An Open-Label Extension Study of Palovarotene Treatment in FOP

• ClinicalTrials.gov Identifier: NCT02279095
• Recruitment Status: Active, not recruiting
• First Posted: October 30, 2014
• Last Update Posted: October 26, 2020
• Sponsor: Clementia Pharmaceuticals Inc.
• Information provided by (Responsible Party): Ipsen ( Clementia Pharmaceuticals Inc. )

Tracking Information

• First Submitted Date: October 26, 2014
• First Posted Date: October 30, 2014
• Last Update Posted Date: October 26, 2020
• Actual Study Start Date: October 27, 2014
• Estimated Primary Completion Date: October 31, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 9, 2017)

Change in New HO Volume [ Time Frame: Screening, every 12 months up to 60 months ]

Annualized change in new HO volume as assessed by low-dose, WBCT (excluding head).

Original Primary Outcome Measures (submitted: October 28, 2014)

• Percentage of subject responders at the original flare-up site, as assessed by plain radiographs (Follow-up Component). [ Time Frame: Study Month 6 ]
• Percentage of subject responders at the original flare-up site, as assessed by plain radiographs (Follow-up Component). [ Time Frame: Study Month 12 ]
• Percentage of subject responders at subsequent distinct flare-up site(s), as assessed by plain radiographs (Flare-up Component). [ Time Frame: Flare-up Day 42 ]

Current Secondary Outcome Measures (submitted: October 9, 2017)

• Subjects with New HO [ Time Frame: Baseline, every 12 months up to 60 months ]
  The proportion of subjects with any new HO.
• Range of Motion [ Time Frame: Baseline, every 6 months up to 60 months ]
  Change from baseline in range of motion as assessed by the Cumulative Analogue Joint Involvement Scale for FOP (CAJIS).
• FOP-Physical Function Questionnaire [ Time Frame: Baseline, every 6 months up to 60 months ]
  Change from baseline in physical function using age-appropriate forms of the FOP-Physical Function Questionnaire (PFQ).
• PROMIS Global Health Scale [ Time Frame: Baseline, every 6 months up to 60 months ]
  Change from baseline in mental and/or physical health function for subjects using age-appropriate forms of the PROMIS Global Health Scale.
• Incidence of Adverse Events [ Time Frame: every month up to 60 months ]
  Monitor adverse events.
• Pharmacokinetics of Palovarotene [ Time Frame: Pre-dose and 3, 6, 10, and 24 hours post-dose ]
  Steady-state pharmacokinetics assessed during treatment with 10 and 20 mg palovarotene.

Original Secondary Outcome Measures (submitted: October 28, 2014)

• Numeric heterotopic ossification scores at the flare-up site as assessed by plain radiograph. [ Time Frame: Study Months 6 and 12 (Follow-up Component); and Flare-up Days 42 and 84 (Flare-up Component). ]
• Amount (area) of new heterotopic bone formed at the flare-up site assessed by plain radiographs. [ Time Frame: Study Months 6 and 12 (Follow-up Component); and baseline, Flare-up Days 42 and 84 (Flare-up Component). ]
• Plasma biomarker levels. [ Time Frame: Study Months 6 and 12 (Follow-up Component); and baseline, Flare-up Days 14, 28, 42, 63, and 84 (Flare-up Component). ]
• Pain and swelling at the flare-up site using a numeric rating scale for each symptom. [ Time Frame: Study Months 6 and 12 (Follow-up Component); and baseline, Flare-up Days 14, 28, 42, 63, and 84 (Flare-up Component). ]
• Patient-reported assessment of physical function. [ Time Frame: Study Months 6 and 12 (Follow-up Component); and baseline, Flare-up Days 14, 28, 42, 63, and 84 (Flare-up Component). ]
• Safety evaluation including adverse events and clinical safety laboratory parameters. [ Time Frame: Study Months 6 and 12 (Follow-up Component); and Flare-up Days 1 (the first day of dosing), 14, 28, 42, 63, and 84 (Flare-up Component). ]
• Percentage of subject responders as assessed by plain radiographs. [ Time Frame: Flare-up Day 84 (Flare-up Component) ]
• Amount of bone formation (volume) as assessed by low-dose CT scan. [ Time Frame: baseline, Flare-up Days 42 and 84 (Flare-up Component). ]
• Presence of soft tissue swelling and/or cartilage as assessed by MRI. [ Time Frame: baseline, Flare-up Days 42 and 84 (Flare-up Component). ]
• Active range of motion measured by goniometer of the relevant joint. [ Time Frame: baseline, Flare-up Days 42 and 84 (Flare-up Component). ]
• Duration of active, symptomatic flare-up. [ Time Frame: Symptom start date to symptom end date (Flare-up Component). ]

