Conditions: Stroke Secondary Prevention
Allocation: RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 5390
Healthy volunteers: no

Brief summary:
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).

Detailed description:

Arms:
arm 1: 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.) arm 2: 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

Interventions: intervention 1: optional ASA as comedication intervention 2: placebo to ASA intervention 3: placebo to optional ASA as comedication intervention 4: placebo to dabigatran etexilate intervention 5: ASA 100 mg intervention 6: dabigatran etexilate
Intervention descriptions: intervention 1: optional concomitant treatment which can be used for patients with coronary artery disease. It is not required for these pts. intervention 2: placebo to comparator drug intervention 3: optional concomitant treatment which can be used for patients with coronary artery disease. It is not required for these pts. intervention 4: placebo intervention 5: active comparator drug intervention 6: active drug

Protocol document:
Prot_001.pdf: 
Clinical Trial Protocol
Doc. No.: c02244185-04
EudraCT No.:
BI Trial No.:            
2013-003444-24
1160.189
BI Investigational
Product:
Pradaxa®, Dabigatran etexilate
Title:
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)
Clinical Phase:
III
Trial Clinical 
Monitor:
Phone: 
     Fax: 
Coordinating 
Investigator:
Phone 
     Fax 
Status:
Final Protocol (Revised Protocol (based on global Amendment 1 and 2)
Version and Date:
3.0
Date: 21 Apr 2016
Page 1 of 158
Proprietary confidential information. 
2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
TITLE PAGE


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Trial Protocol
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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Pradaxa
Name of active ingredient: Dabigatran
Protocol date:
Trial number:
Revision date:
21 Apr 2016
27JUN2014
1160.189
Title of trial:
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)
Co-ordinating 
Investigator:
Phone 
     Fax 
Trial site(s):
Multi-center trial
Clinical phase:
III
Objective(s):
To demonstrate that the efficacy of dabigatran etexilate (110 mg b.i.d. or 150 mg b.i.d., 
with dosing according to age and renal function), is superior to ASA (100 mg once 
daily) for the prevention of stroke recurrence in patients with embolic stroke of 
undetermined source. The trial will also characterize the safety of dabigatran etexilate in 
this setting.
Methodology:
This is a double-blind, randomized, active comparator, event driven phase III superiority 
trial. Patients with ischemic ESUS within the last 3 months will be included (if aged ≥ 
60 years with additional risk factor, patients with ESUS within the last 6 months can be 
included). It is designed to evaluate recurrent strokes (ischemic, hemorrhagic, or 
unspecified) with dabigatran etexilate versus the comparator acetylsalicylic acid 
(aspirin) (ASA), 100 mg quaque die (once a day) (q.d.).
No. of patients: 
total entered:
Approx. 6000*
each treatment:
Approx.  3000* dabigatran etexilate
Approx.  3000* acetylsalicylic acid
* These are approximations, as this is an event driven trial requiring 353 primary 
outcome events (OEs) to be reported to be sufficiently powered.  The actual number of 
patients entered may increase or decrease based upon actual event rate. Sites will be 
notified when recruitment ends.  
Diagnosis :
Recent (< 3 months; up to 6 months in selected patients) ESUS


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BI Trial No.: 1160.189
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Trial Protocol
Page 3 of 158
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Pradaxa
Name of active ingredient: Dabigatran
Protocol date:
Trial number:
Revision date:
21 Apr 2016
27JUN2014
1160.189
Main criteria
for inclusion:
Patients aged 18 years after ESUS within the last three months (six months, if aged ≥ 
60 years with additional risk factor) prior to randomization who are eligible for 
treatment with antithrombotic therapy (i.e. dabigatran etexilate / ASA).
ESUS, defined as follows:
▪  Non-lacunar ischemic stroke detected by Computed Tomography (CT) or Magnetic  
    Resonance Image (MRI)
▪   Absence of extracranial/intracranial atherosclerosis causing ≥50% luminal stenosis
    in artery supplying the area of recent brain ischemia.
▪   No major-risk cardioembolic source of embolism
▪   No other specific cause of stroke identified (e.g. cerebral arteritis, arterial dissection, 
    migraine with aura/vasospasm, drug abuse)
Test product(s):
Dabigatran etexilate (DE)
doses:
110 mg and 150 mg twice daily (b.i.d.)
mode of admin.:
Oral
Comparator products: Acetylsalicylic acid (Aspirin)
dose:
100 mg once daily (q.d.)
mode of admin.:
Oral
Duration of treatment: Expected minimum: 6 months
Expected maximum: 3 years 
This event driven trial may conclude earlier, once adequate number of events are 
reported, or later; if more events are needed.  


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Trial Protocol
Page 4 of 158
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Pradaxa
Name of active ingredient: Dabigatran
Protocol date:
Trial number:
Revision date:
21 Apr 2016
27JUN2014
1160.189
Criteria for efficacy:
Primary efficacy endpoint (adjudicated):
• Time to first recurrent stroke (ischemic, hemorrhagic, or unspecified)
Secondary efficacy endpoints (time to event)
Key secondary efficacy endpoints
• Ischemic Stroke
• Composite endpoint of nonfatal stroke, nonfatal myocardial infarction (MI) and 
cardiovascular death
Other Secondary efficacy endpoint (time to event): 
• Disabling stroke (modified Rankin Scale ≥4, as determined 3 months after recurrent
stroke)
• All-cause death
 
 
 


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Trial Protocol
Page 5 of 158
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Pradaxa
Name of active ingredient: Dabigatran
Protocol date:
Trial number:
Revision date:
21 Apr 2016
27JUN2014
1160.189
Criteria for safety:
Main safety endpoint:
• Time to first major bleed
Other safety endpoints (time to event):
• Intracranial hemorrhage
• Life-threatening bleed
• Fatal bleed
• Any bleed
Statistical methods:
The Cox proportional hazards regression model will be used to analyze time-to-event 
endpoints.


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FLOW CHART
Investigations/Tests and 
Procedures
SCREENING RANDOMIZATION
TREATMENT PERIOD4
FOLLOW UP 
PERIOD
Visit Number
1
2
3
4
5
6
72
8
92
10
112
12
132 EOT
3
FINAL 
VISIT
3, 5
PHONE
CALL6
Months since
Randomization
3
6
9
12
15
18
21
24
27
30
33
Time Window (days) 4
Up to 
-14 days
01
+/-
14
+/-
14
+/-
14
+/-
14
+/-
14
+/-
14
+/-
14
+/-
14
+/-
14
+/-
14
+/-
14
+/- 14
+/- 14
Informed Consent
X
Check Eligibility
X
X
Medical History
X
Demographics
X
Confirm Inclusion/Exclusion 
X
Randomization via IRT
X
Physical Exam 
X
X
Vital Signs (BP, sitting heart 
rate)7
X
X
X
X
X
X
X
X
X
X
X
ECG8
X
(X)
(X)
X
(X)
X
(X)
X
(X)
(X)
Documentation of Cardiac 
Monitoring8
X
(X)
(X)
(X)
(X) (X)
(X)
(X)
(X)
(X)
(X)
Pregnancy Test9 for WOCBP
X
X
X
X
X
X
X
X
X
X
X
Safety Laboratory Tests10
X
(X)10
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
Height
X
 
 
 


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Page 7 of 158
Investigations/Tests and 
Procedures
SCREENING RANDOMIZATION
TREATMENT PERIOD4
FOLLOW UP 
PERIOD
Visit Number
1
2
3
4
5
6
72
8
92
10
112
12
132 EOT
3
FINAL 
VISIT
3, 5
PHONE
CALL6
Months since
Randomization
3
6
9
12
15
18
21
24
27
30
33
Time Window (days) 4
Up to 
-14 days
01
+/-
14
+/-
14
+/-
14
+/-
14
+/-
14
+/-
14
+/-
14
+/-
14
+/-
14
+/-
14
+/-
14
+/- 14
+/- 14
 
NIHSS17
X
Stop Restricted Meds18
X
Brain re-imaging in select 
patients19
(X)19
(X)19 
Dispense Study Meds
X
X
X
X
X
X
X
X
Study Med Compliance 
Check
X
X
X
X
X
X
X
X
Concomitant Therapy20
X
X
X
X
X
X
X
X
X
X
X
X
Study Med. Termination
X3
Record OEs21
SAEs, bleeds, AEs 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
 
 
Transition to SOC per PI’s   
discretion
X
Remind  patients of plan to  
collect Vital Status  
(regardless of status of study 
drug administration)
X


