A Rollover Study to Further Evaluate the Safety and Efficacy of Palovarotene Capsules in Male and Female Participants Aged ≥14 Years With Fibrodysplasia Ossificans Progressiva (FOP) Who Have Completed the Relevant Parent Studies.

Phase 3

Completed

Conditions: Fibrodysplasia Ossificans Progressiva (FOP)

Interventions: Drug: Palovarotene

Registration Number: NCT05027802

Lead Sponsor: Ipsen

Brief Summary: The main objective of this study is to further evaluate the safety and efficacy of palovarotene in adult and paediatric participants with FOP.

The aim of the study is also to ensure treatment continuity to participants who have completed one of the parent studies (Study PVO-1A-301, Study PVO-1A-202 and Study PVO-1A-204) and who, in the investigator's judgement, may benefit from palovarotene therapy.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 61

Inclusion Criteria

Participant has completed the EOS or End of Treatment Visit of Study PVO-1A-301 or PVO-1A-202 (PVO-1A-202 Parts C and D correspond to Study PVO-1A-204 in France) and did not previously withdraw consent from any of the parent studies to be eligible for Study CLIN-60120-452.
Participant must be ≥14 years of age (aligned with the age of treated participants in the ongoing parent studies PVO-1A-301 and PVO-1A-202/PVO-1A-204) and qualify as 100% skeletally mature (if <18 years, based on assessments carried out at parent EOS Visit; if ≥18 years, automatically considered 100% skeletally mature) or have reached final adult height based on investigator's assessment, at the time the Study CLIN- 60120-452 informed consent is signed.

Exclusion Criteria

History of allergy or hypersensitivity to retinoids, gelatin, lactose (note that lactose intolerance is not exclusionary) or palovarotene, or unresponsiveness to prior treatment with palovarotene.
Uncontrolled cardiovascular, hepatic, pulmonary, gastrointestinal, endocrine, metabolic, ophthalmologic, immunologic, psychiatric, or other significant disease.
Symptomatic vertebral fracture.
Intercurrent known or suspected non-healed fracture at any location;
Any other medical condition/clinically significant abnormalities that would expose the participant to undue risk or interfere with study assessments.
Amylase or lipase >2× above the upper limit of normal (ULN) or with a history of chronic pancreatitis.
Elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5× ULN.
Fasting triglycerides >400 mg/dL with or without therapy.
Suicidal ideation (type 4 or 5) or any suicidal behaviour at the Inclusion Visit as defined by the Columbia-Suicide Severity Rating Scale (C-SSRS).
Current use of vitamin A or beta carotene, multivitamins containing vitamin A or beta carotene, or herbal preparations, fish oil, and unable or unwilling to discontinue use of these products during palovarotene treatment.
Exposure to synthetic oral retinoids other than palovarotene within 4 weeks of the Inclusion Visit.
Concurrent treatment with tetracycline or any tetracycline derivatives due to the potential increased risk of pseudotumor cerebri.
Use of concomitant medications that are strong inhibitors or inducers of cytochrome P450 (CYP450) 3A4 activity; or kinase inhibitors such as imatinib.
Palovarotene is reimbursed in the country where the study is being conducted.
Any reason that, in the opinion of the investigator, would lead to the inability of the participant and/or family to comply with the protocol.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Palovarotene Chronic/Flare-Up Regimen	Palovarotene	Chronic treatment: participants will receive 5 mg palovarotene or the dose received during participation in the parent study at the time of transition to Study CLIN-60120-452 or prior to interrupting/stopping palovarotene treatment. Flare-up treatment: at the time of a flare-up (or substantial high-risk traumatic event likely to lead to a flare-up) participants will receive 20 mg palovarotene for 28 days, followed by 10 mg palovarotene for 56 days.

Primary Outcome Measures

Name	Time	Method
Number of Participants With All Treatment-emergent Adverse Events (TEAEs), Serious and Non-serious Treatment-emergent Adverse Events and Serious and Non-serious Treatment-related Treatment-emergent Adverse Events	From signing the informed consent form (Day 1) up to 30 days post last dose, approximately 32 months	An adverse event (AE) was any untoward medical occurrence in a clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An SAE was defined as any untoward medical occurrence that, at any dose, resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect or significant medical event. A TEAE was defined as any AE that occurred after signing the informed consent form of this study or an ongoing AE from the parent study with a worsening in severity or relationship to the study treatment following transition to this study.

Secondary Outcome Measures

Name	Time	Method
Change From the Inclusion Visit in Cumulative Analogue Joint Involvement Scale (CAJIS) Total Score at Months 6, 12, 18, 24 and 30	Inclusion Visit (Day 1) and Months 6, 12, 18, 24 and 30	The CAJIS is an objective measure of joint movement completed by the investigator to document total joint involvement. This scale assesses functional disability by categorizing range of motion across 12 joints (both right and left shoulder, elbow, wrist, hip, knee and ankle joints) and 3 body regions (cervical spine, thoracic/lumbar spine and jaw), with each joint/region assessed as: 0=normal (\<10% deficit); 1=partially impaired (10% to 90% deficit) and 2=functionally ankylosed (\>90% deficit). The CAJIS total score is calculated as the sum of the scores of all joints/regions and ranges from 0 (no involvement) to 30 (maximally involved). Higher score indicated worse outcome. The Inclusion Visit was the first study visit (Day 1) and first administration of palovarotene in this study.
Change From the Inclusion Visit in the Use of Assistive Devices and Adaptations (Aids) for Daily Living at Months 6, 12, 18, 24 and 30	Inclusion Visit (Day 1) and Months 6, 12, 18, 24 and 30	The use of assistive devices and adaptations (aids) for daily living was collected using the FOP assistive devices assessment at each visit. Assistive devices and adaptations include mobility aids, eating tools, personal care tools, bathroom aids and devices, bedroom aids and devices, home adaptions, work environment adaptions, technology adaptions, sports and recreation adaptions, school adaptions and medical therapies for daily living. The mean of total number of assistive devices and adaptations for daily living being used is presented. The Inclusion Visit was the first study visit (Day 1) and first administration of palovarotene in this study.
Change From the Inclusion Visit in Percentage of Worst Score Using the Adult Form of the Fibrodysplasia Ossificans Progressiva Physical Function Questionnaire (FOP-PFQ) at Months 6, 12, 18, 24 and 30	Inclusion Visit (Day 1) and Months 6, 12, 18, 24 and 30	The FOP-PFQ is a disease-specific patient-reported outcome measure of physical impairment; includes 28 questions related to activities of daily living and physical performance scored on a scale of 1 to 5 with lower scores indicating that participant has more difficulty completing those tasks. Total score, upper extremities subscore and mobility subscore is calculated as follows: total score: sum of the scores from each question (range 28 to 140); upper extremities subscore: sum of the scores from 15 questions (questions 1-12, 14, 25 and 26; range 15 to 75); mobility subscore: the sum of the scores from 13 questions (questions 13, 15-24, 27 and 28; range 13 to 65). The scores were transformed to reflect a percentage of worst score which ranged from 0% to 100% with 0% indicating the best possible function and 100% (higher score) indicating the worst possible function. Mean is presented. Inclusion Visit was first study visit (Day 1) and first administration of palovarotene in this study.
Annualized Rate of Healthcare Utilization (HU) in Participants With Fibrodysplasia Ossificans Progressiva	Up to approximately 32 months	Annualized HU rate was defined as the (number of HU during the study/duration of participant participation in the study in days) \* 365.25. Annualized rate for total health care services utilized is presented.
Change From the Inclusion Visit in Percent Predicted Forced Vital Capacity (FVC) at Months 6, 12, 18, 24 and 30	Inclusion Visit (Day 1) and Months 6, 12, 18, 24 and 30	Lung function parameters including FVC were obtained by spirometry. The Inclusion Visit was the first study visit (Day 1) and first administration of palovarotene in this study.
