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Global Study to Assess the Safety and Effectiveness of Edoxaban (DU-176b) vs Standard Practice of Dosing With Warfarin in Patients With Atrial Fibrillation (EngageAFTIMI48)

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00781391
First Posted: October 29, 2008
Last Update Posted: March 25, 2015
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborator:
The TIMI Study Group
Information provided by (Responsible Party):
Daiichi Sankyo, Inc.
  Purpose
This study is to demonstrate the safety and efficacy profile, in two different dose regimens of Edoxaban (DU-176b), (an investigational new drug being tested for the prevention of stroke/systemic embolic events (SEE)), in individuals with atrial fibrillation. Patients will be randomized to one of three treatment groups: High Dose Regimen, Low Dose Regimen, & Warfarin. The expected duration of the study is 24 months.

Condition Intervention Phase
Stroke Atrial Fibrillation Embolism Drug: warfarin tablets Drug: Edoxaban tablets (high dose regimen-60mg) Drug: Edoxaban tablets (low dose regimen-30mg) Drug: placebo warfarin Drug: placebo edoxaban Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: A Phase 3, Randomized, Double-Blind, Double-Dummy, Parallel Group, Multi-Center, Multi-National Study for Evaluation of Efficacy and Safety of Edoxaban (DU-176b) Versus Warfarin In Subjects With Atrial Fibrillation - Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation (ENGAGE - AF TIMI - 48)

Resource links provided by NLM:


Further study details as provided by Daiichi Sankyo, Inc.:

Primary Outcome Measures:
  • Compare Edoxaban to Warfarin for Composite of Stroke and Systemic Embolic Events (SEE). [ Time Frame: on-treatment period 2.5 years of median study drug exposure and 2.8 year of median follow-up ]
    The composite of stroke and Systemic Embolic Events (SEE) during the on treatment period in the mITT analysis population with a non-inferiority analysis.

  • Compare Edoxaban to Warfarin for Composite of Stroke and Systemic Embolic Events (SEE). [ Time Frame: overall study period 2.5 years of median study drug exposure and 2.8 year of median follow-up ]
    The composite of stroke and Systemic Embolic Events (SEE) during the overall study period in the mITT analysis population.

  • Compare Edoxaban to Warfarin for Composite of Stroke and Systemic Embolic Events (SEE). [ Time Frame: on-treatment period 2.5 years of median study drug exposure and 2.8 year of median follow-up ]
    The composite of stroke and Systemic Embolic Events (SEE) during the on treatment period in the PP (per protocol) analysis set population.

  • Compare Edoxaban to Warfarin for Composite of Stroke and Systemic Embolic Events (SEE). [ Time Frame: overall study period 2.5 years of median study drug exposure and 2.8 year of median follow-up ]
    The composite of stroke and Systemic Embolic Events (SEE) during the overall study period in the PP (per protocol) analysis set population.

  • Compare Edoxaban to Warfarin for Superiority for Composite of Stroke and Systemic Embolic Events (SEE). [ Time Frame: overall study period 2.5 years of median study drug exposure and 2.8 year of median follow-up ]
    Compare edoxaban to warfarin for the composite of stroke and Systemic Embolic Events (SEE) during the overall study period in the ITT analysis set with a superiority analysis.


Secondary Outcome Measures:
  • Compare Edoxaban to Warfarin for Composite of Stroke, Systemic Embolic Event (SEE), and Cardiovascular (CV) Mortality [ Time Frame: overall study period 2.5 years of median study drug exposure and 2.8 year of median follow-up ]
    Compare edoxaban to warfarin for the composite of stroke, Systemic Embolic Events, and Cardiovascular mortality during the overall study period in the ITT analysis set.