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1.
It is preferred randomization to occur as soon as possible after confirming eligibility.  Informed consent will be signed any time before screening procedures.  Randomization 
must occur within 3 months of index stroke event. In patients ≥ 60 years plus additional risk factor (see inclusion criteria Section 3.3.2) the time window is 6 months after 
index stroke event.
2.
Visits 7, 9, 11, 13 can be conducted via phone to assess OEs and AEs.
3.
Patients who discontinue study treatment early should complete EOT assessments and continue to attend regularly scheduled visits.   Refer to Section 3.3.4.1 for details on 
management of patients that wish to reduce study participation for any reason.  Collection of vital status, adverse events and endpoints for all patients at the end of the trial is 
important and described in Section 6.2.3.  For patients that continue on treatment until the end of the trial, EOT and Final Visit assessments can be done at the same visit.
4.
Follow-up visits should be scheduled every three months within the specified visit window (+/- 14 days) where feasible.
5.
Final Visit will take place at the conclusion of the trial.  This event-driven trial is expected to take place over 3 years, however, the trial can conclude earlier, if adequate 
number of events are reported sooner.  It can conclude later (or enroll additional patients) if more time is needed to observe the minimum number of required events. If it 
continues beyond 3 years, follow-up visits will occur every 3 months (with alternating phone and office visits with same assessments as for example in visits 9 and 10).  At 
the time of trial conclusion (when adequate number of events were reported), all patients would be notified of study conclusion and have a final study visit scheduled instead 
of their next scheduled follow-up visit (with assessments as outlined in the Final Visit).   
6.
A follow-up phone call will be conducted one month after the EOT visit (for patients with premature study medication discontinuation) or one month after the Final Visit (for 
patients without premature study medication discontinuation).  
7.
Recording of vital signs will include blood pressure (BP) and sitting heart rate with palpation of the pulse for 1 minute.  Also, the subject should be queried about new 
palpitations that would warrant additional cardiac rhythm monitoring at the discretion of the investigator.  An Electrocardiogram (12-lead ECG) is required at follow-up visits 
per instructions in footnote 8.
8.
A 12-lead ECG should be performed at Visits 1, 6, 10 and at the EOT visit and will be documented in the Electronic Case Report Form (eCRF). It will be documented, 
whether the patient carries an implantable cardiac monitor for continuous cardiac monitoring. A subsequent ECG should also be done, if palpation of the pulse (for one 
minute) in subsequent visits indicates irregular rhythm or symptoms of irregular pulse have been reported. If any ECGs are performed during the course of the trial as part of 
patient normal care and demonstrate a clinically relevant change from Visit 1 or a newly developed pathology, this should be documented in the Electronic Case Report Form 
(eCRF) and the ECG will be provided to the Sponsor`s designee. Additional cardiac monitoring (e.g. Holter-ECGs) may be performed at the discretion of the Investigator 
according to local standard of care. Where this is done, the results of these cardiac monitoring efforts will be documented in the eCRF.
9.
Women of child-bearing potential (WOCBP) who are not sterilized should have a urine pregnancy test at screening, at each clinic visit and at least 7 days after the EOT (urine 
dipstick result to be reported back at final phone visit). Pregnancy testing is one indicator of pregnancy. Changes in a patients’ menstrual cycle that may indicate pregnancy 
must also be considered and a further pregnancy test can be taken if the Investigator feels it to be appropriate.
10. Standard safety lab panel to be analyzed by central lab (hematology and chemistry, including renal function and liver function tests (LFTs) will be collected).  Lab testing is 
specified in Section 5.2.3.    Local labs (within 14 days prior to randomisation) can be used to verify eligibility (in addition to collection of central labs) where it is necessary 
to avoid delaying the initiation of study drug. Refer to Section 5.2.3 for calculation of Creatinine Clearance (CrCl) and Section 4.1.3 for information about dose changes 
based upon CrCl value. Central labs must also be collected from all patients to provide a baseline for the study. This should preferably occur at Visit 1, however, it can 
alternatively be collected at Visit 2 prior to first study drug intake.  Follow-up safety labs do not need to be drawn on the actual day of the visit.  They may be drawn earlier as 
long as it is within the visit time window.
 
 
 
 
 


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17. National Institutes of Health Stroke Scale (NIHSS) is a tool used to evaluate impairment after a stroke outlined in Section 5.3.2.  This neurological assessment is to be 
completed for qualifying stroke only. NIHSS is not required after recurrent stroke.
18. Restricted medications are listed in Section 4.2.2.
19. Recommendations on timing of starting study medication after index stroke and recurrent stroke are provided in Table 4.1.4:1.  Patients with mRS of 1,2 or 3 AND initiating 
study medication within 10 days of index event require repeat imaging of the brain to rule out bleeding into the brain (per Exclusion #6).  For index strokes, this repeat 
imaging must occur prior to randomization. This repeat imaging done specifically to initiate study drug is required per protocol in select patients.  Conversely, brain imaging 
for initial evaluation of index and recurrent strokes should occur according to local clinical practice (i.e. not done specifically for this trial).
20. Concomitant medication will include medications of interest taken during the 30 days prior to randomization plus those given as treatment for index stroke.
21. For endpoint events which require adjudication as per Section 3.1.1.4., copies of relevant source documentation (e.g. imaging reports) should be collected and submitted. 
 


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................6
TABLE OF CONTENTS ......................................................................................................10
ABBREVIATIONS................................................................................................................14
1.
INTRODUCTION...............................................................................................18
1.1
MEDICAL BACKGROUND.............................................................................18
1.2
DRUG PROFILE................................................................................................20
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ....................................................................................................23
2.1
RATIONALE FOR PERFORMING THE TRIAL.........................................23
2.2
TRIAL OBJECTIVES........................................................................................24
2.3
BENEFIT - RISK ASSESSMENT.....................................................................24
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................27
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................27
3.1.1
Administrative structure of the trial .................................................................28
3.1.1.1
Executive Committee..........................................................................................28
3.1.1.2
Steering Committee.............................................................................................29
3.1.1.3
Data Monitoring Committee..............................................................................29
3.1.1.4
Independent Event Adjudication Committee...................................................30
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................30
3.3
SELECTION OF TRIAL POPULATION .......................................................30
3.3.1
Main diagnosis for study entry ..........................................................................31
3.3.2
Inclusion criteria .................................................................................................32
3.3.3
Exclusion criteria ................................................................................................33
3.3.4
Removal of patients from therapy or assessment ...........................................37
3.3.4.1
Removal of individual patients ..........................................................................37
3.3.4.2
Discontinuation of the trial by the Sponsor......................................................38
4.
TREATMENTS...................................................................................................40
4.1
TREATMENTS TO BE ADMINISTERED.....................................................40
4.1.1
Identity of BI investigational product and comparator product(s)................40
4.1.2
Method of assigning patients to treatment groups...........................................42
4.1.3
Selection of doses in the trial..............................................................................43
4.1.4
Drug assignment and administration of doses for each patient......................44
4.1.5
Blinding and procedures for unblinding...........................................................47
4.1.5.1
Blinding
.................................................................................................47
4.1.5.2
Procedures for emergency unblinding..............................................................48
4.1.6
Packaging, labeling, and re-supply....................................................................48


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4.1.7
Storage conditions...............................................................................................49
4.1.8
Drug accountability.............................................................................................49
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT.....................................................................................................51
4.2.1
Rescue medication, emergency procedures, and additional treatment..........51
4.2.2
Restrictions ..........................................................................................................60
4.2.2.1
Restrictions regarding concomitant treatment ................................................60
4.2.2.2
Restrictions on diet and life style.......................................................................63
4.3
TREATMENT COMPLIANCE........................................................................63
5.
VARIABLES AND THEIR ASSESSMENT ....................................................64
5.1
EFFICACY..........................................................................................................64
5.1.1
Endpoints of efficacy...........................................................................................64
5.1.2
Assessment of efficacy.........................................................................................65
5.1.2.1
Recurrent stroke .................................................................................................65
5.1.2.2
Systemic embolism..............................................................................................66
5.1.2.3
Death
.................................................................................................66
5.1.2.6
Venous Thromboembolism ................................................................................69
 
5.1.2.8 
Cardiovascular hospitalization..........................................................................70
5.2
SAFETY...............................................................................................................70
5.2.1 
Endpoint(s) of safety...........................................................................................70
5.2.2
Assessment of safety............................................................................................71
5.2.2.1
Assessment of bleeding events............................................................................71
5.2.2.2
Definition of adverse events ...............................................................................73
5.2.2.3
Adverse event and SAE reporting.....................................................................75
5.2.3
Assessment of safety laboratory parameters....................................................76
5.2.4
Electrocardiogram ..............................................................................................78
5.2.5
Assessment of other safety parameters .............................................................79
5.2.5.1 
Full Physical Examination..................................................................................79
5.2.5.2
Vital Signs
.................................................................................................79
5.4
APPROPRIATENESS OF MEASUREMENTS..............................................81
 


