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

Sponsor

Clementia Pharmaceuticals Inc. (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT03312634

Collaborator

(none)

110

Enrollment

Locations

Arm

59.1

Anticipated Duration (Months)

7.3

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

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 that will be conducted in three parts: Part A, the main part of the study; Part B, the 24-month extension. Eligible subjects will receive a chronic/flare-up dosing regimen of palovarotene for 48 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).

And Part C, the up-to-2-year post last dose of study treatment follow-up for skeletally immature subjects. No new subjects will be enrolled into Part C. Subjects who were enrolled in Parts A or B who have discontinued the study and were skeletally immature will be invited back to participate in the off-treatment Part C safety follow-up.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

110 participants

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.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

Official Title:

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

Actual Study Start Date :

Nov 28, 2017

Actual Primary Completion Date :

Jan 24, 2020

Anticipated Study Completion Date :

Nov 1, 2022

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.

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

Change in New HO Volume [Screening, every 6 months 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

Subjects with New HO [Screening, every 6 months for 2 years, then annually up to 4 years]
The proportion of subjects with any new HO.
Number of Body Regions with HO [Screening, every 6 months for 2 years, then annually up to 4 years]
Change from baseline in the number of body regions with new HO.
Subjects with Flare-Ups [Up to 4 years]
The proportion of subjects reporting flare-ups.
Rate of Flare-Ups [Up to 4 years]
The rate of flare-ups per subject-month exposure.
Incidence of Adverse Events [Up to 4 years]
Monitor adverse events.
Palovarotene Area Under the Curve (AUC) [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

Range of Motion [Screening, every 6 months up to 4 years]
Change from baseline in range of motion as assessed by the Cumulative Analogue Joint Involvement Scale for FOP (CAJIS).
FOP-Physical Function Questionnaire [Screening, every 6 months up to 4 years]
Change from baseline in physical function using age-appropriate forms of the FOP-Physical Function Questionnaire (PFQ).
PROMIS Global Health Scale [Screening, every 6 months up to 4 years]
Change from baseline in physical/mental function using age-appropriate forms of the PROMIS Global Health Scale.

Eligibility Criteria

Criteria

Ages Eligible for Study:

4 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

	Site	City	State	Country	Postal Code
1	University of California San Francisco, Division of Endocrinology and Metabolism	San Francisco	California	United States	94143
2	Mayo Clinic - 200 1st Street Southwest	Rochester	Minnesota	United States	55905
3	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
4	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
5	Hospital Italiano de Buenos Aires, Tte General Juan Domingo Peron 4190	Buenos Aires		Argentina	C1199ABB
6	Royal North Shore Hospital	Saint Leonards	New South Wales	Australia	2065
7	Hospital Israelita Albert Einstein	Sao Paulo	SP	Brazil	05652-900
8	Hospital for Sick Children, 555 University Avenue	Toronto	Ontario	Canada	M5G 1X8
9	Toronto General Hospital	Toronto	Ontario	Canada	M5G 2C4
10	Groupe Hospitalier Necker Enfants Malades	Paris		France	75015
11	Istituto Giannina Gaslini, Department of Pediatrics, Unit of Rare Diseases	Genova	Liguria	Italy	16148
12	The University of Tokyo Hospital	Tokyo	Bunkyo-ku	Japan	113-8655
13	Hospital Universitari i Politècnic La Fe, Unidad de Reumatología Pediatrica	Valencia	Avinguda De Fernando Abril Martorell, Nº 106	Spain	46026
14	Norrlands Universitetssjukhus	Umeå		Sweden	SE-90185
15	Royal National Orthopaedic Hospital, Brockely Hill	Stanmore		United Kingdom	HA7 4LP