  • Compare Edoxaban to Warfarin for Major Adverse Cardiac Event (MACE): a Composite of Non-fatal MI, Non-fatal Stroke, Non-fatal SEE, and Death Due to CV Cause or Bleeding [ Time Frame: overall study period 2.5 years of median study drug exposure and 2.8 year of median follow-up ]
    Compare edoxaban to warfarin for Major Adverse Cardiac Event (MACE): a composite of non-fatal Myocardial Infarction, non-fatal stroke, non-fatal Systemic Embolic Events, and death due to Cardiovascular cause or bleeding during the overall study period in the ITT analysis set.

  • Compare Edoxaban to Warfarin for Composite of Stroke, SEE, and All-cause Mortality [ Time Frame: overall study period 2.5 years of median study drug exposure and 2.8 year of median follow-up ]
    Compare Edoxaban to warfarin for Composite of stroke, Systemic Embolic Events, and all-cause mortality during the overall study period in the ITT analysis set.

  • Adjudicated Bleeding Events [ Time Frame: on-treatment period 2.5 years of median study drug exposure and 2.8 year of median follow-up ]

    Compare edoxaban versus warfarin for Adjudicated Bleeding Events during the on-treatment period in the Safety Analysis set.

    Major bleeding was adjudicated by the Clinical Events Committee (CEC) and defined based on published guidance from the International Society on Thrombosis and Haemostasis (ISTH), with minor modifications for Hgb decrease and blood transfusion requirements.



Enrollment: 21105
Study Start Date: November 2008
Study Completion Date: May 2013
Primary Completion Date: April 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Warfarin/placebo edoxaban
Warfarin tablets plus placebo Edoxaban tablets
Drug: warfarin tablets
Warfarin tablets plus Edoxaban placebo tablets each taken once daily for 24 months
Drug: placebo edoxaban
placebo edoxaban
Experimental: high dose edoxaban/placebo warfarin
Edoxaban tablets (60mg) plus warfarin placebo tablets
Drug: Edoxaban tablets (high dose regimen-60mg)
Edoxaban tablets plus warfarin placebo tablets each taken once daily for 24 months
Drug: placebo warfarin
placebo warfarin
Experimental: low dose edoxaban/placebo warfarin
Edoxaban tablets (30mg) plus warfarin placebo tablets
Drug: Edoxaban tablets (low dose regimen-30mg)
Edoxaban tablets plus warfarin placebo tablets each taken once daily for 24 months
Drug: placebo warfarin
placebo warfarin

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   21 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 21 years of age or older; male or female.
  • Able to provide written informed consent.
  • History of documented AF within the prior 12 months
  • A moderate to high risk of stroke, as defined by CHADS2 index score of at least 2

Exclusion Criteria:

  • Transient atrial fibrillation secondary to other reversible disorders
  • Subjects with moderate or severe mitral stenosis, unresected atrial myxoma, or a mechanical heart valve
  • Subjects with any contraindication for anticoagulant agents;
  • Subjects with conditions associated with high risk of bleeding or have known or suspected hereditary or acquired bleeding disorders
  • Females of childbearing potential including the following:

    • Females with a history of tubal-ligation
    • Females less than 2 years post-menopausal
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00781391


  Show 1017 Study Locations
Sponsors and Collaborators
Daiichi Sankyo, Inc.
The TIMI Study Group
  More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Link MS, Giugliano RP, Ruff CT, Scirica BM, Huikuri H, Oto A, Crompton AE, Murphy SA, Lanz H, Mercuri MF, Antman EM, Braunwald E; ENGAGE AF-TIMI 48 Investigators. Stroke and Mortality Risk in Patients With Various Patterns of Atrial Fibrillation: Results From the ENGAGE AF-TIMI 48 Trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48). Circ Arrhythm Electrophysiol. 2017 Jan;10(1). pii: e004267. doi: 10.1161/CIRCEP.116.004267.
Ruff CT, Giugliano RP, Braunwald E, Murphy SA, Brown K, Jarolim P, Mercuri M, Antman EM, Morrow DA. Cardiovascular Biomarker Score and Clinical Outcomes in Patients With Atrial Fibrillation: A Subanalysis of the ENGAGE AF-TIMI 48 Randomized Clinical Trial. JAMA Cardiol. 2016 Dec 1;1(9):999-1006. doi: 10.1001/jamacardio.2016.3311.
Steffel J, Giugliano RP, Braunwald E, Murphy SA, Mercuri M, Choi Y, Aylward P, White H, Zamorano JL, Antman EM, Ruff CT. Edoxaban Versus Warfarin in Atrial Fibrillation Patients at Risk of Falling: ENGAGE AF-TIMI 48 Analysis. J Am Coll Cardiol. 2016 Sep 13;68(11):1169-1178. doi: 10.1016/j.jacc.2016.06.034.
Eisen A, Ruff CT, Braunwald E, Nordio F, Corbalán R, Dalby A, Dorobantu M, Mercuri M, Lanz H, Rutman H, Wiviott SD, Antman EM, Giugliano RP. Sudden Cardiac Death in Patients With Atrial Fibrillation: Insights From the ENGAGE AF-TIMI 48 Trial. J Am Heart Assoc. 2016 Jul 8;5(7). pii: e003735. doi: 10.1161/JAHA.116.003735.
Rost NS, Giugliano RP, Ruff CT, Murphy SA, Crompton AE, Norden AD, Silverman S, Singhal AB, Nicolau JC, SomaRaju B, Mercuri MF, Antman EM, Braunwald E; ENGAGE AF-TIMI 48 Investigators. Outcomes With Edoxaban Versus Warfarin in Patients With Previous Cerebrovascular Events: Findings From ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48). Stroke. 2016 Aug;47(8):2075-82. doi: 10.1161/STROKEAHA.116.013540. Epub 2016 Jul 7.
Bohula EA, Giugliano RP, Ruff CT, Kuder JF, Murphy SA, Antman EM, Braunwald E. Impact of Renal Function on Outcomes With Edoxaban in the ENGAGE AF-TIMI 48 Trial. Circulation. 2016 Jul 5;134(1):24-36. doi: 10.1161/CIRCULATIONAHA.116.022361.
Kato ET, Giugliano RP, Ruff CT, Koretsune Y, Yamashita T, Kiss RG, Nordio F, Murphy SA, Kimura T, Jin J, Lanz H, Mercuri M, Braunwald E, Antman EM. Efficacy and Safety of Edoxaban in Elderly Patients With Atrial Fibrillation in the ENGAGE AF-TIMI 48 Trial. J Am Heart Assoc. 2016 May 20;5(5). pii: e003432. doi: 10.1161/JAHA.116.003432.
Xu H, Ruff CT, Giugliano RP, Murphy SA, Nordio F, Patel I, Shi M, Mercuri M, Antman EM, Braunwald E. Concomitant Use of Single Antiplatelet Therapy With Edoxaban or Warfarin in Patients With Atrial Fibrillation: Analysis From the ENGAGE AF-TIMI48 Trial. J Am Heart Assoc. 2016 Feb 23;5(2). pii: e002587. doi: 10.1161/JAHA.115.002587.
Ruff CT, Giugliano RP, Braunwald E, Morrow DA, Murphy SA, Kuder JF, Deenadayalu N, Jarolim P, Betcher J, Shi M, Brown K, Patel I, Mercuri M, Antman EM. Association between edoxaban dose, concentration, anti-Factor Xa activity, and outcomes: an analysis of data from the randomised, double-blind ENGAGE AF-TIMI 48 trial. Lancet. 2015 Jun 6;385(9984):2288-95. doi: 10.1016/S0140-6736(14)61943-7. Epub 2015 Mar 11.
