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:

Collaborator:

The TIMI Study Group

Information provided by (Responsible Party):

Daiichi Sankyo, Inc.

ClinicalTrials.gov Identifier:

NCT00781391

First received: October 28, 2008

Last updated: March 12, 2015

Last verified: March 2015

History of Changes

Results First Received: February 5, 2015

Study Type:	Interventional
Study Design:	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Prevention
Conditions:	Stroke Atrial Fibrillation Embolism
Interventions:	Drug: warfarin tablets Drug: Edoxaban tablets (high dose regimen-60mg) Drug: Edoxaban tablets (low dose regimen-30mg) Drug: placebo warfarin Drug: placebo edoxaban

Participant Flow

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Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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Reporting Groups

Description

Warfarin/Placebo Edoxaban

Warfarin tablets plus placebo Edoxaban tablets

warfarin tablets: Warfarin tablets plus Edoxaban placebo tablets each taken once daily for 24 months

placebo edoxaban: placebo edoxaban

High Dose Edoxaban/Placebo Warfarin

Edoxaban tablets plus warfarin placebo tablets

60mg Edoxaban tablets (high dose regimen): Edoxaban tablets plus warfarin placebo tablets each taken once daily for 24 months

placebo warfarin: placebo warfarin

Low Dose Edoxaban/Placebo Warfarin

Edoxaban tablets plus warfarin placebo tablets

30mg Edoxaban tablets (low dose regimen): Edoxaban tablets plus warfarin placebo tablets each taken once daily for 24 months

placebo warfarin: placebo warfarin

Participant Flow: Overall Study

	Warfarin/Placebo Edoxaban	High Dose Edoxaban/Placebo Warfarin	Low Dose Edoxaban/Placebo Warfarin
STARTED	7036	7035	7034
Safety Analysis Set (Received Drug)	7012	7012	7002
mITT Analysis Set (Received Drug)	7012	7012	7002
Per Protocol Analysis Set	6993	6995	6982
COMPLETED	6157	6228	6250
NOT COMPLETED	879	807	784
never received study drug	24	23	32
Protocol Violation	19	17	20
Death	789	730	706
Withdrawal by Subject	47	37	25
Lost to Follow-up	0	0	1

Baseline Characteristics

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Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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Reporting Groups

	Description
Warfarin/Placebo Edoxaban	Warfarin tablets plus placebo Edoxaban tablets warfarin tablets: Warfarin tablets plus Edoxaban placebo tablets each taken once daily for 24 months placebo edoxaban: placebo edoxaban
High Dose Edoxaban/Placebo Warfarin	Edoxaban tablets plus warfarin placebo tablets 60mg Edoxaban tablets (high dose regimen): Edoxaban tablets plus warfarin placebo tablets each taken once daily for 24 months placebo warfarin: placebo warfarin
Low Dose Edoxaban/Placebo Warfarin	Edoxaban tablets plus warfarin placebo tablets 30mg Edoxaban tablets (low dose regimen): Edoxaban tablets plus warfarin placebo tablets each taken once daily for 24 months placebo warfarin: placebo warfarin
Total	Total of all reporting groups

Baseline Measures

	Warfarin/Placebo Edoxaban	High Dose Edoxaban/Placebo Warfarin	Low Dose Edoxaban/Placebo Warfarin	Total
Overall Participants Analyzed [Units: Participants]	7012	7012	7002	21026

Age [Units: Participants]
<=18 years	0	0	0	0
Between 18 and 65 years	1869	1830	1784	5483
>=65 years	5143	5182	5218	15543

Age [Units: Years] Mean (Standard Deviation)	70.5 (9.44)	70.6 (9.51)	70.6 (9.31)	70.6 (9.42)

Gender [Units: Participants]
Female	2629	2659	2718	8006
Male	4383	4353	4284	13020

Race (NIH/OMB) [Units: Participants]
American Indian or Alaska Native	0	0	0	0
Asian	963	956	975	2894
Native Hawaiian or Other Pacific Islander	0	0	0	0
Black or African American	88	96	94	278
White	5679	5679	5650	17008
More than one race	0	0	0	0
Unknown or Not Reported	282	281	283	846

Region of Enrollment [Units: Participants]
Portugal	46	71	61	178
United States	1297	1288	1308	3893
Serbia	95	107	74	276
Philippines	43	36	45	124
Estonia	76	55	60	191
Taiwan	77	72	85	234
Slovakia	143	133	129	405
Greece	14	27	9	50
Spain	44	65	54	163
Thailand	40	40	33	113
Ukraine	360	386	402	1148
Israel	104	88	88	280
Chile	74	91	88	253
Russian Federation	375	406	369	1150
Colombia	51	42	48	141
Switzerland	0	1	4	5
Italy	60	55	54	169
India	232	220	234	686
France	40	38	32	110
Peru	64	46	60	170
Denmark	68	80	70	218
Australia	30	40	32	102
South Africa	97	92	90	279
Netherlands	64	49	40	153
China	163	150	152	465
Korea, Republic of	64	84	78	226
Finland	9	18	15	42
Guatemala	48	48	39	135
Turkey	40	39	31	110
United Kingdom	132	121	145	398
Hungary	151	143	167	461
Czech Republic	410	369	386	1165
Mexico	60	70	60	190
Canada	259	271	242	772
Argentina	352	345	362	1059
Brazil	236	242	225	703
Belgium	41	44	64	149
Poland	395	424	454	1273
Croatia	53	33	39	125
Romania	141	144	124	409
Bulgaria	179	174	165	518
Norway	11	8	15	34
Germany	308	293	307	908
Japan	337	336	337	1010
New Zealand	40	50	40	130
Sweden	89	78	86	253

Outcome Measures

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1. Primary:

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 ]

Show Outcome Measure 1

2. Primary:

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 ]

Show Outcome Measure 2

3. Primary:

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 ]

Show Outcome Measure 3

4. Primary:

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 ]

Show Outcome Measure 4

5. Primary:

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 ]

Show Outcome Measure 5

6. Secondary:

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 ]

Show Outcome Measure 6

7. Secondary:

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 ]

Show Outcome Measure 7

8. Secondary:

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 ]

Show Outcome Measure 8

9. Secondary:

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

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Serious Adverse Events

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Other Adverse Events

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Limitations and Caveats

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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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More Information

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Certain Agreements:

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: A study site may not publish results of a study until after a coordinated multicenter publication has been submitted for publication or until one year after the study has ended, whichever occurs first. The study site will have the opportunity to publish results of the study, provided Daiichi Sankyo has had the opportunity to review and comment on the study site’s proposed publication prior to being submitted for publication with the advice of patent council and need for subject protection.

Results Point of Contact:

Name/Title: James Hanyok, Sr. Director
Organization: Daiichi Sankyo, Inc.
phone: 732-590-5000
e-mail: jhanyok@dsi.com

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
Study First Received:	October 28, 2008
Results First Received:	February 5, 2015
Last Updated:	March 12, 2015

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