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

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

doi:10.1160/TH15-03-0192

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2015; 114(01): 198-205
DOI: 10.1160/TH15-03-0192

Trial Protocol Design Paper

Schattauer GmbH

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

Authors

Charles V. Pollack Jr.

¹Pennsylvania Hospital, Philadelphia, Pennsylvania, USA
Paul A. Reilly

²Boehringer Ingelheim Pharmaceuticals, Ridgefield, Conneticut, USA
Richard Bernstein

³Northwestern University, Chicago, Illinois, USA
Robert Dubiel

²Boehringer Ingelheim Pharmaceuticals, Ridgefield, Conneticut, USA
John Eikelboom

⁴McMaster University, Hamilton, Ontario, Canada
Stephan Glund

⁵Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
Menno V. Huisman

⁶Leiden University Medical Center, Leiden, Netherlands
Elaine Hylek

⁷Boston University School of Medicine, Boston, Massachusetts, USA
Chak-Wah Kam

⁸Tuen Mun Hospital, Tuen Mun, NT, Hong Kong
Pieter W. Kamphuisen

⁹University Medical Center, Groningen, Netherlands
Joerg Kreuzer

¹⁰Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany
Jerrold H. Levy

¹¹Duke University Medical Center, Durham, North Carolina, USA
Frank Sellke

¹²Brown Medical School, Providence, Rhode Island, USA
Joachim Stangier

⁵Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
Thorsten Steiner

¹³University of Heidelberg, Heidelberg, Germany
Bushi Wang

²Boehringer Ingelheim Pharmaceuticals, Ridgefield, Conneticut, USA
Jeffrey I. Weitz

⁴McMaster University, Hamilton, Ontario, Canada

Abstract

Summary

Idarucizumab, a Fab fragment directed against dabigatran, produced rapid and complete reversal of the anticoagulation effect of dabigatran in animals and in healthy volunteers. The Study of the REVERS al E ffects of Idarucizumab in Patients on A ctive D abigatran (RE-VERSE AD™) is a global phase 3 prospective cohort study aimed at investigating idarucizumab in dabigatran-treated patients who present with uncontrollable or life-threatening bleeding, and in those requiring urgent surgery or intervention. We describe the rationale for, and design of the trial (clinicaltrials.gov NCT02104947).

