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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 1 | Experimental | AZD0837 450 mg |
|
| 2 | Experimental | AZD0837 200 mg |
|
| 3 | Experimental | AZD0837 300 mg |
|
| 4 | Experimental | AZD0837 150 mg |
|
| 5 | Active Comparator | Vitamin-K antagonist at INR 2-3 |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| AZD0837 | Drug | ER tablet, PO, once daily for a period of 3-9 months. |
| |
| 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) |
| 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) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Gregory Y Lip, Prof | University Department of Medicine, City Hospital, Birmingham, B18 7QH, England, UK | Principal Investigator |
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| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 19690349 | Derived | 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. |
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Participants were enrolled in the study up to two weeks before randomisation and treatment assignment. Participants that were already treated with Vitamin K Antagonists (VKA) at the time of enrollment had their dose adjusted to achive INR <2.0 at the time of randomisation. If this was not achieved the participant was discontinued from the study.
The study population included male and female participants >18 years of age with chronic non-valvular Atrial Fibrillation. The participants were recruited during the time period from 20 February 2007 to 5 June 2008 at medical clinics in Europe.
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| ID | Title | Description |
|---|---|---|
| FG000 | 150 mg od | AZD0837 150 mg od |
| FG001 | 300 mg od | AZD0837 300 mg od |
| FG002 | 450 mg od | AZD0837 450 mg od |
| FG003 | 200 mg bd | AZD0837 200 mg bd |
| FG004 | VKA INR 2-3 |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 150 mg od | AZD0837 150 mg od |
| BG001 | 300 mg od | AZD0837 300 mg od |
| BG002 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Bleeding Events | Number of patients with a bleeding event while on study drug. Patients with multiple events are counted once | Posted | Number | Participants | 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) |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | AZD0837 150 mg od |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Haemorrhagic Anaemia | Blood and lymphatic system disorders | MedDRA 10.0 | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| DIARRHOEA | Gastrointestinal disorders | MedDRA 10.0 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Gerard Lynch | AstraZeneca | aztrial_results_posting@astrazeneca.com |
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| ID | Term |
|---|---|
| C551586 | AZD 0837 |
| D014859 | Warfarin |
| ID | Term |
|---|---|
| D015110 | 4-Hydroxycoumarins |
| D003374 | Coumarins |
| D001578 | Benzopyrans |
| D011714 | Pyrans |
| D006573 |
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| Vitamin-K antagonist at INR 2-3 |
| Drug |
Tablet, PO for a period of 3-9 months. |
|
|
| AZD0837 | Drug | ER tablet, PO, twice daily for a period of 3-9 months |
|
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 |
| Development of increasing Liver Function |
|
| Fullfillment of exclusion criteria |
|
| Incorrect enrolment or randomization |
|
| Interupted IP for more than 7 days |
|
| Severe non compliance to protocol |
|
| Participant not willing to continue |
|
| Criteria from the CSR |
|
| 450 mg od |
AZD0837 450 mg od |
| BG003 | 200 mg bd | AZD0837 200 mg bd |
| BG004 | VKA INR 2-3 |
| BG005 | Total | Total of all reporting groups |
| Years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| OG003 | 200 mg bd | AZD0837 200 mg bd |
| OG004 | VKA INR 2-3 |
|
|
| Primary | Creatinine | Change in Creatinine values from baseline to week 12 visit for patients while on study drug (week 12 visit-baseline) | Posted | Mean | Standard Deviation | umol/L | 12 weeks according to protocol.(baseline to week 12 visit) |
|
|
|
| Primary | Alanine Aminotransferase (ALAT) | Number of patients while on study drug with ALAT>=3 times upper limit of normal.l | Posted | Number | Participants | 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) |
|
|
|
| Primary | Bilirubin | Number of patients while on study drug with Bilirubin>=2 times upper limit of normal | Posted | Number | Participants | 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 | 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) | Posted | Median | Full Range | ng/mL | 14 weeks according to protocol.(enrolment to week 12 visit) |
|
|
|
| Secondary | 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) | Posted | Median | Full Range | sec | 12 weeks according to protocol.(baseline to week 12 visit) |
|
|
|
| Secondary | 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) | Posted | Median | Full Range | sec | 12 weeks according to protocol.(baseline to week 12 visit) |
|
|
|
| Secondary | Plasma Concentration of AZD0837 (Prodrug) | Assessment made on the week 12 visit | Posted | Median | Full Range | nmol/L | 12 weeks after baseline according to protocol |
|
|
|
| Secondary | Plasma Concentration of AR-H067637XX (Active Metabolite) | Assessment made on the week 12 visit | Posted | Median | Full Range | nmol/L | 12 weeks after baseline according to protocol |
|
|
|
| Secondary | 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 | Posted | Median | Full Range | L/h | 36 weeks according to protocol |
|
|
|
| Secondary | 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 | Posted | Median | Full Range | L/h | 36 weeks according to protocol |
|
|
|
| Secondary | 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 | Posted | Median | Full Range | L/h | 36 weeks according to protocol |
|
|
|
| 12 |
| 166 |
| 46 |
| 166 |
| EG001 | AZD0837 300 mg od | 20 | 152 | 62 | 152 |
| EG002 | AZD0837 450 mg od | 31 | 157 | 46 | 157 |
| EG003 | AZD0837 200 mg bd | 27 | 161 | 59 | 161 |
| EG004 | VKA INR 2-3 | 50 | 319 | 67 | 319 |
| Cardiac Failure | Cardiac disorders | MedDRA 10.0 | Systematic Assessment |
|
| Atrial Fibrillation | Cardiac disorders | MedDRA 10.0 | Systematic Assessment |
|
| Acute Myocardial Infarction | Cardiac disorders | MedDRA 10.0 | Systematic Assessment |
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| Angina Pectoris | Cardiac disorders | MedDRA 10.0 | Systematic Assessment |
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| Angina Unstable | Cardiac disorders | MedDRA 10.0 | Systematic Assessment |
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| Atrial Flutter | Cardiac disorders | MedDRA 10.0 | Systematic Assessment |
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| Atrioventricular Block Complete | Cardiac disorders | MedDRA 10.0 | Systematic Assessment |
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| Bradycardia | Cardiac disorders | MedDRA 10.0 | Systematic Assessment |
|
| Cardiac Failure Acute | Cardiac disorders | MedDRA 10.0 | Systematic Assessment |
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| Cardiac Failure Congestive | Cardiac disorders | MedDRA 10.0 | Systematic Assessment |
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| Coronary Artery Occlusion | Cardiac disorders | MedDRA 10.0 | Systematic Assessment |
|
| Myocardial Infarction | Cardiac disorders | MedDRA 10.0 | Systematic Assessment |
|
| Myocardial Ischaemia | Cardiac disorders | MedDRA 10.0 | Systematic Assessment |
|
| Sick Sinus Syndrome | Cardiac disorders | MedDRA 10.0 | Systematic Assessment |
|
| Ventricular Tachycardia | Cardiac disorders | MedDRA 10.0 | Systematic Assessment |
|
| Vertigo | Ear and labyrinth disorders | MedDRA 10.0 | Systematic Assessment |
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| Cataract | Eye disorders | MedDRA 10.0 | Systematic Assessment |
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| Glaucoma | Eye disorders | MedDRA 10.0 | Systematic Assessment |
|
| Vitreous Haemorrhage | Eye disorders | MedDRA 10.0 | Systematic Assessment |
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| Abdominal Hernia | Gastrointestinal disorders | MedDRA 10.0 | Systematic Assessment |
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| Abdominal Pain | Gastrointestinal disorders | MedDRA 10.0 | Systematic Assessment |
|
| Anal Ulcer | Gastrointestinal disorders | MedDRA 10.0 | Systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA 10.0 | Systematic Assessment |
|
| Gastric Ulcer | Gastrointestinal disorders | MedDRA 10.0 | Systematic Assessment |
|
| Haematemesis | Gastrointestinal disorders | MedDRA 10.0 | Systematic Assessment |
|
| Haematochezia | Gastrointestinal disorders | MedDRA 10.0 | Systematic Assessment |
|
| Inguinal Hernia | Gastrointestinal disorders | MedDRA 10.0 | Systematic Assessment |
|
| Periodontal Disease | Gastrointestinal disorders | MedDRA 10.0 | Systematic Assessment |
|
| Rectal Haemorrhage | Gastrointestinal disorders | MedDRA 10.0 | Systematic Assessment |
|
| Asthenia | Gastrointestinal disorders | MedDRA 10.0 | Systematic Assessment |
|
| Chest Pain | Gastrointestinal disorders | MedDRA 10.0 | Systematic Assessment |
|
| Non-Cardiac Chest Pain | Gastrointestinal disorders | MedDRA 10.0 | Systematic Assessment |
|
| Sudden Death | Gastrointestinal disorders | MedDRA 10.0 | Systematic Assessment |
|
| Cholelithiasis | Hepatobiliary disorders | MedDRA 10.0 | Systematic Assessment |
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| Chronic Hepatitis | Hepatobiliary disorders | MedDRA 10.0 | Systematic Assessment |
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| Corneal Graft Rejection | Immune system disorders | MedDRA 10.0 | Systematic Assessment |
|
| Hypersensitivity | Immune system disorders | MedDRA 10.0 | Systematic Assessment |
|
| Appendicitis | Infections and infestations | MedDRA 10.0 | Systematic Assessment |
|
| Abscess Limb | Infections and infestations | MedDRA 10.0 | Systematic Assessment |
|
| Arthritis Bacterial | Infections and infestations | MedDRA 10.0 | Systematic Assessment |
|
| Erysipelas | Infections and infestations | MedDRA 10.0 | Systematic Assessment |
|
| Gastroenteritis | Infections and infestations | MedDRA 10.0 | Systematic Assessment |
|
| Infective Spondylitis | Infections and infestations | MedDRA 10.0 | Systematic Assessment |
|
| Lower Respiratory Tract Infection | Infections and infestations | MedDRA 10.0 | Systematic Assessment |
|
| Postoperative Wound Infection | Infections and infestations | MedDRA 10.0 | Systematic Assessment |
|
| Pyelonephritis Acute | Infections and infestations | MedDRA 10.0 | Systematic Assessment |
|
| Urinary Tract Infection | Infections and infestations | MedDRA 10.0 | Systematic Assessment |
|
| Contusion | Injury, poisoning and procedural complications | MedDRA 10.0 | Systematic Assessment |
|
| Femoral Neck Fracture | Injury, poisoning and procedural complications | MedDRA 10.0 | Systematic Assessment |
|
| Limb Injury | Injury, poisoning and procedural complications | MedDRA 10.0 | Systematic Assessment |
|
| Road Traffic Accident | Injury, poisoning and procedural complications | MedDRA 10.0 | Systematic Assessment |
|
| Tibia Fracture | Injury, poisoning and procedural complications | MedDRA 10.0 | Systematic Assessment |
|
| Haemoglobin Decreased | Injury, poisoning and procedural complications | MedDRA 10.0 | Systematic Assessment |
|
| Alanine Aminotransferase Increased | Injury, poisoning and procedural complications | MedDRA 10.0 | Systematic Assessment |
|
| Blood Glucose Increased | Injury, poisoning and procedural complications | MedDRA 10.0 | Systematic Assessment |
|
| Diabetes Mellitus | Metabolism and nutrition disorders | MedDRA 10.0 | Systematic Assessment |
|