Change From the Inclusion Visit in Percent Predicted Forced Expiratory Volume in One Second (FEV1) at Months 6, 12, 18, 24 and 30	Inclusion Visit (Day 1) and Months 6, 12, 18, 24 and 30	Lung function parameters including FEV1 were obtained by spirometry. The Inclusion Visit was the first study visit (Day 1) and first administration of palovarotene in this study.
Change From the Inclusion Visit in Predicted FEV1/FVC Ratio at Months 6, 12, 18, 24 and 30	Inclusion Visit (Day 1) and Months 6, 12, 18, 24 and 30	The ratio of FEV1 to FVC was calculated. Lung function parameters were obtained by spirometry. The Inclusion Visit was the first study visit (Day 1) and first administration of palovarotene in this study.
Change From the Inclusion Visit in Percent Predicted Diffusion Capacity of the Lung for Carbon Monoxide (DLCO) at Months 6, 12, 18, 24 and 30	Inclusion Visit (Day 1) and Months 6, 12, 18, 24 and 30	The DLCO test provides information on the efficiency of gas transfer from alveolar air into the bloodstream. The Inclusion Visit was the first study visit (Day 1) and first administration of palovarotene in this study.
Change From the Inclusion Visit in Physical and Mental Function Using Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale at Months 6, 12, 18, 24 and 30	Inclusion Visit (Day 1) and Months 6, 12, 18, 24 and 30	The PROMIS Global Health Scale is a patient-reported outcome measure of physical and mental function. The adult form (developed for participants \>=15 years old) was used for all participants,consists of 10 questions from which 2 scores are calculated: global physical health score (GPH) and global mental health (GMH) score, each ranging from 4 (worse health) to 20 (better health). GPH score:sum of scores from Questions 3, 6, 7 and 8 and GMH score:sum of scores from Questions 2, 4, 5 and 10.These scores were converted to a T-score whose distributions were standardized such that value of 50 represented average (mean) for general population and increments of +/- 10 points represented +/- 1 standard deviation away from the norm.Higher T-scores indicated better physical/mental health. A T-score \<50 indicated worse health than general population, while a T-score \>50 indicated better health. Inclusion Visit was first study visit (Day 1) and first administration of palovarotene in this study.
Number of Participants With Flare-ups and Flare-up Outcomes	Months 6, 12, 18 and 24	Number of participants with at least 1 flare-up and intercurrent flare-ups since last visit is presented. Intercurrent flare-ups were defined as a new flare-up or marked worsening of the original flare up at any time during a flare-up-based treatment cycle. Outcome of flare-ups resulting in movement restriction and bone formations in participants is presented. Movement restriction includes categories like better, same, slightly worse, moderately worse and severely worse movement than before.
Number of Participants With Flare-ups by Body Location	Months 6, 12, 18 and 24	Number of participants with flare-ups by body locations including shoulder, elbow, hip, knee, ankle or foot, back, jaw and submandibular area and other (includes all other locations than mentioned) is presented.
Percentage of Participants With Extra Bone Growth at Months 6, 12, 18 and 24	Months 6, 12, 18 and 24	Percentage of participants with at least 1 extra bone growth associated or not with a flare-up since last visit is presented.
Duration of Flare-up at Months 6, 12, 18 and 24	Months 6, 12, 18 and 24	Duration of flare-up was defined as (date of end of flare-up - date of start of flare-up + 1).

Trial Locations

Locations (13): University of California San Francisco (UCSF)
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San Francisco, California, United States
Mayo Clinic
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Rochester, Minnesota, United States
Children's Hospital of Philidelphia
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Philadelphia, Pennsylvania, United States
The Perelman School of Medicine - The University of Pennsylvania
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Philadelphia, Pennsylvania, United States
Hospital Italiano de Buenos Aires
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Buenos Aires, Argentina
Royal North Shore Hospital
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Saint Leonards, New South Wales, Australia
Hospital Israelita Albert Einstein
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Morumbi, Sao-Paulo, Brazil
Toronto General Hospital
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Toronto, Canada
Groupe Hospitalier Necker Enfants Malades
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Paris, France
Istituto Giannina Gaslini
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Genoa, Italy
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University of California San Francisco (UCSF)
🇺🇸San Francisco, California, United States