Efficacy and safety of FXI antibody cenvacibart compared with aspirin for venous thromboprophylaxis in patients after total knee arthroplasty (ROXI-ASPEN): study protocol for a phase 3, double-blinded, randomized trial

Venous thromboembolism (VTE) remains a common and serious complication following total knee arthroplasty (TKA). Despite guideline variability, acetylsalicylic acid (aspirin; ASA) is widely used for postoperative thromboprophylaxis, particularly in the United States. While anticoagulants are associated with lower VTE rates than ASA, concerns regarding bleeding risk continue to limit their use in routine practice. Therapeutic strategies that target thrombosis while preserving hemostasis may offer an improved balance of risks and benefits; inhibition of factor XI (FXI) represents one such approach. Cenvacibart (previously REGN7508) is a human monoclonal antibody that binds to the catalytic domain of FXI, resulting in suppression of activated FXI (FXIa) activity and downstream coagulation. Phase 2 clinical data demonstrated that cenvacibart reduced postoperative VTE events more effectively than enoxaparin following TKA. ROXI-ASPEN is a phase 3, randomized, double-blind, multicenter trial designed to compare cenvacibart with ASA for VTE prophylaxis in adults undergoing elective, primary TKA. A target of 2000 adults from the USA will be randomized in a 1:1 ratio to receive either cenvacibart administered within three hours of wound closure with oral placebo twice daily, or placebo administered within three hours of wound closure followed by oral ASA 81 mg twice daily. Randomization will be stratified by geographic region and performed prior to surgery. Study treatment will continue for 30 days, with clinical follow-up through postoperative day 90. The primary efficacy endpoint is a composite of symptomatic VTE and VTE-related death through day 30. Key secondary endpoints include major and clinically relevant non-major bleeding. All suspected outcome events will be centrally adjudicated by an independent, blinded committee. ROXI-ASPEN addresses the common clinical scenario in which ASA is selected for postoperative thromboprophylaxis following primary TKA because of bleeding concerns associated with anticoagulants. By directly comparing FXI inhibition with ASA, this study seeks to clarify whether enhanced VTE protection can be achieved without a corresponding increase in bleeding risk. The findings may help define the role of FXI inhibition in contemporary orthopedic practice. ClinicalTrials.gov identifier: NCT07213778 ( https://clinicaltrials.gov/study/NCT07213778 ); Date of registration: October 3, 2025.