Phase 3 study on novel oral direct thrombin inhibitor

Boehringer Ingelheim has announced that the September 15 issue of The Lancet will publish results from the RE-NOVATE study, which investigated dabigatran etexilate as a potential therapy for patients undergoing total hip replacement surgery.

The results from this study demonstrate that both doses (220mg and 150mg) of the oral direct thrombin inhibitor, dabigatran etexilate, administered for a median of 33 days, were non-inferior to injectable enoxaparin in reducing the risk of venous thromboembolism (VTE) after total hip replacement surgery with similar safety.

The primary endpoint of this trial was a composite consisting of total venous thromboembolic events and all-cause mortality during treatment, which occurred in 6.0% of the 220mg group and 8.6% of the 150mg group taking dabigatran etexilate, versus 6.7% of the enoxaparin group. Importantly, a pre-specified secondary outcome of major venous thromboembolism and venous thromboembolism-related mortality was also similar between groups, occurring in 3.1% of the 220mg group and 4.3% of the 150mg group taking dabigatran etexilate, versus 3.9% of the enoxaparin group.

Anticoagulation-related bleeding is the primary safety concern during hip replacement surgery, since major bleeding into the replaced joint can have a detrimental impact on clinical outcome. Generally, few major bleeding events were reported, occurring at 2.0% in the 220mg group and 1.3% in the 150mg group for dabigatran etexilate, versus 1.6% in the enoxaparin group. Notably about half of all major bleeding events started after surgery and before the first dose of dabigatran etexilate. There were no major bleeding events reported after hospital discharge in the dabigatran etexilate groups.

Data from frequent liver function monitoring showed that the frequency of increases in liver enzyme concentrations with dabigatran etexilate is low during the entire extended treatment period. Results showed that alanine aminotransferase (ALT) elevation greater than three times the upper limit of normal occurred in 5.3% enoxaparin group, as compared to 3.0% in the 150mg group and 3.0% in the 220mg group taking dabigatran etexilate. Similarly, the incidence of acute coronary events was low, with no significant differences between all groups.

Current treatment guidelines recommend that patients undergoing knee or hip replacement surgery receive thromboprophylaxis (treatment to prevent VTE) with low molecular weight heparin (LMWH), fondaparinux or warfarin for at least 10 days after surgery. For patients undergoing hip replacement surgery, extended thromboprophylaxis for up to 28-35 days is recommended. The RE- NOVATE study was designed consistent with these guidelines.

Dabigatran etexilate is an investigational oral direct thrombin inhibitor that specifically and reversibly inhibits thrombin, the key enzyme for blood clot formation, and is currently in phase 3 development. In the RE-NOVATE study, dabigatran etexilate was dosed once a day without routine coagulation monitoring. Patients in the study received a fixed dose of dabigatran etexilate and were not titrated during the duration of the study.

Dabigatran etexilate is being investigated in multiple phase 3 trials that are designed to investigate the oral direct thrombin inhibitor as a potential treatment and prophylaxis for several thromboembolic disease conditions. The phase 3 clinical trial program is expected to involve more than 27,000 patients from Asia, Australia, Europe, the Americas, and South Africa.