E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Fibrodysplasia Ossificans Progressiva (FOP) |
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E.1.1.1 | Medical condition in easily understood language |
Fibrodysplasia Ossificans Progressiva |
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E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10068715 |
E.1.2 | Term | Fibrodysplasia ossificans progressiva |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To further evaluate the safety of palovarotene in adult and paediatric participants with FOP.
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E.2.2 | Secondary objectives of the trial |
• To describe range of motion, as assessed by the Cumulative Analogue Joint Involvement Scale (CAJIS) for FOP, at the Inclusion Visit and over time under palovarotene treatment. • To describe the use of assistive devices and adaptations for daily living by FOP participants, at the Inclusion Visit and over time under palovarotene treatment. • To describe physical function, using the adult form of the FOP Physical Function Questionnaire, at the Inclusion Visit and over time under palovarotene treatment. • To describe the FOP healthcare utilization in patients with FOP. • To describe the parameters of lung function at the Inclusion Visit and over time under palovarotene treatment. • To describe physical and mental health, using the adult form of the Patient Reported Outcomes Measurement Information System Global Health Scale, at the Inclusion Visit and over time under palovarotene treatment.
Please refer to protocol for other secondary objectives. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Participants are eligible to be included in the study only if all of the following criteria apply: 1. 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. 2. In the investigator’s judgment, the participant may benefit from continued participation in a palovarotene study.
Age 3. 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 CLIN60120-452 informed consent is signed. *The above criteria can be reached at any point after parent study end for the participant to be eligible for Study CLIN-60120-452, as long as it is prior to palovarotene becoming reimbursed in the country where the study is being conducted.
Sex 4. Male, or female who is not pregnant or breastfeeding, and has met all of the following conditions: • Females of child-bearing potential (FOCBP) (defined in Section 10.2.1 of the protocol) must have a negative blood or urine pregnancy test (with sensitivity of at least 50 mIU/mL) prior to administration of palovarotene; • FOCBP must agree to remain abstinent from heterosexual sex during treatment and for one month after treatment or, if sexually active, to use two effective methods of birth control (described in Section 10.2.2 of the protocol) during and for one month after treatment; Additionally, sexually active FOCBP must already be using two effective methods of birth control one month before treatment is to start; • Specific risk of the use of retinoids during pregnancy, and the agreement to remain abstinent or use two effective methods of birth control will be clearly defined in the informed consent and the participant or legally authorised representatives (e.g. parents, caregivers or legal guardians) must specifically sign this section. Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
Informed Consent and Assent 5. Capable of giving signed informed consent or providing assent as described in Section 10.1.3 of the protocol.
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E.4 | Principal exclusion criteria |
Participants will not be included in the study if any of the following criteria apply:
Medical conditions 1. 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. 2. Uncontrolled cardiovascular, hepatic, pulmonary, gastrointestinal, endocrine, metabolic, ophthalmologic, immunologic, psychiatric, or other significant disease. 3. Symptomatic vertebral fracture. 4. Any other medical condition/clinically significant abnormalities that would expose the participant to undue risk or interfere with study assessments. 5. Amylase or lipase >2× above the upper limit of normal (ULN) or with a history of chronic pancreatitis. 6. Elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5× ULN. 7. Fasting triglycerides >400 mg/dL with or without therapy. 8. Suicidal ideation (type 4 or 5) or any suicidal behaviour at Inclusion Visit as defined by the Columbia-Suicide Severity Rating Scale (C-SSRS).
Prior/concomitant therapy 9. 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. 10. Exposure to synthetic oral retinoids other than palovarotene within 4 weeks of the Inclusion Visit. 11. Concurrent treatment with tetracycline or any tetracycline derivatives due to the potential increased risk of pseudotumor cerebri. 12. Use of concomitant medications that are strong inhibitors or inducers of cytochrome P450 (CYP450) 3A4 activity (see Section 6.8 and 10.5 of protocol); or kinase inhibitors such as imatinib.
Other exclusion criteria 13. Palovarotene is reimbursed in the country where the study is being conducted. 14. 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.
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E.5 End points |
E.5.1 | Primary end point(s) |
• Incidence and description of all treatment emergent adverse events (TEAEs) whether or not they are considered as related to the study intervention; • Incidence and description of all serious and nonserious treatment-related TEAEs; • Incidence and description of all serious TEAEs, whether or not they are considered as related to the study intervention; • Incidence and description of all nonserious TEAEs whether or not they are considered as related to the study intervention.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
At Inclusion Visit (Day 1) and then every 6 months at Follow-up Visits until End of Study or Early Withdrawal. |
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E.5.2 | Secondary end point(s) |
• Raw values and change from the Inclusion Visit in CAJIS total score at each Follow-up Visit; • Raw values and shift from the Inclusion Visit in the use of assistive devices and adaptations for daily living at each Follow-up Visit; • 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 for all participants, at each Follow-up Visit; • Type and frequency of healthcare utilization • Raw values and change from the Inclusion Visit in observed and % predicted FVC at each Follow-up Visit; • Raw values and change from the Inclusion Visit in observed and % predicted FEV1 at each Follow-up Visit; • Raw values and change from the Inclusion Visit in absolute and % predicted FEV1/FVC ratio at each Follow-up Visit; • Raw values and change from the Inclusion Visit in observed and % predicted DLCO at each Follow-up Visit; • 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 Global Health Scale for all participants, at each Follow-up Visit; • 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 at each Follow-up Visit by body location and overall; • Percentage of participants with new bone growth overall and by flare-up status at each Follow-up Visit;
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
At Inclusion Visit (Day 1) and then every 6 months at Follow-up Visits until End of Study or Early Withdrawal. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 4 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Australia |
Brazil |
Canada |
United States |
France |
Sweden |
Spain |
Italy |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Last Patient Last Visit (LPLV)
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 17 |