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

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

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.

Study Overview

• Status: Completed
• Conditions: Nonvalvular Atrial Fibrillation
• Intervention / Treatment: Drug: AZD0837; Drug: AZD0837; Drug: Vitamin-K antagonist at INR 2-3

• Study Type: Interventional
• Enrollment (Actual): 1084
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

5

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: AstraZeneca
• Investigators: Principal Investigator: Gregory Y Lip, Prof, University Department of Medicine, City Hospital, Birmingham, B18 7QH, England, UK

Publications and helpful links

General Publications

• Lip GY, Rasmussen LH, Olsson SB, Jensen EC, Persson AL, Eriksson U, Wahlander KF; Steering Committee. Oral direct thrombin inhibitor AZD0837 for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation: a randomized dose-guiding, safety, and tolerability study of four doses of AZD0837 vs. vitamin K antagonists. Eur Heart J. 2009 Dec;30(23):2897-907. doi: 10.1093/eurheartj/ehp318. Epub 2009 Aug 18.

Study record dates

Study Major Dates

• Study Start: February 1, 2007
• Primary Completion (Actual): June 1, 2008
• Study Completion (Actual): June 1, 2008

Study Registration Dates

• First Submitted: May 22, 2008
• First Submitted That Met QC Criteria: May 23, 2008
• First Posted (Estimate): May 26, 2008

Study Record Updates

• Last Update Posted (Estimate): March 23, 2012
• Last Update Submitted That Met QC Criteria: March 20, 2012
• Last Verified: March 1, 2012

More Information

Terms related to this study

• Keywords: Anticoagulant Treatment; Risk Factors For Stroke
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Atrial Fibrillation; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Fibrin Modulating Agents; Micronutrients; Vitamins; Anticoagulants; Antifibrinolytic Agents; Hemostatics; Coagulants; Vitamin K; Warfarin
• Other Study ID Numbers: D1250C00008