A Study to Assess Safety, Tolerability and Efficacy of Garetosmab Versus Placebo Administered Intravenously (IV) in Adult Participants With Fibrodysplasia Ossificans Progressiva (FOP)

Study Overview
=================
Brief Summary
-----------------
This study is researching an experimental drug called garetosmab. The study is focused on adult patients with fibrodysplasia ossificans progressiva (FOP). The aim of the study is to see how safe and effective the study drug is in patients with FOP. The study is looking at several other research questions, including: What side effects may happen from receiving the study drug How much study drug is in your blood at different times Whether the body makes antibodies against the study drug (which could make the drug less effective or could lead to side effects)

Official Title
-----------------
Phase 3 Randomized, Placebo-Controlled Study to Assess Safety, Tolerability, and Efficacy of Garetosmab in Patients With Fibrodysplasia Ossificans Progressiva

Conditions
-----------------
Fibrodysplasia Ossificans Progressiva

Intervention / Treatment
-----------------
* Drug: Garetosmab
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: 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)] Confirmation of FOP diagnosis with documentation of Type I activin A receptor (ACVR1) FOP causing mutation 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 Willing and able to undergo CT imaging procedures and other procedures as defined in the protocol Key Exclusion Criteria: Cumulative Analog Joint Involvement Scale (CAJIS) score at screening >19 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 Previous history or diagnosis of cancer 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 Uncontrolled diabetes defined as hemoglobin A1C (HbA1c) >9% at screening History of poorly controlled hypertension, as defined by: Systolic blood pressure ≥180 mm Hg or diastolic blood pressure ≥110 mm Hg at the screening visit 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 Known history of cerebral vascular malformation 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 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 Prior use in the past year and concomitant use of bisphosphonates 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). 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 Pregnant or breastfeeding women Women of childbearing potential (WOCBP) who are unwilling to practice highly effective contraception, as defined in the protocol Male patients with WOCBP partners who are not willing to use condoms with WOCBP partners to prevent potential fetal exposure, as defined in the protocol Note: Other protocol defined Inclusion/Exclusion Criteria apply

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High dose Garetosmab<br>Garetosmab is administered by intravenous (IV) administration every 4 weeks (Q4W) | Drug: Garetosmab<br>* Garetosmab is supplied as a liquid drug product and will be administered IV.<br>* Other names: REGN2477;|
| Experimental: Low dose Garetosmab<br>Garetosmab is administered by IV administration Q4W | Drug: Garetosmab<br>* Garetosmab is supplied as a liquid drug product and will be administered IV.<br>* Other names: REGN2477;|
| Experimental: Placebo<br>Placebo to match garetosmab, is supplied as a liquid solution without the monoclonal antibody (or the protein) and is administered IV Q4W. | Drug: Placebo<br>* Placebo to match garetosmab, is supplied as a liquid solution without the monoclonal antibody (or the protein) and is administered IV.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of new HO lesions adjudicated as positive based on computed tomography (CT) |  | At Week 56 | 
| Incidence and severity of treatment-emergent adverse events of special interest (AESIs) |  | Baseline to Week 56 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of clinician-assessed flare-ups | Investigator assess flare-up events according to his/her medical judgment. A FOP flare-up is characterized as episodic, painful inflammatory soft tissue swelling. Week 84 Only for Patients on Extended Treatment | Through Week 28, Week 56 and Week 84 | 
| Occurrence of clinician-assessed flare-ups | Reported as Yes/No Week 84 Only for Patients on Extended Treatment | Through Week 28, Week 56 and Week 84 | 
| Number of patient-reported flare-ups | Flare-up is defined as two or more of the following: pain, swelling, joint stiffness, or decrease in movement. The FOP flare-up dairy is a questionnaire and is self-completed by the participant daily. | Through Week 28 and Week 56 | 
| Occurrence of patient-reported flare-ups | Reported as Yes/No | Through Weeks 28 and Week 56 | 
| Occurrence of new HO lesions adjudicated as positive based on CT | Reported as Yes/No Week 84 Only for Patients on Extended Treatment | At Week 28, Week 56 and Week 84 | 
| Total volume of new HO lesions adjudicated as positive based on CT | Week 84 Only for Patients on Extended Treatment | At Week 28, Week 56 and Week 84 | 
| Number of new HO lesions adjudicated as positive based on CT | Week 84 Only for Patients on Extended Treatment | At Week 28 and Week 84 | 
| Change in joint function assessment by physician using cumulative analog joint involvement scale (CAJIS) | CAJIS is a clinician assessment of 15 major joints; each major joint rated normal unaffected (0), affected (1), or completely functionally ankylosed (2). The total score ranges from 0 to 30 | Baseline to Week 28 and Week 56 | 
| Change in pulmonary function as assessed by spirometry | Forced vital capacity (FVC) and Forced expiratory volume in 1 second (FEV1) and the ratio of FEV1/FVC will be determined by spirometry. | Baseline to Week 28 and Week 56 | 
| Change in disease severity as assessed by the Patient Global Impression of Severity (PGIS) | PGIS is a single item, self-administered questionnaire to assess the patient's global impression of severity | Baseline to Week 28 and Week 56 | 
| Change in disease severity as assessed by the Patient's Global Impression of Change (PGIC) | PGIC is a single item, self-administered questionnaire to assess the patient's global impression of change | Baseline to Week 28 and Week 56 | 
| Change in disease severity as assessed by the Clinician's Global Impression of Change (CGIC) | CGIC is a single-item questionnaire to assess the clinician's global impression of change | Baseline to Week 28 and Week 56 | 
| Concentration of total activin A in serum over time |  | Through Week 56 | 
| Concentrations of garetosmab in serum over time |  | Through Week 56 | 
| Incidence of anti-drug antibodies (ADA) to garetosmab over time |  | Through Week 56 | 
| Titer of ADA to garetosmab over time |  | Through Week 56 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Optima, Heterotopic Ossification (HO) Lesions, Type I activin A receptor (ACVR1), LUMINA-1, Flare-Ups