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An Open-Label Extension Study of Palovarotene Treatment in Fibrodysplasia Ossificans Progressiva (FOP)

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ClinicalTrials.gov Identifier: NCT02279095
Recruitment Status : Active, not recruiting
First Posted : October 30, 2014
Last Update Posted : September 21, 2021
Sponsor:
Information provided by (Responsible Party):
Ipsen ( Clementia Pharmaceuticals Inc. )

Brief Summary:

Fibrodysplasia Ossificans Progressiva (FOP) is a rare, severely disabling disease characterized by heterotopic ossification (HO), i.e., abnormal bone formation, often associated with painful, recurrent episodes of soft tissue swelling (flare-ups). Lesions begin in early childhood and lead to progressive ankyloses of major joints with resultant loss of movement.

In this study, the ability of different palovarotene dosing regimens to prevent the formation of new HO will be evaluated in adult and pediatric participants with FOP.


Condition or disease Intervention/treatment Phase
Fibrodysplasia Ossificans Progressiva Drug: Palovarotene dose level 1 Drug: Palovarotene dose level 2 Drug: Palovarotene dose level 3 Drug: Palovarotene dose level 4 Phase 2

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 participants with FOP. 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.

The study was divided into four parts: Part A (completed on July 2017), Part B (completed on October 2018), Part C (ongoing) and Part D (ongoing). Each part was associated with revised palovarotene treatment regimens.

In Part A, all pediatric and adult participants who successfully completed Study PVO-1A-201 were enrolled and followed for up to 36 months. Participants who had an eligible flare-up received 10 mg palovarotene daily for 14 days, followed by 5 mg palovarotene daily for 28 days (or weight-based equivalent).

In Part B, participants who successfully completed Study PVO-1A-201 (including any participant who participated in Part A of Study PVO-1A-202) as well as up to 20 new adult participants were followed for up to 24 months. The Adult Cohort included all participants with at least 90% skeletal maturity, regardless of age. The Pediatric Cohort included all participants with less than 90% skeletal maturity. Any Pediatric Cohort participant who achieved ≥90% skeletal maturity during Part B was considered for enrollment into the Adult Cohort at the discretion of the Investigator. Part B added a 5 mg palovarotene daily chronic treatment regimen administered between flare-ups for participants in the Adult Cohort for up to 24 months. Part B also increased the flare-up dosing to 20 mg palovarotene daily for 28 days, followed by 10 mg palovarotene daily for 56 days (or weight-adjusted equivalents in the Pediatric Cohort). Treatment could be extended if the flare-up was still ongoing.

In Part C, participants from Part B are being followed for up to an additional 48 months. There will be no new participants in Part C. All eligible participants, including skeletally immature participants, are receiving 5 mg palovarotene daily chronic treatment regimen (weight-adjusted doses for skeletally immature participants).

In Part D, annual post last dose of study treatment assessments for up to 2 years will be obtained in participants who were skeletally immature at the time of study treatment discontinuation in order to obtain longer-term safety data. No new participants will be enrolled into Part D.

Part C plus Part D duration will not exceed 48 months.

All participants will undergo all study procedures as specified in the respective schedule of assessments and for as long as they are not 100% skeletally mature.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 54 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2, Open-Label Extension, Efficacy and Safety Study of a Retinoic Acid Receptor Gamma (RARγ) Specific Agonist (Palovarotene) in the Treatment of Preosseous Flare-ups in Subjects With Fibrodysplasia Ossificans Progressiva (FOP)
Actual Study Start Date : October 27, 2014
Estimated Primary Completion Date : October 31, 2022
Estimated Study Completion Date : October 31, 2022


Arm Intervention/treatment
Experimental: Palovarotene dose level 1 (completed)
Participants received 10 mg palovarotene for 14 days, followed by 5 mg palovarotene for 28 days (or weight-based equivalent) for eligible flare-ups (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
Participants with at least 90% skeletal maturity received 5 mg palovarotene 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
Participants with less than 90% skeletal maturity received weight-adjusted doses of 20 mg palovarotene for 28 days, followed by 10 mg for 56 days for eligible flare-ups (Part B).
Drug: Palovarotene dose level 3
Palovarotene will be taken orally once daily at approximately the same time each day.

Experimental: Palovarotene dose level 4
All participants will receive 5 mg palovarotene for up to 48 months and 20 mg palovarotene for 28 days, followed by 10 mg for 56 days for eligible flare-ups (Part C). Skeletally immature participants will receive weight-adjusted doses.
Drug: Palovarotene dose level 4
Palovarotene will be taken orally once daily at approximately the same time each day.




Primary Outcome Measures :
  1. Part A and Part B - Proportion of flare-up with no new HO ("responders") [ Time Frame: Week 12 ]
    Assessed by computed tomography (CT) scan (or plain radiographs for participants unable to undergo CT scan)

  2. Part C - Annualized change in new HO volume [ Time Frame: Every 12 months for up to 72 months ]
    Assessed by low-dose whole body computed tomography (WBCT) (excluding head)


Secondary Outcome Measures :
  1. Part A - Proportion of participants across the seven HO scores (0-6) [ Time Frame: Study Months 6 and 12 (Follow-up Component); Flare-up Weeks 6 and 12 (Flare-up Component) ]
    Assessed by plain radiographs

  2. Part A - Change from baseline in amount (area) of new heterotopic bone formed [ Time Frame: Study Months 6 and 12 (Follow-up Component); Flare-up Weeks 6 and 12 (Flare-up Component) ]
    Assessed by plain radiographs

