Stroke and Systemic Embolism Prevention in Adult Participants With Atrial Fibrillation for Whom Oral Anticoagulation is Unsuitable (ROXI-INCLINE)

A Master Protocol for a Phase 3, Randomized, Multicenter, Double-blind Study to Assess Stroke and Systemic Embolism Prevention With REGN7508 and REGN9933, Monoclonal Antibodies Against Factor XI, Versus Placebo in Participants With Atrial Fibrillation for Whom Oral Anticoagulation is Unsuitable (ROXI-INCLINE)

This study is researching 2 different experimental drugs called REGN7508 and REGN9933 (called "study drugs"). The study is focused on people who have atrial fibrillation, which means that the heart beats too fast and unevenly. When this happens, blood cannot move smoothly through the heart; it can slow down or pool in one spot, which can lead to the formation of blood clots.

REGN7508 and REGN9933 are designed to help stop blood clots forming in patients with atrial fibrillation. The aim of the study is to see how effective and safe REGN7508 and REGN9933, individually, are in preventing ischemic stroke or systemic embolism in people with atrial fibrillation who cannot or may choose to not take blood thinners.

The study is looking at several other research questions, including:

• What side effects may happen from taking REGN7508 or REGN9933
• How well does REGN7508 or REGN9933 lower the risk of having an ischemic stroke and/or systemic embolism compared to the placebo
• How well does REGN7508 or REGN9933 lower the risk of having a major health problem affecting heart and blood circulation compared to placebo
• How well does REGN7508 or REGN9933 lower the risk of death compared to placebo
• How much REGN7508 or REGN9933 is in the blood at different times
• Whether the body makes antibodies against REGN7508 or REGN9933 (which could make the study drugs less effective or could lead to side effects)

Study Overview

• Status: Recruiting
• Conditions: Atrial Fibrillation (AF)
• Intervention / Treatment: Drug: Placebo; Drug: REGN7508; Drug: REGN9933

• Study Type: Interventional
• Enrollment (Estimated): 2628
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Clinical Trials Administrator; Phone Number: 844-734-6643; Email: clinicaltrials@regeneron.com

Study Locations

• United States
  • Alabama
    • Dothan, Alabama, United States, 36305
      • Recruiting
      • SEC Clinical Research
  • California
    • Fremont, California, United States, 94538
      • Recruiting
      • Mission Cardiovascular Research Institute
    • Huntington Beach, California, United States, 92648
      • Recruiting
      • National Institute of California Heart and Vein Specialists
    • Pasadena, California, United States, 91105
      • Recruiting
      • Profound Research LLC at Southern California Heart Specialists
    • Ventura, California, United States, 93003
      • Recruiting
      • Cardiology Associates Medical Group
    • West Hills, California, United States, 91307
      • Recruiting
      • Interventional Cardiology Medical Group
  • Florida
    • Medley, Florida, United States, 33166
      • Recruiting
      • South Florida Research Organization LLC
    • Winter Park, Florida, United States, 32789
      • Recruiting
      • Clinical Site Partners, LLC dba Flourish Research
  • Georgia
    • Johns Creek, Georgia, United States, 30024
      • Recruiting
      • NSC Research, Inc
  • Louisiana
    • West Monroe, Louisiana, United States, 71291
      • Recruiting
      • Monroe Research, LLC
  • Michigan
    • Flint, Michigan, United States, 48504
      • Recruiting
      • AA Medical Research Center (MRC)
  • Ohio
    • Marion, Ohio, United States, 43302
      • Recruiting
      • K&R Research LLC
  • Texas
    • Amarillo, Texas, United States, 79106
      • Recruiting
      • PharmaTex Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

1. Has AF or flutter (paroxysmal or persistent), not considered to be secondary to a reversible cause

2. At moderate to high risk for stroke defined as:

   1. CHA2DS2-VA [C: Congestive heart failure; H: Hypertension; A2: Age ≥75 years (double points); D: Diabetes mellitus; S2: Stroke or TIA or Systemic embolism (double points); V: Vascular disease; A: Age 65-74 years] score ≥4 OR
   2. CHA2DS2-VA score of 3 AND at least 1 enrichment criteria as described in the protocol
3. Shared decision making between the participant and provider determining that the bleeding risk of Oral Anticoagulant (OAC) therapy outweighs the benefits, making the participant unsuitable for OAC therapy as described in the protocol

