotene for 28 days, followed by 10 mg for 56 days for eligible flare-ups (Part B).
Drug: Palovarotene dose level 2
Palovarotene will be taken orally once daily at approximately the same time each day.
Experimental: Palovarotene dose level 3
During an eligible flare-up, Pediatric Cohort subjects (those with less than 90% skeletal maturity) will receive weight-adjusted doses of 20 mg palovarotene for 28 days, followed by 10 mg for 56 days (Part B).
Drug: Palovarotene dose level 3
Palovarotene will be taken orally once daily at approximately the same time each day.

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   6 Years to 65 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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).

Exclusion Criteria:

  • 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02279095

Locations
United States, California
University of California San Francisco, Division of Endocrinology and Metabolism
San Francisco, California, United States, 94143
United States, Minnesota
Mayo Clinic, Department of Medicine
Rochester, Minnesota, United States, 55905
United States, Pennsylvania
University of Pennsylvania, Center for FOP & Related Bone Disorders
Philadelphia, Pennsylvania, United States, 19104
Argentina
Hospital Italiano de Buenos Aires, Department of Pediatrics
Buenos Aires, Argentina
Australia, Queensland
Queensland University of Technology (QUT) Institute of Health and Biomedical Innovation (IHBI)
Woolloongabba, Queensland, Australia, 4102
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 Mayo Clinic, Department of Medicine
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
Principal Investigator: Carmen L De Cunto, MD Hospital Italiano de Buenos Aires
Principal Investigator: Mona Al Mukaddam, MD, MS, CCD University of Pennsylvania
Principal Investigator: Matthew Brown, MD Queensland University of Technology (QUT) Institute of Health and Biomedical Innovation (IHBI)
  More Information

Additional Information:
Publications:
Responsible Party: Clementia Pharmaceuticals Inc.
ClinicalTrials.gov Identifier: NCT02279095     History of Changes
Other Study ID Numbers: PVO-1A-202
Study First Received: October 26, 2014
Last Updated: April 20, 2017

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

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

ClinicalTrials.gov processed this record on June 26, 2017