The Examination of Safety and Efficacy of Garetosmab Versus Placebo Administered Intravenously (IV) in Adult Participants With Fibrodysplasia Ossificans Progressiva (FOP) (OPTIMA)

• ClinicalTrials.gov Identifier: NCT05394116
• Recruitment Status: Recruiting
• First Posted: May 27, 2022
• Last Update Posted: January 18, 2023
• Sponsor: Regeneron Pharmaceuticals
• Information provided by (Responsible Party): Regeneron Pharmaceuticals

Study Description

Brief Summary:

The study population consists of patients with Fibrodysplasia ossificans progressiva (FOP).

Key primary objectives are:

1. To assess the effect of high dose garetosmab versus placebo on the formation of new heterotopic ossification (HO) lesions from baseline to week 56, as determined by low-dose computed tomography (CT)
2. To assess the safety and tolerability of garetosmab versus placebo from baseline to week 56

Key Secondary Objectives:

1. To assess the effect of high dose garetosmab versus placebo on the number per participant of clinician-assessed flare-up episodes to week 56
2. 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
3. To assess the effect of low dose garetosmab versus placebo on the number per patient of clinician-assessed flare-up episodes to week 56

Condition or disease	Intervention/treatment	Phase
Fibrodysplasia Ossificans Progressiva	Drug: Garetosmab; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 66 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Phase 3 Randomized, Placebo-Controlled Study to Assess Safety, Tolerability, and Efficacy of Garetosmab in Patients With Fibrodysplasia Ossificans Progressiva
• Actual Study Start Date: November 21, 2022
• Estimated Primary Completion Date: March 5, 2025
• Estimated Study Completion Date: March 5, 2026

Arms and Interventions

Arm	Intervention/treatment
Experimental: High dose Garetosmab; Garetosmab is administered by intravenous (IV) administration every 4 weeks (Q4W)	Drug: Garetosmab; Garetosmab is supplied as a liquid drug product and will be administered IV.; Other Name: R2477
Experimental: Low dose Garetosmab; Garetosmab is administered by IV administration Q4W	Drug: Garetosmab; Garetosmab is supplied as a liquid drug product and will be administered IV.; Other Name: R2477
Experimental: Placebo; Placebo to match garetosmab, is supplied as a liquid solution without the monoclonal antibody (or the protein) and is administered IV.	Drug: Placebo; Placebo to match garetosmab, is supplied as a liquid solution without the monoclonal antibody (or the protein) and is administered IV.

Outcome Measures

Primary Outcome Measures :

1. Number of new HO lesions adjudicated as positive based on CT [ Time Frame: Through week 56 ]
2. Incidence and severity of treatment-emergent adverse events of special interest (AESIs) [ Time Frame: Baseline to Week 56 ]

Secondary Outcome Measures :

1. Number of clinician-assessed flare-ups [ Time Frame: Through Week 28 and Week 56 ]
   Investigator assess flare-up events according to his/her medical judgment. A FOP flare-up is characterized as episodic, painful inflammatory soft tissue swelling
2. Occurrence of clinician-assessed flare-ups [ Time Frame: Through Weeks 28 and 56 ]
   Reported as Yes/No
3. Number of patient-reported flare-ups [ Time Frame: Through Weeks 28 and 56 ]
   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.
4. Occurrence of patient-reported flare-ups [ Time Frame: Through Weeks 28 and 56 ]
   Reported as Yes/No
5. Occurrence of new HO lesions adjudicated as positive based on CT [ Time Frame: Weeks 28 and 56 ]
   Reported as Yes/No
6. Total volume of new HO lesions adjudicated as positive based on CT [ Time Frame: Weeks 28 and 56 ]
7. Number of new HO lesions adjudicated as positive based on CT [ Time Frame: Week 28 ]
8. Change in joint function assessment by physician using cumulative analog joint involvement scale (CAJIS) [ Time Frame: Baseline to Week 28 and 56 ]
   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
9. Change in pulmonary function as assessed by spirometry [ Time Frame: Baseline to Week 28 and 56 ]
   Forced vital capacity (FVC) and Forced expiratory volume in 1 second (FEV1) and the ratio of FEV1/FVC will be determined by spirometry.
10. Change in disease severity as assessed by the Patient Global Impression of Severity (PGIS) [ Time Frame: Baseline to Week 28 and 56 ]
    PGIS is a single item, self-administered questionnaire to assess the patient's global impression of severity
11. Change in disease severity as assessed by the Patient's Global Impression of Change (PGIC) [ Time Frame: Baseline to Week 28 and 56 ]
    PGIC is a single item, self-administered questionnaire to assess the patient's global impression of change
12. Change in disease severity as assessed by the Clinician's Global Impression of Change (CGIC) [ Time Frame: Baseline to Week 28 and 56 ]
    CGIC is a single-item questionnaire to assess the clinician's global impression of change
13. Concentration of total activin A in serum over time [ Time Frame: Baseline to Week 56 ]
14. Concentrations of garetosmab in serum [ Time Frame: Baseline to Week 56 ]
15. Incidence of anti-drug antibodies (ADA) to garetosmab [ Time Frame: Baseline to Week 56 ]
16. Titer of ADA to garetosmab [ Time Frame: Baseline to Week 56 ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Key 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

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:

   1. Systolic blood pressure ≥180 mm Hg or diastolic blood pressure ≥110 mm Hg at the screening visit
   2. 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
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 Inclusion/Exclusion Criteria apply

Contacts and Locations

Contacts

Contact: Clinical Trials Administrator; 844-734-6643; clinicaltrials@regeneron.com

Locations

Japan

Nagoya University Hospital; Recruiting

Nagoya, Aichi, Japan, 466-8560

United Kingdom

Royal National Orthropaedic Hospital NHS Trust; Recruiting

Middlesex, Greater London, United Kingdom, HA7 4LP

Sponsors and Collaborators

Regeneron Pharmaceuticals

Investigators

• Study Director: Clinical Trial Management; Regeneron Pharmaceuticals

More Information

• Responsible Party: Regeneron Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT05394116
• Other Study ID Numbers: R2477-FOP-2175; 2022-000880-40 ( EudraCT Number )
• First Posted: May 27, 2022
• Last Update Posted: January 18, 2023
• Last Verified: November 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: All Individual Patient Data (IPD) that underlie publicly available results will be considered for sharing
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code
• Time Frame: When Regeneron has received marketing authorization from major health authorities (e.g., FDA, European Medicines Agency (EMA), Pharmaceuticals and Medical Devices Agency (PMDA), etc.) for the product and indication, has made the study results publicly available (e.g., scientific publication, scientific conference, clinical trial registry), has the legal authority to share the data, and has ensured the ability to protect participant privacy
• Access Criteria: Qualified researchers can submit a proposal for access to individual patient or aggregate level data from a Regeneron-sponsored clinical trial through Vivli. Regeneron's Independent Research Request Evaluation Criteria can be found at: https://www.regeneron.com/sites/default/files/Regeneron-External-Data-Sharing-Policy-and-Independent-Research-Request-Evaluation-Criteria.pdf
• URL: https://vivli.org/

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Regeneron Pharmaceuticals:

Heterotopic Ossification (HO) Lesions; Type I activin A receptor (ACVR1); Optima; LUMINA-1; Flare-Ups

Additional relevant MeSH terms:

Myositis Ossificans; Myositis; Muscular Diseases; Musculoskeletal Diseases