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

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ClinicalTrials.gov Identifier: NCT02979769
Recruitment Status : Active, not recruiting
First Posted : December 2, 2016
Last Update Posted : June 2, 2020
Sponsor:
Information provided by (Responsible Party):
Ipsen ( Clementia Pharmaceuticals Inc. )

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. Study PVO-1A-201 as well as up to two new adult subjects were followed for up to 24 months. Subjects who participated under Amendment 1 will be followed for up to an additional 36 months. No new subjects will be enrolled.

Condition or disease Intervention/treatment Phase
Fibrodysplasia Ossificans Progressiva Drug: Palovarotene dose level 1 Drug: Palovarotene dose level 2 Phase 2

Detailed Description:

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. Efficacy will be assessed based on the ability of palovarotene to prevent the formation of new heterotopic ossification (HO) as assessed by low-dose whole body computed tomography (WBCT) scan, excluding head.

All subjects will be treated with 5 mg palovarotene daily (weight adjusted dose for skeletally immature subjects) for up to 36 months. Site visits will occur at baseline/screening and at Study Months 12, 24 and 36; 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 under 18 years) will be the same as for Adult Cohort subjects except doses will adjusted for weight.

All weight-based dosing will cease when subjects are 18 years old, but radiographic assessment of the growth plate will continue until these subjects achieve 100% skeletal maturity at both knee and hand/wrist locations.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 9 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
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)
Actual Study Start Date : November 28, 2016
Estimated Primary Completion Date : July 2021
Estimated Study Completion Date : July 2021


Arm Intervention/treatment
Experimental: Palovarotene dose level 1
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.
Drug: Palovarotene dose level 1
Palovarotene will be taken orally once daily at approximately the same time each day.

Experimental: Palovarotene dose level 2
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.
Drug: Palovarotene dose level 2
Palovarotene will be taken orally once daily at approximately the same time each day.




Primary Outcome Measures :
  1. Annualized change in new HO volume as assessed by low-dose WBCT scan, excluding head [ Time Frame: Annually until the end of study (36 months) ]
    The annualized change from the original protocol, and Amendments 1 and 3, will be compared to data collected from the Natural History Study (NHS).


Secondary Outcome Measures :
  1. Percent of subjects with new HO [ Time Frame: baseline, 12, 24, 36 months and overall ]
  2. Change from baseline in range of motion (ROM) as assessed by CAJIS [ Time Frame: baseline, 6, 12, 18, 24, 30 and 36 months ]

    Cumulative Analogue Joint Involvement Scale (CAJIS) for FOP assesses functional disability by categorizing range of motion across 12 joints and three body regions with each joint/region assessed as: 0=uninvolved;

    1=affected; 2=functionally ankylosed.


  3. Change from baseline in physical function using age-appropriate forms of the FOP-Physical Function Questionnaire (FOP-PFQ) [ Time Frame: baseline, 6, 12, 18, 24, 30 and 36 months ]


Information from the National Library of Medicine

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Ages Eligible for Study:   6 Years to 65 Years   (Child, Adult, Older 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:

  • Simultaneous participation in another clinical research study (except for Studies PVO-1A-201, PVO-1A-202, PVO-1A-203, or PVO 1A-001) within the 4 weeks prior to Screening.
  • 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.
  • Subjects with uncontrolled cardiovascular, hepatic, pulmonary, gastrointestinal, endocrine, metabolic, ophthalmologic, immunologic, psychiatric, or other significant disease.
  • Subjects experiencing suicidal ideation (type 4 or 5) or any suicidal behavior within the past month as defined by the Columbia Suicide Severity Rating Scale (C-SSRS).
  • 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.

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): NCT02979769


Locations
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France
Hôpital Necker-Enfants Malades, Department of Genetics
Paris, France
Sponsors and Collaborators
Clementia Pharmaceuticals Inc.
Investigators
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Study Director: Ipsen Medical Director Ipsen
Additional Information:
Publications:
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Responsible Party: Clementia Pharmaceuticals Inc.
ClinicalTrials.gov Identifier: NCT02979769    
Other Study ID Numbers: PVO-1A-204
2016-002526-36 ( EudraCT Number )
First Posted: December 2, 2016    Key Record Dates
Last Update Posted: June 2, 2020
Last Verified: May 2020
Keywords provided by Ipsen ( Clementia Pharmaceuticals Inc. ):
Open-label extension study
Clinical trial Phase 2
Efficacy and safety
Heterotopic ossification
Flare-up
Palovarotene
Retinoic acide receptor agonist
Retinoic acide receptor gamma agonist
Clementia
Myositis Ossificans
Munchmeyer's Disease
FOP
Additional relevant MeSH terms:
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Myositis Ossificans
Myositis
Muscular Diseases
Musculoskeletal Diseases