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

• ClinicalTrials.gov Identifier: NCT02521792
• Recruitment Status: Terminated
• First Posted: August 13, 2015
• Results First Posted: October 19, 2020
• Last Update Posted: October 19, 2020
• Sponsor: Clementia Pharmaceuticals Inc.
• Information provided by (Responsible Party): Ipsen ( Clementia Pharmaceuticals Inc. )

Tracking Information

• First Submitted Date: August 6, 2015
• First Posted Date: August 13, 2015
• Results First Submitted Date: July 17, 2020
• Results First Posted Date: October 19, 2020
• Last Update Posted Date: October 19, 2020
• Actual Study Start Date: December 7, 2015
• Actual Primary Completion Date: August 4, 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 23, 2020)

Number of Subjects With Treatment-emergent Adverse Events (TEAEs) [ Time Frame: 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). ]

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.

• Original Primary Outcome Measures (submitted: August 10, 2015): Safety of palovarotene as assessed by the incidence of treatment-emergent adverse events (including those known to be associated with retinoids) and serious adverse events monitored throughout the treatment period. [ Time Frame: Treatment period (up to 36 months) ]

Current Secondary Outcome Measures (submitted: September 23, 2020)

• Subject Global Assessment of Movement as Determined by a Subject Completed Questionnaire, or Proxy Completed Questionnaire in Subjects Under 8 Years of Age [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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. ]
• Change From Baseline in Physical Function Using Age-appropriate Forms of the FOP-Physical Function Questionnaire [ Time Frame: 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, and 6-month intervals for duration of study. ]
• Change From Baseline in Physical and Mental Health Using Age-appropriate Forms of the Patient-Reported Outcomes Measurement Information System (PROMIS) Global Health Scale [ Time Frame: Baseline (flare-up screening), every 6 weeks while on study drug, at the end of treatment (should treatment be extended beyond 6 weeks), 6 weeks after the end of treatment, and 6-month intervals for duration of study. ]
• Duration of Active, Symptomatic Flare-up as Assessed by the Subject and the Investigator [ Time Frame: Baseline (flare-up screening), after 6 weeks on study drug, and every 2 weeks after Week 6 until flare-up resolution. ]
• Change From Baseline in the Use of Assistive Devices and Adaptations for Daily Living by FOP Subjects [ Time Frame: Baseline (flare-up screening), 6 weeks after the end of treatment, and 6-month intervals for duration of study. ]

Original Secondary Outcome Measures (submitted: August 10, 2015)

• Global assessment of movement by category as determined by a subject/proxy completed questionnaire [ Time Frame: Every 6 weeks, end of treatment (an expected average of 6 weeks), and 6 weeks after end of treatment ]
• Change from baseline in Cumulative Analogue Joint Involvement Scale (CAJIS) for FOP [ Time Frame: Study screening, every 6 months during follow-up; Flare-up screening and every 6 weeks, end of treatment (an expected average of 6 weeks), and 6 weeks after end of treatment ]
• Change from baseline in extent of heterotopic ossification by whole body low-dose computerized tomography (CT) scan [ Time Frame: Study screening and 36 months ]
• Change from baseline in extent of heterotopic ossification by whole body dual-energy x-ray absorptiometry (DEXA) scan [ Time Frame: Study screening and 36 months ]
• Change from baseline in pain at flare-up site using numeric rating scale (NRS) or Faces Pain Scale-Revised (FPS-R) [ Time Frame: Flare-up screening, every 2 weeks, end of treatment (an expected average of 6 weeks), and 6 weeks after end of treatment ]
• Change from baseline in swelling at flare-up site using numeric rating scale (NRS) [ Time Frame: Flare-up screening, every 2 weeks, end of treatment (an expected average of 6 weeks), and 6 weeks after end of treatment ]
• Change from baseline in physical function using the FOP-Physical Function Questionnaire (FOP-PFQ) [ Time Frame: Study screening, every 6 months during follow-up. Flare-up screening, every 6 weeks on study drug, end of treatment (an expected average of 6 weeks), and 6 weeks after end of treatment ]
• Change from baseline in physical and mental health using PROMIS Global Health Scale [ Time Frame: Study screening, every 6 months during follow-up. Flare-up screening, every 6 weeks on study drug, end of treatment (an expected average of 6 weeks), 6 weeks after end of treatment. ]
• Duration of active, symptomatic flare-up as assessed by subject and Investigator [ Time Frame: Flare-up screening, after 6 weeks on study drug, every 2 weeks after week 6 until flare-up resolution ]
• Use of assistive devices and adaptations for daily living [ Time Frame: Study screening, every 6 months during follow-up. Flare-up screening, 6 weeks after end of treatment (an expected average treatment of 6 weeks), and 6-month intervals for duration of study ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: In-Home Evaluation of Episodic Administration of Palovarotene in Fibrodysplasia Ossificans Progressiva (FOP) Subjects
• Official Title: A Phase 2, In-Home, Safety and Efficacy Evaluation of Episodic Administration of Open-Label Palovarotene in Subjects With Fibrodysplasia Ossificans Progressiva (FOP)
• 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.

