PETRO Stroke Prevention in Patients With AF by Treatment With Dabigatran, With and Without Aspirin, Compared to Warfarin

Study Overview
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Brief Summary
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The purpose of this trial is to evaluate the safety of different doses of BIBR 1048, alone or in combination with acetylsalicylic acid (ASA), as determined by the rates of bleeding and other adverse events. A secondary objective of this trial is to evaluate the anticoagulant effect of different doses of BIBR 1048, based on the reduction of plasma concentrations of D-dimer, a laboratory marker for activated coagulation in patients with atrial fibrillation (AF), and to correlate bleeding and other events with pharmacokinetic (PK) and pharmacodynamic (PD) data.

Official Title
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Dose Exploration in Patients With Atrial Fibrillation

Conditions
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Atrial Fibrillation

Intervention / Treatment
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* Drug: dabigatran with ASA
* Drug: dabigatran with ASA
* Drug: dabigatran with ASA
* Drug: dabigatran with ASA
* Drug: dabigatran with ASA
* Drug: dabigatran with ASA
* Drug: warfarin
* Drug: dabigatran without ASA
* Drug: dabigatran without ASA
* Drug: dabigatran without ASA


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Non-rheumatic atrial fibrillation. Coronary artery disease (CAD), documented by previous myocard infarction (MI), angina, positive stress test, previous coronary intervention or bypass surgery, or atherosclerotic lesion(s) diagnosed by coronary angiography) is only considered as one of several possible qualifying risk factors. After recruitment of ca. 30%, a protocol amendment 4 was issued so that CAD was only considered as one of several possible qualifying risk factors, 2. see (3 f) below. An additional risk factor for stroke, i.e. one or more of the following conditions/events: hypertension (defined as systolic bloodpressure (SBP) > 140 mmHg and/or diastolic bloodpressure (DBP) > 90 mm Hg) requiring antihypertensive medical treatment. diabetes mellitus (type I and II). symptomatic heart failure or left ventricular dysfunction (ejection fraction (EF) < 40%). a previous ischemic stroke or transient ischemic attack. age greater than 75 years. history of coronary artery disease (by amendment 4) Treatment with warfarin or other vitamin K dependent anticoagulants for at least 8 weeks prior to inclusion. International normalised ratio (INR) should be within therapeutic range (i.e. INR 2.0 - 3.0) at visit 1 otherwise the visit should be rescheduled. Age > = 18 years at entry. Written, informed consent. Exclusion criteria Valvular heart disease. Planned cardioversion. Recent (=< 1 month) myocardial infarction, stroke or transient ischemic attack (TIA), or patients who have received a coronary stent within the last 6 months. Intolerance or contraindications to acetylsalicylic acid (ASA). Any contraindication to anticoagulant therapy. Major bleeding within the last 6 months (other than gastrointestinal (GI) hemorrhage). Severe renal impairment (estimated glomerular filtration rate (GFR) =< 30 mL/min). Uncontrolled hypertension (SBP > 180 mmHg and/or DBP > 100 mmHg). Abnormal liver function as defined by aspartat-aminotransferase (AST), alanin-aminotransferase (ALT), serum bilirubin or alkaline phosphatase (AP) above the reference range, or history of liver disease. Women who are pregnant or of childbearing potential who refuses to use a medically acceptable form of contraception throughout the study. Patients who have received an investigational drug within the last 30 days. Patients scheduled for major surgery or invasive procedures which may cause bleeding, or those who have had major surgery or percutaneous coronary intervention (PCI) within 6 weeks. Patients considered unreliable by the investigator. Another indication for anticoagulant treatment. Patients suffering from anemia. Patients suffering from thrombocytopenia. Any other condition which, in the discretion of the investigator, would not allow safe participation in the study. Concomitant treatment with antiplatelet agents other than ASA. Recent malignancy or radiation therapy (=< 6 month).

