Safety, Tolerability, and Efficacy of Idarucizumab for the Reversal of the Anticoagulant Effect of Dabigatran in Healthy Men
abstract
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Access this abstract now Full Text Available for ClinicalKey SubscribersBACKGROUND
Idarucizumab is a monoclonal antibody fragment that binds dabigatran with high affinity in a 1:1 molar ratio. We investigated the safety, tolerability, and efficacy of increasing doses of idarucizumab for the reversal of anticoagulant effects of dabigatran in a two-part phase 1 study (rising-dose assessment and dose-finding, proof-of-concept investigation). Here we present the results of the proof-of-concept part of the study.
METHODS
In this randomised, placebo-controlled, double-blind, proof-of-concept phase 1 study, we enrolled healthy volunteers (aged 18-45 years) with a body-mass index of 18·5-29·9 kg/m(2) into one of four dose groups at SGS Life Sciences Clinical Research Services, Belgium. Participants were randomly assigned within groups in a 3:1 ratio to idarucizumab or placebo using a pseudorandom number generator and a supplied seed number. Participants and care providers were masked to treatment assignment. All participants received oral dabigatran etexilate 220 mg twice daily for 3 days and a final dose on day 4. Idarucizumab (1 g, 2 g, or 4 g 5-min infusion, or 5 g plus 2·5 g in two 5-min infusions given 1 h apart) was administered about 2 h after the final dabigatran etexilate dose. The primary endpoint was incidence of drug-related adverse events, analysed in all randomly assigned participants who received at least one dose of dabigatran etexilate. Reversal of diluted thrombin time (dTT), ecarin clotting time (ECT), activated partial thromboplastin time (aPTT), and thrombin time (TT) were secondary endpoints assessed by measuring the area under the effect curve from 2 h to 12 h (AUEC2-12) after dabigatran etexilate ingestion on days 3 and 4. This trial is registered with ClinicalTrials.gov, number NCT01688830.
FINDINGS
Between Feb 23, and Nov 29, 2013, 47 men completed this part of the study. 12 were enrolled into each of the 1 g, 2 g, or 5 g plus 2·5 g idarucizumab groups (nine to idarucizumab and three to placebo in each group), and 11 were enrolled into the 4 g idarucizumab group (eight to idarucizumab and three to placebo). Drug-related adverse events were all of mild intensity and reported in seven participants: one in the 1 g idarucizumab group (infusion site erythema and hot flushes), one in the 5 g plus 2·5 g idarucizumab group (epistaxis); one receiving placebo (infusion site haematoma), and four during dabigatran etexilate pretreatment (three haematuria and one epistaxis). Idarucizumab immediately and completely reversed dabigatran-induced anticoagulation in a dose-dependent manner; the mean ratio of day 4 AUEC2-12 to day 3 AUEC2-12 for dTT was 1·01 with placebo, 0·26 with 1 g idarucizumab (74% reduction), 0·06 with 2 g idarucizumab (94% reduction), 0·02 with 4 g idarucizumab (98% reduction), and 0·01 with 5 g plus 2·5 g idarucizumab (99% reduction). No serious or severe adverse events were reported, no adverse event led to discontinuation of treatment, and no clinically relevant difference in incidence of adverse events was noted between treatment groups.
INTERPRETATION
These phase 1 results show that idarucizumab was associated with immediate, complete, and sustained reversal of dabigatran-induced anticoagulation in healthy men, and was well tolerated with no unexpected or clinically relevant safety concerns, supporting further testing. Further clinical studies are in progress.
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Additional Info
Safety, Tolerability, and Efficacy of Idarucizumab for the Reversal of the Anticoagulant Effect of Dabigatran in Healthy Male Volunteers: a Randomised, Placebo-Controlled, Double-Blind Phase 1 Trial
Lancet 2015 Jun 15;[EPub Ahead of Print], S Glund, J Stangier, M Schmohl, D Gansser, S Norris, J van Ryn, B Lang, S Ramael, V Moschetti, F Gruenenfelder, P Reilly, J KreuzerFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
The non-vitamin K antagonist oral anticoagulants (NOACs) are widely used instead of warfarin for stroke prevention in atrial fibrillation and for treatment of venous thromboembolism. A concern with the NOACs is the lack of specific reversal agents for management of patients with life-threatening bleeding or for those requiring urgent interventions. This concern has triggered the development of antidotes to rapidly reverse the anticoagulant effects of the NOACs. Three such agents are under investigation: idarucizumab for reversal of dabigatran, andexanet for reversal of the oral factor Xa inhibitors, and aripazine, which is reported to reverse dabigatran and the oral factor Xa inhibitors. All of these agents have been given breakthrough therapy designation by the United States Food and Drug Administration and by other regulatory agencies and are on a fast track for approval.
The pathway to registration of the antidotes starts with their evaluation in healthy volunteers taking NOACs. Idarucizumab is a humanized monoclonal antibody fragment that binds dabigatran with an affinity that is 350-fold higher than the affinity of dabigatran for thrombin. It neutralizes dabigatran activity by forming a 1:1 stoichiometric complex that is then cleared by the kidneys.1 In the phase 1 placebo-controlled study reported by Glund and colleagues,2 47 healthy men were given oral dabigatran at a dose of 220 mg twice daily for 3 days. This dose was chosen to produce dabigatran concentrations similar to those found in older individuals taking 150 mg twice daily. After the final dose on day 4, volunteers were randomized 3:1 to receive either an intravenous bolus infusion of idarucizumab or placebo. Idarucizumab was administered at doses of 1, 2, 4, or 5 g. The primary endpoint was the incidence of drug-related adverse events. Reversal of the anticoagulant effects of dabigatran was a secondary endpoint, and the diluted thrombin time (dTT), ecarin clotting time, activated partial thromboplastin time (aPTT), and thrombin time (TT) were measured before and serially after the administration of idarucizumab or placebo.
Drug-related adverse events were mild, and idarucizumab rapidly reversed the anticoagulant effects of dabigatran in a concentration-dependent manner. There was complete and sustained reversal with the 5-g dose of idarucizumab, and this was the dose that was selected to carry forward in the phase 3 study: Reversal Effects of Idarucizumab on Active Dabigatran (REVERSE-AD).
The results from the first 90 patients enrolled in REVERSE-AD were recently reported.3 This prospective cohort study enrolled dabigatran-treated patients who presented with serious bleeding (group A) or required an urgent intervention that could not be postponed for at least 8 hours (group B). All patients received 5 g intravenous idarucizumab. The primary endpoint was maximum reversal of the dTT or ECT within 4 hours of idarucizumab administration. A key secondary endpoint was restoration of hemostasis.
Among the 68 patients with an elevated dTT and the 81 with an elevated ECT at baseline, there was complete reversal at 4 hours. In the 35 of 51 patients in group A that could be assessed, hemostasis, as determined by the local investigators, was restored at a median of 11 hours. Among the 39 patients in group B who underwent a procedure, hemostasis was reported as normal in 33 and mildly or moderately abnormal in 2 patients and 1 patient, respectively. There was 1 thrombotic event within 72 hours of idarucizumab administration. There were 18 deaths (9 in each group), but these could all be attributed to co-existing conditions, including intracranial hemorrhage, septic shock, respiratory failure and cardiac arrest. There were no hypersensitivity reactions. Therefore, based on the Glund study and the initial results of REVERSE-AD, idarucizumab is a promising antidote for dabigatran and it likely will soon be licensed for this indication. The availability of an antidote should alleviate concerns about serious bleeding and will enhance the safety of dabigatran.
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