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

Glund, Stephan; Stangier, Joachim; Schmohl, Michael; Ganßer, Dietmar; Norris, Stephen H.; Ryn, Joanne van; Lang, Benjamin; Ramael, Steven; Moschetti, Viktoria; Gruenenfelder, Fredrik; Reilly, Paul; Kreuzer, Jörg

doi:10.1016/s0140-6736(15)60732-2

Cited by 299 publications

(278 citation statements)

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“…Administration of idarucizumab at doses of 4 and 2.5+2.5 g led to immediate, complete, and sustained reversal of dabigatran‐induced anticoagulation for the duration of the observation period (up to 72 hour); at 1 and 2 g doses of idarucizumab, a partial return of the anticoagulant effect of dabigatran was observed (1‐2 hour after idarucizumab administration); idarucizumab was safe and well tolerated at all doses. These findings support results obtained in a largely Caucasian population 18, 19…”

Section: Discussionsupporting

confidence: 92%

“…Idarucizumab administered alone at doses up to 8 g demonstrated no effect on coagulation (assessed by dTT, ECT, aPTT, or TT) in these healthy Japanese volunteers. These findings are consistent with preclinical and clinical studies showing no prothrombotic effect resulting from idarucizumab use 19, 20, 21…”

Section: Discussionsupporting

confidence: 90%

“…Idarucizumab doses were selected based on the phase I trial of healthy Caucasian male volunteers 18, 19. In both parts of the present study, idarucizumab was started at a dose of 1 g as a safety precaution.…”

Section: Methodsmentioning

confidence: 99%

“…The same dosing schedule for DE was repeated on day 8 and ended on day 11 to examine the efficacy of idarucizumab to reverse the anticoagulant activity of DE. This dose of DE was selected to cover peak plasma concentration levels in the RE‐LY trial where plasma concentration around 2‐hour post‐dose achieved was 184 ng/mL20 and corresponded with the dosing schedule of the phase I trial in Caucasian subjects (males)19 (NCT identifier, NCT01688830). At this dosage, the C max of dabigatran at steady state covers the C max of dabigatran after administration of 150 mg bid to the patient population in the phase III global study conducted in patients with nonvalvular atrial fibrillation including Japanese individuals (unpublished data).…”

Section: Methodsmentioning

confidence: 99%

“…Idarucizumab treatment in Caucasian volunteers receiving dabigatran led to immediate, complete, and sustained reversal of anticoagulation and was well tolerated 19. In an interim analysis of a phase III trial in dabigatran‐treated patients with severe bleeding or in need of an urgent surgery/procedure, idarucizumab completely reversed the anticoagulant effect of dabigatran within minutes 17.…”

Section: Introductionmentioning

confidence: 96%

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Safety, pharmacokinetics and pharmacodynamics of idarucizumab, a specific dabigatran reversal agent in healthy Japanese volunteers: a randomized study

Yasaka

Ikushima

Harada

et al. 2017

Research and Practice in Thrombosis and Haemostasis

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Essentials Idarucizumab, a monoclonal antibody fragment, binds dabigatran with high affinity and specificity.In this phase 1 trial, healthy Japanese males received idarucizumab alone or with dabigatran.Idarucizumab achieved immediate, complete and sustained reversal of dabigatran anticoagulation.Idarucizumab was well tolerated and demonstrated no pro‐coagulant effects. BackgroundIdarucizumab is a humanized monoclonal antibody fragment that specifically binds with high affinity to dabigatran.ObjectivesThis study investigated the safety, tolerability and pharmacokinetics of idarucizumab alone and with dabigatran at steady state, and the effects of idarucizumab on dabigatran‐induced anticoagulation.Patients/MethodsThis was a two‐part, phase I, randomized, placebo‐controlled, double‐blind, rising‐dose trial in healthy Japanese males. Part 1: 32 subjects (males) received single idarucizumab doses (1, 2, 4 or 8 g [n=6/dose group]) or placebo (n=2/dose group). Part 2: 48 males received dabigatran (220 mg bid) followed by idarucizumab (n=9/dose group) 1, 2, 4 or 5 g (2×2.5 g), or placebo (n=3/dose group). Anti‐idarucizumab antibodies (ADAs) and idarucizumab effect on anticoagulation parameters (diluted thrombin time [dTT], ecarin clotting time [ECT], activated partial thromboplastin time [aPTT] and thrombin time [TT]) were assessed.ResultsNo adverse events were reported in subjects receiving idarucizumab. After single doses of idarucizumab (alone or at steady state of dabigatran), maximum plasma concentration was achieved around the end of each infusion. Mean all anticoagulation parameters fell below the upper limit of normal immediately after idarucizumab infusion in all dose groups; the effect was sustained at 4 and 2×2.5 g over the entire measurement period until 72 h. At 1‐ and 2‐g doses, partial return of the anticoagulant effect occurred. Idarucizumab alone had no effect on coagulation parameters. Treatment‐emergent ADAs occurred in 6/60 males receiving idarucizumab.ConclusionsIdarucizumab infusion achieved immediate, complete and sustained reversal of dabigatran‐induced anticoagulation in Japanese volunteers. Idarucizumab was well tolerated with no procoagulant effects. Trial registration number: ClinicalTrials.gov NCT02028780 (completed)

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Section: Discussionsupporting

confidence: 92%