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

A Phase 3, Efficacy and Safety Study of Oral Palovarotene for the Treatment of Fibrodysplasia Ossificans Progressiva (FOP)

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.

Study Overview

• Status: Completed
• Conditions: Fibrodysplasia Ossificans Progressiva
• Intervention / Treatment: Drug: Palovarotene

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 Type: Interventional
• Enrollment (Actual): 107
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1199ACH
    • Hospital Italiano de Buenos Aires, Tte General Juan Domingo Peron 4190
• Australia
  • New South Wales
    • Saint Leonards, New South Wales, Australia, 2065
      • Royal North Shore Hospital
  • Queensland
    • Woolloongabba, Queensland, Australia, 4102
      • Queensland University of Technology
• Brazil
  • SP
    • Sao Paulo, SP, Brazil, 05652-900
      • Hospital Israelita Albert Einstein
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2C4
      • Toronto General Hospital
    • Toronto, Ontario, Canada, M5G 1X8
      • Hospital for Sick Children, 555 University Avenue
• France
  • Paris, France, 75015
    • Groupe Hospitalier Necker Enfants Malades
• Italy
  • Liguria
    • Genoa, Liguria, Italy, 16147
      • Istituto Giannina Gaslini
• Japan
  • Bunkyo-ku
    • Tokyo, Bunkyo-ku, Japan, 113-8655
      • The University of Tokyo Hospital
• Spain
  • Avinguda De Fernando Abril Martorell, Nº 106
    • Valencia, Avinguda De Fernando Abril Martorell, Nº 106, Spain, 46026
      • Hospital Universitari i Politècnic La Fe, Unidad de Reumatología Pediatrica
• Sweden
  • Umeå, Sweden, SE-90185
    • Norrlands Universitetssjukhus
• United Kingdom
  • Stanmore, United Kingdom, HA7 4LP
    • Royal National Orthopaedic Hospital, Brockely Hill
• United States
  • California
    • San Francisco, California, United States, 94143
      • University of California San Francisco, Division of Endocrinology and Metabolism
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania, Internal Medicine

Participation Criteria

Eligibility Criteria

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

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Annualized New Heterotopic Ossification (HO)	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.	Baseline (within one month of screening/Day 1) and up to 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Flare-Ups	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.	Month 12
Percentage of Participants With Any New HO	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.	From Baseline (Day 1) up to end of 4-year follow-up period (approximately 57 months)
Number of Body Regions With New HO	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	From Baseline (Day 1) up to end of 4-year follow-up period (approximately 57 months)
Ratio of Flare-Up Per Participant-Month of Exposure	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.	From Baseline (Day 1) up to end of 4-year follow-up period (approximately 57 months)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Range of Motion	Change from baseline in range of motion as assessed by the Cumulative Analogue Joint Involvement Scale for FOP (CAJIS).	Screening, every 6 months up to 4 years
FOP-Physical Function Questionnaire	Change from baseline in physical function using age-appropriate forms of the FOP-Physical Function Questionnaire (PFQ).	Screening, every 6 months up to 4 years
PROMIS Global Health Scale	Change from baseline in physical/mental function using age-appropriate forms of the PROMIS Global Health Scale.	Screening, every 6 months up to 4 years

Collaborators and Investigators

• Sponsor: Clementia Pharmaceuticals Inc.
• Investigators: Study Director: Ipsen Medical Director, Ipsen

Publications and helpful links

General 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.

Helpful Links

• Website for the International FOP Association

Study record dates

Study Major Dates

• Study Start (Actual): November 30, 2017
• Primary Completion (Actual): January 24, 2020
• Study Completion (Actual): September 7, 2022

Study Registration Dates

• First Submitted: October 9, 2017
• First Submitted That Met QC Criteria: October 12, 2017
• First Posted (Actual): October 18, 2017

Study Record Updates

• Last Update Posted (Actual): November 29, 2023
• Last Update Submitted That Met QC Criteria: November 28, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Efficacy and safety; Interventional study; Heterotopic ossification; Flare-up; Palovarotene; Retinoic acid receptor agonist; Retinoic acid receptor gamma agonist; Clementia; Myositis Ossificans Progressiva; Munchmeyer's Disease; FOP; Clinical trial phase 3; FOP variants
• Additional Relevant MeSH Terms: Musculoskeletal Diseases; Muscular Diseases; Myositis; Myositis Ossificans
• Other Study ID Numbers: PVO-1A-301; 2017-002541-29 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No