The safety and effectiveness of PRAXBIND was investigated in three randomized placebo-controlled healthy volunteer trials, Trials 1321.1, 1321.2 and 1321.5 (NCT01688830, NCT01955720, NCT02028780), and in RE-VERSE-AD (RE-VERSal Effects of idarucizumab on Active Dabigatran) trial (NCT02104947), a single cohort case series trial with dabigatran-treated patients who have life-threatening or uncontrolled bleeding, or who require emergency surgery or urgent procedure.

Healthy Volunteers

Trials 1321.1, 1321.2 and 1321.5 in a total of 283 subjects assessed the safety, dose-response, and effect of idarucizumab on reducing unbound dabigatran and coagulation parameters. Of the 283 subjects, 224 received at least one dose of idarucizumab. These trials included 19 females and 30 subjects aged 65 years or older (overall mean age 36 years).

The tables below summarize the idarucizumab effect on coagulation parameters dTT, aPTT, ECT, TT, and ACT over time for 14 subjects treated in Trial 1321.2. Fourteen subjects received dabigatran 220 mg orally twice daily for three days and an additional single 220 mg dose of dabigatran on day four, two hours before receiving idarucizumab. Idarucizumab was administered as one 5 g intravenous infusion over five minutes. Table 1 shows the results of the idarucizumab treatment group and Table 2 shows the results of the placebo treatment group.

The effect of idarucizumab on reducing unbound dabigatran in healthy volunteers is summarized in section 12.2, Pharmacodynamics.

RE-VERSE-AD Patient Experience

In RE-VERSE-AD, 5 g idarucizumab was administered to patients treated with dabigatran who presented with dabigatran-related life-threatening or uncontrolled bleeding (Group A) or who required emergency surgery or urgent procedures (Group B). The primary endpoint was the maximum percentage reversal of the pharmacodynamic anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab, based on central laboratory determination of dTT or ECT. 

RE-VERSE-AD included data for 503 patients: 301 patients with serious bleeding (Group A) and 202 requiring an urgent procedure (Group B). Approximately half of the patients in each group were male. The median age was 78 years and the median creatinine clearance was 53 mL/min. Approximately 62% of patients in Group A and 62% of patients in Group B had been treated with dabigatran 110 mg BID. 

Reversal was evaluable only for those patients showing prolonged coagulation times prior to idarucizumab treatment. Among the evaluable patients, the median maximum reversal of the pharmacodynamic anticoagulant effect of dabigatran as measured by ECT, aPTT or dTT in the first 4 hours after administration of 5 g idarucizumab was 100%, with most patients achieving complete reversal as measured by ECT (82%), aPTT (93%) or dTT (99%). Reversal of the pharmacodynamics effects was evident immediately after administration. Results for Groups A and B were similar. In a limited number of patients, between 12 and 24 hours after administration of 5 g idarucizumab, elevated coagulation parameters (e.g., aPTT or ECT) have been observed. Eight patients were treated with more than 5 g idarucizumab due to rebleeding, a second emergency procedure and/or bleeding after an emergency surgical procedure. ECT measures over the 24-hour observation time are shown in Figure 6.

Figure 6 Change of ECT from Baseline in Dabigatran-exposed Patients (n=487) 

Activated partial thromboplastin time (aPTT) showed similar results to ECT (see Figure 7).

Figure 7 Change of aPTT from Baseline in Dabigatran-exposed Patients (n=486)