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: March 14, 2023
• Sponsor: Clementia Pharmaceuticals Inc.
• Information provided by (Responsible Party): Ipsen ( Clementia Pharmaceuticals Inc. )

Tracking Information

• First Submitted Date: October 9, 2017
• First Posted Date: October 18, 2017
• Results First Submitted Date: January 20, 2023
• Results First Posted Date: March 14, 2023
• Last Update Posted Date: March 14, 2023
• Actual Study Start Date: November 30, 2017
• Actual Primary Completion Date: January 24, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 20, 2023)

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.

Original Primary Outcome Measures (submitted: October 12, 2017)

Change in New HO Volume [ Time Frame: Screening, every 6 months up to 2 years ]

Annualized change in new HO volume as assessed by low-dose, WBCT (excluding head) compared to untreated subjects from the NHS.

Current Secondary Outcome Measures (submitted: January 20, 2023)

• Percentage of Participants With Any New HO [ Time Frame: Month 12 ]
  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.
• Number of Participants With Body Regions With New HO [ Time Frame: Month 12 ]
  The number of participants with any new HO (new HO > 0 mm^3) by number of body regions are reported. The presence of HO across various body regions was analyzed using WBCT scan.
• 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.
• Ratio of Flare-Up Per Participant-Month of Exposure Through Month 24 [ Time Frame: From Baseline (Day 1) up to Month 24 ]
  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.

Original Secondary Outcome Measures (submitted: October 12, 2017)

• Subjects with New HO [ Time Frame: Screening, every 6 months up to 2 years ]
  The proportion of subjects with any new HO.
• Number of Body Regions with HO [ Time Frame: Screening, every 6 months up to 2 years ]
  Change from baseline in the number of body regions with new HO.
• Subjects with Flare-Ups [ Time Frame: Up to 2 years ]
  The proportion of subjects reporting flare-ups.
• Rate of Flare-Ups [ Time Frame: Up to 2 years ]
  The rate of flare-ups per subject-month exposure.
• Incidence of Adverse Events [ Time Frame: Up to 2 years ]
  Monitor adverse events.
• Palovarotene Area Under the Curve (AUC) [ Time Frame: Predose, and 3, 6, 10, and 24 hours postdose ]
  Determination of AUC at steady-state assessed during treatment with 5, 10, and 20 mg palovarotene.

• Current Other Pre-specified Outcome Measures: Not Provided

Original Other Pre-specified Outcome Measures (submitted: October 12, 2017)

• Range of Motion [ Time Frame: Screening, every 6 months up to 2 years ]
  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: Screening, every 6 months up to 2 years ]
  Change from baseline in physical function using age-appropriate forms of the FOP-Physical Function Questionnaire (PFQ).
• PROMIS Global Health Scale [ Time Frame: Screening, every 6 months up to 2 years ]
  Change from baseline in physical/mental function using age-appropriate forms of the PROMIS Global Health Scale.

Descriptive Information

• Brief Title: An Efficacy and Safety Study of Palovarotene for the Treatment of Fibrodysplasia Ossificans Progressiva.
• Official Title: A Phase 3, Efficacy and Safety Study of Oral Palovarotene for the Treatment of 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.

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 and Part B, the 2-year (24-month) extension. Eligible participants received a chronic/flare-up dosing regimen of palovarotene for 4 years (48 months) as follows:

• Chronic treatment: orally administered 5 mg palovarotene once daily for 2 years (24 months).
• 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).

Part C was an up-to-2-year post last dose of study treatment follow-up for skeletally immature participants. No new participants were enrolled into 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 Part C safety follow-up.

• Study Type: Interventional
• Study Phase: Phase 3

Study Design

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

• Condition: Fibrodysplasia Ossificans Progressiva

Intervention

Drug: Palovarotene

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

Study Arms

Experimental: Palovarotene Chronic/Flare-Up Regimen

Participants received 5 mg palovarotene once daily for up to 24 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.)

Intervention: Drug: Palovarotene

• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 25, 2022): 107
• Original Estimated Enrollment (submitted: October 12, 2017): 80
• Actual Study Completion Date: September 7, 2022
• Actual Primary Completion Date: January 24, 2020 (Final data collection date for primary outcome measure)

Eligibility 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.
• Previous participation in Clementia's natural history study (NCT02322255); clinically diagnosed with FOP, with the R206H ACVR1 mutation or other FOP variants reported to be associated with progressive HO (who have not participated in any Clementia-sponsored study); participants in Clementia's Phase 2 studies (NCT02279095 and NCT02979769) who cannot currently receive the chronic/flare-up regimen due to country of residence or those traveling long distances to participate in the Phase 2 studies.
• 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 4 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Brazil, Canada, France, Italy, Japan, Spain, Sweden, United Kingdom, United States

Administrative Information

• NCT Number: NCT03312634
• Other Study ID Numbers: PVO-1A-301; 2017-002541-29 ( EudraCT Number )
• 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: Undecided

• Current Responsible Party: Ipsen ( Clementia Pharmaceuticals Inc. )
• Original Responsible Party: Same as current
• Current Study Sponsor: Clementia Pharmaceuticals Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Ipsen Medical Director; Ipsen

• PRS Account: Ipsen
• Verification Date: March 2023