Single intravenous administration of TB-402 for the prophylaxis of venous thromboembolism after total knee replacement: a dose-escalating, randomized, controlled trial.

Background: TB-402 is a novel anticoagulant monoclonal antibody with a prolonged antithrombotic effect resulting from its partial factor (F) VIII inhibition and long half-life. We evaluated the efficacy and safety of a single administration of TB-402 for the prevention of venous thromboembolism (VTE) after total knee replacement (TKR). Patients and methods: This was a phase II, dose-escalating, randomized, enoxaparin-controlled, open-label study. Patients were post-operatively assigned to a single dose of TB-402 (0.3, 0.6 or 1.2 mg kg(-1)) or enoxaparin 40 mg for at least 10 days (n = 75 per group; 3:1 TB-402 to enoxaparin). The primary efficacy outcome was total VTE defined as asymptomatic deep vein thrombosis (DVT) detected by bilateral venography and symptomatic VTE by day 7 to 11. The principal safety outcome was the incidence of major bleeding and clinically relevant non-major bleeding. Results: Total VTE was lower in all TB-402 groups compared with enoxaparin: 16.7%(95% CI 9.8-26.9), 23.9%(95% CI 15.3-35.3), 24.1%(95% CI 16.0-34.5) and 39.0%(95% CI 28.8-50.1) for TB-402 0.3, 0.6, 1.2 mg kg(-1) and enoxaparin, respectively (P = 0.003 for TB-402 0.3 mg kg(-1) vs. enoxaparin). The incidence of total VTE in the pooled TB-402 groups was 21.6% (95% CI 16.6-27.5), an absolute risk reduction vs. enoxaparin of 17.4% (95% CI 5.2-29.6). Major or clinically relevant non-major bleeding was observed in 3/75(4.0%), 4/74(5.4%), 7/87(8.0%) and 3/79(3.8%) patients for TB-402 0.3, 0.6, 1.2 mg kg(-1) and enoxaparin, respectively. Conclusions: TB-402, as a single post-operative administration, was associated with a lower rate of VTE in all doses tested, compared with enoxaparin. The incidence of major and clinically relevant non-major bleeding was similar to enoxaparin 40 mg for TB-402 0.3 and 0.6 mg kg(-1).