Effect of Osocimab in Preventing Venous Thromboembolism Among Patients Undergoing Knee Arthroplasty: The FOXTROT Randomized Clinical Trial

Abstract

Importance: The efficacy of factor XIa inhibition for thromboprophylaxis is unknown. Osocimab is a long-acting, fully human monoclonal antibody that inhibits factor XIa.

Objective: To compare different doses of osocimab with enoxaparin and apixaban for thromboprophylaxis in patients who have undergone knee arthroplasty.

Design, setting, and participants: Randomized, open-label, adjudicator-blinded, phase 2 noninferiority trial with observer blinding for osocimab doses, conducted at 54 hospitals in 13 countries. Adult patients undergoing unilateral knee arthroplasty were randomized from October 2017 through August 2018 and followed up until January 2019.

Interventions: Single intravenous osocimab postoperative doses of 0.3 mg/kg (n = 107), 0.6 mg/kg (n = 65), 1.2 mg/kg (n = 108), or 1.8 mg/kg (n = 106); preoperative doses of 0.3 mg/kg (n = 109) or 1.8 mg/kg (n = 108); or 40 mg of subcutaneous enoxaparin once daily (n = 105) or 2.5 mg of oral apixaban twice daily (n = 105) for at least 10 days or until venography.

Main outcomes and measures: The primary outcome was venous thromboembolism incidence between 10 and 13 days postoperatively (assessed by mandatory bilateral venography performed 10 to 13 days after surgery or confirmed symptomatic deep vein thrombosis or pulmonary embolism). A 5% noninferiority margin compared with enoxaparin was chosen. The primary safety outcome of major or clinically relevant nonmajor bleeding was assessed until 10 to 13 days postoperatively.

Results: Of 813 randomized participants (mean [SD] age, 66.5 years [8.2 years]; body mass index, 32.7 [5.7]; and 74.2% women), 600 were included in the per-protocol population used for the primary analysis. The primary outcome occurred in 18 patients (23.7%) receiving 0.3 mg/kg, 8 (15.7%) receiving 0.6 mg/kg, 13 (16.5%) receiving 1.2 mg/kg, and 14 (17.9%) receiving 1.8 mg/kg of osocimab postoperatively; 23 (29.9%) receiving 0.3 mg/kg and 9 (11.3%) receiving 1.8 mg/kg of osocimab preoperatively; 20 (26.3%) receiving enoxaparin; and 12 (14.5%) receiving apixaban. Osocimab given postoperatively met criteria for noninferiority compared with enoxaparin with risk differences (1-sided 95% CIs) of 10.6% (95% CI, -1.2% to ∞) at the 0.6-mg/kg dose; 9.9% (95% CI, -0.9% to ∞) at the 1.2-mg/kg dose, and 8.4% (95% CI, -2.6 to ∞) at the 1.8-mg/kg dose. The preoperative dose of 1.8 mg/kg of osocimab met criteria for superiority compared with enoxaparin with a risk difference of 15.1%; 2-sided 90% CI, 4.9% to 25.2%). Postoperative and preoperative doses of 0.3 mg/kg of osocimab did not meet the prespecified criteria for noninferiority, with risk differences (1-sided 95% CIs) of 2.6% (95% CI, -8.9% to ∞) and -3.6% (95% CI, -15.5% to ∞), respectively. Major or clinically relevant nonmajor bleeding was observed in up to 4.7% of those receiving osocimab, 5.9% receiving enoxaparin, and 2% receiving apixaban.

Conclusions and relevance: Among patients undergoing knee arthroplasty, postoperative osocimab 0.6 mg/kg, 1.2 mg/kg, and 1.8 mg/kg met criteria for noninferiority compared with enoxaparin, and the preoperative 1.8-mg/kg dose of osocimab met criteria for superiority compared with enoxaparin for the primary outcome of incidence of venous thromboembolism at 10 to 13 days postoperatively. Further studies are needed to establish efficacy and safety of osocimab relative to standard thromboprophylaxis.

Trial registration: ClinicalTrials.gov Identifier: NCT03276143.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Weitz reported receiving compensation for his role in the study and serving as a consultant for which he has received honoraria from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Ionis, Janssen, Merck, Novartis, Pfizer, Anthos, Tetherex, and Portola. Dr Bauersachs reported receiving compensation for his role in the study and receiving personal honoraria from Bayer AG, Bristol-Myers Squibb, Pfizer, and Daiichi Sankyo. Mr Becker and Drs Berkowitz, Freitas, and Metzig reported that they are employees of Bayer AG but did not receive compensation for their roles in this study beyond their usual salary. Dr Lassen reported receiving compensation for his role in the study and serving as a consultant for Bayer AG, Stryker Inc, Medtronic Inc, and Janssen Pharma. Dr Raskob reported receiving compensation for his role in the study and consultancy fees or honoraria for serving on an advisory board for Bayer AG for the current work; receiving consultancy fees or honoraria from Anthos, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Janssen, Novartis, Pfizer, Portola, and Tetherex; and personal fees from Bayer Healthcare, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Daiichi Sankyo, Janssen, Pfizer, Portola, Itreas, Tetherex, Anthos, and Novartis.

Figures

Figure.. Enrollment, Randomization, and Populations for Analysis in the FOXTROT Trial of Osocimab to Prevent Venous Thromboembolism (VTE)

aA patient assigned to receive osocimab 1.2 mg/kg postoperatively received 0.3 mg/kg. bOf these patients, 62 and 43 were randomized as part of the postoperative and preoperative osocimab phases. cRescheduled or canceled knee arthroplasty. dReceived commercial enoxaparin instead of study drug. eDeviations from inclusion or exclusion criteria, use of prohibited concomitant medications impacting on the primary outcome, and significant changes to study drug intake were considered major protocol deviations.