E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Fibrodysplasia Ossificans Progressiva |
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E.1.1.1 | Medical condition in easily understood language |
Rare genetic disease which causes abnormal formation of bone at abnormal locations such as in the muscles, tendons and ligaments. |
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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 |
The primary efficacy objective of the study is to assess the effect of high-dose garetosmab versus placebo on the formation of new HO lesions from baseline to week 56, as determined by low-dose computerized tomography (CT)
The primary safety objective of the study is to assess the safety and tolerability of garetosmab versus placebo from baseline to week 56. |
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E.2.2 | Secondary objectives of the trial |
• To assess the effect of high-dose garetosmab versus placebo on the number per patient of clinician-assessed flare-up episodes to week 56 • To assess the effect of low-dose garetosmab versus placebo on the formation of new HO lesions from baseline to week 56 as determined by CT • To assess the effect of low-dose garetosmab versus placebo on the number per patient of clinician-assessed flare-up episodes to week 56 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female 18 years or older at screening 2. Clinical diagnosis of Fibrodysplasia Ossificans Progressiva (FOP) [(based on findings of congenital malformation of the great toes, episodic soft tissue swelling, and/or progressive Heterotopic Ossification (HO)] 3. Confirmation of FOP diagnosis with documentation of Type I activin A receptor (ACVR1) FOP causing mutation 4. FOP disease activity within 1 year of screening visit. FOP disease activity is defined as pain, swelling, stiffness, or other signs and symptoms associated with FOP flare-ups; or worsening of joint function, or radiographic progression of HO lesions (increase in size or number of HO lesions) with/without being associated with flare-up episodes 5. Willing and able to undergo CT imaging procedures and other procedures as defined in the protocol
Other Protocol Defined Inclusion Criteria Apply |
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E.4 | Principal exclusion criteria |
Key Exclusion Criteria: 1. Cumulative Analog Joint Involvement Scale (CAJIS) score at screening >19 2. Participant has significant concomitant illness or history of significant illness such as but not limited to cardiac, renal, rheumatologic, neurologic, psychiatric, endocrine, metabolic, or lymphatic disease, that in the opinion of the study investigator might confound the results of the study or pose additional risk to the patient by their participation in the study 3. Previous history or diagnosis of cancer 4. Severely impaired renal function defined as estimated glomerular filtration rate <30 milliliter per minute (mL/min) (/1.73 m^2 calculated by the Modification of Diet in Renal Disease equation) 5. Uncontrolled diabetes defined as hemoglobin A1C (HbA1c) >9% at screening 6. History of poorly controlled hypertension as defined by: a. Systolic blood pressure ≥180 mm Hg or diastolic blood pressure ≥110 mm Hg at the screening visit b. Systolic blood pressure of 160 mm Hg to 179 mm Hg or diastolic blood pressure of 100 mm Hg to 109 mm Hg at the screening visit, AND a history of end-organ damage (including history of left-ventricular hypertrophy, heart failure, angina, myocardial infarction, stroke, transient ischemic attack, peripheral arterial disease, end-stage renal disease, and moderate-to-advanced retinopathy) 7. Known history of cerebral vascular malformation 8. Cardiovascular conditions such as New York Heart Association class III or IV heart failure, cardiomyopathy, intermittent claudication, myocardial infarction, or acute coronary syndrome within 6 months prior to screening; symptomatic ventricular cardiac arrhythmia 9. History of severe respiratory compromise requiring oxygen, respiratory support (eg, bilevel positive airway pressure [biPAP] or continuous positive airway pressure [CPAP]), or a history of aspiration pneumonia requiring hospitalization 10. Prior use in the past year and concomitant use of bisphosphonates 11. Concurrent participation in another interventional clinical study or a non-interventional study with radiographic measures or invasive procedures (eg, collection of blood or tissue samples). 12. Treatment with another investigational drug, denosumab, imatinib or isotretinoin in the last 30 days or within 5 half-lives of the investigational drug, whichever is longer 13. Pregnant or breastfeeding women 14. Women of childbearing potential (WOCBP) who are unwilling to practice highly effective contraception or undergo pregnancy tests 15. Male patients with WOCBP partners who are not willing to use condoms with WOCBP partners to prevent potential fetal exposure
Note: Other Protocol Defined Exclusion Criteria Apply |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Primary Efficacy Endpoint: The number of new HO lesions adjudicated as positive based on CT
2. Primary Safety Endpoint: The incidence and severity of treatment-emergent adverse events of special interest (AESIs) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary Efficacy Endpoint: Week 56 Primary Safety Endpoint: Baseline to 56 weeks |
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E.5.2 | Secondary end point(s) |
1. Number of clinician-assessed flare-ups 2. Occurrence of clinician-assessed flare-ups (Yes/No) 3. Number of patient-reported flare-ups 4. Occurrence of patient-reported flare-ups (Yes/No) 5. Occurrence of new HO lesions adjudicated as positive based on CT (Yes/No) 6. Total volume of new HO lesions adjudicated as positive based on CT 7. Number of new HO lesions adjudicated as positive based on CT 8. Change in joint function assessment by physician using cumulative analog joint involvement scale (CAJIS) 9. Change in pulmonary function as assessed by spirometry 10. Change in disease severity as assessed by the Patient’s Global Impression of Severity (PGIS) 11. Change in disease severity as assessed by the Patient’s Global Impression of Change (PGIC) 12. Change in disease severity as assessed by the Clinician’s Global Impression of Change (CGIC) 13. Concentration of total activin A in serum over time 14. Concentrations of garetosmab in serum 15. Incidence and titer of anti-drug antibodies (ADA) to garetosmab |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary endpoint timeframes: 1-6: Week 28 and 56 7: Week 28 8-12: Baseline to Week 28 and 56 13-15 Baseline to Week 56 |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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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 | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
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 | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
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 | 10 |
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 |
Chile |
Colombia |
Malaysia |
Hong Kong |
Korea, Democratic People's Republic of |
Australia |
Brazil |
Canada |
China |
Japan |
Mexico |
South Africa |
United Kingdom |
United States |
Finland |
France |
Italy |
Netherlands |
Poland |
Spain |
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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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The end of study is defined as the date the last patient completes the last study visit (follow-up phone call or remote visit at week 108), withdraws from the study, or is lost to follow-up (i.e., the study patient can no longer be contacted by the investigator). |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |