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

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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Stroke, Atrial Fibrillation, Embolism

Intervention / Treatment
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* Drug: warfarin tablets
* Drug: Edoxaban tablets (high dose regimen-60mg)
* Drug: Edoxaban tablets (low dose regimen-30mg)
* Drug: placebo warfarin
* Drug: placebo edoxaban


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Warfarin/placebo edoxaban<br>Warfarin tablets plus placebo Edoxaban tablets | Drug: warfarin tablets<br>* Warfarin tablets plus Edoxaban placebo tablets each taken once daily for 24 months<br>Drug: placebo edoxaban<br>* placebo edoxaban<br>|
| Experimental: high dose edoxaban/placebo warfarin<br>Edoxaban tablets (60mg) plus warfarin placebo tablets | Drug: Edoxaban tablets (high dose regimen-60mg)<br>* Edoxaban tablets plus warfarin placebo tablets each taken once daily for 24 months<br>Drug: placebo warfarin<br>* placebo warfarin<br>|
| Experimental: low dose edoxaban/placebo warfarin<br>Edoxaban tablets (30mg) plus warfarin placebo tablets | Drug: Edoxaban tablets (low dose regimen-30mg)<br>* Edoxaban tablets plus warfarin placebo tablets each taken once daily for 24 months<br>Drug: placebo warfarin<br>* placebo warfarin<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compare Edoxaban to Warfarin for Composite of Stroke and Systemic Embolic Events (SEE). | The composite of stroke and Systemic Embolic Events (SEE) during the on treatment period in the mITT analysis population with a non-inferiority analysis. | on-treatment 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 and Systemic Embolic Events (SEE). | The composite of stroke and Systemic Embolic Events (SEE) during the overall study period in the mITT analysis population. | 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 and Systemic Embolic Events (SEE). | The composite of stroke and Systemic Embolic Events (SEE) during the on treatment period in the PP (per protocol) analysis set population. | on-treatment 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 and Systemic Embolic Events (SEE). | The composite of stroke and Systemic Embolic Events (SEE) during the overall study period in the PP (per protocol) analysis set population. | overall study period 2.5 years of median study drug exposure and 2.8 year of median follow-up | 
| Compare Edoxaban to Warfarin for Superiority for Composite of Stroke and Systemic Embolic Events (SEE). | 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. | overall study period 2.5 years of median study drug exposure and 2.8 year of median follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compare Edoxaban to Warfarin for Composite of Stroke, Systemic Embolic Event (SEE), and Cardiovascular (CV) Mortality | 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. | 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 MI, Non-fatal Stroke, Non-fatal SEE, and Death Due to CV Cause or Bleeding | 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. | 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, SEE, and All-cause Mortality | 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. | overall study period 2.5 years of median study drug exposure and 2.8 year of median follow-up | 
| Adjudicated Bleeding Events | 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. | on-treatment period 2.5 years of median study drug exposure and 2.8 year of median follow-up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Systemic embolic events