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

• ClinicalTrials.gov Identifier: NCT03312634
• Recruitment Status: Completed
• First Posted: October 18, 2017
• Results First Posted: March 14, 2023
• Last Update Posted: November 29, 2023
• Sponsor: Clementia Pharmaceuticals Inc.
• Information provided by (Responsible Party): Ipsen ( Clementia Pharmaceuticals Inc. )

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Fibrodysplasia Ossificans Progressiva	Drug: Palovarotene	Phase 3

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 107 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: A multicenter, open-label study. NHS data (study PVO-1A-001) will be used as an external control in the analysis.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Efficacy and Safety Study of Oral Palovarotene for the Treatment of Fibrodysplasia Ossificans Progressiva (FOP)
• Actual Study Start Date: November 30, 2017
• Actual Primary Completion Date: January 24, 2020
• Actual Study Completion Date: September 7, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: 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.)	Drug: Palovarotene; Palovarotene was taken orally once daily at approximately the same time each day following a meal.

Outcome Measures

Primary Outcome Measures :

1. Annualized New Heterotopic Ossification (HO) [ Time Frame: Baseline (within one month of screening/Day 1) and up to 24 months ]
   The annualized new HO was assessed by low-dose, whole body computed tomography (WBCT), excluding head. The weighted linear mixed effect method without square-root transformation and negatives included was used for annualized new HO analysis.

Secondary Outcome Measures :

1. Percentage of Participants With Any New HO [ Time Frame: From Baseline (Day 1) up to end of 4-year follow-up period (approximately 57 months) ]
   The new HO was assessed by WBCT scan. The percentage of participants with any new HO (volume > 0 mm^3) were analyzed using the Bayesian distribution. Results are presented for overall ITT period.
2. Number of Body Regions With New HO [ Time Frame: From Baseline (Day 1) up to end of 4-year follow-up period (approximately 57 months) ]
   All participants were analyzed for number of body regions with any new HO (new HO > 0 mm^3). The presence of HO across various body regions was analyzed using WBCT scan. Results are presented for overall ITT period
3. Percentage of Participants With Flare-Ups [ Time Frame: Month 12 ]
   Flare-up as an event with one or more flare-up symptoms, and regardless of flare-up symptom onset. Flare-up was evaluated remotely, or by telephone or video-conferencing, unless the Investigator deemed that a site visit was necessary.
4. Ratio of Flare-Up Per Participant-Month of Exposure [ Time Frame: From Baseline (Day 1) up to end of 4-year follow-up period (approximately 57 months) ]
   Flare-up as an event with one or more flare-up symptoms, and regardless of flare-up symptom onset. Flare-up was evaluated remotely, or by telephone or video-conferencing, unless the Investigator deemed that a site visit was necessary. The flare-up rate per participant-month exposure was analyzed using a negative binomial regression. Results are presented for overall ITT period.

Eligibility Criteria

• Ages Eligible for Study: 4 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Key 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.

Key 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.

Contacts and Locations

Locations

United States, California

University of California San Francisco, Division of Endocrinology and Metabolism

San Francisco, California, United States, 94143

United States, Minnesota

Mayo Clinic

Rochester, Minnesota, United States, 55905

United States, Pennsylvania

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States, 19104

University of Pennsylvania, Internal Medicine

Philadelphia, Pennsylvania, United States, 19104

Argentina

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

Buenos Aires, Argentina, C1199ACH

Australia, New South Wales

Royal North Shore Hospital

Saint Leonards, New South Wales, Australia, 2065

Australia, Queensland

Queensland University of Technology

Woolloongabba, Queensland, Australia, 4102

Brazil

Hospital Israelita Albert Einstein

Sao Paulo, SP, Brazil, 05652-900

Canada, Ontario

Hospital for Sick Children, 555 University Avenue

Toronto, Ontario, Canada, M5G 1X8

Toronto General Hospital

Toronto, Ontario, Canada, M5G 2C4

France

Groupe Hospitalier Necker Enfants Malades

Paris, France, 75015

Italy

Istituto Giannina Gaslini

Genoa, Liguria, Italy, 16147

Japan

The University of Tokyo Hospital

Tokyo, Bunkyo-ku, Japan, 113-8655

Spain

Hospital Universitari i Politècnic La Fe, Unidad de Reumatología Pediatrica

Valencia, Avinguda De Fernando Abril Martorell, Nº 106, Spain, 46026

Sweden

Norrlands Universitetssjukhus

Umeå, Sweden, SE-90185

United Kingdom

Royal National Orthopaedic Hospital, Brockely Hill

Stanmore, United Kingdom, HA7 4LP

Sponsors and Collaborators

Clementia Pharmaceuticals Inc.

Investigators

• Study Director: Ipsen Medical Director; Ipsen

  Study Documents (Full-Text)

Documents provided by Ipsen ( Clementia Pharmaceuticals Inc. ):

Study Protocol  [PDF] October 30, 2020

Statistical Analysis Plan  [PDF] December 13, 2022

More Information

Additional Information:

Website for the International FOP Association 

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.

• Responsible Party: Clementia Pharmaceuticals Inc.
• ClinicalTrials.gov Identifier: NCT03312634
• Other Study ID Numbers: PVO-1A-301; 2017-002541-29 ( EudraCT Number )
• First Posted: October 18, 2017
• Results First Posted: March 14, 2023
• Last Update Posted: November 29, 2023
• Last Verified: November 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

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

Keywords provided by Ipsen ( Clementia Pharmaceuticals Inc. ):

Interventional study; Clinical trial phase 3; 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; FOP variants

Additional relevant MeSH terms:

Myositis Ossificans; Myositis; Muscular Diseases; Musculoskeletal Diseases