A Dose Response Study of Dabigatran Etexilate(BIBR 1048) in Pharmacodynamics and Safety in Patients With Non-valvular Atrial Fibrillation in Comparison to Warfarin

Study Overview
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Brief Summary
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The primary objective was to evaluate the safety of dabigatran etexilate(BIBR 1048) administered orally at doses of 110 and 150 mg, twice daily, for 12 weeks in patients with non-valvular atrial fibrillation (paroxysmal, persistent or permanent) in comparison with warfarin.

Official Title
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Open Label, Randomised Exploratory Dose Response Study in Pharmacodynamics and Safety of BIBR 1048 (110 mg Twice Daily (b.i.d.) and 150 mg b.i.d.) for 12 Weeks in Patients With Non-valvular Atrial Fibrillation in Comparison to Warfarin

Conditions
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Atrial Fibrillation

Intervention / Treatment
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* Drug: Dabigatran etexilate
* Drug: Dabigatran etexilate
* Drug: Warfarin


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Inclusion criteria Patients with non-valvular atrial fibrillation (paroxysmal, persistent or permanent) Patients who had additional risk factor for thromboembolism; one or more of the following conditions/events: Hypertension Diabetes mellitus Left-side heart failure A previous ischemic stroke or transient ischemic attack Age 75 years or older A history of coronary artery diseases Exclusion criteria Exclusion criteria Patients diagnosed as having a valvular heart disease by echocardiography, or patients who had a history of prosthetic valve replacement or valve surgery Patients who were to receive electric defibrillation or pharmacological defibrillation during the study period Patients who developed stroke or transient ischemic attack within 30 days before the date of informed consent Patients who developed myocardial infarction or were admitted to hospital due to acute coronary syndrome or for percutaneous transluminal coronary angioplasty within 3 months before the date of informed consent or patients underwent coronary stenting within 6 months before the date of informed consent Patients with atrial myxoma or left ventricular thrombosis Patients with contraindication to anticoagulant therapies Patients scheduled for major surgery or invasive procedure Patients having major bleeding from non-gastrointestinal organs within 6 months before the date of informed consent Patients with uncontrolled hypertension

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dabigatran etexilate 220 mg daily<br>Dabigatran etexilate 110 mg capsule, twice a day, oral administration | Drug: Dabigatran etexilate<br>* Dabigatran etexilate 110 mg capsule, twice a day, oral administration<br>|
| Experimental: Dabigatran etexilate 300 mg daily<br>Dabigatran etexilate 150 mg capsule, twice a day, oral administration | Drug: Dabigatran etexilate<br>* Dabigatran etexilate 150 mg capsule, twice a day, oral administration<br>|
| Active Comparator: Warfarin<br>Dose-adjusted warfarin based on target INR values | Drug: Warfarin<br>* Dose-adjusted warfarin based on target INR values<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency (Occurrence Rates) of Major Bleeding Event | The percentage of patients with major bleeding event. Major bleeding was defined as any bleed fulfilling one of the following conditions: Fatal or life-threatening Retroperitoneal, intracranial, intraocular, or intraspinal bleeding (verified by objective testing) Bleeding requiring surgical treatment Clinically overt bleeding leading to a transfusion (erythrocyte component transfusion or whole blood transfusion) of 4.5 units (equal to 2 units in EU/US) or more Clinically overt bleeding leading to a fall in haemoglobin of at least 2 g/dL | upto 15 weeks | 
| Frequency (Occurrence Rates) of Clinically Relevant Bleeding Event | The percentage of patients with clinically relevant bleeding event. Any bleed that did not qualify as a major bleed was defined as a minor bleed; minor bleed which fulfilled one of the criteria below was defined as a clinically relevant bleeding event: A skin haematoma of at least 25 sqcm Spontaneous nose bleed lasting for more than 5 minutes Macroscopic haematuria (either spontaneous or, if associated with an intervention, lasting more than 24 hours) Spontaneous rectal bleeding (more than spotting on toilet paper) Gingival bleeding lasting for more than 5 minutes Bleeding leading to hospitalisation Bleeding leading to blood transfusion (erythrocyte component transfusion or whole blood transfusion) of less than 4.5 units (equal to 2 units in EU/US) Any other bleeding considered clinically relevant by the investigator | upto 15 weeks | 
| Frequency (Occurrence Rates) of Nuisance Bleeding Event | The percentage of patients with nuisance bleeding event Any bleed that did not qualify as a major bleed was defined as a minor bleed; all minor bleeding events not fulfilling one of the criteria below was defined as a nuisance bleeding event: A skin haematoma of at least 25 sqcm Spontaneous nose bleed lasting for more than 5 minutes Macroscopic haematuria (either spontaneous or, if associated with an intervention, lasting more than 24 hours) Spontaneous rectal bleeding (more than spotting on toilet paper) Gingival bleeding lasting for more than 5 minutes Bleeding leading to hospitalisation Bleeding leading to blood transfusion (erythrocyte component transfusion or whole blood transfusion) of less than 4.5 units (equal to 2 units in EU/US) Any other bleeding considered clinically relevant by the investigator | Upto 15 weeks | 
| Incidence and Severity of Adverse Events | Intensity of event is categorised as mild, moderate and severe. | Upto 15 weeks | 
| Discontinuation of the Study Drug Due to Adverse Events | Discontinuation of the study drug due to adverse events. | Upto 15 weeks | 
| Changes in Laboratory Test Values | The number of patients with ALT, AST, alkaline phosphatase, or bilirubin exceeded the upper limit of normal (ULN) range | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency (Occurrence Rates) of a Composite Clinical Endpoint. | Percentage of patients with the composite clinical endpoint (ischemic or haemorrhagic stroke (fatal or non-fatal), transient ischemic attacks, systemic embolism, myocardial infarction (fatal or non-fatal), other major adverse cardiac events, and death) | Upto 15 weeks | 
| Frequency (Occurrence Rates) of Ischemic or Haemorrhagic Stroke (Fatal or Non-fatal) | The percentage of patients with ischemic or haemorrhagic stroke (fatal or non-fatal) | Upto 15 weeks | 
| Frequency (Occurrence Rates) of Transient Ischemic Attack | The percentage of patients with transient ischemic attack | Upto 15 weeks | 
| Frequency (Occurrence Rates) of Systemic Embolism | The percentage of patients with systemic embolism | Upto 15 weeks | 
| Frequency (Occurrence Rates) of Myocardial Infarction (Fatal or Non-fatal) | The percentage of patients with myocardial infarction (fatal or non-fatal) | Upto 15 weeks | 
| Frequency (Occurrence Rates) of Other Major Adverse Cardiac Events | The percentage of patients with other major adverse cardiac events | Upto 15 weeks | 
| Frequency (Occurrence Rates) of Death | The percentage of patients with death | Upto 15 weeks | 
| Anticoagulation Effects Trough aPTT (Activated Partial Thromboplastin Time) | The blood coagulation parameter aPTT was assessed in patients allocated to the dabigatran etexilate groups at week 0, prior to drug administration and at the trough at week 1, 4 and 12. | Week 0,1,4 and 12 | 
| Anticoagulation Effects Trough ECT (Ecarin Clotting Time) | The blood coagulation parameter ECT was assessed in patients allocated to the dabigatran etexilate groups at week 0, prior to drug administration and at the trough at week 1, 4 and 12. | Week 0,1,4 and 12 | 
| Anticoagulation Effects Trough INR (International Normalised Ratio) | The blood coagulation parameter INR was assessed in patients allocated to the dabigatran etexilate groups at week 0, prior to drug administration and at the trough at week 1, 4 and 12. | Week 0,1,4 and 12 | 
| Anticoagulation Effects Trough 11-dehydrothromboxane B2 | Analysis based on concomitant use of aspirin compared to no aspirin users. 11-dehydrothromboxane B2 is measured in urine of patients. | Week 0 and 12 | 
| Steady-state Pharmacokinetics of Total Dabigatran Trough Plasma Concentration |  | Week 1,4 and 12 |