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.

Study Overview
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Brief Summary
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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.

Official Title
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Rollover Study; Multicentre, Phase III, Open-label 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 Study PVO-1A-301 or PVO-1A-202/PVO-1A-204 and May Benefit From Palovarotene Therapy.

Conditions
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Fibrodysplasia Ossificans Progressiva (FOP)

Intervention / Treatment
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* Drug: Palovarotene


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 14 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Palovarotene Chronic/Flare-Up Regimen<br>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. | Drug: Palovarotene<br>* Palovarotene will be taken orally once daily at approximately the same time each day.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and description of all serious and non-serious treatment-emergent adverse events (TEAEs) whether or not they are considered as related to the study intervention; | Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and will be classified by PT (Preferred Term) and SOC (System Organ Class) | Three years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Raw values and change from the Inclusion Visit in CAJIS (Cumulative Analogue Joint Involvement Scale) total score |  | Every six months up to three years | 
| Raw values and shift from the Inclusion Visit in the use of assistive devices and adaptations for daily living | The use of assistive devices and adaptations for daily living will be collected using the FOP assistive devices assessment. | Every six months up to three years | 
| Raw values and change from the Inclusion Visit in % of worst score for total score, upper extremities subscore and mobility subscore | Using the adult form of the FOP-PFQ (FOP-Physical Function Questionnaire) for all participants | Every six months up to three years | 
| Frequency of healthcare services utilization |  | Three years | 
| Raw values and change from the Inclusion Visit in observed and % predicted FVC (Forced Vital Capacity) |  | Every six months up to three years | 
| Raw values and change from the Inclusion Visit in observed and % predicted FEV1 (Forced Expiratory Volume in One Second) |  | Every six months up to three years | 
| Raw values and change from the Inclusion Visit in absolute and % predicted FEV1/FVC ratio |  | Every six months up to three years | 
| Raw values and change from the Inclusion Visit in observed and % predicted DLCO (Diffusion Capacity of the Lung for Carbon Monoxide) |  | Every six months up to three years | 
| Raw values and change from the Inclusion Visit in physical and mental function (mean global physical and mental health score converted into T-scores) | Using the adult form of the PROMIS (Patient Reported Outcomes Measurement Information System) Global Health Scale for all participants | Every six months up to three years | 
| Raw values and change from the Inclusion Visit in number of investigator-reported flareups, flare-up outcomes (new bone growth, restricted movement) and flare-up duration by body location and overall; |  | Every six months up to three years | 
| Percentage of participants with new bone growth overall and by flare-up status |  | Every six months up to three years |