Randomized phase 2 trial comparing JNJ-9375, a thrombin-directed antibody, with apixaban for prevention of venous thrombosis.

BACKGROUND: JNJ-9375 is an antibody against exosite 1 on thrombin, inhibits substrate binding but not catalytic activity. OBJECTIVE: To examine the possibility that JNJ-9375 attenuates thrombosis without affecting hemostasis, we compared the efficacy and safety of JNJ-9375 and apixaban. METHODS: In this double-blind, double-dummy phase 2 trial, 308 patients undergoing knee arthroplasty were randomized to receive either a single postoperative intravenous infusion of JNJ-9375 in doses ranging from 0.3 to 1.8 mg/kg or apixaban (2.5 mg twice daily). The primary efficacy endpoint was the incidence of venous thromboembolism (assessed by mandatory unilateral venography or confirmed symptomatic events). The primary safety outcome was the composite of major, clinically relevant nonmajor, and minimal bleeding. Thrombin times were measured to assess JNJ-9375 activity. RESULTS: A total of 239 of the 308 patients (77.6%) were included in the modified intention-to-treat analysis. Of these, 238 had evaluable venograms and one had symptomatic deep-vein thrombosis confirmed by ultrasound. Despite dose-dependent thrombin time prolongation, the primary efficacy outcome occurred in 59 of 190 patients (31.1%) in the combined JNJ-9375 groups as compared with 6 of 49 patients (12.2%) given apixaban (odds ratio 3.2; two-sided 80% confidence interval 1.8-5.8; P = .011). The excess events with JNJ-9375 compared with apixaban were consistent across all JNJ-9375 dosing cohorts and there was no evidence of improved efficacy with higher JNJ-9375 doses. There were no major bleeds with JNJ-9375 or apixaban, and rates of any bleeding were similar with the highest and lowest JNJ-9375 doses. CONCLUSIONS: JNJ-9375 was safe but less effective than apixaban. This may reflect weak thrombin inhibition or inability of JNJ-9375 to attenuate the growth of thrombi that formed before drug administration.