Key Exclusion Criteria:

1. Has a mechanical heart valve prosthesis (Note: transcatheter aortic valve replacement is not an exclusion)
2. Had an ischemic stroke within 2 days prior to randomization
3. Has persistent, uncontrolled hypertension (per investigator's discretion)
4. Has a history of Central Nervous System (CNS) bleeding within 30 days prior to randomization
5. Has a life expectancy less than 12 months
6. Has participated in a prior Factor XI (FXI) inhibitor study

Note: Other protocol-defined Inclusion/ Exclusion criteria apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Administered per the protocol
Experimental: REGN7508	Drug: REGN7508; Administered per the protocol; Other Names: cenvacibart
Experimental: REGN9933	Drug: REGN9933; Administered per the protocol; Other Names: amrecibart

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Time to first occurrence of ischemic stroke or systemic embolism	Up to 36 months
Time to first occurrence of International Society on Thrombosis and Haemostasis (ISTH) major bleeding	Up to 36 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Severity of TEAEs	Up to 39 months
Time to first occurrence of Major Adverse Cardiovascular Event (MACE)	Up to 36 months
Time to first occurrence of MACE, pulmonary embolism, or Venous Thromboembolism (VTE)	Up to 36 months
Time to first occurrence of ischemic stroke	Up to 36 months
Time to Cardiovascular (CV) death	Up to 36 months
Time to all-cause death	Up to 36 months
Occurrence of Treatment-Emergent Adverse Events (TEAEs)	Up to 39 months
Concentrations of REGN7508 over time	Up to 36 months
Concentrations of REGN9933 over time	Up to 36 months
Change from baseline in activated Partial Thromboplastin Time (aPTT) over time	Up to approximately 9 weeks
Change from baseline in Prothrombin time (PT)/International Normalized Ratio (INR) over time	Up to approximately 9 weeks
Occurrence of Anti-Drug Antibody (ADA) to REGN7508 over time	Up to 36 months
Magnitude of ADA to REGN7508 over time	Up to 36 months
Occurrence of ADA to REGN9933 over time	Up to 36 months
Magnitude of ADA to REGN9933 over time	Up to 36 months

Collaborators and Investigators

• Sponsor: Regeneron Pharmaceuticals
• Investigators: Study Director: Clinical Trial Management, Regeneron Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): April 3, 2026
• Primary Completion (Estimated): March 28, 2029
• Study Completion (Estimated): June 26, 2029

Study Registration Dates

• First Submitted: February 18, 2026
• First Submitted That Met QC Criteria: February 18, 2026
• First Posted (Actual): February 24, 2026

Study Record Updates

• Last Update Posted (Actual): May 29, 2026
• Last Update Submitted That Met QC Criteria: May 26, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Pulmonary embolism; Ischemic stroke; Systemic embolism; Venous Thromboembolism (VTE); Blood clots
• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Heart Diseases; Respiratory Tract Diseases; Arrhythmias, Cardiac; Lung Diseases; Embolism and Thrombosis; Embolism; Stroke; Thromboembolism; Pathological Conditions, Signs and Symptoms; Ischemic Stroke; Pulmonary Embolism; Thrombosis; Atrial Fibrillation; Venous Thromboembolism
• Other Study ID Numbers: R9933-CVA-2495; 2025-521618-25-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All Individual Patient Data (IPD) that underlie publicly available results will be considered for sharing.

IPD Sharing 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 or has globally discontinued development of the product for all indications on or after April 2020 and has no plans for future development
• made the study results publicly available (e.g., scientific publication, scientific conference, clinical trial registry)
• the legal authority to share the data, and
• ensured the ability to protect participant privacy

• IPD Sharing 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
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No