Dabigatran Etexilate for Secondary Stroke Prevention in Patients With Embolic Stroke of Undetermined Source (RE-SPECT ESUS)

Study Overview
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Brief Summary
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This trial will enroll approximately 6,000 patients with recent embolic stroke of unknown source (ESUS). Patients will be randomized to dabigatran or acetylsalicyclic acid (ASA) (1:1 ratio) and have visits every three months. The study doctor may prescribe blinded concomitant ASA for pts with coronary artery disease but this is not mandatory. All Adverse Events (AEs), Serious Adverse Events (SAEs), outcome events will be recorded. The trial will conclude when the required number of stroke events are positively adjudicated which is estimated to take 3 years (including 2.5 years of enrollment).

Official Title
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Randomized, Double-blind, Evaluation in Secondary Stroke Prevention Comparing the EfficaCy and Safety of the Oral Thrombin Inhibitor Dabigatran Etexilate (110 mg or 150 mg, Oral b.i.d.) Versus Acetylsalicylic Acid (100 mg Oral q.d.) in Patients With Embolic Stroke of Undetermined Source (RESPECT ESUS)

Conditions
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Stroke, Secondary Prevention

Intervention / Treatment
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* Drug: optional ASA as comedication
* Drug: placebo to ASA
* Drug: placebo to optional ASA as comedication
* Drug: placebo to dabigatran etexilate
* Drug: ASA 100 mg
* Drug: dabigatran etexilate