Mega JL, Walker JR, Ruff CT, Vandell AG, Nordio F, Deenadayalu N, Murphy SA, Lee J, Mercuri MF, Giugliano RP, Antman EM, Braunwald E, Sabatine MS. Genetics and the clinical response to warfarin and edoxaban: findings from the randomised, double-blind ENGAGE AF-TIMI 48 trial. Lancet. 2015 Jun 6;385(9984):2280-7. doi: 10.1016/S0140-6736(14)61994-2. Epub 2015 Mar 11.
Ruff CT, Giugliano RP, Braunwald E, Mercuri M, Curt V, Betcher J, Grip L, Cange AL, Crompton AE, Murphy SA, Deenadayalu N, Antman EM. Transition of patients from blinded study drug to open-label anticoagulation: the ENGAGE AF-TIMI 48 trial. J Am Coll Cardiol. 2014 Aug 12;64(6):576-84. doi: 10.1016/j.jacc.2014.05.028.
Giugliano RP, Ruff CT, Rost NS, Silverman S, Wiviott SD, Lowe C, Deenadayalu N, Murphy SA, Grip LT, Betcher JM, Duggal A, Dave J, Shi M, Mercuri M, Antman EM, Braunwald E; ENGAGE AF-TIMI 48 Investigators. Cerebrovascular events in 21 105 patients with atrial fibrillation randomized to edoxaban versus warfarin: Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48. Stroke. 2014 Aug;45(8):2372-8. doi: 10.1161/STROKEAHA.114.006025. Epub 2014 Jun 19.
Gupta DK, Shah AM, Giugliano RP, Ruff CT, Antman EM, Grip LT, Deenadayalu N, Hoffman E, Patel I, Shi M, Mercuri M, Mitrovic V, Braunwald E, Solomon SD; Effective aNticoaGulation with factor xA next GEneration in AF-Thrombolysis In Myocardial Infarction 48 Echocardiographic Study Investigators. Left atrial structure and function in atrial fibrillation: ENGAGE AF-TIMI 48. Eur Heart J. 2014 Jun 7;35(22):1457-65. doi: 10.1093/eurheartj/eht500. Epub 2013 Dec 2.
Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, Waldo AL, Ezekowitz MD, Weitz JI, Špinar J, Ruzyllo W, Ruda M, Koretsune Y, Betcher J, Shi M, Grip LT, Patel SP, Patel I, Hanyok JJ, Mercuri M, Antman EM; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013 Nov 28;369(22):2093-104. doi: 10.1056/NEJMoa1310907. Epub 2013 Nov 19.
Salazar DE, Mendell J, Kastrissios H, Green M, Carrothers TJ, Song S, Patel I, Bocanegra TS, Antman EM, Giugliano RP, Kunitada S, Dornseif B, Shi M, Tachibana M, Zhou S, Rohatagi S. Modelling and simulation of edoxaban exposure and response relationships in patients with atrial fibrillation. Thromb Haemost. 2012 May;107(5):925-36. doi: 10.1160/TH11-08-0566. Epub 2012 Mar 8.
Ruff CT, Giugliano RP, Antman EM, Crugnale SE, Bocanegra T, Mercuri M, Hanyok J, Patel I, Shi M, Salazar D, McCabe CH, Braunwald E. Evaluation of the novel factor Xa inhibitor edoxaban compared with warfarin in patients with atrial fibrillation: design and rationale for the Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation-Thrombolysis In Myocardial Infarction study 48 (ENGAGE AF-TIMI 48). Am Heart J. 2010 Oct;160(4):635-41. doi: 10.1016/j.ahj.2010.06.042.

Responsible Party: Daiichi Sankyo, Inc.
ClinicalTrials.gov Identifier: NCT00781391     History of Changes
Other Study ID Numbers: DU176b-C-U301
First Submitted: October 28, 2008
First Posted: October 29, 2008
Results First Submitted: February 5, 2015
Results First Posted: March 25, 2015
Last Update Posted: March 25, 2015
Last Verified: March 2015

Keywords provided by Daiichi Sankyo, Inc.:
Systemic embolic events

Additional relevant MeSH terms:
Atrial Fibrillation
Embolism
Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
Pathologic Processes
Embolism and Thrombosis
Vascular Diseases
Edoxaban
Warfarin
Anticoagulants
Factor Xa Inhibitors
Antithrombins
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action


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