An Open-Label Extension Study of Palovarotene Treatment in FOP

Tracking Information
First Submitted Date ICMJE	October 26, 2014
First Posted Date ICMJE	October 30, 2014
Last Update Posted Date	October 10, 2017
Study Start Date ICMJE	October 2014
Estimated Primary Completion Date	March 2021 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (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 ICMJE; (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 ]
Change History	Complete list of historical versions of study NCT02279095 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (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 ICMJE; (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 Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	An Open-Label Extension Study of Palovarotene Treatment in FOP
Official Title ICMJE	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 ICMJE	Interventional
Study Phase	Phase 2
Study Design ICMJE	Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition ICMJE	Fibrodysplasia Ossificans Progressiva
Intervention ICMJE	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.
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Active, not recruiting
Actual Enrollment ICMJE; (submitted: February 10, 2017)	58
Original Estimated Enrollment ICMJE; (submitted: October 28, 2014)	24
Estimated Study Completion Date	March 2021
Estimated Primary Completion Date	March 2021 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	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. 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.
Sex/Gender	Sexes Eligible for Study: All
Ages	6 Years to 65 Years (Child, Adult, Older Adult)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	Argentina, Australia, France, United Kingdom, United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT02279095
Other Study ID Numbers ICMJE	PVO-1A-202
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	Clementia Pharmaceuticals Inc.
Study Sponsor ICMJE	Clementia Pharmaceuticals Inc.
Collaborators ICMJE	Not Provided
Investigators ICMJE	Principal Investigator: Robert J Pignolo, MD, PhD Mayo Clinic, Department of Medicine Principal Investigator: Edward Hsiao, MD, PhD University of California San Francisco, Division of Endocrinology and Metabolism Principal Investigator: Genevieve Baujat, MD Hôpital Necker-Enfants Malades, Department of Genetics Principal Investigator: Richard Keen, BSc, PhD, MD The Royal National Orthopaedic Hospital, Brockley Hill Principal Investigator: Carmen L De Cunto, MD Hospital Italiano de Buenos Aires Principal Investigator: Mona Al Mukaddam, MD, MS, CCD University of Pennsylvania Principal Investigator: Matthew Brown, MD Queensland University of Technology (QUT) Institute of Health and Biomedical Innovation (IHBI)
PRS Account	Clementia Pharmaceuticals Inc.
Verification Date	October 2017
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP