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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
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:
Information provided by (Responsible Party):
Ipsen ( Clementia Pharmaceuticals Inc. )

Tracking Information
First Submitted Date  ICMJE October 9, 2017
First Posted Date  ICMJE October 18, 2017
Results First Submitted Date  ICMJE January 20, 2023
Results First Posted Date  ICMJE March 14, 2023
Last Update Posted Date November 29, 2023
Actual Study Start Date  ICMJE November 30, 2017
Actual Primary Completion Date January 24, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (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  ICMJE
 (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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 28, 2023)
  • 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.
  • 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
  • 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 [ 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.
Original Secondary Outcome Measures  ICMJE
 (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  ICMJE An Efficacy and Safety Study of Palovarotene for the Treatment of Fibrodysplasia Ossificans Progressiva.
Official Title  ICMJE 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, 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  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE 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  ICMJE Fibrodysplasia Ossificans Progressiva
Intervention  ICMJE Drug: Palovarotene
Palovarotene was taken orally once daily at approximately the same time each day following a meal.
Study Arms  ICMJE 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.)
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: November 25, 2022)
107
Original Estimated Enrollment  ICMJE
 (submitted: October 12, 2017)
80
Actual Study Completion Date  ICMJE September 7, 2022
Actual Primary Completion Date January 24, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 4 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Argentina,   Australia,   Brazil,   Canada,   France,   Italy,   Japan,   Spain,   Sweden,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03312634
Other Study ID Numbers  ICMJE 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  ICMJE
Plan to Share IPD: Undecided
Current Responsible Party Ipsen ( Clementia Pharmaceuticals Inc. )
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Clementia Pharmaceuticals Inc.
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Ipsen Medical Director Ipsen
PRS Account Ipsen
Verification Date November 2023

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP