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
Sponsored by
About this trial
This is an interventional prevention trial for Nonvalvular Atrial Fibrillation focused on measuring Anticoagulant Treatment, Risk Factors For Stroke
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
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm Type
Experimental
Experimental
Experimental
Experimental
Active Comparator
Arm Label
1
2
3
4
5
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
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
1
Arm Type
Experimental
Arm Description
AZD0837 450 mg
Arm Title
2
Arm Type
Experimental
Arm Description
AZD0837 200 mg
Arm Title
3
Arm Type
Experimental
Arm Description
AZD0837 300 mg
Arm Title
4
Arm Type
Experimental
Arm Description
AZD0837 150 mg
Arm Title
5
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
No
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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