  3. Part A - Change from baseline in cartilage, bone, angiogenesis, and inflammation biomarkers [ Time Frame: Study Months 6 and 12 (Follow-up Component); Flare-up Weeks 2, 4, 6, and 12 (Flare-up Component) ]
  4. Part A and Part B - Change from baseline in active range of motion (ROM) [ Time Frame: Study Months 6 and 12 (Follow-up Component); Flare-up Weeks 6 and 12 (Flare-up Component) ]
    Assessed by goniometer

  5. Part A and Part B - Change from baseline in ROM [ Time Frame: Study Months 6 and 12 (Follow-up Component); Flare-up Weeks 6 and 12 (Flare-up Component) ]
    Assessed by Cumulative Analogue Joint Involvement Scale (CAJIS)

  6. Part A and Part B - Participant and Investigator global assessment of movement [ Time Frame: Study Months 6 and 12 (Follow-up Component); Flare-up Weeks 6 and 12 (Flare-up Component) ]
  7. Part A - Change from baseline in pain and swelling (for participants under 8 years of age) [ Time Frame: Study Months 6 and 12 (Follow-up Component); Flare-up Weeks 2, 4, 6, 9, and 12 (Flare-up Component) ]
    Assessed by numeric rating scale (NRS) or Faces Pain Scale-Revised (FPS-R)

  8. Part A and Part B - Change from baseline in physical function [ Time Frame: Study Months 6 and 12 (Follow-up Component); Flare-up Weeks 2, 4, 6, 8, 9, and 12 (Flare-up Component) ]
    Assessed by age-appropriate forms of the FOP-Physical Function Questionnaire (FOP-PFQ)

  9. Part A and Part B - Change from baseline in physical and mental health [ Time Frame: Study Months 6 and 12 (Follow-up Component); Flare-up Weeks 2, 4, 6, 8, 9, and 12 (Flare-up Component) ]
    Assessed by age-appropriate forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale

  10. Part A and Part B - Change from baseline in the use of assistive devices and adaptations for daily living by FOP participants [ Time Frame: Study Months 6 and 12 (Follow-up Component); Flare-up Weeks 6 and 12 (Flare-up Component) ]
  11. Part A and Part B - Presence of soft tissue swelling and/or cartilage [ Time Frame: Flare-up Weeks 6 and 12 (Flare-up Component) ]
    Assessed by magnetic resonance imaging (MRI) (or by US in participants unable to undergo MRI)

  12. Part B - Change from baseline in amount of bone formation (volume) [ Time Frame: Flare-up Week 12 ]
    Assessed by low-dose CT scan (or area by plain radiographs for participants unable to undergo CT scan)

  13. Part B - Change from baseline in cartilage, bone, angiogenesis, and inflammation biomarkers [ Time Frame: Flare-up Weeks 4, 8, and 12 ]
  14. Duration of active, symptomatic flare-up (start date and end date) [ Time Frame: Up to 12 weeks ]
    Assessed by the participant and the Investigator

  15. Part B (Chronic treatment) - Change from baseline in whole body burden of HO [ Time Frame: Study Months 12 and 24 ]
    Assessed by low-dose WBCT scan (excluding head)

  16. Part B (Chronic treatment) - Number of flare-ups per participant-month overall, and by edema severity [ Time Frame: Up to 24 months ]
  17. Part C - Percent of participants with new HO [ Time Frame: Every 12 months up to 72 months ]
  18. Part C - Change from baseline in ROM [ Time Frame: Every 6 months up to 72 months ]
    Assessed by CAJIS

  19. Part C - Change from baseline in physical function [ Time Frame: Every 6 months up to 72 months ]
    Assessed by age-appropriate forms of the FOP-PFQ

  20. Part C - Change from baseline in physical and mental function for participants ≥15 years old and mental function for participants <15 years old [ Time Frame: Every 6 months up to 72 months ]
    Assessed by age-appropriate forms of the PROMIS Global Health Scale



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-202/Part B.
  • Written, signed, and dated informed consent and, for participants who are minors, age-appropriate participant assent (performed according to local regulations).
  • Accessible for treatment with palovarotene and follow-up (able and willing to travel to a site for the initial and all follow-up clinic visits).
  • Able to undergo low-dose, WBCT scan, excluding head.
  • Females of child-bearing potential must have a negative blood or urine pregnancy test (with sensitivity of at least 50 mIU/mL) prior to administration of palovarotene.
  • Male and FOCBP participants must agree to remain abstinent from heterosexual sex during treatment and for 1 month after treatment or, if sexually active, to use two effective methods of birth control during and for 1 month after treatment. Additionally, sexually active females of childbearing potential (FOCBP) participants must already be using two effective methods of birth control 1 month before treatment is to start. Specific risk of the use of retinoids during pregnancy, and the agreement to remain abstinent or use two effective methods of birth control will be clearly defined in the informed consent and the participant or legally authorized representatives.

Exclusion Criteria:

  • Any reason that, in the opinion of the Investigator, would lead to the inability of the participant and/or family to comply with the protocol.
  • 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.
  • Currently using vitamin A or beta carotene, multivitamins containing vitamin A or beta carotene, herbal preparations containing vitamin A or beta carotene, or fish oil, and unable or unwilling to discontinue use of these products during palovarotene treatment.
  • Participants 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).

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): NCT02279095


Locations
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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
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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: NCT02279095    
Other Study ID Numbers: PVO-1A-202
2014-002496-28 ( EudraCT Number )
First Posted: October 30, 2014    Key Record Dates
Last Update Posted: September 21, 2021
Last Verified: August 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Ipsen ( Clementia Pharmaceuticals Inc. ):
Fibrodysplasia Ossificans Progressiva
Myositis 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
Munchmeyer's Disease
FOP
Ipsen
Additional relevant MeSH terms:
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Myositis Ossificans
Myositis
Muscular Diseases
Musculoskeletal Diseases