Ages Eligible for Study
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Minimum Age: 18 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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: dabigatran 50 mg twice daily (bid)<br>Dabigatran: one capsule in the morning and 1 capsule in the evening. Twice daily (bis in die = bid). | Drug: dabigatran without ASA<br>* dose comparison<br>|
| Experimental: dabigatran 50 mg bid + 81 mg ASA qd<br>Dabigatran: one capsule in the morning and 1 capsule in the evening. Acetylsalicylic acid (ASA) once daily (quaque dies = qd) in the morning. | Drug: dabigatran with ASA<br>* dose comparison in combination<br>|
| Experimental: dabigatran 50 mg bid + 325 mg ASA qd<br>Dabigatran: one capsule in the morning and 1 capsule in the evening. ASA in the morning | Drug: dabigatran with ASA<br>* dose comparison in combination<br>|
| Experimental: dabigatran 150 mg bid<br>Dabigatran: one capsule in the morning and 1 capsule in the evening | Drug: dabigatran without ASA<br>* dose comparison<br>|
| Experimental: dabigatran 150 mg bid + 81 mg ASA qd<br>Dabigatran: one capsule in the morning and 1 capsule in the evening. ASA in the morning | Drug: dabigatran with ASA<br>* dose comparison in combination<br>|
| Experimental: dabigatran 150 mg bid + 325 mg ASA qd<br>Dabigatran: one capsule in the morning and 1 capsule in the evening. ASA in the morning | Drug: dabigatran with ASA<br>* dose comparison in combination<br>|
| Experimental: dabigatran 300 mg bid<br>Dabigatran: one capsule in the morning and 1 capsule in the evening | Drug: dabigatran without ASA<br>* dose comparison<br>|
| Experimental: dabigatran 300 mg bid + 81 mg ASA qd<br>Dabigatran: one capsule in the morning and 1 capsule in the evening. ASA in the morning | Drug: dabigatran with ASA<br>* dose comparison in combination<br>|
| Experimental: dabigatran 300 mg bid + 325 mg ASA qd<br>Dabigatran: one capsule in the morning and 1 capsule in the evening. ASA in the morning | Drug: dabigatran with ASA<br>* dose comparison in combination<br>|
| Active Comparator: warfarin<br>once daily, dosed to target International Normalised Ratio (INR) 2.0 to 3.0 | Drug: warfarin<br>* comparator<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Fatal or Life-threatening Major Bleeding Events | Retroperitoneal, intracranial, intraocular, or intraspinal bleeding, or requiring surgical treatment, or leading to a transfusion of 2 units or more, or leading to a fall in hemoglobin of 20g/L or more | 12 weeks | 
| Number of Participants With Minor/Relevant Bleeding Events | Haematuria, rectal bleeding, gingival bleeding, skin hematoma of 25cm^2 or more, nose bleed of more than 5 minutes duration, bleeding leading to a hospitalization, leading to a transfusion of less than 2 units or any other clinically relevant bleeding | 12 weeks | 
| Number of Participants With Minor/Nuisance Bleeding Events | All bleeding events not fulfilling one of the criteria for major bleeding event or minor/relevant bleeding events. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Thromboembolic Events: Composite Endpoint | Combination of ischemic stroke (fatal or non fatal), transient ischemic attack, systemic thromboembolism, myocardial infarction (fatal or non fatal), other major adverse cardiac event and all cause mortality | 12 weeks | 
| Number of Participants With Thromboembolic Events: Ischemic Stroke | Occurence of an ischemic stroke (fatal or non-fatal) | 12 weeks | 
| Thromboembolic Events: Number of Participants With Transient Ischemic Attack | Occurence of a transient ischemic attack | 12 weeks | 
| Thromboembolic Events: Number of Participants With Systemic Thromboembolism | Occurence of a systemic thromboembolism | 12 weeks | 
| Thromboembolic Events: Number of Participants With Myocardial Infarction | Occurence of a myocardial infarction | 12 weeks | 
| Thromboembolic Events: Number of Participants With Other Major Cardiac Events | Occurence of other major adverse cardiac events | 12 weeks | 
| Thromboembolic Events: Number of Participants Who Died | Occurence of death by all causes | 12 weeks | 
| D-dimer: Difference From Baseline | Difference in D-dimer from baseline to last available value | baseline and 12 weeks | 
| Soluble Fibrin: Difference From Baseline | Difference from baseline to visit 7 | baseline and 12 weeks | 
| 11-dehydrothromboxane B2 (TXB2): Difference From Baseline | Difference from baseline to visit 7 | baseline and 12 weeks | 
| Ecarin Clotting Time (ECT): Difference From Baseline |  | baseline and 12 weeks | 
| Activated Partial Thromboplastin Time (aPTT): Difference From Baseline |  | baseline and 12 weeks | 
| Trough Plasma Concentration of Dabigatran (BIBR 953) | The values of the trough plasma concentration of dabigatran (BIBR 953) are the by-patient geometric means of week 1, 4 and 12. | 12 weeks | 
| Number of Participants With Increase of Aspartat-Aminotransferase (AST) to >2*Baseline | Increase of AST to more than two times the baseline value | 12 weeks | 
| Number of Participants With Increase of Alkaline Phosphatase (AP) to >2*Baseline | Increase of AP to more than two times the baseline value | 12 weeks | 
| Number of Participants With Increase of Bilirubin to >2*Baseline | Increase of Bilirubin to more than two times the baseline value | 12 weeks | 
| Number of Participants With Increase of Alanine-Aminotransferase (ALT) to >2*Baseline | Number of Participants with Increase of ALT to more than two times the baseline value | 12 weeks | 
| Severity of Adverse Events | Total number of patients with any adverse event of worst intensity 'mild', 'moderate' and 'severe'. | 12 weeks |