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)

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. Identifier: NCT00781391
Recruitment Status : Completed
First Posted : October 29, 2008
Results First Posted : March 25, 2015
Last Update Posted : January 9, 2019
The TIMI Study Group
Information provided by (Responsible Party):
Daiichi Sankyo, Inc.

Brief Summary:
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 or disease Intervention/treatment 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  (Clinical Trial)
Actual Enrollment : 21105 participants
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)
Study Start Date : November 2008
Actual Primary Completion Date : April 2013
Actual Study Completion Date : May 2013

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
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

Primary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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 :
  1. 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.

  2. 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.

  3. 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.

  4. 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.

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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, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

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 identifier (NCT number): NCT00781391

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Hyderabad, AP, India
Vijayawada, AP, India
Angamaly, Kerala, India
Kochi, Kerala, India
Thrissur, Kerala, India
Ahmedabad, India
Anddhra Pradesh, India
Andhra Pradesh, India
Aurangabad, India
Bangalore, India
Bikaner, India
Chennai, India
Coimbatore, India
Delhi, India
Gujrat, India
Indore, India
Jaipur, India
Karnataka, India
Kerala, India
Kolkata, India
Ludhiana, India
Madhya Pradesh, India
Maharashtra, India
Mangalore, India
Mumbai, India
Nagpur, India
Nashik, India
New Delhi, India
Pune, India
Puni, India
Punjab, India
Rajasthan, India
Ramnagar, India
Shimoga, India
Surat, India
Trivandrum, India
Vadodara, India
Afula, Israel
Beer-Sheva, Israel
Dimona, Israel
Givatayim, Israel
Hadera, Israel
Haifa, Israel
Holon, Israel
Jerusalem, Israel
Kfar Saba, Israel
Nahariya, Israel
Nazareth, Israel
Petach Tikva, Israel
Petah-Tikva, Israel
Poriya, Israel
Raanana, Israel
Rehovot, Israel
Tel Aviv, Israel
Tel Hashomer, Israel
Zerifin, Israel
Bologna, Italy
Brescia, Italy
Cantania, Italy
Casarano, Italy
Caserta, Italy
Chieti, Italy
Cremona, Italy
Genova, Italy
Grosseto, Italy
Legnano, Italy
Manerbio, Italy
Milano, Italy
Monserrato, Italy
Napoli, Italy
Novara, Italy
Ostia, Italy
Pavia, Italy
Pisa, Italy
Pozzuoli, Italy
Roma, Italy
Santa Maria Capua Vetere, Italy
Sassari, Italy
Seriate, Italy
Siena, Italy
Trieste, Italy
Venezia Mestre, Italy
Kyoto-shi, Kyoto, Japan
Lida-shi, Nagano, Japan
Ueda-shi, Nagano, Japan
Minato-ku, Tokyo, Japan
Aichi, Japan
Aomori, Japan
Chiaki, Japan
Chiba, Japan
Ehime, Japan
Fukuoka, Japan
Fukushima, Japan
Gifu, Japan
Gunma, Japan
Hiroshima, Japan
Hokkai-do, Japan
Hokkaido, Japan
Hyogo, Japan
Ibaraki, Japan
Isesaki-shi, Japan
Ishikawa, Japan
Iwate, Japan
Kagawa, Japan
Kanagawa, Japan
Kumamoto, Japan
Kyota, Japan
Mie, Japan
