Prevention of Stroke and Systemic Embolic Events in Patients With Atrial Fibrillation - Full Text View

Purpose

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	Intervention	Phase
Nonvalvular Atrial Fibrillation	Drug: AZD0837 Drug: Vitamin-K antagonist at INR 2-3	Phase 2

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, 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

Resource links provided by NLM:

Genetics Home Reference related topics: familial atrial fibrillation

MedlinePlus related topics: Atrial Fibrillation Blood Thinners Vitamin K

Drug Information available for: Menadione Warfarin

U.S. FDA Resources

Further study details as provided by AstraZeneca:

Primary Outcome Measures:

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

Secondary Outcome Measures:

D-Dimer [ Time Frame: 14 weeks according to protocol.(enrolment to week 12 visit) ] [ Designated as safety issue: Yes ]
Change in D-Dimer values from enrolment to week 12 visit for VKA naïve patients while on study drug (week 12 visit-enrolment)
Activated Partial Thromboplastin Time (APTT) [ Time Frame: 12 weeks according to protocol.(baseline to week 12 visit) ] [ Designated as safety issue: Yes ]
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)
Ecarin Clotting Time (ECT) [ Time Frame: 12 weeks according to protocol.(baseline to week 12 visit) ] [ Designated as safety issue: Yes ]
Change in Ecarin clotting time (ECT) from baseline to week 12 visit for patients while on study drug (week 12 visit-baseline)
Plasma Concentration of AZD0837 (Prodrug) [ Time Frame: 12 weeks after baseline according to protocol ] [ Designated as safety issue: No ]
Assessment made on the week 12 visit
Plasma Concentration of AR-H067637XX (Active Metabolite) [ Time Frame: 12 weeks after baseline according to protocol ] [ Designated as safety issue: No ]
Assessment made on the week 12 visit
Oral Clearance (CL/F) of AR-H067637XX (Active Metabolite) for C3435T Genotype TT [ Time Frame: 36 weeks according to protocol ] [ Designated as safety issue: No ]
Oral clearance of AR-H067637XX in subgroup of patients with genotype TT for gene polymorphism ABCB1 C3435T
Oral Clearance (CL/F) of AR-H067637XX (Active Metabolite) for C3435T Genotype TC [ Time Frame: 36 weeks according to protocol ] [ Designated as safety issue: No ]
Oral clearance of AR-H067637XX in subgroup of patients with genotype TC for gene polymorphism ABCB1 C3435T
Oral Clearance (CL/F) of AR-H067637XX (Active Metabolite) for C3435T Genotype CC [ Time Frame: 36 weeks according to protocol ] [ Designated as safety issue: No ]
Oral clearance of AR-H067637XX in subgroup of patients with genotype CC for gene polymorphism ABCB1 C3435T

Enrollment:	1084
Study Start Date:	February 2007
Study Completion Date:	June 2008
Primary Completion Date:	June 2008 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: 1 AZD0837 450 mg	Drug: AZD0837 ER tablet, PO, once daily for a period of 3-9 months. Other Name: AZD0837
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. Other Name: AZD0837
Experimental: 4 AZD0837 150 mg	Drug: AZD0837 ER tablet, PO, once daily for a period of 3-9 months. Other Name: AZD0837
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

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
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

Please refer to this study by its ClinicalTrials.gov identifier: NCT00684307

Sponsors and Collaborators

AstraZeneca

Investigators

Principal Investigator:

Gregory Y Lip, Prof

University Department of Medicine, City Hospital, Birmingham, B18 7QH, England, UK

More Information

No publications provided by AstraZeneca

Additional 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. Epub 2009 Aug 18.

Responsible Party:	AstraZeneca
ClinicalTrials.gov Identifier:	NCT00684307 History of Changes
Other Study ID Numbers:	D1250C00008
Study First Received:	May 22, 2008
Results First Received:	August 17, 2011
Last Updated:	March 20, 2012
Health Authority:	Austria: Agency for Health and Food Safety Denmark: Danish Medicines Agency Hungary: National Institute of Pharmacy Ireland: Irish Medicines Board Norway: Norwegian Medicines Agency Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products Russia: Ministry of Health of the Russian Federation Sweden: Medical Products Agency United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by AstraZeneca:

Anticoagulant Treatment
Risk Factors For Stroke

Additional relevant MeSH terms:

Atrial Fibrillation
Stroke
Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
Pathologic Processes
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Antithrombins
Vitamin K
Vitamins
Serine Proteinase Inhibitors

Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Anticoagulants
Hematologic Agents
Therapeutic Uses
Micronutrients
Growth Substances
Physiological Effects of Drugs
Antifibrinolytic Agents
Fibrin Modulating Agents
Hemostatics
Coagulants

ClinicalTrials.gov processed this record on May 19, 2013