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

Study Description

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Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Nonvalvular Atrial Fibrillation	Drug: AZD0837; Drug: Vitamin-K antagonist at INR 2-3	Phase 2

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	1084 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Triple (Participant, Care Provider, Investigator)
Primary Purpose:	Prevention
Official Title:	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
Study Start Date :	February 2007
Actual Primary Completion Date :	June 2008
Actual Study Completion Date :	June 2008

Arms and Interventions

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Arm	Intervention/treatment
Experimental: 1; AZD0837 450 mg	Drug: AZD0837; ER tablet, PO, once daily for a period of 3-9 months.
Experimental: 2; AZD0837 200 mg	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.
Experimental: 4; AZD0837 150 mg	Drug: AZD0837; ER tablet, PO, once 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 Name: Warfarin

Outcome Measures

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Primary Outcome Measures :

1. Bleeding Events [ Time Frame: 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) ]
   Number of patients with a bleeding event while on study drug. Patients with multiple events are counted once
2. Creatinine [ Time Frame: 12 weeks according to protocol.(baseline to week 12 visit) ]
   Change in Creatinine values from baseline to week 12 visit for patients while on study drug (week 12 visit-baseline)
3. Alanine Aminotransferase (ALAT) [ Time Frame: 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) ]
   Number of patients while on study drug with ALAT>=3 times upper limit of normal.l
4. Bilirubin [ Time Frame: 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) ]
   Number of patients while on study drug with Bilirubin>=2 times upper limit of normal

Secondary Outcome Measures :

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

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

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Sponsors and Collaborators

AstraZeneca

Investigators

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

More Information

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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Lip GY, Rasmussen LH, Olsson SB, Jensen EC, Persson AL, Eriksson U, Wåhlander 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.

Responsible Party:	AstraZeneca
ClinicalTrials.gov Identifier:	NCT00684307 History of Changes
Other Study ID Numbers:	D1250C00008
First Posted:	May 26, 2008
Results First Posted:	September 22, 2011
Last Update Posted:	March 23, 2012
Last Verified:	March 2012

Keywords provided by AstraZeneca:

Anticoagulant Treatment; Risk Factors For Stroke

Additional relevant MeSH terms:

Atrial Fibrillation; Arrhythmias, Cardiac; Heart Diseases; Cardiovascular Diseases; Pathologic Processes; Vitamins; Vitamin K; Micronutrients	Growth Substances; Physiological Effects of Drugs; Antifibrinolytic Agents; Fibrin Modulating Agents; Molecular Mechanisms of Pharmacological Action; Hemostatics; Coagulants