Clinical trial NCT03312634: An Efficacy and Safety Study of Palovarotene for the Treatment of Fibrodysplasia Ossificans Progressiva.
Official title: A Phase 3, Efficacy and Safety Study of Oral Palovarotene for the Treatment of Fibrodysplasia Ossificans Progressiva (FOP)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Fibrodysplasia Ossificans Progressiva
Keywords: 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
Lead sponsor: Ipsen
Sponsor class: INDUSTRY
First posted: 2017-10-18
Enrollment: 107
Sex: ALL
Minimum age (years): 4
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: A multicenter, open-label study. NHS data (study PVO-1A-001) will be used as an external control in the analysis.
Primary purpose: TREATMENT

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.

Eligibility 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.
* 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.

Primary outcomes:
measure: Annualized New Heterotopic Ossification (HO)
timeFrame: Baseline (within one month of screening/Day 1) and up to 24 months
Secondary outcomes:
measure: Percentage of Participants With Any New HO
timeFrame: From Baseline (Day 1) up to end of 4-year follow-up period (approximately 57 months)
measure: Number of Body Regions With New HO
timeFrame: From Baseline (Day 1) up to end of 4-year follow-up period (approximately 57 months)
measure: Percentage of Participants With Flare-Ups
timeFrame: Month 12
measure: Ratio of Flare-Up Per Participant-Month of Exposure
timeFrame: From Baseline (Day 1) up to end of 4-year follow-up period (approximately 57 months)
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California San Francisco, Division of Endocrinology and Metabolism
state: California
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania, Internal Medicine
state: Pennsylvania
city: Buenos Aires
country: Argentina
facility: Hospital Italiano de Buenos Aires, Tte General Juan Domingo Peron 4190
city: Saint Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Woolloongabba
country: Australia
facility: Queensland University of Technology
state: Queensland
city: Sao Paulo
country: Brazil
facility: Hospital Israelita Albert Einstein
state: SP
city: Toronto
country: Canada
facility: Hospital for Sick Children, 555 University Avenue
state: Ontario
city: Toronto
country: Canada
facility: Toronto General Hospital
state: Ontario
city: Paris
country: France
facility: Groupe Hospitalier Necker Enfants Malades
city: Genoa
country: Italy
facility: Istituto Giannina Gaslini
state: Liguria
city: Tokyo
country: Japan
facility: The University of Tokyo Hospital
state: Bunkyo-ku
city: Valencia
country: Spain
facility: Hospital Universitari i Politècnic La Fe, Unidad de Reumatología Pediatrica
state: Avinguda De Fernando Abril Martorell, Nº 106
city: Umeå
country: Sweden
facility: Norrlands Universitetssjukhus
city: Stanmore
country: United Kingdom
facility: Royal National Orthopaedic Hospital, Brockely Hill
Study officials:
affiliation: Ipsen
name: Ipsen Medical Director
role: STUDY_DIRECTOR
References:
citation: 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.