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

Fibrodysplasia Ossificans Progressiva Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02279095
• Other study ID #: PVO-1A-202
• Secondary ID: 2014-002496-28
• Status: Completed
• Phase: Phase 2
• Start date: October 27, 2014
• Est. completion date: September 20, 2022

Study information

• Verified date: October 2022
• Source: Ipsen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 (completed) and Part D (completd). 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 54
• Est. completion date: September 20, 2022
• Est. primary completion date: September 20, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Years to 65 Years

Eligibility

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).

Related Conditions & MeSH terms

• Fibrodysplasia Ossificans Progressiva

Intervention

Drug:
• Palovarotene dose level 1
Palovarotene was taken orally once daily at approximately the same time each day.
• Palovarotene dose level 2
Palovarotene will be taken orally once daily at approximately the same time each day.
• Palovarotene dose level 3
Palovarotene will be taken orally once daily at approximately the same time each day.
• Palovarotene dose level 4
Palovarotene will be taken orally once daily at approximately the same time each day.

Locations

Country	Name	City	State
Argentina	Hospital Italiano de Buenos Aires, Department of Pediatrics	Buenos Aires
Australia	Queensland University of Technology (QUT) Institute of Health and Biomedical Innovation (IHBI)	Woolloongabba	Queensland
France	Hôpital Necker-Enfants Malades, Department of Genetics	Paris
United Kingdom	The Royal National Orthopaedic Hospital, Brockley Hill	Stanmore	Middlesex
United States	University of Pennsylvania, Center for FOP & Related Bone Disorders	Philadelphia	Pennsylvania
United States	Mayo Clinic, Department of Medicine	Rochester	Minnesota
United States	University of California San Francisco, Division of Endocrinology and Metabolism	San Francisco	California

Sponsors (1)

Lead Sponsor	Collaborator
Clementia Pharmaceuticals Inc.

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  France,  United Kingdom, 

References & Publications (1)

Shimono K, Tung WE, Macolino C, Chi AH, Didizian JH, Mundy C, Chandraratna RA, Mishina Y, Enomoto-Iwamoto M, Pacifici M, Iwamoto M. Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-? agonists. Nat Med. 2011 Apr;17(4):454-60. doi: 10.1038/nm.2334. Epub 2011 Apr 3. Erratum in: Nat Med. 2012 Oct;18(10):1592. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part A and Part B - Proportion of flare-up with no new HO ("responders")	Assessed by computed tomography (CT) scan (or plain radiographs for participants unable to undergo CT scan)	Week 12
Primary	Part C - Annualized change in new HO volume	Assessed by low-dose whole body computed tomography (WBCT) (excluding head)	Every 12 months for up to 72 months
Secondary	Part A - Proportion of participants across the seven HO scores (0-6)	Assessed by plain radiographs	Study Months 6 and 12 (Follow-up Component); Flare-up Weeks 6 and 12 (Flare-up Component)
Secondary	Part A - Change from baseline in amount (area) of new heterotopic bone formed	Assessed by plain radiographs	Study Months 6 and 12 (Follow-up Component); Flare-up Weeks 6 and 12 (Flare-up Component)
Secondary	Part A - Change from baseline in cartilage, bone, angiogenesis, and inflammation biomarkers		Study Months 6 and 12 (Follow-up Component); Flare-up Weeks 2, 4, 6, and 12 (Flare-up Component)
Secondary	Part A and Part B - Change from baseline in active range of motion (ROM)	Assessed by goniometer	Study Months 6 and 12 (Follow-up Component); Flare-up Weeks 6 and 12 (Flare-up Component)
Secondary	Part A and Part B - Change from baseline in ROM	Assessed by Cumulative Analogue Joint Involvement Scale (CAJIS)	Study Months 6 and 12 (Follow-up Component); Flare-up Weeks 6 and 12 (Flare-up Component)
Secondary	Part A and Part B - Participant and Investigator global assessment of movement		Study Months 6 and 12 (Follow-up Component); Flare-up Weeks 6 and 12 (Flare-up Component)
Secondary	Part A - Change from baseline in pain and swelling (for participants under 8 years of age)	Assessed by numeric rating scale (NRS) or Faces Pain Scale-Revised (FPS-R)	Study Months 6 and 12 (Follow-up Component); Flare-up Weeks 2, 4, 6, 9, and 12 (Flare-up Component)
Secondary	Part A and Part B - Change from baseline in physical function	Assessed by age-appropriate forms of the FOP-Physical Function Questionnaire (FOP-PFQ)	Study Months 6 and 12 (Follow-up Component); Flare-up Weeks 2, 4, 6, 8, 9, and 12 (Flare-up Component)
Secondary	Part A and Part B - Change from baseline in physical and mental health	Assessed by age-appropriate forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale	Study Months 6 and 12 (Follow-up Component); Flare-up Weeks 2, 4, 6, 8, 9, and 12 (Flare-up Component)
Secondary	Part A and Part B - Change from baseline in the use of assistive devices and adaptations for daily living by FOP participants		Study Months 6 and 12 (Follow-up Component); Flare-up Weeks 6 and 12 (Flare-up Component)
Secondary	Part A and Part B - Presence of soft tissue swelling and/or cartilage	Assessed by magnetic resonance imaging (MRI) (or by US in participants unable to undergo MRI)	Flare-up Weeks 6 and 12 (Flare-up Component)
Secondary	Part B - Change from baseline in amount of bone formation (volume)	Assessed by low-dose CT scan (or area by plain radiographs for participants unable to undergo CT scan)	Flare-up Week 12
Secondary	Part B - Change from baseline in cartilage, bone, angiogenesis, and inflammation biomarkers		Flare-up Weeks 4, 8, and 12
Secondary	Duration of active, symptomatic flare-up (start date and end date)	Assessed by the participant and the Investigator	Up to 12 weeks
Secondary	Part B (Chronic treatment) - Change from baseline in whole body burden of HO	Assessed by low-dose WBCT scan (excluding head)	Study Months 12 and 24
Secondary	Part B (Chronic treatment) - Number of flare-ups per participant-month overall, and by edema severity		Up to 24 months
Secondary	Part C - Percent of participants with new HO		Every 12 months up to 72 months
Secondary	Part C - Change from baseline in ROM	Assessed by CAJIS	Every 6 months up to 72 months
Secondary	Part C - Change from baseline in physical function	Assessed by age-appropriate forms of the FOP-PFQ	Every 6 months up to 72 months
Secondary	Part C - Change from baseline in physical and mental function for participants =15 years old and mental function for participants <15 years old	Assessed by age-appropriate forms of the PROMIS Global Health Scale	Every 6 months up to 72 months

External Links

•   Click here for more information about this study: A Phase 2, Open-Label Extension, Efficacy and Safety Study of a RAR?-Specific Agonist (Palovarotene) in the Treatment of Preosseous Flare-ups in Subjects with Fibrodysplasia Ossificans Progressiva (FOP)
•   Website for the French FOP Association
•   Website for the International FOP Association