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.

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.

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT05027802

Acronym

PIVOINE

Enrollment

Registered

2021-08-30

Start date

2022-03-14

Completion date

2024-11-30

Last updated

2025-06-22

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Fibrodysplasia Ossificans Progressiva (FOP)

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.

Interventions

DRUGPalovarotene

Palovarotene will be taken orally once daily at approximately the same time each day.

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

14 Years to No maximum

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
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

Measure	Time frame	Description
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 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 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.
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).
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.
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.

Countries

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

Participant flow

Recruitment details

This single-arm, rollover, multicenter, Phase III, open-label study was conducted at 12 investigational sites in 9 countries from 14-Mar-2022 to 30-Nov-2024 in participants \>=14 years with fibrodysplasia ossificans progressiva (FOP) who had completed parent study PVO-1A-301 (NCT03312634) or PVO-1A-202 (NCT02279095)/PVO-1A-204 (NCT02979769) and continued to benefit from palovarotene therapy. A total of 61 participants were enrolled in the study of which 59 received treatment.

Pre-assignment details

This study consisted of an Inclusion visit which included signing of informed consent form (Day 1), a continuous dosing treatment period (including a follow-up visit every 6 months), and an end of study/early withdrawal visit. Participants were eligible for the study whether they received chronic or flare-up treatment in the parent study at the time of transition.

Participants by arm

Arm	Count
Palovarotene Participants continued to receive palovarotene 5 mg orally once daily until it was reimbursed in the country where the study was being conducted or another access program became available or until the study end date, whichever occurred first, up to approximately 32 months. In case of flare-up symptoms or substantial high risk traumatic events (likely to lead to a flare-up), participants received palovarotene 20 mg orally once daily for 4 weeks followed by 10 mg orally once daily for 8 weeks for a total of 12 weeks even if symptoms resolved earlier.	59
Total	59

Arm

Count

Palovarotene

Participants continued to receive palovarotene 5 mg orally once daily until it was reimbursed in the country where the study was being conducted or another access program became available or until the study end date, whichever occurred first, up to approximately 32 months. In case of flare-up symptoms or substantial high risk traumatic events (likely to lead to a flare-up), participants received palovarotene 20 mg orally once daily for 4 weeks followed by 10 mg orally once daily for 8 weeks for a total of 12 weeks even if symptoms resolved earlier.

Total

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Adverse Event	2
Overall Study	Death	2
Overall Study	Other	1
Overall Study	Withdrawal by Subject	18

Baseline characteristics

Characteristic	Palovarotene
Age, Continuous	22.4 years STANDARD_DEVIATION 8.9
Ethnicity (NIH/OMB) Hispanic or Latino	10 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	33 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	16 Participants
Race/Ethnicity, Customized Asian	3 Participants
Race/Ethnicity, Customized Black or African American	0 Participants
Race/Ethnicity, Customized Multiple	2 Participants
Race/Ethnicity, Customized Not Reported	15 Participants
Race/Ethnicity, Customized Other	1 Participants
Race/Ethnicity, Customized White	38 Participants
Sex: Female, Male Female	28 Participants
Sex: Female, Male Male	31 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	2 / 59
other Total, other adverse events	45 / 59
serious Total, serious adverse events	9 / 59

Outcome results

Primary

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

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.

Time frame: From signing the informed consent form (Day 1) up to 30 days post last dose, approximately 32 months

Population: The FAS/safety set included all participants who received at least 1 dose of palovarotene in this study.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Palovarotene	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	All TEAEs	54 Participants
Palovarotene	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	Serious TEAEs	9 Participants
Palovarotene	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	Non-serious TEAEs	53 Participants
Palovarotene	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	Serious treatment-related TEAEs	1 Participants
Palovarotene	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	Non-serious treatment-related TEAEs	38 Participants

Secondary

Annualized Rate of Healthcare Utilization (HU) in Participants With Fibrodysplasia Ossificans Progressiva

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.

Time frame: Up to approximately 32 months