An Efficacy and Safety Study of Palovarotene for the Treatment of Fibrodysplasia Ossificans Progressiva.

NCT ID: NCT03312634

Last Updated: 2023-11-29

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 107 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-11-30
• Study Completion Date: 2022-09-07

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.

Detailed Description

One of the primary objectives was to evaluate the efficacy of palovarotene in decreasing new HO in participants with FOP as assessed by low-dose, whole body computed tomography (WBCT), excluding head, compared to untreated participants from Clementia's FOP natural history study (Study PVO-1A-001, NHS). The other primary objective was to evaluate the safety of palovarotene in participants with FOP.

This study was conducted in three parts. Part A was the main part of the study, Part B, the 2-year (24-month) extension and Part C was an up-to-2-year post last dose of study treatment follow-up for skeletally immature participants.

Participants in Part A and B received a chronic/flare-up dosing regimen of palovarotene for up to 4 years (48 months) as follows:

• Chronic treatment: orally administered 5 mg palovarotene once daily.
• Flare-up treatment: orally administered 20 mg palovarotene once daily for 4 weeks (28 days) followed by orally administered 10 mg palovarotene once daily for 8 weeks (56 days). Flare-up treatment may be extended until the Investigator determines that the flare-up has resolved.

Note that all dosing was weight-adjusted in skeletally immature participants (those under the age of 18 years with less than 90% skeletal maturity on hand/wrist x-rays performed at Screening).

In part C, participants who were enrolled in Parts A or B who discontinued the study and were skeletally immature were invited back to participate in the off-treatment safety follow-up. No new participants were enrolled into Part C.

Conditions

Fibrodysplasia Ossificans Progressiva

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Palovarotene Chronic/Flare-Up Regimen

Participants received 5 mg palovarotene once daily for up to 48 months; and 20 mg palovarotene once daily for 28 days, followed by 10 mg for 56 days for flareups. (Dosing was adjusted for weight in skeletally immature subjects.)

Group Type: EXPERIMENTAL

Palovarotene

Intervention Type: DRUG

Palovarotene was taken orally once daily at approximately the same time each day following a meal.

Interventions

Palovarotene

Palovarotene was taken orally once daily at approximately the same time each day following a meal.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Written, signed, and dated informed subject/parent consent; and for subjects who are minors, age-appropriate assent (performed according to local regulations).
• Males or females at least 4 years of age.
• No flare-up symptoms within the past 4 weeks, including at the time of enrollment.
• Abstinent or using two highly effective forms of birth control.
• Accessible for treatment and follow-up; able to undergo all study procedures including low-dose WBCT (excluding head) without sedation.

Exclusion Criteria

• Weight <10 kg.
• Concomitant medications that are strong inhibitors or inducers of cytochrome P450 (CYP450) 3A4 activity; or kinase inhibitors such as imatinib.
• Amylase or lipase >2x above the upper limit of normal (ULN) or with a history of chronic pancreatitis.
• Elevated aspartate aminotransferase or alanine aminotransferase >2.5x ULN.
• Fasting triglycerides >400 mg/dL with or without therapy.
• Female subjects who are breastfeeding.
• Subjects with uncontrolled cardiovascular, hepatic, pulmonary, gastrointestinal, endocrine, metabolic, ophthalmologic, immunologic, psychiatric, or other significant disease.
• Simultaneous participation in another clinical research study (other than palovarotene studies) within 4 weeks prior to Screening; or within five half-lives of the investigational agent, whichever is longer.
• 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.

• Minimum Eligible Age: 4 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Clementia Pharmaceuticals Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Ipsen Medical Director

Role: STUDY_DIRECTOR

Ipsen

Locations

University of California San Francisco, Division of Endocrinology and Metabolism

San Francisco, California, United States

Mayo Clinic

Rochester, Minnesota, United States

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

University of Pennsylvania, Internal Medicine

Philadelphia, Pennsylvania, United States

Hospital Italiano de Buenos Aires, Tte General Juan Domingo Peron 4190

Buenos Aires, , Argentina

Royal North Shore Hospital

Saint Leonards, New South Wales, Australia

Queensland University of Technology

Woolloongabba, Queensland, Australia

Hospital Israelita Albert Einstein

São Paulo, São Paulo, Brazil

Hospital for Sick Children, 555 University Avenue

Toronto, Ontario, Canada

Toronto General Hospital

Toronto, Ontario, Canada

Groupe Hospitalier Necker Enfants Malades

Paris, , France

Istituto Giannina Gaslini

Genoa, Liguria, Italy

The University of Tokyo Hospital

Tokyo, Bunkyo-ku, Japan

Hospital Universitari i Politècnic La Fe, Unidad de Reumatología Pediatrica

Valencia, Avinguda de Fernando Abril Martorell, Nº 106, Spain

Norrlands Universitetssjukhus

Umeå, , Sweden

Royal National Orthopaedic Hospital, Brockely Hill

Stanmore, , United Kingdom

Countries

United States; Argentina; Australia; Brazil; Canada; France; Italy; Japan; Spain; Sweden; United Kingdom

References

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.

Reference Type: BACKGROUND

PMID: 21460849 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 37156007 (View on PubMed)

Pignolo RJ, Hsiao EC, Al Mukaddam M, Baujat G, Berglund SK, Brown MA, Cheung AM, De Cunto C, Delai P, Haga N, Kannu P, Keen R, Le Quan Sang KH, Mancilla EE, Marino R, Strahs A, Kaplan FS. Reduction of New Heterotopic Ossification (HO) in the Open-Label, Phase 3 MOVE Trial of Palovarotene for Fibrodysplasia Ossificans Progressiva (FOP). J Bone Miner Res. 2023 Mar;38(3):381-394. doi: 10.1002/jbmr.4762. Epub 2023 Jan 25.

Reference Type: DERIVED

PMID: 36583535 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

http://ifopa.org

Website for the International FOP Association

Other Identifiers

2017-002541-29

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

PVO-1A-301

Identifier Type: -

Identifier Source: org_study_id