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6.
INVESTIGATIONAL PLAN.............................................................................85
6.1
VISIT SCHEDULE.............................................................................................85
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................85
6.2.1
Screening and run-in periods.............................................................................85
6.2.2
Treatment periods...............................................................................................86
6.2.2.1
Interim Telephone Calls.....................................................................................88
6.2.3
End of trial and follow-up period......................................................................88
6.2.3.1
End of Treatment Visit.......................................................................................88
6.2.3.2
Final Visit
.................................................................................................89
6.2.3.3
Post Treatment Phone Call ................................................................................89
6.2.3.4
Vital Status and Event Collection......................................................................89
6.2.3.5
Withdrawal of consent........................................................................................89
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE....................................................................................................91
7.1
STATISTICAL DESIGN - MODEL.................................................................91
7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................91
7.3
PLANNED ANALYSES.....................................................................................91
7.3.1
Primary analyses.................................................................................................92
7.3.2
Secondary analyses .............................................................................................92
7.3.3
Safety analyses.....................................................................................................93
7.3.4
Interim analyses ..................................................................................................94
7.4
HANDLING OF MISSING DATA ...................................................................94
7.5
RANDOMISATION ...........................................................................................95
7.6
DETERMINATION OF SAMPLE SIZE .........................................................95


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8. 
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS...........................................................................................................98
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ...........................................................................................................98
8.2
DATA QUALITY ASSURANCE ......................................................................99
8.3
RECORDS.........................................................................................................100
8.3.1
Source documents .............................................................................................100
8.3.2
Direct access to source data and documents...................................................101
8.3.3
Storage of records .............................................................................................101
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
............................................................................................................................101
8.4.1
Listedness...........................................................................................................101
8.4.2
Expedited reporting to health authorities and IECs/IRBs............................102
8.5
STATEMENT OF CONFIDENTIALITY......................................................102
8.6
COMPLETION OF TRIAL.............................................................................102
8.7
PROTOCOL VIOLATIONS ...........................................................................102
8.8
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT 
OF TRIAL RELATED INJURY.....................................................................102
9.
REFERENCES..................................................................................................103
9.1
PUBLISHED REFERENCES..........................................................................103
9.2
UNPUBLISHED REFERENCES....................................................................109
10.
APPENDICES...................................................................................................111
10.1
CHA2DS2-VASC SCORE.................................................................................112
10.2  
STUDY DRUG START, THROMBOSIS PROPHYLAXIS AND 
TRANSITION TO NON-STUDY MEDICATION........................................114
10.2.1
When to start study drug following treatment with parenteral 
anticoagulants, Vitamin K antagonists, or antiplatelets................................114
10.2.2
Thrombosis prophylaxis or temporary requirement for parenteral 
anticoagulant or antiplatelet(s)........................................................................114
10.2.3
Transition to non-study antithrombotic treatment with early study 
drug discontinuation or at the end of the trial ...............................................115
10.4
HANDLING OF OUTCOME EVENTS (BLEEDS AND 
MORTALITY/MORBIDITY EVENTS)........................................................121
10.5
NATIONAL INSTITUTE OF HEALTH STROKE SCALE........................122
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .......................................125
GLOBAL AMENDMENT 1 ...............................................................................................125
GLOBAL AMENDMENT 2 ...............................................................................................156


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ABBREVIATIONS
ACCP
ACT
APCC
ACS
AE
AF
AHA
ALT (SGPT)
ANCOVA
AP
aPTT
ASA
ASS
AST (SGOT)
American College of Chest Physicians 
Activated Clotting Time
Activated prothrombin complex concentrates
Acute Coronary Syndrome
Adverse Event
Atrial fibrillation
American Heart Association
Alanine aminotransferase
Analysis of covariance
Alkaline Phosphatase
Activated Partial Thromboplastin Time
Acetylsalicylic acid (Aspirin)
Acetylsalicylsäure (German brand name for ASA)
Aspartate transaminase
AUC
b.i.d.
BI
BMI
BP
BRPM
CA
Area under the Curve
Twice daily
Boehringer Ingelheim
Body Mass Index
Blood Pressure
Blinded Report Planning Meeting
Competent Authority
CABG
CAD
CI
CK
CKD-EPI
CK-MB
Coronary Artery Bypass Grafting
Coronary Artery Disease
Confidence Interval
Creatine kinase
Chronic Kidney Disease Epidemiology Collaboration
Creatine kinase myoglobin
CML
CoI
Local Clinical Monitor 
Coordinating Investigator
CRA
CrCl
Clinical Research Associate
Creatinine Clearance
CRNMBE
CT
Clinically Relevant Non Major Bleeding Event
Computed Tomography
cTn
CTP
Cardiac Troponin
Clinical Trial Protocol
CTR
CUS
CV
DBP
DE
Clinical Trial Report
Compression Ultrasound
Cardiovascular
Diastolic Blood Pressure
Dabigatran etexilate
DMC
dTT
DVT
Data Monitoring Committee
Diluted thrombin time
Deep vein thrombosis
eCRF
Electronic Case Report Form


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EC
ECG
ECT
Ethics Committee
Electrocardiogram
Ecarin clotting time
EDC
EDTA
EOT
ESUS
Electronic Data Capture
Ethylenediaminetetraacetic acid
End of Treatment
Embolic stroke of undetermined source
EU
EudraCT
European Union
European Clinical Trials Database
FDA
FEIBA
Food and Drug Administration
Factor Eight Inhibitor Bypassing Activity
GCP
gCV
GFR
Good Clinical Practice
Geometric coefficient of variation
Glomerular Filtration Rate
gMean
HPMC
HPLC-MS/MS
HR
hscTnI
hsCRP
IAC
Geometric mean
Hydroxyl, propyl-methyl cellulose
High-Performance Liquid Chromatography tandem mass spectrometry
Hazard Ratio
High-sensitivity cardiac troponin I
High-sensitivity C-reactive protein
Independent Adjudication Committee
IB
Investigator’s Brochure
ICH
IEC
INR
IL-6
International Conference on Harmonization
Independent Ethics Committee
International Normalized Ratio
Interleukin 6
IRB
Institutional Review Board
ISF
ISTH
Investigator Site File
International Society of Thrombosis and Hemostasis
i.v.
Intravenous
IRT
Interactive Response Technology
IUDs/IUSs
LBBB
LFTs
LMWH
LPO
LTFU
LVH
MBE
MCP-1
MDRD
Intra Uterine Devices/Systems
Left Bundle Branch Block
Liver Function Tests
Low-molecular Weight Heparin
Last Patient Out
Lost to Follow-Up
Left Ventricular Hypertrophy
Major Bleeding Event
Monocyte chemotactic protein-1
Modification of Diet in Renal Disease
mean
MedDRA
MI
MRI
Arithmetic mean
Medical Dictionary for Regulatory Activities
Myocardial Infarction
Magnetic Resonance Image


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mRS
N
Modified Rankin Scale
Number
NCB
NIHSS
NOAC
NSAIDs
NT-pro-BNP
NYHA
OE
Net Clinical Benefit
National Institutes of Health Stroke Scale
Novel oral anticoagulant
Non-Steroidal Anti-Inflammatory Drugs
N-terminal pro-brain natriuretic peptide
New York Heart Association
Outcome Event
OPU
P-gp
Operative Unit
P-glycoprotein
p.o.
per os (oral)
PAD
PCI
PCR
PD
PE
PFO
PK
PR
PT
Peripheral Artery Disease
Percutaneous Coronary Intervention
Polymerase Chain Reaction
Pharmacodynamic
Pulmonary embolism
Patent foramen ovale
Pharmacokinetic
Pulse Rate
Prothrombin time
q.d.
quaque die (once a day)
REP
Residual Effect Period
RS
Randomized set
SAE
SBP
Serious Adverse Event
Systolic Blood Pressure
s.c.
SC
SD
SE
SPAF
Subcutaneous
Steering Committee
Standard deviation
Systemic Embolism
Stroke prevention in atrial fibrillation
SPC
Summary of Product Characteristics
SUSARs
TCD
TE
TEE
TGF-β1
Suspected Unexpected Serious Adverse Reactions
Transcranial Doppler
Thromboembolism
Transesophageal echocardiogram
Transforming growth factor beta 1
TIA
TMA
TMF
Transient Ischemic Attack
Transcription-mediated amplification
Trial Master File
TOAST
TS
Trial of ORG 10172 in Acute Stroke Treatment
Treated Set
TSAP
TT
TTE
UFH
Trial Statistical Analysis Plan
Thrombin time
Transthoracic echocardiogram
Unfractionated Heparin


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ULN
URL
VKA
VPLS
vs.
VTE
vWF
WARSS
WHO
WOCBP
Upper Limit of Normal
Upper Reference Limit
Vitamin K antagonist
Ventilation/perfusion lung scan
Versus
Venous thromboembolism (i.e. DVT and/or PE)
von Willebrand Factor
Warfarin-Aspirin Recurrent Stroke Study
World Health Organization
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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
About 20-25% of ischemic strokes are not lacunar (i.e. due to small artery disease), are not 
associated with occlusive atherosclerotic stenosis, and do not have a major cardioembolic 
source, such as in atrial fibrillation (AF) (P14-04527). Recent monitoring and imaging studies 
have characterized a substantial number of potential sources of embolism in these patients, 
supporting that most strokes that were formerly called “cryptogenic” can be more usefully 
characterized as Embolic Stroke of Undetermined Source (ESUS) (P14-04527).
Improvements in imaging technologies and a better understanding of the underlying 
pathophysiology of ESUS have resulted in a pragmatic clinical definition. An International 
“ESUS Working Group” has been established consisting of lead neurologists and 
cardiologists in the field. The ESUS working group has defined “ESUS” as a new stroke 
entity (P14-04527). These patients can be reliably and consistently identified using widely-
available diagnostic techniques. The ESUS definition is pragmatic and offers the potential for 
randomized trials of secondary prevention. The ESUS definition has been derived from the 
former definition of “cryptogenic” stroke. However, cryptogenic stroke is a diagnosis by 
exclusion, including cases, where certain diagnostic examinations have not been performed. 
Thus, cryptogenic stroke is rather defined by what it is not, whereas the ESUS concept 
postulates an embolic pathophysiological mechanism for the ischemic stroke, and is thus 
positively defined. Embolic Stroke of Undetermined Source is not considered a diagnosis of 
exclusion, but rather a diagnosis based on a visualized non-lacunar infarct in the absence of 
proximal occlusive atherosclerosis or major-risk cardioembolic source such as AF or 
intracardiac thrombus.
The sources of embolism underlying ESUS include the heart (the left heart valves or 
chambers, or via paradoxical embolism from a venous source), aortic arch, or the large 
cervical and cerebral arteries. Confident identification of the embolic source in individual 
patients is not feasible. Multiple potential embolic sources occur in the same patient with 
sufficient frequency that a causal relationship is unclear; sophisticated diagnostic testing is of 
limited availability and often not illuminating. However, the embolic mechanism implies a 
common potential treatment strategy (i.e. anticoagulation), making precise characterization of 
the embolic source of uncertain clinical value.
Underlying Causes of ESUS
There seems to be no single, dominant cause of ESUS. In studies in which patients with 
cryptogenic ischemic stroke undergo prolonged cardiac rhythm monitoring for silent AF, 
paroxysmal AF is detected in 10% - 20% (R11-4017, R13-4009, R13-4062). Cardiac rhythm 
abnormalities other than AF, which can lead to formation of atrial thrombi and embolic 
stroke, include for example atrial asystole and paroxysmal atrial tachycardia. Additional other 
cardioembolic sources such as moderate left ventricular systolic dysfunction/heart failure, left 
ventricular diastolic dysfunction promoting atrial stasis, remote MI with left ventricular 
regional wall motion abnormalities, myxomatous mitral valves with prolapse, mitral annular 
calcification, and calcific aortic stenosis are likely to contribute to ESUS in some patients


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(P92-68903).  Patent foramen ovale (PFO) can cause ESUS via paradoxical embolism of 
thrombi originating in the venous system entering the arterial system through an inter-atrial 
defect; case-control studies consistently show a higher frequency of PFO in patients with
cryptogenic stroke (R13-4063). Another important cause of ESUS is atherosclerosis of the 
aortic arch serving as a source of arteriogenic embolism (R13-4059, R13-4058). There is a 
persuasive relationship between nonstenotic ulcerated plaques of the carotid artery and distal 
brain ischemia mediated through embolism (R13-4064).
Characterization and Description ESUS
Investigations to establish the diagnosis of ESUS must be sufficient to exclude major-risk 
cardioembolic sources, proximal occlusive atherosclerosis of intra and extra-cranial great 
arteries, and cerebral small artery disease causing lacunar strokes (for diagnostic criteria see 
Table 1.1: 1). 
Evaluation must also be sufficient to exclude recognized major-risk cardioembolic sources 
such as AF and left ventricular thrombus that would warrant anticoagulation (P14-04527).  
Table 1.1: 1 Criteria for diagnosis of ESUS (all must be fulfilled)1
1.  Stroke detected by CT or MRI that is not lacunar2  
2.  Absence of extracranial or intracranial atherosclerosis causing ≥ 50% luminal stenosis
  in artery supplying the area of recent brain ischemia.
3. No major-risk cardioembolic source of embolism.3
4. No other specific cause of stroke identified (e.g. autoimmune arteritis, arterial
   dissection, migraine with aura, vasospasm, drug abuse).
                                                          
1 Requires completion of minimum diagnostic evaluation (see Table 3.3.1: 1) 
2 Lacunar is defined in Section 3.3.3 exclusion criterion No. 21
3 Paroxysmal, persistent or permanent AF (please see inclusion criterion 4 for guidance on the detection of AF), atrial flutter, intracardiac 
thrombus, prosthetic cardiac valve (mitral or aortic, bioprosthetic or mechanical), atrial myxoma or other cardiac tumors, moderate or severe 
mitral stenosis, recent (<4weeks) MI, valvular vegetations, or infective endocarditis.


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Prevalence
An estimated 300,000 patients have an incident of ESUS annually in North America and 
Europe (P12-14353, R06-2203). Among them, the stroke recurrence rate is substantial. 
Approximately 3-4% per year occur despite antiplatelet treatment which is the standard 
guideline-recommended therapy for secondary stroke prevention for patients with 
cryptogenic stroke (P14-04527, P11-00444). 
Current guideline recommendations on antithrombotic treatment for secondary stroke 
prevention.
The routine use of anticoagulants (such as warfarin) in clinical practice is not established for
cryptogenic stroke nor in patients with ESUS.  The 2008 American College of Chest 
Physicians (ACCP) guideline and 2008 American Heart Association (AHA) guideline 
specifically recommend antiplatelet therapy for patients with cryptogenic ischemic stroke
(P08-06684, P08-09258). The European Stroke Organization guideline, the 2011 and 2014 
AHA/American Stroke Association revised guidelines, the 2012 ACCP guideline and the 
2010 Canadian Best Practice Recommendations for Stroke Care do not comment specifically 
on cryptogenic stroke, but recommend antiplatelet therapy for secondary stroke prevention in 
patients with non-cardioembolic ischemic stroke (P13-11327, P08-08481, P11-00444, P14-
07233). As acetylsalicylic acid (ASA) monotherapy is currently recommended by 
international guidelines for acute treatment of ischemic stroke and TIA and secondary 
prevention of recurrent stroke, most ESUS patients will have been treated with ASA during 
the interval between qualifying stroke and randomization. A once daily dosage of 100 mg of 
ASA is included in all guidelines and is acceptable to most clinicians around the world.
There is clear evidence of the superiority of warfarin anticoagulation over acetylsalicylic acid 
for stroke prevention in AF (P07-07953). The novel oral anticoagulant (NOAC) dabigatran 
etexilate (DE) has been demonstrated to be effective against cardioembolic stroke related to 
AF with significantly reduced risk of intracranial hemorrhage compared to warfarin. Thus, it 
is hypothesized that DE may be a safe and effective therapy for secondary prevention of 
stroke in patients with ESUS (see Section 2.3 for Benefit-Risk Assessment).
Patients are at highest risk of recurrent stroke in the first days after index stroke as 
demonstrated by the CHANCE trial (R15-2975).  The RE-SPECT ESUS study will assess the 
effectiveness and safety of DE versus ASA with study medication started early during this 
high risk period.  Providing cerebral hemorrhage is ruled out, study drug can be started as 
early as one day after index stroke. For details on recommended earliest study drug start 
according to stroke severity, refer to Table 4.1.4:1.
1.2
DRUG PROFILE
Dabigatran etexilate is the orally bioavailable prodrug of dabigatran, a novel, synthetic, direct 
thrombin inhibitor. Following oral administration DE is rapidly converted to the active 
moiety dabigatran, which is a potent, competitive, and reversible inhibitor of thrombin.