Full Text

References

References
1 Connolly SJ, Ezekowitz MD, Yusuf S. et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139-1151.
2 Schulman S, Kearon C, Kakkar AK. et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361: 2342-2352.
3 Schulman S, Kakkar AK, Goldhaber SZ. et al. the RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation 2014; 129: 764-772.
4 Desai J, Kolb JM, Weitz JI. et al. Gastrointestinal bleeding with the new oral anticoagulants--defining the issues and the management strategies. Thromb Hae-most 2013; 110: 205-212.
5 Eikelboom JW, Wallentin L, Connolly SJ. et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation. Circulation 2011; 123: 2363-2372.
6 Graham DJ, Reichman ME, Wernecke M. et al. Cardiovascular, bleeding, and mortality risks in elderly Medicare patients treated with dabigatran or warfarin for non-valvular atrial fibrillation. Circulation 2015; 131: 157-164.
7 Majeed A, Hwang HG, Connolly SJ. et al. Management and outcomes of major bleeding during treatment with dabigatran or warfarin. Circulation 2013; 128: 2325-2332.
8 Abbas S, Ihle P, Harder S. et al. Risk of bleeding and antibiotic use in patients receiving continuous phenprocoumon therapy. A case-control study nested in a large insurance- and population-based German cohort. Thromb Haemost 2014; 111: 912-922.
9 Seeger JD, Bartels DB, Huybrechts K. et al. Safety and effectiveness of dabigatran relative to warfarin in routine care. Circulation. 2014 Epub ahead of print.
10 Villines TC, Schnee J, Fraeman K. et al. The comparative safety and effectiveness of the oral anticoagulant (OAC) dabigatran versus warfarin utilized in a large healthcare system in non-valvular atrial fibrillation (NVAF) patients. Circulation. 2014 Epub ahead of print.
11 van Ryn J, Stangier J, Haertter S. et al. Dabigatran etexilate--a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010; 103: 1116-1127.
12 Schiele F, van Ryn J, Canada K. et al. A specific antidote for dabigatran: functional and structural characterisation. Blood 2013; 121: 3554-3562.
13 Honickel M, Grottke O, van Ryn J. et al. Use of a specific antidote to dabigatran (idarucizumab) reduces blood loss and mortality in dabigatran-induced and trauma-induced bleeding in pigs. Crit Care 2014; 18 (Suppl. 01) P99.
14 van Ryn J, Litzenburger T, Schurer J. Reversal of anticoagulant activity of dabigatran and dabigatran-induced bleeding in rats by a specific antidote (antibody fragment). Circulation 2012; 126: A9928.
15 Glund S, Moschetti V, Norris S. et al. A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatran. Thromb Haemost 2015; 113: 943-951.
16 Glund S, Stangier J, Schmohl M. et al. Idarucizumab, a specific antidote for dabigatran: Immediate, complete and sustained reversal of dabigatran induced anticoagulation in elderly and renally impaired subjects. 56th Ann Mtg of the American Society of Hematology (ASH),. San Francisco. 6–9 Dec 2014 (Oral Presentation) Blood 2014 124 Abstract 344.
17 http://www.boehringer-ingelheim.com/news/news_releases/press_releases/2014/30_june_2014_dabigatranetexilate.html accessed May 14, 2015.
18 Reilly PA, Lehr T, Haertter S. et al. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). Am Coll Cardiol 2014; 63: 321-328.
19 Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet 2008; 47: 285-295.
20 Stangier J, Feuring M. Using the HAEMOCLOT direct thrombin inhibitor assay to determine plasma concentrations of dabigatran. Blood Coagul Fibrinolysis 2012; 23: 138-143.
21 Blech S, Ebner T, Ludwig-Schwellinger E. et al. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos 2008; 36: 386-399.
22 Schulman S, Angerås U, Bergqvist D. et al. Definition of major bleeding in clinical investigations of antihaemostatic medicinal products in surgical patients. J Thromb Haemost 2010; 08: 202-204.
23 Chesebro JH, Knatterud G, Roberts R. et al. Thrombolysis in Myocardial Infarction (TIMI) Trial, phase I: a comparison between intravenous tissue plasminogen activator and intravenous streptokinase: clinical findings through hospital discharge. Circulation 1987; 76: 142-154.
24 GUSTO Investigators.. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993; 329: 673-682.
25 Wilson JL, Hareendran A, Grant M. et al. Improving the assessment of outcomes in stroke: Use of a structured interview to assign grades on the Modified Rankin Scale. Stroke 2002; 33: 2243-2246.
26 Dennis M, Mead G, Doubal F. et al. Determining the modified Rankin score after stroke by postal and telephone questionnaires. Stroke 2012; 43: 851-853.
27 Pragst I, Zeitler SH, Doerr B. et al. Reversal of dabigatran anticoagulation by prothrombin complex concentrate (Beriplex P/N) in a rabbit model. J Thromb Haemost 2012; 10: 1841-1848.
28 Grottke O, Honickel M, van Ryn J. et al. Blood loss in dabiagtran-anticoagulated pigs with polytraumna is significantly reduced by early therapy with activated and nonactivated prothrombin complex concentrates. 87th Scientific Session 2014 of the American Heart Association (AHA), Chicago, November 15–19, 2014. Circulation. 2014 130. (Suppl 2): Abstract 18544.
29 Pragst I, Kaspereit F, Dörr B. et al. Prothrombin complex concentrate (Beriplex P/N) for control of bleeding after kidney trauma in a rabbit dilutional coagulopathy model. Thromb Res 2010; 125: 272-277.
30 Heidbuchel H, Verhamme P, Alings M. et al. European Heart Rhythm Association practical guide on the use of new oral anticoagulants in patients with nonvalvular atrial fibrillation. Europace 2013; 15: 625-651.
31 Holbrook A, Schulman S, Witt DM. et al. Evidence-based management of anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012; 141 (Suppl) e152S-e184S.
32 Steiner T, Bohm M, Dichgans M. et al. Recommendations for the emergency management of complications associated with new direct oral anticoagulants (DOAC) Apixaban, dabigatran, and Rivaroxaban. Clin Res Cardiol 2013; 102: 399-412.
33 Kyrle P, Binder K, Eichinger S. et al. Dabigatran: Patient management in specific clinical settings. Wien Klin Wochenschr 2014; 126: 503-508.
34 Awad NI, Brunetti L, Juurlink DN. Enhanced elimination of dabigatran through extracorporeal methods. J Med Toxicol. 2014 Epub ahead of print.
35 Miesbach W, Seifried E. New direct oral anticoagulants: Current therapeutic options and treatment recommendations for bleeding complications. Thromb Haemost 2012; 108: 625-632.
36 Lazo-Langner A, Lang ES, Douketis J. Clinical review: Clinical management of new oral anticoagulants: A structured review with emphasis on the reversal of bleeding complications. Crit Care 2013; 17: 230-241.
37 Franchini M, Lippi G. Prothrombin complex concentrates: An update. Blood Transfus 2010; 08: 149-154.
38 Cabral KP, Fraser GL, Duprey J. et al. Prothrombin complex concentrates to reverse warfarin-induced coagulopathy in patients with intracranial bleeding. Clin Neurol Neurosurg 2013; 115: 77074.
39 Bauer KA. Reversal of antithrombotic agents. Am J Hematol 2012; 87: S119-126.
40 Sarich TC, Seltzer JH, Berkowitz SD. et al. Novel oral anticoagulants (NOAC) and reversal agents: Considerations for clinical development. Am Heart J. 2015 In press (available online).
41 Siegal DM, Garcia DA, Crowther MA. How I treat: Target specific oral anticoagulant related bleeding. Blood 2014; 123: 1152-1158.
42 Gold AM, Crowther M, Levy G. et al. Annexa-R: A pahse 3, randomized, double-blind, placebo-controlled triall demonstratring reversal of rivaroxaban-induced anticoagulation in older subjects by andexanet alfa (PRT064445), a universal antidote for factor Xa (FXa) inhibitors. J Am Coll Cardiol. 2015 Epub ahead of print.
43 Ansell JE, Bakhry SH, Laulicht BE. et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med 2014; 371: 2141-2142.