In-Home Evaluation of Episodic Administration of Palovarotene in Fibrodysplasia Ossificans Progressiva (FOP) Subjects

NCT02521792 | Terminated Phase 2 Results

• 1 other identifier: PVO-1A-203
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 2

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 to prevent HO following injury. This 36-month study will evaluate the long-term safety and efficacy of episodic treatment with palovarotene for flare-ups in FOP subjects who successfully complete two flare-up treatment periods (6 weeks duration) and two follow-up periods (6 weeks duration) in Study PVO-1A-202.

Conditions

Fibrodysplasia Ossificans Progressiva

Keywords

Open-label 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

Outcome Measures

Primary Outcomes (1)

• Number of Subjects With Treatment-emergent Adverse Events (TEAEs)

  The primary endpoint was the safety of palovarotene as assessed by the incidence of TEAEs (including those known to be associated with retinoids) and serious adverse event (SAEs) monitored throughout the treatment period. TEAEs were adverse events reported during treatment with palovarotene or within 6 weeks after the end of treatment. Day 1 was the first day that study drug was administered for a flare-up. The number of subjects experiencing at least one TEAE or treatment-emergent SAE are presented.

  Day 1 until 6 weeks after the end of treatment (an expected average treatment of 6 weeks). Assessed until data cut-off for study termination (maximum of 35 days).

Secondary Outcomes (9)

• Subject Global Assessment of Movement as Determined by a Subject Completed Questionnaire, or Proxy Completed Questionnaire in Subjects Under 8 Years of Age

  Every 6 weeks while on study drug, at the end of treatment (should treatment be extended beyond 6 weeks), and 6 weeks after the end of treatment.

• Change From Baseline in Cumulative Analogue Joint Involvement Scale for FOP as Assessed by the Investigator Using Remote Video-conferencing

  Baseline (flare-up screening), every 6 weeks while on study drug, at the end of treatment (should treatment be extended beyond 6 weeks), and 6 weeks after the end of treatment.

• Change From Baseline in Extent of Heterotopic Ossification (HO) by Whole Body Low-dose Computerized Tomography (CT) Scan, Excluding the Head

  Baseline (final visit for Study PVO-1A-202/Part A) and at end of study (36 months).

• Change From Baseline in Extent of HO by Whole Body Dual Energy X-ray Absorptiometry (DEXA) Scan

  Baseline (screening/enrollment visit) and at end of study (36 months).

• Change From Baseline in Pain and Swelling at the Flare-up Site Using Numeric Rating Scales, or Faces Pain Scale-Revised in Subjects Under 8 Years of Age

  Baseline (flare-up screening), every 2 weeks while on study drug, at the end of treatment (should treatment be extended beyond 6 weeks), and 6 weeks after the end of treatment.

Study Arms (1)

Palovarotene

EXPERIMENTAL

The protocol is open only to the subjects who completed Clementia Study PVO-1A-202. Eligible subjects will receive a weight-based equivalent dose of palovarotene 10 mg once daily for 14 days, followed by 5 mg once daily for 28 days. Should treatment be extended beyond 6 weeks, a weight-based equivalent dose of 5 mg will be administered in 2-week increments.

Drug: Palovarotene

Interventions

Palovarotene DRUG

Palovarotene will be taken orally once daily at approximately the same time each day. Powder filled hard gelatin capsules may be opened and the contents added onto specific food.

Palovarotene

Eligibility Criteria

• Age: 6 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• For study enrollment
• Completed Study PVO-1A-202 having been treated with palovarotene (ie, 6 weeks on-treatment and 6-weeks follow-up) for two flare-ups.
• Written, signed, and dated informed consent or age-appropriate subject/parent assent (this must be performed according to local regulations).
• For treatment with palovarotene for subsequent flare-ups
• Symptomatic onset of a new, distinct flare-up within 10 days of the first dose of study drug. Symptoms must be reported by the subject, be consistent with their previous flare-ups, and include a subject-reported onset date. The flare-up must be confirmed by the physician at screening via telephone contact and/or video-conferencing.
• Females of child-bearing potential (FOCBP) 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 subjects must agree to remain abstinent during treatment and for 1 month after treatment or, if sexually active, to use two highly effective methods of birth control during and for 1 month after treatment. Additionally, sexually active FOCBP subjects must already be using two highly 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 highly effective methods of birth control will be clearly defined in the informed consent, and the subject or legally authorized representatives (eg, parents, caregivers, or legal guardians) must specifically sign this section.
• Subjects must be accessible for treatment with palovarotene and follow-up.

You may not qualify if:

• For study enrollment
• 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.
• For treatment with palovarotene for subsequent flare-ups:
• Weight \<20 kg.
• The flare-up is at a completely ankylosed joint.
• Intercurrent non-healed fracture at any location.
• 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 during palovarotene treatment.
• Exposure to synthetic oral retinoids in the past 30 days prior to screening (signature of the informed consent or age-appropriate subject assent).
• Concurrent treatment with tetracycline or any tetracycline derivatives due to the potential increased risk of pseudotumor cerebri
• History of allergy or hypersensitivity to retinoids or lactose.
• Female subjects who are breastfeeding.
• Subjects with uncontrolled cardiovascular, hepatic, pulmonary, gastrointestinal, endocrine, metabolic, ophthalmologic, immunologic, psychiatric, clinically significant abnormal laboratory findings, or other significant disease.
• Simultaneous participation in another interventional clinical research study within the past 4 weeks (except for Study PVO-1A-202).
• Subjects experiencing suicidal ideation (type 4 or 5) or any suicidal behavior within the past month prior to Screening as defined by the Columbia Suicide Severity Rating Scale.
• 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.

Sponsors & Collaborators

• Clementia Pharmaceuticals Inc.: lead

Study Sites (2)

University of California San Francisco, Division of Endocrinology and Metabolism

San Francisco, California, 94143, United States

Location

University of Pennsylvania, Center for Research in FOP & Related Disorders

Philadelphia, Pennsylvania, 19104, United States

Location

Related 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-gamma agonists. Nat Med. 2011 Apr;17(4):454-60. doi: 10.1038/nm.2334. Epub 2011 Apr 3.

  PMID: 21460849 BACKGROUND

Related Links

• Website for the International FOP Association
• Click here for more information about this study: A Phase 2, In-Home, Safety and Efficacy Evaluation of Episodic Administration of Open-Label Palovarotene in Subjects with Fibrodysplasia Ossificans Progressiva (FOP)

MeSH Terms

Conditions

Myositis Ossificans; Ossification, Heterotopic

Interventions

Palovarotene

Condition Hierarchy (Ancestors)

Myositis; Muscular Diseases; Musculoskeletal Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Limitations and Caveats

The study was stopped prematurely and due to the small number of evaluable subjects, there was insufficient data to conduct any efficacy analyses. Consequently, no summary statistics are available for any of the secondary outcome measures.

Results Point of Contact

• Title: Medical Director
• Organization: Ipsen

clinical.trials@ipsen.com

see email

Study Officials

• Ipsen Medical Director

  Ipsen

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 6, 2015
• First Posted: August 13, 2015
• Study Start: December 7, 2015
• Primary Completion: August 4, 2016
• Study Completion: August 4, 2016
• Last Updated: October 19, 2020
• Results First Posted: October 19, 2020

Record last verified: 2020-09

Locations

US (2)