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Ischemic stroke with a brain lesion visualized by neuroimaging (either brain Computed Tomography (CT) or Magnetic Resonance Image (MRI)). The visualized stroke is a non-lacunar infarct , e.g. involving the cortex or >1.5 cm (>2.0 cm if measured on MRI diffusion-weighted images) in largest diameter if exclusively subcortical.Visualization by CT usually requires delayed imaging >24-48 hours after stroke onset. The index stroke must have occurred either up to 3 months before randomization (Modified Rankin Scale(mRS) <=3 at randomization) or up to 6 months before randomization (mRS <=3 at randomization) in selected patients that are >= 60 years plus at least one additional risk factor for recurrent stroke. Arterial imaging or cervical plus Transcranial Doppler (TCD) ultrasonography does not show extra-cranial or intracranial atherosclerosis with >= 50% luminal stenosis in artery supplying the area of acute ischemia. As evidenced by cardiac monitoring for >= 20 hours with automated rhythm detection, there is absence of AF > 6 minutes in duration (within a 20 hour period, either as single episode or cumulative time of multiple episodes). Further inclusion criteria apply. Exclusion criteria: Modified Rankin Scale of >=4 at time of randomization or inability to swallow medications. Major risk cardioembolic source of embolism such as: a) intracardiac thrombus as evidenced by transthoracic or transesophageal echocardiography, b) paroxysmal, persistent or permanent Atrial fibrillation (AF), c) atrial flutter, d) prosthetic cardiac valve (mitral or aortic, bioprosthetic or mechanical), e) atrial myxoma, f) other cardiac tumors, g) moderate or severe mitral stenosis, h) recent (< 4weeks) myocardial infarction, i) valvular vegetations, or j) infective endocarditis. Any indication that requires treatment with an anticoagulant as per Investigator's judgment. History of atrial fibrillation (unless it was due to reversible causes such as hyperthyroidism or binge drinking, and has been permanently resolved). Other specific stroke etiology (i.e. cerebral arteritis or arterial dissection, migraine with aura/vasospasm, drug abuse). Renal impairment with estimated creatinine clearance (as calculated by Cockcroft-Gault equation) <30mL/min at screening, or where Investigator expects creatinine clearance is likely to drop below 30mL/min during the course of the study. Further exclusion criteria apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 150 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: Single Group Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: dabigatran etexilate 110 or 150 mg<br>Patients will be assigned Dabigatran 150 mg b.i.d. (unless they are 75 years or older, or have a Creatinine Clearance (CrCl) of greater than or equal to 30 to less than 50ml/min (or experience GI bleed during trial), in which case they will receive Dabigatran 110 mg b.i.d.). All patients in this arm will also receive ASA placebo (q.d.) | Drug: optional ASA as comedication<br>* optional concomitant treatment which can be used for patients with coronary artery disease. It is not required for these pts.<br>Drug: placebo to ASA<br>* placebo to comparator drug<br>Drug: dabigatran etexilate<br>* active drug<br>|
| Active Comparator: ASA 100 mg<br>All patients will receive blinded ASA 100 mg q.d. and dabigatran placebo 150 mg b.i.d. (unless they are 75 years or older, or have a CrCl of greater than or equal to 30 to less than 50ml/min (or experience GI bleed during trial), in which case they will receive placebo Dabigatran 110 mg b.i.d | Drug: placebo to optional ASA as comedication<br>* optional concomitant treatment which can be used for patients with coronary artery disease. It is not required for these pts.<br>Drug: placebo to dabigatran etexilate<br>* placebo<br>Drug: ASA 100 mg<br>* active comparator drug<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adjudicated Recurrent Stroke | Adjudicated recurrent stroke (ischemic, hemorrhagic, or unspecified) is presented. The annualised event rate represents the average number of events per patient during a 1-year period. | From randomisation until full follow up period, approximately 43 months. | 
| First Major Bleed (Adjudicated) | First major bleed is primary safety endpoint. Major bleeds were defined according to the International Society of Thrombosis and Haemostasis (ISTH) definition as follows: Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome and/or, Bleeding (which should be overt) associated with a reduction in haemoglobin of at least 2 grams/ decilitre (g/dL) (1.24 millimoles Per Litre (mmol/L)), or leading to transfusion of ≥2 units of blood or packed cells (equivalent to ≥4.5 units in Japan); the haemoglobin drop should be considered to be due to and temporally related to the bleeding event and/or, Fatal bleed. The annualised event rate represents the average number of events per patient during a 1-year period. | Between the first trial medication intake up to 6 days after the last trial medication intake, approximately 42 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adjudicated Ischaemic Stroke | Adjudicated ischaemic stroke is a key secondary endpoint. The annualised event rate represents the average number of events per patient during a 1-year period. | From randomisation until full follow up period, up to 43 months | 
| Adjudicated Composite of Non-fatal Stroke, Non-fatal Myocardial Infarction, or Cardiovascular Death | Adjudicated composite of non-fatal stroke, non-fatal myocardial infarction (MI), or cardiovascular death is a key secondary endpoint. The annualised event rate represents the average number of events per patient during a 1-year period. | From randomisation until full follow up period, up to 43 months | 
| Disabling Stroke | Disabling stroke (modified Rankin Scale greater than or equal to 4, as determined 3 months after recurrent stroke) is presented. The annualised event rate represents the average number of events per patient during a 1-year period. | From randomisation until full follow up period, up to 43 months | 
| All-cause Death | All-cause death is presented. The annualised event rate represents the average number of events per patient during a 1-year period. | From randomisation until full follow up period, up to 43 months | 
| Adjudicated Intracranial Hemorrhage | Adjudicated intracranial haemorrhage comprised the subtypes of intracerebral bleeds, intraventricular bleeds, subdural bleeds, epidural bleeds, and subarachnoid bleeds. Microbleeds did not qualify as intracranial haemorrhage, except when they were symptomatic. The annualised event rate represents the average number of events per patient during a 1-year period. | Between the first trial medication intake up to 6 days after the last trial medication intake, approximately 42 months. | 
| Adjudicated Fatal Bleed | Adjudicated fatal bleeding was defined as a bleeding event which the Independent Event Adjudication Committee (IAC) determined as the primary cause of death or contributed directly to death. The annualised event rate represents the average number of events per patient during a 1-year period. Because there were 0 events in one treatment group, the hazard ratio is unable to be calculated. | Between the first trial medication intake up to 6 days after the last trial medication intake, approximately 42 months. | 
| Adjudicated Life-threatening Bleed | Major bleeds were to be classified as life-threatening if they met one or more of the following criteria: fatal bleed, symptomatic intracranial bleed, reduction in haemoglobin of at least 5 grams/ deciliter (g/dL), transfusion of at least 4 units of packed red blood cells (equivalent to 9 units in Japan), associated with hypotension requiring the use of intravenous inotropic agents, or necessitated surgical intervention. The annualised event rate represents the average number of events per patient during a 1-year period. | Between the first trial medication intake up to 6 days after the last trial medication intake, approximately 42 months. | 
| Any Bleed (Investigator-reported) | This was the sum of all major and minor bleeds (Minor bleeds were clinical bleeds that did not fulfil the criteria for major bleeds), regardless of severity. The annualised event rate represents the average number of events per patient during a 1-year period. | Between the first trial medication intake up to 6 days after the last trial medication intake, approximately 42 months. |