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In vivo and ex vivo animal studies have demonstrated antiaggregatory efficacy and 
anticoagulant activity of dabigatran after both intravenous (i.v.) administration and oral 
administration in various animal models of arterial and venous thrombosis. 
Dabigatran etexilate was well tolerated in more than 40 Phase I studies to date at all doses 
evaluated (up to 400 mg three times a day) with no evidence of major bleeding. These studies 
have established the PK, pharmacodynamics (PD) and tolerability of dabigatran, including 
selected populations (Japanese, elderly, those with renal and hepatic impairment) and its 
potential for food-drug and drug-drug interactions and QT prolongation. 
The PK profile is characterized by peak plasma concentrations of dabigatran that occur 
approximately two hours after oral administration of the prodrug and half-life depending on 
renal function (see Table 4.2.1: 1 and U98-3208 for prolongation of half-life with decline in 
renal function). Dabigatran maximum plasma concentrations and area under curve increase in 
a dose proportional manner. Pharmacokinetic steady state is reached by three days with twice 
daily (b.i.d.) dosing, PD (anticoagulant) activity is closely correlated with dabigatran plasma 
concentrations. Dabigatran is eliminated primarily by the kidneys with urinary excretion 
accounting for approximately 80% of the dose administered intravenously. The absolute 
bioavailability of the current capsule formulation of DE is approximately 6.5%.
In Phase I drug-drug interaction studies there was no significant influence of DE on the PK of 
atorvastatin, diclofenac or digoxin (P-glycoprotein (P-gp) substrate), and the exposure of 
dabigatran was not significantly altered by these drugs. Dabigatran etexilate and dabigatran 
are not metabolized by the cytochrome P450 system and have no in vitro effects on human 
cytochrome P450 enzymes. There was, however, an effect on DE bioavailability after co-
administration with some P-gp inhibitors or inducers. The maximum increase, approximately 
2.5 fold, in dabigatran exposure was observed after ketoconazole single and multiple dose co-
administration while chronic rifampicin reduced the dabigatran exposure to 1/3 of control 
values. However, co-administration of P-gp inhibitors (such as amiodarone, quinidine and 
verapamil) in the long-term Phase III study, Randomized Evaluation of Long-Term 
Anticoagulant Therapy with Dabigatran Etexilate (RE-LY) (1160.26) had much smaller 
effects (increase of dabigatran plasma concentration of up to 16%) (U09-3249-02) than those 
observed in Phase I studies. 
The PK and PD of dabigatran in subjects with normal renal function in comparison to 
patients with varying degrees of renal impairment (mild, moderate, severe and dialysis 
dependent end stage renal disease) have been studied in an open, group-comparison design 
trial of 36 subjects. In otherwise healthy volunteers with mild (CrCl ≥50 and <80mL/min), 
moderate (CrCl ≥30 and <50mL/min), and severe (CrCl <30mL/min) renal impairment, the 
area under the curves (AUCs) of dabigatran were increased 1.8, 2.7 and 6.8 fold respectively, 
compared to healthy volunteers with normal renal function (CrCl >80mL/min) (U06-1704). 
This is in accordance with the fact that dabigatran is mainly renally excreted. 
The RE-LY trial was a Phase III, prospective, randomized, open-label, multinational trial of 
stroke prevention in patients with non-valvular AF at risk of stroke. A total of 18,113 patients
were randomized to one of two blinded doses of DE (110 mg b.i.d. or 150 mg b.i.d.) or to 
warfarin (target INR 2.0-3.0) (U09-3249-02). 


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RE-LY demonstrated that DE, 150 mg b.i.d., was superior to warfarin for the prevention of 
stroke and SE in patients with non-valvular AF and at least one risk factor for stroke with 
comparable rates of major bleeding. Dabigatran etexilate 150 mg b.i.d. resulted in reductions 
of intracranial hemorrhage, total bleeding and vascular mortality. Dabigatran etexilate 110
mg b.i.d. was non-inferior to warfarin for the primary endpoint of stroke and SE and reduced 
intracranial hemorrhage, major bleeding and total bleeding. In RE-LY, ischemic stroke and 
bleeding outcomes were correlated with dabigatran plasma concentrations: Lower plasma 
concentrations were associated with a higher risk of ischemic stroke, whereas the risk of 
major bleeding increased with higher plasma concentrations (P13-12662). However, the 
plasma concentration in an individual patient must be interpreted in the context of the patient 
profile taking all potential covariates, such as age and renal function, into account. Renal 
function and age are equally important in determining a patient`s overall risk of bleeding.
By considering the characteristics of the targeted population for this trial (specifically renal 
function and age) PK dose modeling shows that the median trough plasma level of dabigatran 
is predicted to be 89 ng/mL in patients with ESUS receiving DE 110 mg b.i.d., which is only 
slightly higher compared to patients receiving DE 150 mg b.i.d. in this trial (median of 74 
ng/mL). The overall exposure target in this trial (77 ng/mL) is thus higher than the level 
achieved with 110 mg b.i.d. in RE-LY (median 65 ng/ml) but below the level obtained with 
150 mg b.i.d. (median 93 ng/ml). This target is chosen based on the fact that that treatment 
start will be early after the index stroke event in patients with an ischemic brain lesion and 
due to the fact this is a different patient population compared to RE-LY, i.e. patients with AF
are excluded from this trial. 
Antiplatelet agents (ASA or clopidogrel) are known to increase bleeding. In RE-LY 
(U09-3249-02), the yearly major bleeding events (MBEs) were about twice as high in 
patients receiving additional ASA or clopidogrel, but this effect was similar to that observed 
when ASA or clopidogrel was administered with warfarin (P13-00071). The use of 
concomitant antiplatelet medication in this trial will increase the risk of bleeding and is thus 
prohibited in this trial with the exception of selected patients who may receive masked ASA 
or ASA-placebo via Interactive Response Technology (IRT) (see Section 4.1.1).
Given the common thromboembolic mechanism in both AF and ESUS, it is likely that DE
would reduce recurrent brain ischemia in patients with ESUS more effectively than 
antiplatelet therapy. The overall benefit of dabigatran to treat this indication, specifically to 
reduce the risk of recurrent stroke, is hypothesized to outweigh known bleeding risks.
The current version of the Investigator’s Brochure (IB) (U98-3208) contains additional 
information on drug-drug interaction studies, completed Phase II/III trials and studies in 
special patient populations.


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
There is uncertainty over the optimal stroke prevention treatment for patients with ESUS.  
The current treatment recommendations of ASA alone, sometimes given with clopidogrel or 
ticlopidine (P08-06684, P08-08481) are based on limited data.  
There is some evidence from subanalyses of secondary stroke prevention trials that the use of 
anticoagulants (such as warfarin) may provide benefits over antiplatelets after strokes with a 
clear embolic pattern, although a prospective randomized trial in this specific patient 
population has not yet been conducted. The only randomized evaluation of anticoagulation in 
cryptogenic stroke is the subgroup analysis of the Warfarin-Aspirin Recurrent Stroke Study 
(WARSS) (R03-0581, R13-4061). Patients with recent (<30 days) ischemic stroke were 
randomized to ASA 325 mg/d or adjusted-dose warfarin (target INR 1.4-2.8, median 
achieved INR = 1.9). Of the 2206 patients, 26% (n=576) were deemed cryptogenic/of 
undetermined etiology based on Trial of ORG 10172 in Acute Stroke Treatment (TOAST) 
criteria, although the extent of diagnostic evaluation was not reported (R97-1235). In 
cryptogenic stroke patients, the primary outcome of ischemic stroke or death occurred in 
15.0% assigned to warfarin vs. 16.5% assigned to acetylsalicylic acid over two years 
(Hazard Ratio (HR) 0.92, 95% Confidence Interval (CI) 0.6-1.4) (R03-0581).  For 338 
participants of the WARSS trial with cryptogenic stroke whose CT showed an “embolic 
topography” (i.e. eliminating lacunar strokes), the two-year rate of recurrent ischemic stroke 
or death was 12% with warfarin vs. 18% with acetylsalicylic acid (HR=0.66, 95% CI 0.4-1.2) 
(R13-4061).  In another substudy of WARSS (PFO in Cryptogenic Stroke Study), 260 of the 
576 patients with cryptogenic stroke underwent transesophageal echocardiography (R13-
3472). In this subset of patients, the primary outcome (two-year rate of recurrent ischemic 
stroke or death) was halved in those assigned to warfarin (9% warfarin vs. 17% 
acetylsalicylic acid) despite the low achieved intensity of warfarin anticoagulation. The 
WARSS subgroup data support the hypothesis that anticoagulation may be more efficacious 
than acetylsalicylic acid for patients with cryptogenic ischemic stroke when those with 
lacunar stroke topography are excluded. 
In the ESPRIT trial involving 1068 patients with presumed arteriogenic ischemic stroke (i.e. 
not restricted to cryptogenic stroke) randomized to an oral vitamin K antagonist (mean 
achieved INR 2.6) vs. ASA, recurrent ischemic stroke was reduced by 24% (HR: 0.76; 95% 
CI 0.51-1.15) by anticoagulation (P07-00680). Of note, the relationship between achieved 
INRs and stroke rates in each of the three modern randomized trials comparing vitamin K 
antagonists with ASA for secondary prevention of non-cardioembolic stroke (P07-00680, 
P05-03338, R03-0581) paralleled those from trials testing warfarin in AF patients (R13-4120, 
R13-4060).
For major-risk cardiogenic sources of embolism (i.e. AF), randomized trials have 
demonstrated that anticoagulants markedly reduce embolic strokes relative to antiplatelet 


