Design and rationale for RE-VERSE AD: A phase 3 study of idarucizumab, a specific reversal agent for dabigatran

Pollack, Charles V.; Reilly, Paul; Bernstein, Richard A.; Dubiel, Robert; Eikelboom, John W.; Glund, Stephan; Huisman, Menno V.; Hylek, Elaine M.; Kam, CW; Kamphuisen, Pieter Willem; Kreuzer, Joerg; Levy, Jerrold H.; Sellke, Frank W.; Stangier, Joachim; Steiner, Thorsten; Wang, Bushi; Weitz, Jeffrey I.

doi:10.1160/th15-03-0192

Cited by 118 publications

(34 citation statements)

References 41 publications

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“…Interim data from bleeding patients or patients requiring emergency surgery have not identified any safety concerns. The rapid, complete and sustained reversal of anticoagulant effects in patients with a 5‐g dose was similar to that seen in healthy subjects 29. The effect of idarucizumab on bleeding was not determined in this study, although reversal of anticoagulation was demonstrably effective through measurement of objective parameters.…”

Section: Discussionsupporting

confidence: 60%

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: 60%

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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“…Idarucizumab is a recombinant humanized Fab directed against dabigatran that has been shown to be effective for rapid and complete reversal of the anticoagulant effects of dabigatran 10, 11, 15, 30. There is no evidence of any impact of anti‐idarucizumab antibodies on efficacy or safety outcomes 10, 15, 24.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the immunogenicity of the dabigatran reversal agent idarucizumab during Phase I studies

Norris

Ramael

Ikushima

et al. 2017

Brit J Clinical Pharma

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AimsIdarucizumab, a humanized monoclonal anti‐dabigatran antibody fragment, is effective in emergency reversal of dabigatran anticoagulation. Pre‐existing and treatment‐emergent anti‐idarucizumab antibodies (antidrug antibodies; ADA) may affect the safety and efficacy of idarucizumab. This analysis characterized the pre‐existing and treatment‐emergent ADA and assessed their impact on the pharmacokinetics and pharmacodynamics (PK/PD) of idarucizumab.MethodsData were pooled from three Phase I, randomized, double‐blind idarucizumab studies in healthy Caucasian subjects; elderly, renally impaired subjects; and healthy Japanese subjects. In plasma sampled before and after idarucizumab dosing, ADA were detected and titrated using a validated electrochemiluminescence method. ADA epitope specificities were examined using idarucizumab and two structurally related molecules. Idarucizumab PK/PD data were compared for subjects with and without pre‐existing ADA.ResultsPre‐existing ADA were found in 33 out of 283 individuals (11.7%), seven of whom had intermittent ADA. Titres of pre‐existing and treatment‐emergent ADA were low, estimated equivalent to <0.3% of circulating idarucizumab after a 5 g dose. Pre‐existing ADA had no impact on dose‐normalized idarucizumab maximum plasma levels and exposure and, although data were limited, no impact on the reversal of dabigatran‐induced anticoagulation by idarucizumab. Treatment‐emergent ADA were detected in 20 individuals (19 out of 224 treated [8.5%]; 1 out of 59 received placebo [1.7%]) and were transient in ten. The majority had specificity primarily toward the C‐terminus of idarucizumab. There were no adverse events indicative of immunogenic reactions.ConclusionPre‐existing and treatment‐emergent ADA were present at extremely low levels relative to the idarucizumab dosage under evaluation. The PK/PD of idarucizumab appeared to be unaffected by the presence of pre‐existing ADA.

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“…6 These patients are also being enrolled in the currently ongoing, multicenter open-label, single-arm phase III study RE-VERSE AD (Reversal Effects of Idarucizumab on Active Dabigatran), 9,12 where efficacy and tolerability of idarucizumab is being studied in clinical practice. Thus, patients requiring thrombolysis could also be enrolled in the RE-VERSE AD study as those requiring an urgent procedure after dabigatran reversal.…”

Section: Discussionmentioning

confidence: 99%

“…In the RE-VERSE AD trial (Reversal Effects of Idarucizumab on Active Dabigatran; group B), no clinical restrictions were prespecified. 9,12 Fab indicates fragment antigen binding.…”

Section: Indications and Usagementioning

confidence: 99%

Intravenous Thrombolysis With Recombinant Tissue-Type Plasminogen Activator in a Stroke Patient Receiving Dabigatran Anticoagulant After Antagonization With Idarucizumab

Berrouschot

Stoll

Hogh

et al. 2016

Stroke

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Background and Purpose-Therapeutic options for acute ischemic stroke patients presenting on effective anticoagulation are limited. Idarucizumab, a humanized, monoclonal antibody fragment for immediate reversal of dabigatran, may allow this subgroup of orally anticoagulated patients to regain eligibility for thrombolysis. Methods-We report the first successful acute antagonization of dabigatran by idarucizumab before intravenous thrombolysis with recombinant tissue-type plasminogen activator. Results-Idarucizumab was given to a 76-year-old male patient on dabigatran ≈3.5 hours after his last dose. Neurological status on admission was NIHSS (National Institutes of Health Stroke Scale) 11. Recombinant tissue-type plasminogen activator was initiated immediately after dabigatran reversal. The patient was discharged with a favorable outcome of NHISS 1 on day 7. No complications were observed. Conclusions-This case represents a new therapeutic paradigm. It is further supported by in vitro data showing no nonspecific interactions of idarucizumab with recombinant tissue-type plasminogen activator-induced thrombolysis. Thus, patients effectively anticoagulated with dabigatran who were previously contraindicated for thrombolytic therapy in this situation may now receive treatment because of the ability to rapidly reverse the anticoagulant activity of dabigatran with idarucizumab.

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Design and rationale for RE-VERSE AD: A phase 3 study of idarucizumab, a specific reversal agent for dabigatran

Cited by 118 publications

References 41 publications

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

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

Evaluation of the immunogenicity of the dabigatran reversal agent idarucizumab during Phase I studies

Intravenous Thrombolysis With Recombinant Tissue-Type Plasminogen Activator in a Stroke Patient Receiving Dabigatran Anticoagulant After Antagonization With Idarucizumab

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