An Efficacy and Safety Study of Palovarotene to Treat Preosseous Flare-ups in FOP Subjects

NCT02190747 | Completed Phase 2 Results DMC

• 2 other identifiers: PVO-1A-2012014-001453-17
• Study Type: interventional
• Target: 40
• Locations: 3 countries
• Sites: 4

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 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 (RAR) gamma agonists to prevent heterotopic ossification (HO) following injury. The purpose of the study is to evaluate whether palovarotene, an RAR gamma agonist, will prevent HO during and following a flare-up in subjects with FOP.

Conditions

Fibrodysplasia Ossificans Progressiva

Keywords

Intervention study; Clinical trial Phase 2; Efficacy and safety; Heterotopic ossification; 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)

• Percentage of Responders at Week 6

  A responder was defined as a subject with no or minimal new heterotopic ossification (HO) at flare-up site versus baseline as assessed by plain radiographs at Week 6. Minimal new HO is defined as new HO with an HO score \<=3 in both anterior/posterior (AP) and lateral projections (or if one view is non-interpretable or non-evaluable, then remaining evaluable view is used). The HO score ranges from 0 to 6 where, 0 = no HO and 6 = single contiguous HO with longest dimension \>2 diameters of reference normotopic bone in any projection. The highest HO score from the 2 projections was used. Results from Primary Read reviews are presented. The Primary Read process included a double-read radiology review paradigm with consensus adjudication. Radiography and CT scans were examined independently by scan type, flare-up region, and imaging time point in order to determine whether radiography would be sufficient to measure new HO formation. Only subjects with interpretable outcomes were evaluated.

  Baseline (Day 1) and Week 6 (Day 42)

Secondary Outcomes (23)

• Percentage of Subjects With New HO at Weeks 6 and 12

  Weeks 6 and 12 (Day 84)

• Change From Baseline in Amount (Area) of New HO Formed at the Flare-up Site at Weeks 6 and 12

  Baseline, Weeks 6 and 12

• Percentage of Responders at Week 12

  Baseline and Week 12

• Change From Baseline in Bone Specific Alkaline Phosphatase at Weeks 2, 4, 6 and 12

  Baseline, Weeks 2, 4, 6 and 12

• Change From Baseline in C-Reactive Protein at Weeks 2, 4, 6 and 12

  Baseline, Weeks 2, 4, 6 and 12

Study Arms (4)

Palovarotene dose level 1 (Cohort 1)

EXPERIMENTAL

Doses of palovarotene in dose level 1 are 10 mg once daily for 14 days, followed by 5 mg once daily for 28 days.

Drug: Palovarotene

Palovarotene dose level 2 (Cohort 2)

EXPERIMENTAL

Weight-adjusted doses of palovarotene in dose level 2 are 10 mg palovarotene once daily, followed by 5 mg once daily for 28 days.

Drug: Palovarotene

Palovarotene dose level 3 (Cohort 2)

EXPERIMENTAL

Weight-adjusted doses of palovarotene in dose level 3 are 5 mg palovarotene once daily, followed by 2.5 mg once daily for 28 days.

Drug: Palovarotene

Sugar pill

PLACEBO COMPARATOR

The placebo comparator will be taken once daily for the same duration as the palovarotene dose groups in both Cohorts 1 and 2.

Drug: Placebo

Interventions

Palovarotene DRUG

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

Palovarotene dose level 1 (Cohort 1); Palovarotene dose level 2 (Cohort 2); Palovarotene dose level 3 (Cohort 2)

Placebo DRUG

Sugar pill

Eligibility Criteria

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

You may qualify if:

• Written, signed, and dated informed subject/parent consent or age-appropriate assent.
• Subjects clinically diagnosed with classic Fibrodysplasia Ossificans Progressiva (FOP).
• Symptomatic onset of a distinct flare-up within 7 days of Study Day 1 (start of study drug) and defined by the presence of at least two of six of the following symptoms: pain, soft tissue swelling, decreased range of motion, stiffness, redness, and warmth. Flare-up must be confirmed by the physician at the Screening visit.
• Flare-up is at an appendicular area (upper or lower extremity), abdomen, or chest; and subject has received, is receiving, or is willing to receive treatment per standard of care, which may or may not include oral prednisone (2 mg/kg PO to a maximum dose of 100 mg daily) for 4 days.
• Abstinent or using two highly effective forms of birth control.
• Subjects must be accessible for treatment and follow-up. Subjects living at distant locations from the investigational site must be able and willing to travel to a site for the initial and all follow-up visits.

You may not qualify if:

• Weight \<20 kg.
• Intercurrent non-healed fracture at any location.
• Complete immobilization of joint at site of flare-up.
• The inability of the subject to undergo imaging assessments using plain radiographs.
• 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 for the duration of the study.
• Exposure to synthetic oral retinoids in the past 30 days prior to Screening (signature of the informed consent).
• Concurrent treatment with tetracycline due to the potential increased risk of pseudotumor cerebri.
• History of allergy or hypersensitivity to retinoids or lactose.
• Concomitant medications that are inhibitors or inducers of CYP450 3A4 activity.
• Amylase or lipase \>1.5x above the upper limit of normal or with a history of chronic pancreatitis.
• Elevated aspartate aminotransferase or alanine aminotransferase \>2.5x the upper limit of normal.
• Fasting triglycerides \>400 mg/dL with or without therapy.

Sponsors & Collaborators

• Clementia Pharmaceuticals Inc.: lead

Study Sites (4)

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

Hôpital Necker-Enfants Malades, Department of Genetics

Paris, France

Location

The Royal National Orthopaedic Hospital, Brockley Hill

Stanmore, Middlesex, HA7 4LP, United Kingdom

Location

Related Publications (5)

• 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

• Pignolo RJ, Al Mukaddam M, Baujat G, Brown MA, De Cunto C, Hsiao EC, Keen R, Le Quan Sang KH, Grogan DR, Marino R, Strahs AR, Kaplan FS. Study methodology and insights from the palovarotene clinical development program in fibrodysplasia ossificans progressiva. BMC Med Res Methodol. 2023 Nov 13;23(1):269. doi: 10.1186/s12874-023-02080-7.

  PMID: 37957586 DERIVED

• Lindborg CM, Al Mukaddam M, Baujat G, Cho TJ, De Cunto CL, Delai PLR, Eekhoff EMW, Haga N, Hsiao EC, Morhart R, de Ruiter R, Scott C, Seemann P, Szczepanek M, Tabarkiewicz J, Pignolo RJ, Kaplan FS. Most Fractures Treated Nonoperatively in Individuals With Fibrodysplasia Ossificans Progressiva Heal With a Paucity of Flareups, Heterotopic Ossification, and Loss of Mobility. Clin Orthop Relat Res. 2023 Dec 1;481(12):2447-2458. doi: 10.1097/CORR.0000000000002672. Epub 2023 May 8.

  PMID: 37156007 DERIVED

• Pignolo RJ, Kimel M, Whalen J, Kawata AK, Artyomenko A, Kaplan FS. The Fibrodysplasia Ossificans Progressiva Physical Function Questionnaire (FOP-PFQ): A patient-reported, disease-specific measure. Bone. 2023 Mar;168:116642. doi: 10.1016/j.bone.2022.116642. Epub 2022 Dec 13.

  PMID: 36526263 DERIVED

• Pignolo RJ, Baujat G, Hsiao EC, Keen R, Wilson A, Packman J, Strahs AL, Grogan DR, Kaplan FS. Palovarotene for Fibrodysplasia Ossificans Progressiva (FOP): Results of a Randomized, Placebo-Controlled, Double-Blind Phase 2 Trial. J Bone Miner Res. 2022 Oct;37(10):1891-1902. doi: 10.1002/jbmr.4655. Epub 2022 Aug 17.

  PMID: 35854638 DERIVED

Related Links

• Website for the International FOP Association
• Click here for more information about this study: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of a RARγ-Specific Agonist (Palovarotene) in the Treatment of Preosseous Flare-ups in Subjects With 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

Radiography was less sensitive than CT for detecting new HO. Thus, Global Read data are presented where available using more sensitive CT scans at Week 12 in the PP population.

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: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 13, 2014
• First Posted: July 15, 2014
• Study Start: July 14, 2014
• Primary Completion: May 23, 2016
• Study Completion: May 23, 2016
• Last Updated: February 16, 2021
• Results First Posted: June 24, 2020

Record last verified: 2021-01

Locations

FR (1); GB (1); US (2)