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agents (P07-07953, P06-06455, R11-0578, R12-2020). The novel factor Xa inhibitors 
apixaban, endoxaban and rivaroxaban and the direct thrombin inhibitor DE have 
demonstrated to be at least as effective as warfarin for prevention of stroke in AF patients 
with significantly lower rates of intracranial bleeding (P09-11669, R11-4223, R11-4190,
R13-5082).
A randomized trial comparing an oral anticoagulant with antiplatelet therapy for secondary 
prevention among ESUS patients is warranted and justified by the effectiveness of warfarin 
for stroke prevention in patients with major-risk cardioembolic sources such as AF, subgroup 
analyses from prior warfarin trials, and the introduction of safer and more effective novel 
anticoagulants. The NOAC DE is highly effective against embolic stroke in AF and has an 
excellent safety profile with a low risk of intracranial hemorrhage (U09-3249-02). Dabigatran 
etexilate is likely to reduce stroke recurrence in ESUS compared with ASA and to be 
associated with an acceptably low rate of major hemorrhage. The current trial intends to 
deliver evidence of the effectiveness and safety of DE in ESUS patients with the goal of 
expanding the market authorization of dabigatran etexilate and improving patient care.
2.2
TRIAL OBJECTIVES
The objective of this study is to demonstrate that the efficacy of DE (110 mg b.i.d. or 150 mg 
b.i.d., with dosing according to age and renal function), is superior to ASA (100 mg once 
daily) for the prevention of stroke recurrence in patients with stroke of undetermined source. 
The trial will also characterize the safety of DE in this setting. See Section 4.1.3 for more 
details on DE dose assignments.
Refer to Section 5 for list of primary, secondary and other endpoints.
2.3
BENEFIT - RISK ASSESSMENT
At the time this protocol was prepared, the safety and efficacy of DE had been evaluated in 
more than 27,000 patients in over 40 Phase I studies, nine completed Phase II studies, and 10 
completed Phase III studies within multiple populations including:

Venous thromboembolism (i.e. DVT and/or PE) prevention in patients who have 
undergone major orthopedic surgery

prevention of stroke and SE in patients with nonvalvular AF

acute treatment and secondary prevention of VTE (deep venous thrombosis and 
pulmonary embolism (PE)) 
The most commonly reported adverse reactions of DE are bleedings events. Although rare in 
frequency in clinical trials, major or severe bleeding may occur and, regardless of location, 
may lead to disabling, life-threatening or even fatal outcomes. Standard management for 
bleeding (such as transfusion of blood products, etc.) needs to be applied as described in 
Section 4.2.1 and in Figure 4.2.1: 1.   A specific reversal agent (idarucizumab) has been 
developed and is currently being reviewed for registration in various countries.  When 
clinically indicated and available, it can be given to a patient in the context of a clinical trial 


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(e.g. BI trial 1321.3) or from commercial supply when it becomes approved.  See Section 
4.2.1 Overdose, for more information regarding the specific reversal agent for dabigatran.    
The risk of major bleeding correlates with dabigatran plasma concentrations (P13-12662), but 
also depends on individual patient characteristics, such as age and renal function. Bleeding 
risk may also be higher in patients concomitantly treated with an antiplatelet agent, such as 
ASA or clopidogrel. Factors, such as decreased renal function (CrCl 30-50 mL/min), age ≥ 
75 years, low body weight (< 50 kg), or mild to moderate P-gp inhibitor co-medication (e.g. 
amiodarone, quinidine or verapamil) are associated with increased dabigatran plasma levels, 
thereby contributing to the overall risk of bleeding in an individual patient.
Therefore, the doses of DE which will be used in this clinical trial have been carefully chosen 
taking individual patient characteristics into account (i.e. age and moderate renal impairment) 
to offer the best likelihood of preventing recurrent strokes with the least chance of causing 
bleeding side effects.
Additional safeguards will be implemented to protect patient safety:

The use of concomitant antiplatelet medication in this trial may increase the risk of 
bleeding and is thus prohibited in this trial with the exception of selected patients with 
coronary artery disease (CAD) who may receive masked ASA or ASA-placebo via 
IRT (see Section 4.1.1).

Patients will undergo CrCl measurements at screening and patients with CrCl 
<30mL/min (at screening) will be excluded from participation to reduce the risk of 
bleeding, see Section 3.3.3 exclusion criteria.

If a patient experiences severe renal impairment (CrCl <30mL/min) during the study, 
study drug will be withheld or stopped (see Section 3.3.4.1 and Section 5.2.3).

If a patient experiences worsening of renal function (CrCl < 50 mL/min but greater 
than or equal 30 mL/min), experiences a gastrointestinal (GI) bleed (see Section 4.1.3
and Section 5.2.3), or reaches the age of 75 years during the course of the trial, DE
dose assignment will be changed to 110 mg b.i.d. (see Section 3.3.4.1 and Section 
5.2.3).

Due to the high rate of stroke recurrence early after the index event, patients included 
in this trial will be randomized preferably early after ESUS (see Table 4.1.4: 1) to 
prevent stroke recurrence.

Severely disabled patients with a mRS of 4 or higher will be excluded from this trial, 
because their size of ischemic brain lesion may predispose them to secondary 
bleeding into the brain when receiving an anticoagulant.

Re-imaging of the brain is required in patients with mRS of 1, 2 or 3 if starting study 
medication within 10 days after index stroke to reduce the possibility of initiating 
study drug in patients with bleeding into the brain that was not detected at onset of 


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index stroke event. Randomization should only occur after re-imaging of the brain has 
been performed and eligibility has been confirmed (see Table 4.1.4: 1).

Based on the findings on the nonclinical studies with DE conducted to date and in
accordance with international regulatory guidelines, the inclusion of women of 
childbearing potential in this study is justified. To minimize the risk of unintentional 
exposure of an embryo or fetus to the investigational drug, WOCBP must agree to the 
requirements for pregnancy testing and contraceptive methods described in this 
protocol.

Female patients are required to immediately contact the investigator if they experience 
signs and/or symptoms suggesting a potential pregnancy, or know that they are 
pregnant.

A Data Monitoring Committee (DMC) will be established to monitor safety data of 
the study throughout the trial, and will recommend to the Sponsor whether to 
continue, modify or terminate the study (refer to Section 3.1.1.3 for details).
Given the common thromboembolic mechanism in both AF and ESUS, it is likely that DE
would reduce recurrent brain ischemia in patients with ESUS more effectively than 
antiplatelet therapy. The overall benefit of DE to treat this indication, specifically to reduce 
the risk of recurrent stroke, is expected to outweigh known bleeding risks of DE. Thus, the 
risk benefit assessment is considered favorable for the initiation and conduct of this trial.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This is a phase III, event-driven, double blind, randomized controlled trial of DE versus (vs.) 
ASA. Patients with qualifying ESUS must be randomized within 3 months of the index stroke
or within 6 months in selected patients as described in Section 3.3.2, Inclusion 2.b.  
Eligible patients will be randomized (1:1 ratio) to double-blind treatment of one of the 
following two arms:

Dabigatran etexilate plus placebo (matching ASA)
or

Acetylsalicylic acid plus placebo (matching DE)
Figure 3.1: 1 Study Design
All patients will be followed until the end of the trial (regardless of study drug 
discontinuation status).  To conclude the trial, at least 353 stroke events must be reported.  
The definition of stroke will be in accordance to the 2013 published recommendations of the 
AHA/American Stroke Association (R13-4110). Symptom resolution within 24 hours with 


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pathological imaging evidence of infarction (formerly classified as TIA) will be considered a 
stroke and the patient is eligible for this trial.
It is estimated that 6,000 patients and a total observation period of approximately 3 years will 
be necessary to achieve this number of events.  The actual duration of the trial and number of 
patients enrolled may be increased or decreased as appropriate in order to achieve the 
necessary number of events. The Sponsor will monitor the observed cumulative blinded event 
rate and based upon this, the forecasted time to end of study will be calculated.
With recruitment estimated to take place during the first 2.5 years of the trial, average 
individual patient participation will be 21 months.
3.1.1
Administrative structure of the trial
The Sponsor of this trial is Boehringer Ingelheim (BI).
Investigators selected for participation will be neurologists or other physicians that are 
preferably affiliated with stroke centers or other healthcare institutions that routinely conduct 
work-up on stroke patients.
A central laboratory will perform all protocol specified blood analyses. To allow for early 
randomization, it is permitted, in exceptional cases, to randomize patients based on local 
laboratory results; for details see Section 6.2.1. Randomization based on central laboratory
results is strongly encouraged and preferred. 
Urine pregnancy testing will also be done (see Section 5.2.3).  
An IRT will perform the randomization of patients and ensure appropriate distribution of trial 
medication to trial sites during the course of the trial.
All trial-related documents will be stored in the Trial Master File (TMF) at each individual BI 
Operative Unit (OPU) in accordance with standard operating procedures. 
3.1.1.1
Executive Committee
Overall organization will be overseen by an Executive Committee, consisting of one
Coordinating Investigator (CoI), two Co-chairs (one of which is the CoI), several Sponsor
representatives and other experts in Neurology and Cardiology.  The Executive Committee 
will provide the scientific leadership for the trial.  They will oversee the conduct and 
execution of the trial, provide input on study design, provide advice on implementation of the 
trial and interactions with National Coordinators of the Steering Committee (SC) and/or 
Investigators to facilitate enrolment, patient retention and provide advice on issues that may 
arise during the conduct of the study. The activities of the Executive Committee will be 
described in a separate charter.
The CoI is selected based on expertise in this therapeutic area and reputation for being a 
leader in 
field. The CoI will review and sign the Clinical Trial Protocol (CTP) and 
Clinical Trial Report (CTR). 


