A Study to Assess the Safety of a Potential New Drug in Comparison to the Standard Practice of Dosing With Warfarin for Non-valvular Atrial Fibrillation

Study Overview
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Brief Summary
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This study is to assess the safety of a potential new drug DU-176b for the prevention of stroke/systemic embolic event (SEE) in individuals with non-valvular atrial fibrillation (AF). The duration is 3 months of treatment and a 30 day follow-up visit.

Official Title
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A Phase 2, Randomized, Parallel Group, Multi Center, Multi National Study for the Evaluation of Safety of Four Fixed Dose Regimens of DU-176b in Subjects With Non- Valvular Atrial Fibrillation

Conditions
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Atrial Fibrillation, Thromboembolism

Intervention / Treatment
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* Drug: Edoxaban (DU-176b)
* Drug: Edoxaban (DU-176b)
* Drug: Edoxaban (DU-176b)
* Drug: Edoxaban (DU-176b)
* Drug: warfarin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, 18 to 80 years old. Able to provide written informed consent. Persistent non-valvular AF supported by abnormal electrocardiogram (ECG) A congestive heart failure, hypertension, age ≥ 75 years, diabetes, and prior stroke (CHADS2) index score of at least 2 Exclusion Criteria: Subjects with mitral valve disease or previous valvular heart surgery Known contraindication to any anticoagulant including vitamin K antagonists such as warfarin Known or suspected hereditary or acquired bleeding or coagulation disorder

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>DU-176b 30mg tablet once daily | Drug: Edoxaban (DU-176b)<br>* 30mg tablet once daily<br>|
| Experimental: 2<br>DU-176b 60mg once daily | Drug: Edoxaban (DU-176b)<br>* 60mg tablet once daily<br>|
| Experimental: 3<br>DU-176b 30mg b.i.d. | Drug: Edoxaban (DU-176b)<br>* 30mg tablet two times a day<br>|
| Experimental: 4<br>DU-176b 60mg tablets two times a day | Drug: Edoxaban (DU-176b)<br>* 60mg tablet two times a day<br>|
| Active Comparator: 5<br>warfarin tablets | Drug: warfarin<br>* warfarin tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adjudicated Incidence of Bleeding Events | Adjudicated Incidence of Bleeding Events during treatment period | 3 months | 
| Percent of Subjects With Liver-related Laboratory Marked Abnormalities (MA) | liver enzyme (ALT and/or AST) and/or bilirubin (TBL) abnormalities | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Major Adverse Cardiac Events MACE) | MACE is defined as the composite of stroke [ischemic or hemorrhagic], Systemic embolic event (SEE), Myocardial Infarction (MI), Cardiovascular (CV) death, and hospitalization for any cardiac condition | 3 months | 
| Effects on Biomarker D-dimer | Mean (SD) change from baseline in D-dimer | 3 months | 
| Effects on Biomarker Prothrombin Fragments | Mean (SD) change from baseline in Prothrombin Fragments 1 and 2 (F1 and F2) | 3 months | 
| Pharmacokinetics (Cmin, Cmax) of DU-176b in Subjects Receiving DU-176b | Median (min, max) values of Cmin,ss; Cmax,ss | 3 months | 
| Pharmacokinetics (AUC) of DU-176b in Subjects Receiving DU-176b | Median (min, max) values of AUCss | 3 months | 
| Effects on Pharmacodynamic Biomarker Anti-Factor Xa Activity in Subjects Receiving DU-176b | Mean (SD) change from baseline in biomarker anti-Factor Xa [FXa] activity on Day 28, 1-3 hours post dose. | Day 28 | 
| Effects on Pharmacodynamic Biomarker (Endogenous FX Activity) in Subjects Receiving DU-176b | Mean (SD) change from baseline in biomarker endogenous FX activity on Day 28, 1-3 hours post dose. | Day 28 | 
| Effects on Pharmacodynamic Biomarker PICT Activity in Subjects Receiving DU-176b | Mean (SD) change from baseline in biomarker prothrombinase induced clotting time [PICT] on Day 28, 1-3 hours post dose. PICT was determined by PICT aasay which is a plasma based functional assay to determine the anticoagulant activity on FXa and FIIa inhibition. | Day 28 | 
| Effects on Pharmacodynamic Biomarker PT in Subjects Receiving DU-176b | Mean (SD) change from baseline in biomarker prothrombin time (PT) on Day 28, 1-3 hours post dose. | Day 28 | 
| Effects on Pharmacodynamic Biomarker INR in Subjects Receiving DU-176b | Mean (SD) change from baseline in biomarker International Normalized Ratio (INR) on Day 28, 1-3 hours post dose. | Day 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anti-coagulant, Non-valvular, Venous Thromboembolism, Prevention of Blood Clots, Atrial Fibrillation, Non-valvular atrial fibrillation