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

Fibrodysplasia Ossificans Progressiva Clinical Trial

— MOVE  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03312634
• Other study ID #: PVO-1A-301
• Secondary ID: 2017-002541-29
• Status: Completed
• Phase: Phase 3
• Start date: November 30, 2017
• Est. completion date: September 7, 2022

Study information

• Verified date: November 2023
• Source: Ipsen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 107
• Est. completion date: September 7, 2022
• Est. primary completion date: January 24, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 4 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Fibrodysplasia Ossificans Progressiva

Intervention

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

Locations

Country	Name	City	State
Argentina	Hospital Italiano de Buenos Aires, Tte General Juan Domingo Peron 4190	Buenos Aires
Australia	Royal North Shore Hospital	Saint Leonards	New South Wales
Australia	Queensland University of Technology	Woolloongabba	Queensland
Brazil	Hospital Israelita Albert Einstein	Sao Paulo	SP
Canada	Hospital for Sick Children, 555 University Avenue	Toronto	Ontario
Canada	Toronto General Hospital	Toronto	Ontario
France	Groupe Hospitalier Necker Enfants Malades	Paris
Italy	Istituto Giannina Gaslini	Genoa	Liguria
Japan	The University of Tokyo Hospital	Tokyo	Bunkyo-ku
Spain	Hospital Universitari i Politècnic La Fe, Unidad de Reumatología Pediatrica	Valencia	Avinguda De Fernando Abril Martorell, Nº 106
Sweden	Norrlands Universitetssjukhus	Umeå
United Kingdom	Royal National Orthopaedic Hospital, Brockely Hill	Stanmore
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	University of Pennsylvania, Internal Medicine	Philadelphia	Pennsylvania
United States	Mayo Clinic	Rochester	Minnesota
United States	University of California San Francisco, Division of Endocrinology and Metabolism	San Francisco	California

Sponsors (1)

Lead Sponsor	Collaborator
Clementia Pharmaceuticals Inc.

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Brazil,  Canada,  France,  Italy,  Japan,  Spain,  Sweden,  United Kingdom, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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)
Secondary	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)
Secondary	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
Secondary	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)

External Links

•   Website for the International FOP Association