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3.1.1.2
Steering Committee
A SC will be composed of the Executive Committee plus Country National Coordinators, 
other experts and representatives of the Sponsor. Country National Coordinators will provide 
scientific leadership for the conduct of the study within their country. This committee will be 
led by a member (non-Sponsor) of the Executive Committee.  They will review the final 
protocol and other trial documents, and provide support for the organization of national 
logistics in the initiation and conduct of the study.  Further details regarding the activities of 
the SC will be described in the SC charter filed in the Trial Master File (TMF).
3.1.1.3
Data Monitoring Committee
An independent DMC will review patient data to monitor patient safety and trial conduct. A 
DMC charter will be written to govern the activities of this committee and be filed in the 
TMF. The DMC analyses and operations will be formally separated from the Sponsor, the 
Investigators, the Executive Committee and the Steering Committees.  The use of electronic 
data capture (EDC) and a central laboratory will support quick turnaround times and up to 
date data for the independent DMC to provide an unbiased review of data.
The DMC Charter will be used to document their objectives and working practices. The 
DMC will hold regular meetings with a view to protecting the safety of the trial participants, 
in particular with respect to the incidence of all-cause mortality, stroke, and bleeding. If the 
data at hand would precipitate a substantial safety concern about treatment with dabigatran 
etexilate, the DMC will carefully balance the observed risk profile against possible signs of 
improved efficacy.
The DMC will seriously consider recommending early termination of the trial when 
dabigatran treatment would show a statistically significant (two-sided p < 0.05) increased rate 
of the incidence of stroke or of all-cause mortality that is not potentially attributable to any 
confounding baseline imbalance, would not be mitigated by other observed benefits and 
could not be controlled by modification of the protocol. Similar action will be considered 
when an excess in clinically relevant bleeding events is observed in the patients treated with 
dabigatran etexilate that exceeds the expected bleeding rates and leads to either excess deaths 
or life-threatening events (two-sided p<0.05).
While monitoring guidelines have been provided, the DMC will use all available evidence 
and its collective judgment to base its recommendation to continue, stop or modify the study.
In any scenario, the DMC will consider the net clinical benefit of the tested interventions in 
its recommendations to the steering committee.
There will be no formal interim analysis with efficacy stopping rules. In order to change the 
future clinical practice of a majority of clinicians who would know the results of this and 
other trials in the field, any benefit from dabigatran etexilate observed would need to be 
sustained, statistically overwhelming and consistent across a range of subgroups and 
secondary endpoints, for which the full sample size and follow-up period are likely to be 
necessary. The DMC should only under exceptional circumstances consider early termination 


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of the trial for overwhelming evidence of efficacy of dabigatran etexilate relative to ASA, 
because this would compromise the scientific validity of the final analysis.
3.1.1.4
Independent Event Adjudication Committee
An Independent Event Adjudication Committee will be established for the blinded 
adjudication of these selected OEs: death (including cause of death), stroke, SE, TIA, MI, 
VTE and major bleeding including intracranial hemorrhage, life threatening and fatal bleeds. 
An Adjudication Committee Charter will govern their activities. The charter will describe the 
processes by which adjudication will occur, including how blinding will be preserved.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
A double-blind design was selected to reduce Investigator and patient bias in reporting 
outcome and adverse events. As an event driven, superiority trial, the actual recruitment and 
trial duration will be flexible in order to ensure an adequate number of events are collected 
and subsequently produce meaningful trial results (see Section 7.6).
As noted in Section 1.1, ASA once daily dose of 100mg was selected as the comparator based 
upon its inclusion in treatment guidelines and acceptability to most clinicians around the 
world.  Dose and dose-interval selection is described in Section 4.1.3 and Section 4.1.4.
3.3
SELECTION OF TRIAL POPULATION
An estimated 6,000 patients will be randomized at approximately 550 sites in approximately
40 countries. It is anticipated that each of the sites will enter an average of 11 patients during 
the 30-month recruitment period (i.e. 0.5 patients per month per site). 
Predefined site selection criteria will be applied to identify appropriate sites for participation. 
A special focus will be on stroke units to allow for an early inclusion of patients after the 
index stroke where recurrence risk is highest. Qualification of stroke units is available in 
many countries. It is preferred that sites have received qualification/certification, either on a 
national or local level. Among sites without certification, participation will be restricted to 
those sites that routinely perform or have access to the diagnostic pathway specified in Table 
3.3.1: 1 and who fulfill site selection criteria.   If other healthcare providers perform some of 
the diagnostic pathway, this is also acceptable providing investigator can obtain 
documentation.
Reasonable attempts should be made to include diverse populations during recruitment and to 
ensure retention in the trial. Greater diversity in clinical trial enrolment allows for broader 
generalization of study results, improved standards of care, decreased disparities in disease 
treatment and outcomes, and improved external validity supported by a more representative 
sample. 


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Investigators should consider regional disease prevalence demographics (e.g. race, gender, 
age) when screening potential study participants. 
Enrollment will be competitive and the trial will be terminated when the total number of 
events has been observed, regardless of enrolment at individual centers. If enrolment is
delayed, additional study centers may be recruited.
A log of all patients included into the study (i.e. having given informed consent) will be 
maintained in the Investigator Site File (ISF) at the investigational site irrespective of 
whether they have been treated with investigational drug or not.
If a patient is deemed ineligible for a reason which later resolves and all eligibility criteria 
can be met (e.g. time since an exclusionary event), patients can be rescreened up to one time 
provided it is still within 3 months since index stroke (within 6 months for select patients).  
Patients cannot be re-screened if any of the following exclusions were met: # 4, 7e, 8, 9, 19,
20, or 21; during the initial screening.  
3.3.1
Main diagnosis for study entry
Patients with ESUS within 3 months before randomization (6 months in patients ≥ 60 years + 
additional risk factor) who are eligible for treatment with antithrombotic therapy (i.e. DE / 
ASA) may be screened for participation in this trial.
There are several steps required to identify patients with ESUS. The minimum required 
diagnostic tests are listed in Table 3.3.1: 1. The order in which tests are completed can be 
done according to local standard of care and at the investigator’s discretion:

Visualization of the acute ischemia on neuroimaging to confirm the diagnosis (stroke 
mimics are not uncommon) and to exclude lacunar infarcts. 

Exclude occlusive atherosclerosis in the arteries supplying the ischemic brain by 
means of arterial imaging. 

Assess for major-risk cardioembolic sources (primarily to detect AF through ECG-
monitoring or to detect intra-cardiac thrombus by transthoracic or transesophageal 
echocardiography1).

Consider other uncommon causes of brain ischemia (migraine-related, arteritis, 
arterial dissection). A focused review of the medical history should be performed to 
exclude rare causes of stroke, e.g. migraine with aura.
                                                          
1 Transesophageal echocardiogram (TEE) is not mandatory.


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Table 3.3.1: 1
Minimum required diagnostic evaluations for embolic stroke of       
undetermined source1 (all of the following procedures 1 through 5 are 
required prior to screening potential study patients):
1. Brain CT or MRI
2. 12-lead ECG
3. Precordial or transesophageal echocardiography
4. Cardiac monitoring for ≥20 hours with automated rhythm detection2
5. Imaging of both extracranial and intracranial arteries supplying the area of brain 
ischemia (by one or more of the following: catheter angiography, MRI angiography, 
computed tomographic angiography, cervical ultrasonography plus transcranial Doppler
(TCD) ultrasonography).
3.3.2
Inclusion criteria
The patient must meet all the inclusion criteria:
1) Age ≥ 60 years
or:
Age 18-59 years plus at least one of the following additional risk factors for stroke:
a) Mild to moderate heart failure, i.e. NYHA Class ≤3 with left 
ventricular ejection fraction ≤ 40% as documented by e.g. 
echocardiogram, radionuclide or contrast angiogram in the last 6 
months
b) Diabetes mellitus (either type 1 or type 2)
c) Hypertension requiring medical treatment with antihypertensive 
medication
d) Patent foramen ovale3 with no interventional occlusion planned
e) Prior stroke or TIA (before index stroke)
                                                          
1 Imaging of the aortic arch is not required; special blood tests for prothrombotic states may be performed at the discretion of 
the Investigator only if there is a personal or family history of unusual thrombosis or associated systematic signs or disorder.
Rare causes of stroke, such as migraine (with aura) should be excluded by focused review of medical history.
2 Cardiac telemetry is not sufficient unless the data of telemetry had been recorded and summarized results are available. 
Monitoring duration can be extended at the discretion of the Investigator, if the patient is suspected for higher likelihood of 
paroxysmal AF.  Eligible patients can be enrolled with a minimum of 20 hours of cardiac monitoring completed and results 
demonstrate  < 6 min AF.  Cardiac monitoring with interruption is acceptable, if the total recording time of at least 20 hours 
is completed within the same hospital stay or within consecutive 10 days. 
3 Open foramen ovale with confirmed right-to left shunting at normal breathing (not only after Valsalva) in precordial 
echocardiogram. Transesophageal echocardiogram is not mandatory to establish diagnosis of PFO.