Miyagi, Japan
Nagaoka-shi, Japan
Nagasaki, Japan
Niigata, Japan
Okayama, Japan
Osaka, Japan
Saitama, Japan
Shimane, Japan
Shizuoka, Japan
Tokushima, Japan
Tokyo, Japan
Yamaguchi, Japan
Yokohama-shi, Japan
Korea, Republic of
Busan, Korea, Republic of
Daegu, Korea, Republic of
Daejeon, Korea, Republic of
Gangwon-do, Korea, Republic of
Gwangju-si, Korea, Republic of
Gyeonggi-do, Korea, Republic of
Incheon, Korea, Republic of
Pusan, Korea, Republic of
Seoul, Korea, Republic of
Guadalajara, Jalisco, Mexico
Xalapa, Veracruz, Mexico
Aguascalientes, Mexico
Chihuahua, Mexico
Distrito Federal, Mexico
Durango, Mexico
Monterrey, Mexico
San Luis Potosi, Mexico
Yucatan, Mexico
Almere, Netherlands
Amstelveen, Netherlands
Amsterdam, Netherlands
Dordrecht, Netherlands
Eindhoven, Netherlands
Ewijk, Netherlands
Leiderdorp, Netherlands
Maastricht, Netherlands
Rotterdam, Netherlands
Venlo, Netherlands
Wildervlank, Netherlands
New Zealand
Lower Hutt, Wellington, New Zealand
Auckland, New Zealand
Christchurch, New Zealand
Dunedin, New Zealand
Hamilton, New Zealand
Nelson, New Zealand
Tauranga, New Zealand
Bodo, Norway
Harstad, Norway
Haugesund, Norway
Oslo, Norway
Rud, Norway
Arequipa, Peru
Callao, Peru
Lima, Peru
Cebu City, Philippines
Cebu, Philippines
Davao City, Philippines
Pasig City, Philippines
Quezon City, Philippines
Ostrow, Mazowiecka, Poland
Bydgoszcz, Poland
Chojnice, Poland
Elblag, Poland
Elk, Poland
Gdansk, Poland
Inowroclaw, Poland
Jaroslaw, Poland
Katowice, Poland
Kolobrzeg, Poland
Komenskiego, Poland
Krakow, Poland
Kutno, Poland
Libiaz, Poland
Lodz, Poland
Lubartow, Poland
Lublin, Poland
Plock, Poland
Pomorskie, Poland
Pulawy, Poland
Ruda Slaska, Poland
Rzeszow, Poland
Skierniewice, Poland
Sopot, Poland
Sucharskiego, Poland
Szczecin, Poland
Tarnow, Poland
Torun, Poland
Warszawa, Poland
Warzawa, Poland
Wroclaw, Poland
Amadora, Portugal
Aveiro, Portugal
Braga, Portugal
Coimbra, Portugal
Leiria, Portugal
Lisboa, Portugal
Lisbon, Portugal
Ponta Delgada, Portugal
Setubal, Portugal
Viseu, Portugal
Bacau, Romania
Braila, Romania
Brasov, Romania
Buccuresti, Romania
Bucuresti, Romania
Buzau, Romania
Covasna, Romania
Dambovita, Romania
Iasi, Romania
Judetul Maramures, Romania
Judetul Mures, Romania
Judetul Suceava, Romania
Judetul Vrancea, Romania
Oradea, Romania
Timisoara, Romania
Russian Federation
Barnaul, Russian Federation
Chelyabinsk, Russian Federation
Kemerovo, Russian Federation
Krasnoyarsk, Russian Federation
Moscow, Russian Federation
Nizhny Novgorod, Russian Federation
Novosibirsk, Russian Federation
Omsk, Russian Federation
Orenburg, Russian Federation
Perm, Russian Federation
Ryazan, Russian Federation
Saratov, Russian Federation
Smolensk, Russian Federation
St-Petersburg, Russian Federation
St. Petersburg, Russian Federation
Tula, Russian Federation
Tyumen, Russian Federation
Volgograd, Russian Federation
Voronezh, Russian Federation
Yaroslavl, Russian Federation
Belgrade, Serbia
Niska Banja, Serbia
Nis, Serbia
Sremska Kamenica, Serbia
Zemun, Serbia
Zmaj Jovina, Serbia
Bardejov, Slovakia
Bratislava, Slovakia
Dolny Kubin, Slovakia
Galanta, Slovakia
Kosice, Slovakia
Levice, Slovakia
Lucenec, Slovakia
Nitra, Slovakia
Nove Zamky, Slovakia
Presov, Slovakia
Rimavska Sobota, Slovakia
South Africa
Alberton, South Africa
Benoni, South Africa
Bloemfontein, South Africa
Cape Town, South Africa
Diepkloof, South Africa
Durban, South Africa
Lyttelton, South Africa
Parktown West, South Africa
Port Elizabeth, South Africa
Potchefstroom, South Africa
Pretoria, South Africa
Somerset West, South Africa
Worcester, South Africa
Alcoy, Spain
Almeria, Spain
Barcelona, Spain
Bilbao, Spain
De La Castellana, Spain
Donostia-San Sebastian, Spain
Figueras, Spain
Jaen, Spain
La Coruna, Spain
Lleida, Spain
Madrid, Spain
Murcia, Spain
Santiago De Compostela, Spain
Sevilla, Spain
Vigo, Spain
Vitoria, Spain
Alingsas, Sweden
Enkoping, Sweden
Goteborg, Sweden
Halmstad, Sweden
Karlshamn, Sweden
Koping, Sweden
Lindesberg, Sweden
Lulea, Sweden
Lund, Sweden
Malmo, Sweden
Molndal, Sweden
Mora, Sweden
Orebro, Sweden
Skene, Sweden
Umea, Sweden
Uppsala, Sweden
Varberg, Sweden
Lausanne, Switzerland
Lugano, Switzerland
Changhua City, Taiwan
Hualien City, Taiwan
Kaohsiung City, Taiwan
Taichung City, Taiwan
Taipei City, Taiwan
Taipei, Taiwan
Taoyuan County, Taiwan
Yongkang City, Taiwan
Bangkok, Thailand
Chang Mai, Thailand
Khon Kaen, Thailand
Nakhon Ratchasima, Thailand
Pathumthani, Thailand
Sai Mai, Thailand
Songkhla, Thailand
Adana, Turkey
Ankara, Turkey
Antalya, Turkey
Aydin, Turkey
Erzurum, Turkey
Eskisehir, Turkey
Isparta, Turkey
Istanbul, Turkey
Izmir, Turkey
Konya, Turkey
Sivas, Turkey
Cherkasy, Ukraine
Chernigiv, Ukraine
Dnipropetrovsk, Ukraine
Donetsk, Ukraine
Ivano-Frankivsh, Ukraine
Ivano-Frankivsk, Ukraine
Kharkiv, Ukraine
Kherson, Ukraine
Kyiv, Ukraine
Lugansk, Ukraine
Lutsk, Ukraine
Lviv, Ukraine
Mykolayiv, Ukraine
Odesa, Ukraine
Poltava, Ukraine
Uzhgorod, Ukraine
Vinnytsya, Ukraine
Zaporizhzhya, Ukraine
United Kingdom
Birmingham, United Kingdom
Blackpool, United Kingdom
Bournemouth, United Kingdom
Bradford, United Kingdom
Cambridge, United Kingdom
Chesterfield, United Kingdom
Coventry, United Kingdom
Devon, United Kingdom
Dundee, United Kingdom
East Horsley, United Kingdom
East Sussex, United Kingdom
Edinburgh, United Kingdom
Essex, United Kingdom
Glasgow, United Kingdom
Harrow, United Kingdom
Leicester, United Kingdom
Liverpool, United Kingdom
London, United Kingdom
Middlesbrough, United Kingdom
Orpington, United Kingdom
Peterborough, United Kingdom
Portadown, United Kingdom
Sheffield, United Kingdom
Stirling, United Kingdom
Stockport, United Kingdom
Surrey, United Kingdom
Sutton Coldfield, United Kingdom
Swindon, United Kingdom
Warwickshire, United Kingdom
Wolverhampton, United Kingdom
York, United Kingdom
Sponsors and Collaborators
Daiichi Sankyo, Inc.
The TIMI Study Group

Publications automatically indexed to this study by Identifier (NCT Number):

Responsible Party: Daiichi Sankyo, Inc. Identifier: NCT00781391     History of Changes
Other Study ID Numbers: DU176b-C-U301
First Posted: October 29, 2008    Key Record Dates
Results First Posted: March 25, 2015
Last Update Posted: January 9, 2019
Last Verified: March 2015
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address:
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Analytic Code
Time Frame: Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.
Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.

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

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