Detailed Description

The primary objective of this Phase 2, open-label, multicenter, single-arm, extension study is to investigate the safety and efficacy of episodic treatment with palovarotene in FOP subjects with flare-ups.

Secondary objectives are:

The effect of episodic treatment of flare-ups with palovarotene on range of motion (ROM) as assessed by the subject global assessment of movement.

• The effect of episodic treatment of flare-ups with palovarotene on ROM as assessed by the Cumulative Analogue Joint Involvement Scale for FOP (CAJIS) for subjects with video-conferencing capability.
• The effect of episodic treatment of flare-ups with palovarotene on the total burden of heterotopic ossification (HO) as assessed by low-dose whole body computerized tomography (WBCT), excluding the head; and whole body dual energy x-ray absorptiometry (DEXA).
• The effect of episodic treatment of flare-ups with palovarotene on physical function using age-appropriate forms of the FOP-Physical Function Questionnaire (FOP-PFQ).
• The effect of episodic treatment of flare-ups with palovarotene on physical and mental health using age appropriate forms of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale.
• The effects of episodic treatment of flare-ups with palovarotene on pain and swelling associated with the flare-up using numeric rating scales (NRS) or the Faces Pain Scale-Revised (FPS-R) in subjects under 8 years of age.
• The use of assistive devices and adaptations for daily living by FOP subjects.

The follow-up portion of the study will consist of a Screening visit that will correspond to the last day (Study Day 84) of Study PVO-1A-202 and bi-annual assessments at Months 6, 12, 18, 24, 30, and 36.

Subjects experiencing a new, distinct flare-up during the 36-month follow-up will be evaluated and if eligible, receive palovarotene at the weight-adjusted equivalent of 10 mg for 14 days followed by 5 mg for at least 28 days. Any subject who received a lower dosing regimen due to tolerability issues during Study PVO-1A-202 will receive that tolerated dose.

For each flare-up there will be two periods:

1. A Screening period to occur within 7 days of the start of a new, distinct flare-up. The first dose of palovarotene will be taken within 10 days of the flare-up onset to allow for shipment of study medication to the subject's home.
2. A treatment period of at least 6 weeks duration. Subjects experiencing a new, distinct flare-up will be evaluated

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Fibrodysplasia Ossificans Progressiva

Intervention

Drug: Palovarotene

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.

Study Arms

Experimental: Palovarotene

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.

Intervention: Drug: Palovarotene

• Publications *: 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. Erratum In: Nat Med. 2012 Oct;18(10):1592.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: April 29, 2020): 6
• Original Estimated Enrollment (submitted: August 10, 2015): 40
• Actual Study Completion Date: August 4, 2016
• Actual Primary Completion Date: August 4, 2016 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

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.

Exclusion Criteria:

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 6 Years to 65 Years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States
• Removed Location Countries: France, United Kingdom

Administrative Information

• NCT Number: NCT02521792
• Other Study ID Numbers: PVO-1A-203
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Ipsen ( Clementia Pharmaceuticals Inc. )
• Original Responsible Party: Same as current
• Current Study Sponsor: Clementia Pharmaceuticals Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Ipsen Medical Director; Ipsen

• PRS Account: Ipsen
• Verification Date: September 2020