| Gout | Metabolism and nutrition disorders | MedDRA 10.0 | Systematic Assessment |
|
| Arthritis | Musculoskeletal and connective tissue disorders | MedDRA 10.0 | Systematic Assessment |
|
| Back Pain | Musculoskeletal and connective tissue disorders | MedDRA 10.0 | Systematic Assessment |
|
| Muscular Weakness | Musculoskeletal and connective tissue disorders | MedDRA 10.0 | Systematic Assessment |
|
| Myalgia | Musculoskeletal and connective tissue disorders | MedDRA 10.0 | Systematic Assessment |
|
| Myositis | Musculoskeletal and connective tissue disorders | MedDRA 10.0 | Systematic Assessment |
|
| Osteoarthritis | Musculoskeletal and connective tissue disorders | MedDRA 10.0 | Systematic Assessment |
|
| Basal Cell Carcinoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 10.0 | Systematic Assessment |
|
| Bladder Cancer | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 10.0 | Systematic Assessment |
|
| Brain Neoplasm | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 10.0 | Systematic Assessment |
|
| Breast Cancer | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 10.0 | Systematic Assessment |
|
| Colon Neoplasm | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 10.0 | Systematic Assessment |
|
| Prostatic Adenoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 10.0 | Systematic Assessment |
|
| Ischaemic Stroke | Nervous system disorders | MedDRA 10.0 | Systematic Assessment |
|
| Syncope | Nervous system disorders | MedDRA 10.0 | Systematic Assessment |
|
| Dizziness | Nervous system disorders | MedDRA 10.0 | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA 10.0 | Systematic Assessment |
|
| Syncope Vasovagal | Nervous system disorders | MedDRA 10.0 | Systematic Assessment |
|
| Transient Ischaemic Attack | Nervous system disorders | MedDRA 10.0 | Systematic Assessment |
|
| Vascular Encephalopathy | Nervous system disorders | MedDRA 10.0 | Systematic Assessment |
|
| Vertebrobasilar Insufficiency | Nervous system disorders | MedDRA 10.0 | Systematic Assessment |
|
| Depression | Psychiatric disorders | MedDRA 10.0 | Systematic Assessment |
|
| Haematuria | Renal and urinary disorders | MedDRA 10.0 | Systematic Assessment |
|
| Asthma | Respiratory, thoracic and mediastinal disorders | MedDRA 10.0 | Systematic Assessment |
|
| Epistaxis | Respiratory, thoracic and mediastinal disorders | MedDRA 10.0 | Systematic Assessment |
|
| Pleural Effusion | Respiratory, thoracic and mediastinal disorders | MedDRA 10.0 | Systematic Assessment |
|
| Pulmonary Embolism | Respiratory, thoracic and mediastinal disorders | MedDRA 10.0 | Systematic Assessment |
|
| Arterial Stenosis Limb | Vascular disorders | MedDRA 10.0 | Systematic Assessment |
|
| Axillary Vein Thrombosis | Vascular disorders | MedDRA 10.0 | Systematic Assessment |
|
| Deep Vein Thrombosis | Vascular disorders | MedDRA 10.0 | Systematic Assessment |
|
| Hypertension | Vascular disorders | MedDRA 10.0 | Systematic Assessment |
|
| Hypotension | Vascular disorders | MedDRA 10.0 | Systematic Assessment |
|
| Orthostatic Hypotension | Vascular disorders | MedDRA 10.0 | Systematic Assessment |
|
| Peripheral Artery Aneurysm | Vascular disorders | MedDRA 10.0 | Systematic Assessment |
|
| Peripheral Embolism | Vascular disorders | MedDRA 10.0 | Systematic Assessment |
|
| Subclavian Vein Thrombosis | Vascular disorders | MedDRA 10.0 | Systematic Assessment |
|
| NAUSEA | Gastrointestinal disorders | MedDRA 10.0 | Systematic Assessment |
|
| FLATULENCE | Gastrointestinal disorders | MedDRA 10.0 | Systematic Assessment |
|
| ABDOMINAL PAIN UPPER | Gastrointestinal disorders | MedDRA 10.0 | Systematic Assessment |
|
| NASOPHARYNGITIS | Infections and infestations | MedDRA 10.0 | Systematic Assessment |
|
| DIZZINESS | Nervous system disorders | MedDRA 10.0 | Systematic Assessment |
|
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| Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |