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

Primary Purpose

Nonvalvular Atrial Fibrillation

Status

Completed

Phase

Phase 2

Locations

Study Type

Interventional

Intervention

AZD0837

Vitamin-K antagonist at INR 2-3

AZD0837

About this trial

This is an interventional prevention trial for Nonvalvular Atrial Fibrillation focused on measuring Anticoagulant Treatment, Risk Factors For Stroke

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Active Comparator

Arm Label

Arm Description

AZD0837 450 mg

AZD0837 200 mg

AZD0837 300 mg

AZD0837 150 mg

Vitamin-K antagonist at INR 2-3

Outcomes

Primary Outcome Measures

Bleeding Events

Number of patients with a bleeding event while on study drug. Patients with multiple events are counted once

Creatinine

Change in Creatinine values from baseline to week 12 visit for patients while on study drug (week 12 visit-baseline)

Alanine Aminotransferase (ALAT)

Number of patients while on study drug with ALAT>=3 times upper limit of normal.l

Bilirubin

Number of patients while on study drug with Bilirubin>=2 times upper limit of normal

Secondary Outcome Measures

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)

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)

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)

Plasma Concentration of AZD0837 (Prodrug)

Assessment made on the week 12 visit

Plasma Concentration of AR-H067637XX (Active Metabolite)

Assessment made on the week 12 visit

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

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

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

Full Information

NCT ID

NCT00684307

First Posted

May 22, 2008

Last Updated

March 20, 2012

Sponsor

AstraZeneca

1. Study Identification

Unique Protocol Identification Number

NCT00684307

Brief Title

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

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 Type

Interventional

2. Study Status

Record Verification Date

March 2012

Overall Recruitment Status

Completed

Study Start Date

February 2007 (undefined)

Primary Completion Date

June 2008 (Actual)

Study Completion Date

June 2008 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

AstraZeneca

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Nonvalvular Atrial Fibrillation

Keywords

Anticoagulant Treatment, Risk Factors For Stroke

7. Study Design

Primary Purpose

Prevention

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigator

Allocation

Randomized

Enrollment

1084 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm Type

Experimental

Arm Description

AZD0837 450 mg

Arm Title

Arm Type

Experimental

Arm Description

AZD0837 200 mg

Arm Title

Arm Type

Experimental

Arm Description

AZD0837 300 mg

Arm Title

Arm Type

Experimental

Arm Description

AZD0837 150 mg

Arm Title

Arm Type

Active Comparator

Arm Description

Vitamin-K antagonist at INR 2-3

Intervention Type

Drug

Intervention Name(s)

AZD0837

Intervention Description

ER tablet, PO, once daily for a period of 3-9 months.

Intervention Type

Drug

Intervention Name(s)

Vitamin-K antagonist at INR 2-3

Other Intervention Name(s)

Warfarin

Intervention Description

Tablet, PO for a period of 3-9 months.

Intervention Type

Drug

Intervention Name(s)

AZD0837

Intervention Description

ER tablet, PO, twice daily for a period of 3-9 months

Primary Outcome Measure Information:

Title

Bleeding Events

Description

Number of patients with a bleeding event while on study drug. Patients with multiple events are counted once

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)

Title

Creatinine

Description

Change in Creatinine values from baseline to week 12 visit for patients while on study drug (week 12 visit-baseline)

Time Frame

12 weeks according to protocol.(baseline to week 12 visit)

Title

Alanine Aminotransferase (ALAT)

Description

Number of patients while on study drug with ALAT>=3 times upper limit of normal.l

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)

Title

Bilirubin

Description

Number of patients while on study drug with Bilirubin>=2 times upper limit of normal

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)

Secondary Outcome Measure Information:

Title

D-Dimer

Description

Change in D-Dimer values from enrolment to week 12 visit for VKA naïve patients while on study drug (week 12 visit-enrolment)

Time Frame

14 weeks according to protocol.(enrolment to week 12 visit)

Title

Activated Partial Thromboplastin Time (APTT)

Description

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)

Time Frame

12 weeks according to protocol.(baseline to week 12 visit)

Title

Ecarin Clotting Time (ECT)

Description

Change in Ecarin clotting time (ECT) from baseline to week 12 visit for patients while on study drug (week 12 visit-baseline)

Time Frame

12 weeks according to protocol.(baseline to week 12 visit)

Title

Plasma Concentration of AZD0837 (Prodrug)

Description

Assessment made on the week 12 visit

Time Frame

12 weeks after baseline according to protocol

Title

Plasma Concentration of AR-H067637XX (Active Metabolite)

Description

Assessment made on the week 12 visit

Time Frame

12 weeks after baseline according to protocol

Title

Oral Clearance (CL/F) of AR-H067637XX (Active Metabolite) for C3435T Genotype TT

Description

Oral clearance of AR-H067637XX in subgroup of patients with genotype TT for gene polymorphism ABCB1 C3435T

Time Frame

36 weeks according to protocol

Title

Oral Clearance (CL/F) of AR-H067637XX (Active Metabolite) for C3435T Genotype TC

Description

Oral clearance of AR-H067637XX in subgroup of patients with genotype TC for gene polymorphism ABCB1 C3435T

Time Frame

36 weeks according to protocol

Title

Oral Clearance (CL/F) of AR-H067637XX (Active Metabolite) for C3435T Genotype CC

Description

Oral clearance of AR-H067637XX in subgroup of patients with genotype CC for gene polymorphism ABCB1 C3435T

Time Frame

36 weeks according to protocol

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Gregory Y Lip, Prof

Organizational Affiliation

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

Official's Role

Principal Investigator

12. IPD Sharing Statement

Citations:

PubMed Identifier

19690349

Citation

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.

Results Reference

derived

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

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