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

Study Description

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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

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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

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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

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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

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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

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Contacts

Contact: Clinical Trials Information	1-800-750-8710	ClinicalTrials@clementiapharma.com
Contact: Clinical Trials Information

Locations

United States, California
University of California San Francisco, Division of Endocrinology and Metabolism	Recruiting
San Francisco, California, United States, 94143
Contact: Tea Chan 415-316-8308 tea.chan@ucsf.edu
Principal Investigator: Edward Hsiao, MD, PhD
Sub-Investigator: Umesh Masharani, MD
United States, Minnesota
Mayo Clinic - 200 1st Street Southwest	Recruiting
Rochester, Minnesota, United States, 55905
Contact: Nicole Bernal 507-266-1944 bernal.nicole@mayo.edu
Principal Investigator: Robert J Pignolo, MD, PhD
Sub-Investigator: Mark Adkins, MD
Sub-Investigator: Matthew Drake, MD
Sub-Investigator: Stephen Broski, MD
United States, Pennsylvania
Children's Hospital of Philadelphia	Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Edna Mancilla, MD 215-590-3174 mancillae@email.chop.edu
Principal Investigator: Edna Mancilla, MD
Sub-Investigator: Michael Levine, MD
University of Pennsylvania	Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Katherine S. Toder, CCRC 215-294-9144 Katherine.Toder@uphs.upenn.edu
Principal Investigator: Mona Al Mukaddam, MD, MS
Sub-Investigator: Frederick Kaplan, MD
Argentina
Hospital Italiano de Buenos Aires, Tte General Juan Domingo Peron 4190	Recruiting
Buenos Aires, Argentina, C1199ABB
Contact: Carmen Laura De Cunto, MD +541149590578 carmen.decunto@hospitalitaliano.org.ar
Principal Investigator: Carmen Laura De Cunto, MD
Sub-Investigator: Maria Laura Acosta, MD
Australia, Queensland
Queensland University of Technology, Institute of Health and Biomedical Innovation, TRI, Level 3	Recruiting
Woolloongabba, Queensland, Australia, 4102
Contact: Matthew Brown, MD +61 7 3443 7364 matt.brown@qut.edu.au
Principal Investigator: Matthew Brown, MD
Sub-Investigator: Hans Peter Sayer, MD
Brazil
Hospital Israelita Albert Einstein	Recruiting
Sao Paulo, SP, Brazil, 05652-900
Contact: Patricia Longo Ribeiro Delai, MD +541149590578 pdelai@pvo-trials.com
Principal Investigator: Patricia Longo Ribeiro Delai, MD
Sub-Investigator: Alessandro Rozim Zorzi, MD
Canada, Ontario
Hospital for Sick Children, 555 University Avenue	Recruiting
Toronto, Ontario, Canada, M5G 1X8
Contact: Peter Kannu, MB ChB (Otago), PhD, DCH (416) 813-7654 ext 309300 peter.kannu@sickkids.ca
Principal Investigator: Peter Kannu, MB ChB (Otago), PhD, DCH
Sub-Investigator: Irene Lara-Corrales, MD
Sub-Investigator: Jennifer Stimec, MD
Sub-Investigator: Roberto Mendoza-Londono, MD, MSc, FCCMG
Toronto General Hospital	Recruiting
Toronto, Ontario, Canada, M5G 2C4
Contact: Irene Ho 416-340-3680 irene.ho@uhn.ca
Contact: Suzanne Cohen 416-340-4850 suzanne.cohen@uhn.ca
Principal Investigator: Angela Cheung, MD, PhD
Sub-Investigator: Lianne Tile, MD
France
Groupe Hospitalier Necker Enfants Malades	Recruiting
Paris, France, 75015
Contact: Genevieve Baujat, MD 331 44 49 51 53 genevieve.baujat@aphp.fr
Principal Investigator: Genevieve Baujat, MD
Sub-Investigator: Caroline Michot, MD
Sub-Investigator: Philippe Blakime Aalem, MD
Sub-Investigator: Breton Sylvain, MD
Italy
Istituto Giannina Gaslini, Department of Pediatrics, Unit of Rare Diseases	Recruiting
Genova, Liguria, Italy, 16148
Contact: Maja Di Rocco, MD 0039 0105636794 majadirocco@gaslini.org
Principal Investigator: Maja Di Rocco, MD
Sub-Investigator: Marta Bertamino, MD
Sub-Investigator: Annalisa Amodeo, MD
Japan
The University of Tokyo Hospital	Recruiting
Tokyo, Bunkyo-ku, Japan, 113-8655
Contact: Nobuhiko Haga, MD +81 3 3815 5411
Principal Investigator: Nobuhiko Haga, MD
Sub-Investigator: Yusuke Shinoda, MD
Sub-Investigator: Sayaka Fujiwara, MD
Sub-Investigator: Hiroshi Mano, MD
Sub-Investigator: Ryoko Sawada, MD
Sub-Investigator: Sakae Tanaka, MD
Sub-Investigator: Keita Okada, MD
Spain
Hospital Universitari i Politècnic La Fe, Unidad de Reumatología Pediatrica	Recruiting
Valencia, Avinguda De Fernando Abril Martorell, Nº 106, Spain, 46026
Contact: Inmaculada Calvo, MD, PhD 0034 96 124 4792 calvo_inm@gva.es
Principal Investigator: Inmaculada Calvo, MD, PhD
Sub-Investigator: Maria Isabel Gonzalez, MD
Sub-Investigator: Berta Lopez, MD
Sub-Investigator: Miguel Martí, MD, PhD
Sweden
Norrlands Universitetssjukhus	Recruiting
Umeå, Sweden, SE-90185
Contact: Staffan Berglund, MD, PhD +46 90 7850225 staffan.berglund@umu.se
Principal Investigator: Staffan Berglund, MD, PhD
Sub-Investigator: Maria Björmsjö, MD
United Kingdom
Royal National Orthopaedic Hospital, Brockely Hill	Recruiting
Stanmore, United Kingdom, HA7 4LP
Contact: Richard Keen, MD +447956309461 richard.keen1@nhs.net
Contact: Jackie Vinton 0208 909 5425 jvinton@nhs.net
Principal Investigator: Richard Keen, MD
Sub-Investigator: Judith Bubbear, MD

Sponsors and Collaborators

Clementia Pharmaceuticals Inc.

More Information

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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.

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:	July 13, 2018
Last Verified:	October 2017
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 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