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

Descriptive Information

• Brief Title: An Open-Label Extension Study of Palovarotene Treatment in FOP
• 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)
• Brief Summary: Fibrodysplasia Ossificans Progressiva (FOP) is a rare, severely disabling disease characterized by heterotopic ossification (HO) often associated with painful, recurrent episodes of soft tissue swelling (flare-ups) that lead to ankyloses of major joints with cumulative and irreversible loss of movement and disability. In this study, the ability of palovarotene to prevent HO formation will be evaluated.

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 subjects with FOP.

In Part A, all subjects who completed Study PVO-1A-201 and enrolled into the current study received daily treatment with open-label palovarotene for an eligible flare-up at a dose of 10 mg for 14 days, followed by 5 mg for 28 days (or the weight-based equivalent). Part A is completed.

In Part B, subjects with at least 90% skeletal maturity were treated with 5 mg palovarotene on a daily basis (ie, chronically). In the event of an eligible flare-up, all subjects received 20 mg palovarotene daily for 28 days, followed by 10 mg for 56 days (dosing was weight-based in subjects who were skeletally immature). Dosing could be extended if the flare-up was not resolved by Flare-up Day 84 and continued until the flare-up resolved. Dose reduction, as directed by the Investigator, occurred in the event of intolerable side effects. The duration of Part B is up to 24 months.

In Part C, the dosing regimens implemented in Part B will continue except that subjects with less than 90% skeletal maturity will now receive chronic daily administration of palovarotene (5 mg, or the weight-based equivalent). The assessment of HO will occur every 12 months using low-dose, whole body computed tomography (WBCT), excluding head; other efficacy and safety outcomes will be evaluated remotely every 3 months, or monthly during flare-up based treatment. The duration of Part C is 36 months.

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

Intervention

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

Study Arms

• Experimental: Palovarotene dose level 1 (completed)
  Subjects received weight-adjusted doses of palovarotene equivalent to 10 mg once daily for 14 days, followed by 5 mg once daily for 28 days for an eligible flare-up (Part A).
  Intervention: Drug: Palovarotene dose level 1
• Experimental: Palovarotene dose level 2
  Subjects with at least 90% skeletal maturity received 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 (Part B).
  Intervention: Drug: Palovarotene dose level 2
• Experimental: Palovarotene dose level 3
  Subjects 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).
  Intervention: Drug: Palovarotene dose level 3
• Experimental: Palovarotene dose level 4
  All subjects will receive 5 mg palovarotene once daily for up to 36 months; and 20 mg palovarotene for 28 days, followed by 10 mg for 56 days for eligible flare-ups (Part C). Doses are adjusted for weight in skeletally immature subjects
  Intervention: Drug: Palovarotene dose level 4

• 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-γ 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: Active, not recruiting
• Actual Enrollment (submitted: October 23, 2020): 54
• Original Estimated Enrollment (submitted: October 28, 2014): 24
• Estimated Study Completion Date: October 31, 2021
• Estimated Primary Completion Date: October 31, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Completion of Study PVO-1A-202/Part B.
• Written, signed, and dated informed consent and, for subjects who are minors, age-appropriate subject 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 subjects 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 FOCBP subjects 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 subject or legally authorized representatives.

Exclusion Criteria:

• 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.
• 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.
• If 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.
• 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).

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

Administrative Information

• NCT Number: NCT02279095
• Other Study ID Numbers: PVO-1A-202; 2014-002496-28 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Ipsen ( Clementia Pharmaceuticals Inc. )
• Study Sponsor: Clementia Pharmaceuticals Inc.
• Collaborators: Not Provided

Investigators

• Study Director: Ipsen Medical Director; Ipsen

• PRS Account: Ipsen
• Verification Date: October 2020