Late Phase 2 Study of DU-176b in Patients With Non-Valvular Atrial Fibrillation

Study Overview
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Brief Summary
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The primary objective of this study is to compare the incidence of hemorrhagic events in patients treated for non-valvular atrial fibrillation with DU-176b at each dose level versus warfarin potassium (warfarin). The secondary objective includes between-group comparisons with regard to incidence of thromboembolic events, pharmacodynamic parameters, and biomarkers for the efficacy evaluation, as well as incidence of adverse events and adverse reaction for the safety evaluation.

Official Title
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A Randomized Dose-ranging Controlled Trial of DU-176b Versus Warfarin Potassium in Patients With Non-valvular Atrial Fibrillation

Conditions
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Atrial Fibrillation

Intervention / Treatment
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* Drug: DU-176b tablets
* Drug: Warfarin potassium tablets


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with non-valvular atrial fibrillation who meet all of the following requirements will be considered for admission to the study: Age≧20years Atrial fibrillation confirmed by at least 2 electrocardiographic(ECG) tracings taken at an interval of ≧1week during the year before enrollment Presence of any (at least )one of the following risk factors for embolism: Hypertension Diabetes mellitus Congestive heart failure Previous transient ischemic attack (TIA) or cerebral infarction (more than 30 days before giving informed consent ) Age≧75 years At time of giving informed consent. To be confirmed on ECG charts, etc. Exclusion Criteria: Presence of any of the following conditions with increased risk of hemorrhage: History of intracranial, intraocular (excluding bleeding beneath the bulbar conjunctiva ), intrathecal, retroperitoneal, or non-traumatic intraarticular hemorrhage History of gastrointestinal hemorrhage during the year before giving informed consent History of peptic ulcers during the 90 days before giving informed consent Surgical treatment or trauma requiring hospitalization during the 30 days before giving informed consent Hemoglobin level <10 g/dL platelet count <10 ×10000 /μL at screening examinations Active hemorrhage* present at giving informed consent or at enrollment Any invasive therapeutic or diagnostic procedure (e.g., surgery, tissue, biopsy, and tooth extraction) scheduled during the period from the time of informed consent until completion of the trial treatment. Any congenital hemorrhagic disease History of cerebral infarction or TIA within 30 days before giving informed consent Current treatment with any anticoagulant(other than warfarin) Concurrent rheumatic valvular disease History of valvular surgery Concurrent infectious endocarditis Concurrent cardiac myxoma Confirmed left ventricular or left atrial thrombosis Any congenital condition with a tendency toward thrombosis Electrical or pharmacological defibrillation scheduled during the trial treatment Uncontrolled hypertension (persistently high systolic ［>160mmHg］or diastolic [>100mmHg] pressure) Uncontrolled diabetes mellitus Renal or hepatic dysfunction (as defined below ), confirmed at screening examinations Serum creatinine>1.5mg/dL AST(GOT)or ALT(GPT)≧twice the upper limit of the reference range Total bilirubin ≧twice the upper limit of the reference range Current antiplatelet therapy for any concomitant illness that may be aggravated after discontinuation of the therapy. Any concurrent severe cardiac disease Known allergy to warfarin or any condition contraindicating its use Inability to discontinue current treatment with vitamin K Confirmed or potential pregnancy, wish to become pregnant during the study period, or current breast feeding Previous treatment with DU-176b Participation in a trial of any other drug during the 6 month before giving informed consent Any other condition that disqualifies the patient for the study in the opinion of the investigator/subinvestigator *This includes ecchymosis identified as at least one hematoma sized ≧5 cm in longer diameter, macroscopic hematuria, and microscopic hematuria defined as a ≧2+test or a 1+ test for occult blood with a urine sediment containing ≧10 red cells per high-power field (except for a 2+ occult blood test persisting for 1 year before giving informed consent).

Ages Eligible for Study
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Minimum Age: 20 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 |
| --- | --- |
| Experimental: 1<br>DU-176b low dose | Drug: DU-176b tablets<br>* DU-176b tablets taken once daily for up to 12 weeks<br>|
| Experimental: 2<br>DU-176b intermediate dose | Drug: DU-176b tablets<br>* DU-176b tablets taken once daily for up to 12 weeks<br>|
| Experimental: 3<br>DU-176b high dose | Drug: DU-176b tablets<br>* DU-176b tablets taken once daily for up to 12 weeks<br>|
| Active Comparator: 4<br>Warfarin | Drug: Warfarin potassium tablets<br>* Warfarin potassium tablets taken once daily for up to 12 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Bleeding Events (Major Bleeding, Clinically Relevant Non-major Bleeding and Minor Bleeding ) Identified During the Period From the Entry Into the Treatment Period Until Completion or Termination of the Treatment. | The primary endpoint was the incidence of bleeding events (major bleeding, clinically relevant non-major bleeding, or minor bleeding) that occurred during the treatment period. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Thromboembolic Events (Cerebral Infarction and Systemic Embolism) Identified During the Period From the Entry to the Treatment Period Until Completion or Termination of the Treatment. |  | 12 weeks | 
| Incidence of Adverse Events and Adverse Reactions Identified During the Period From the Entry to the Treatment Period Until Completion or Termination of the Treatment |  | 12 weeks | 
| Pharmacodynamic Parameters (PT, PT-INR, and APTT) | PT - prothrombin time INR - International Normalized Ratio APTT - Activated Partial Thromboplastin time | 12 weeks | 
| Plasma DU-176 Concentration |  | 12 weeks | 
| Pharmacodynamic Biomarkers (F1+2, TAT, and D-dimer ) |  | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Atrial fibrillation, Factor Xa inhibition