Prevention of Stroke and Systemic Embolic Events in Patients With Atrial Fibrillation

Study Overview
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Brief Summary
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The main purpose of this study is to provide dose-guiding information by assessing the safety and tolerability of 4 different dosing regimens of an extended-release (ER) formulation of AZD0837 compared with well-controlled, dose-adjusted Vitamin-K antagonists (VKA) (aiming for an international normalized ratio (INR) 2.0 to 3.0) in patients with non-valvular atrial fibrillation (AF) with one or more additional risk factors for stroke.

Official Title
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A Controlled, Randomized, Parallel, Multicentre Study to Assess Safety and Tolerability of the Oral Direct Thrombin Inhibitor AZD0837, Given as an Extended-release Formulation, in the Prevention of Stroke and Systemic Embolic Events in Patients With Atrial Fibrillation

Conditions
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Nonvalvular Atrial Fibrillation

Intervention / Treatment
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* Drug: AZD0837
* Drug: Vitamin-K antagonist at INR 2-3
* Drug: AZD0837


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Nonvalvular AF (NVAF) verified by at least two ECGs in the last year separated by at least one week. Previous cerebral ischemic attack (stroke or TIA, >30 days prior to randomization) Previous systemic embolism. Symptomatic congestive heart failure (CHF) Impaired left ventricular systolic function Diabetes mellitus Hypertension requiring anti-hypertensive treatment. Exclusion Criteria: AF secondary to reversible disorders, eg hyperthyroidism, drugs and pulmonary embolism Known contraindication to VKA treatment Presence of a valvular heart disease, mechanical heart valves, active endocarditis, left ventricular aneurysm or thrombus, atrial myxoma or any condition other than AF requiring chronic anticoagulation treatment Conditions associated with increased risk of major bleeding for example: history of intracranial bleeding, history of bleeding gastrointestinal disorder or major surgical procedure or trauma two weeks prior to randomization

Ages Eligible for Study
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Minimum Age: 18 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>AZD0837 450 mg | Drug: AZD0837<br>* ER tablet, PO, once daily for a period of 3-9 months.<br>|
| Experimental: 2<br>AZD0837 200 mg | Drug: AZD0837<br>* ER tablet, PO, twice daily for a period of 3-9 months<br>|
| Experimental: 3<br>AZD0837 300 mg | Drug: AZD0837<br>* ER tablet, PO, once daily for a period of 3-9 months.<br>|
| Experimental: 4<br>AZD0837 150 mg | Drug: AZD0837<br>* ER tablet, PO, once daily for a period of 3-9 months.<br>|
| Active Comparator: 5<br>Vitamin-K antagonist at INR 2-3 | Drug: Vitamin-K antagonist at INR 2-3<br>* Tablet, PO for a period of 3-9 months.<br>* Other names: Warfarin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bleeding Events | Number of patients with a bleeding event while on study drug. Patients with multiple events are counted once | 36 weeks according to protocol. For patients who discontinued treatment the time frame was <36 weeks. Mean number of weeks was 21 weeks (baseline to end of treatment visit) | 
| Creatinine | Change in Creatinine values from baseline to week 12 visit for patients while on study drug (week 12 visit-baseline) | 12 weeks according to protocol.(baseline to week 12 visit) | 
| Alanine Aminotransferase (ALAT) | Number of patients while on study drug with ALAT>=3 times upper limit of normal.l | 36 weeks according to protocol. For patients who discontinued treatment the time frame was <36 weeks. Mean number of weeks was 21 weeks (baseline to end of treatment visit) | 
| Bilirubin | Number of patients while on study drug with Bilirubin>=2 times upper limit of normal | 36 weeks according to protocol. For patients who discontinued treatment the time frame was <36 weeks. Mean number of weeks was 21 weeks (baseline to end of treatment visit) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| D-Dimer | Change in D-Dimer values from enrolment to week 12 visit for VKA naïve patients while on study drug (week 12 visit-enrolment) | 14 weeks according to protocol.(enrolment to week 12 visit) | 
| Activated Partial Thromboplastin Time (APTT) | Change in Activated partial thromboplastin time (APTT) from baseline to week 12 visit for VKA naïve patients while on study drug (week 12 visit-baseline) | 12 weeks according to protocol.(baseline to week 12 visit) | 
| Ecarin Clotting Time (ECT) | Change in Ecarin clotting time (ECT) from baseline to week 12 visit for patients while on study drug (week 12 visit-baseline) | 12 weeks according to protocol.(baseline to week 12 visit) | 
| Plasma Concentration of AZD0837 (Prodrug) | Assessment made on the week 12 visit | 12 weeks after baseline according to protocol | 
| Plasma Concentration of AR-H067637XX (Active Metabolite) | Assessment made on the week 12 visit | 12 weeks after baseline according to protocol | 
| Oral Clearance (CL/F) of AR-H067637XX (Active Metabolite) for C3435T Genotype TT | Oral clearance of AR-H067637XX in subgroup of patients with genotype TT for gene polymorphism ABCB1 C3435T | 36 weeks according to protocol | 
| Oral Clearance (CL/F) of AR-H067637XX (Active Metabolite) for C3435T Genotype TC | Oral clearance of AR-H067637XX in subgroup of patients with genotype TC for gene polymorphism ABCB1 C3435T | 36 weeks according to protocol | 
| Oral Clearance (CL/F) of AR-H067637XX (Active Metabolite) for C3435T Genotype CC | Oral clearance of AR-H067637XX in subgroup of patients with genotype CC for gene polymorphism ABCB1 C3435T | 36 weeks according to protocol | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anticoagulant Treatment, Risk Factors For Stroke