An Efficacy and Safety Study of Palovarotene for the Treatment of FOP

• Sponsor: Clementia Pharmaceuticals Inc.
• Information provided by (Responsible Party): 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 primary objective is to evaluate the efficacy of palovarotene in decreasing new HO in subjects with FOP as assessed by low-dose, whole body computed tomography (WBCT), excluding head, compared to untreated subjects from Clementia's FOP natural history study (Study PVO-1A-001, NHS). The other primary objective is to evaluate the safety of palovarotene in subjects with FOP.

This is a Phase 3, multicenter, open-label study. Eligible subjects will receive a chronic/flare-up dosing regimen of palovarotene for 24 months as follows:

• Chronic treatment: orally administered 5 mg palovarotene once daily for 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 will be weight-adjusted in skeletally immature subjects (those under the age of 18 years with less than 90% skeletal maturity on hand/ wrist x-rays performed at Screening).

Study Design

Layout table for study information

Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	90 participants
Intervention Model:	Single Group Assignment
Intervention Model Description:	A multicenter, open-label study. Untreated subjects from the FOP NHS will serve as the control arm.
Masking:	None (Open Label)
Masking Description:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	MOVE TRIAL: A Phase 3, Efficacy and Safety Study of Oral Palovarotene for the Treatment of Fibrodysplasia Ossificans Progressiva (FOP)
Actual Study Start Date :	November 28, 2017
Estimated Primary Completion Date :	September 2020
Estimated Study Completion Date :	November 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Palovarotene Chronic/Flare-Up Regimen; Subjects will receive 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 will be adjusted for weight in skeletally immature subjects.)	Drug: Palovarotene; Palovarotene will be taken orally once daily at approximately the same time each day following a meal.

Outcome Measures

Primary Outcome Measures :

1. 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.

Secondary Outcome Measures :

1. Subjects with New HO [ Time Frame: Screening, every 6 months up to 2 years ]
   The proportion of subjects with any new HO.
2. 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.
3. Subjects with Flare-Ups [ Time Frame: Up to 2 years ]
   The proportion of subjects reporting flare-ups.
4. Rate of Flare-Ups [ Time Frame: Up to 2 years ]
   The rate of flare-ups per subject-month exposure.
5. Incidence of Adverse Events [ Time Frame: Up to 2 years ]
   Monitor adverse events.
6. 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.

Other Outcome Measures:

1. 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).
2. 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).
3. 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.

Eligibility Criteria

Layout table for eligibility information

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.
• 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.

Contacts and Locations

Locations

Layout table for location information

United States, California
University of California San Francisco, Division of Endocrinology and Metabolism
San Francisco, California, United States, 94143
United States, Minnesota
Mayo Clinic - 200 1st Street Southwest
Rochester, Minnesota, United States, 55905
United States, Pennsylvania
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104
University of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104
Argentina
Hospital Italiano de Buenos Aires, Tte General Juan Domingo Peron 4190
Buenos Aires, Argentina, C1199ABB
Australia, Queensland
Queensland University of Technology, Institute of Health and Biomedical Innovation, TRI, Level 3
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, Department of Pediatrics, Unit of Rare Diseases
Genova, Liguria, Italy, 16148
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.

More Information

Additional Information:

Website for the International FOP Association  More information about this study 

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-γ 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.

Layout table for additonal information

Responsible Party:	Clementia Pharmaceuticals Inc.
ClinicalTrials.gov Identifier:	NCT03312634 History of Changes
Other Study ID Numbers:	PVO-1A-301
First Posted:	October 18, 2017
Last Update Posted:	January 30, 2019
Last Verified:	January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Undecided

Layout table for additional information

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

Keywords provided by 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:

Layout table for MeSH terms

Myositis Ossificans; Myositis; Muscular Diseases; Musculoskeletal Diseases