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f)
CHA2DS2-VASc score ≥ 3 (see Appendix 10.1)
2) 2a) Ischemic stroke with a brain lesion visualized by neuroimaging (either brain CT1 or
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.  See Exclusion 21 for definition of lacunar stroke.
2b) The index stroke must have occurred either:
a.
up to 3 months before randomization (mRS ≤3 at randomization)
OR
b. 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 (see stroke risk factors a - f as outlined in Inclusion 1).
3) Arterial imaging or cervical plus TCD ultrasonography2 does not show extra-cranial or 
intracranial atherosclerosis with ≥ 50% luminal stenosis in artery supplying the area of 
acute ischemia3.
4) As evidenced by cardiac monitoring for ≥ 20 hours4 with automated rhythm detection,
there is absence of AF > 6 minutes in duration5 (within a 20 hour period, either as single 
episode or cumulative time of multiple episodes).
5) The patient must give informed consent in accordance with International Conference on 
Harmonization (ICH) Good Clinical Practice (GCP) guidelines and local legislation 
and/or regulations.
3.3.3
Exclusion criteria
The patient must not meet any exclusion criteria:
1. Modified Rankin Scale of >4 at time of randomization or inability to swallow 
medications.
                                                          
1  Visualization by CT usually requires delayed imaging >24-48 hours after stroke onset.
2 Arterial imaging may be done with catheter arteriography, MRI angiography, computed tomographic angiography, or 
cervical plus TCD ultrasonography. The recommended cut-off point to exclude a moderate (i.e. ≥ 50%) stenosis of 
intracranial arteries by TCD ultrasonography is a Peak systolic velocity (PSV) ≥200 cm/s (R14-0781). 
3 Plaque characteristics (e.g. ruptured/ calcified/irregular) do not affect eligibility. Aortic arch atheroma is not an exclusion 
to enrolment. Cases with acute full artery occlusion deemed by Investigator to be of embolic origin are allowed.
4 Cardiac telemetry is not sufficient, unless the data of telemetry had been recorded and summarized results are available. 
Cardiac monitoring efforts (beyond minimum required per Inclusion 4) may continue after randomization at the Investigator 
or a treating physician’s discretion.  All cardiac monitoring data and findings collected during the trial will be recorded in 
the eCRF.
5 If < 6 minutes of AF is detected, the patient will be eligible depending on local Investigator judgment.


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2. Major risk cardioembolic source of embolism such as:
a.
intracardiac thrombus as evidenced by transthoracic or transesophageal 
echocardiography,
b. paroxysmal1, persistent or permanent 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) MI, 
i.
valvular vegetations, or
j.
infective endocarditis. 
3. Any indication that requires treatment with an anticoagulant as per Investigator`s 
judgment. 
4. History of AF (unless it was due to reversible causes such as hyperthyroidism or 
binge drinking, and has been permanently resolved).
5. Other specific stroke etiology (i.e. cerebral arteritis or arterial dissection, migraine
with aura/vasospasm, drug abuse).
6. Primary intracerebral hemorrhage on qualifying neuroimaging2
7. Conditions associated with increased risk of bleeding3 such as:
a) Major3 surgery in the previous month (in which case the patient may be 
eligible when one month has passed)
b) Planned major surgery or intervention in the next 3 months
c) History of intraocular, spinal, retroperitoneal or atraumatic intra-articular 
bleeding unless the causative factor has been permanently eliminated or 
repaired per Investigator judgment (e.g. by surgery)
d) Gastrointestinal hemorrhage within the past six months unless the
cause has been permanently eliminated or repaired per Investigator judgment
(e.g. by surgery), or endoscopically documented gastroduodenal ulcer disease 
in the previous 30 days
e) Hemorrhagic disorder or bleeding diathesis, e.g. history of thrombocytopenia 
or platelet count <100 x10^3/ µL at screening, von Willebrand disease, 
                                                          
1 Please see inclusion 4 for guidance on the detection of AF.
2 A hemorrhagic transformation of a primarily ischemic stroke may be included as per Investigator`s judgment. Sporadic 
microbleeds may be included as per Investigator`s judgment. As a general recommendation, a cerebral microbleed is 
considered to be ≤ 5mm, but sometimes up to 10mm, in greatest diameter on gradient recalled echo (GRE), or T2*, MRI 
sequences. Any blood visualized on a CT will be classified as a macrobleed. A macrobleed is an exclusion criterion for the 
trial.
3 Definition of “increased bleeding risk” and “major” is per Investigator judgment


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hemophilia A or B or other hereditary bleeding disorder, history of prolonged 
bleeding after surgery/intervention.
f)
Fibrinolytic agents within 48 hours of study entry
g) Uncontrolled hypertension Systolic Blood Pressure (SBP) >180mmHg and/or 
Diastolic Blood Pressure (DBP) >100 mmHg)
h) Any history of intracranial aneurysm (unless it was permanently resolved with 
either clipping or coiling at least one year prior to the study entry)
8. History of symptomatic nontraumatic intracranial hemorrhage with risk of recurrence 
according to Investigator judgment.
9. Renal impairment with estimated CrCl (as calculated by Cockcroft-Gault equation) 
<30mL/min at screening, or where Investigator expects CrCl is likely to drop below 
30mL/min during the course of the study.
10. History of hypersensitivity or known contraindication to DE or ASA.
11. Known requirement for treatment of a concomitant disease (i.e. other than the index 
ESUS stroke) with ASA (with the exception of optional concomitant medication as 
provided by the Sponsor for patients with coronary artery disease, see section 4.1.1), 
clopidogrel, dipyridamole, dipyridamole+ASA, prasugrel, ticagrelor or ticlopidine at 
Visit 1, known need for continuous dual antiplatelet therapy after randomization.
12. Known requirement for treatment with methotrexate ≥15mg/week systemic 
ketoconazole, itraconazole, posaconazole, cyclosporine, tacrolimus, dronedarone, 
rifampicin, phenytoin, carbamazepine, St. John’s Wort or any
cytotoxic/myelosuppressive therapy. See Section 4.2.2.
13. Concomitant disease that increases the risk of an adverse reaction to study 
interventions or with life expectancy < 6 months (for any reason) per Investigator
judgment. 
14. Any recent malignancy or radiation therapy (≤ 6 months) unless the malignancy was 
a basal cell carcinoma that was completely removed.
15. Pre-menopausal women (last menstruation ≤1 year prior to informed consent) who: 
o
are nursing or pregnant, 
or
o
are of child bearing potential and are not practicing an acceptable method 
of birth control, or do not plan to continue using this method throughout the 
study and/or do not agree to adhere to pregnancy testing required by this 
protocol. 
Women of childbearing potential must be ready and able to use highly 
effective methods of birth control per ICH M3 (R2) (R15-5904) that result 
in a low failure rate of less than 1% per year when used consistently and 


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correctly.  A list of contraception methods meeting these criteria is 
provided in the patient information. 
16. Patients who participated in another trial within 14 days prior to screening.  Patients 
with residual effect from another investigational product remaining at time of 
screening. Patients participating in a purely observational study will not be excluded.
17. Patients considered unreliable by the Investigator concerning the requirements for 
follow-up during the study or at the end of the study (e.g. not able to comply with 
regular medication intake)
18. Any condition the Investigator believes would not allow safe participation in the 
study, e.g. other neurological condition that would complicate assessment of 
outcomes (e.g. severe dementia, high propensity for falls where Investigator deems a 
patient’s potential risk for bleeding exceeds the potential benefits of study drug).
19. Active liver disease, as indicated by at least one of the following:
a) Prior and persistent Alanine aminotransferase (ALT (SGPT)) or Aspartate 
transaminase (AST (SGOT)) or Alkaline Phosphatase (AP) >3 upper limit of 
normal (ULN) 
and/or
b) Known Active hepatitis C (as evidenced by positive hepatitis C virus ribonucleic 
acid assay by sensitive polymerase chain reaction (PCR) based assay, such as 
Roche Monitor or Bayer TMA assay)
c) Known Active hepatitis B (HBs antigen + or  anti HBc IgM+1)
and/or
d) Known Active hepatitis A. 
20. Severe2 glucose-6-phosphate dehydrogenase deficiency
21. Lacunar stroke.  Lacunar infarcts of restricted size in the deep parts of the brain in 
the territories of small penetrating arteries. They are absent from the cerebral and 
cerebellar cortex. On brain CT and MR images they are <1.5 cm in largest diameter 
or <2.0 cm if measured on MRI diffusion sequences. In several pathological studies, 
sites of predilection included the lenticular nucleus, thalamus, central white matter, 
internal capsule, centrum ovale, corpus callosum, basis pontis, and, rarely, the 
cerebellum, midbrain and medulla. Infarcts <1.5 cm in largest diameter, or <2.0 cm if 
measured on MRI diffusion sequences, in the dorsal or lateral areas of the brainstem, 
                                                          
1 Patients having received recent hepatitis B vaccination and thus tests positive for these antibodies will not be excluded.
2 Definition of “severe” is per Investigator Judgement.


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in the territory of circumferential, rather than deep penetrating, arteries are not 
lacunar infarcts (note: history of lacunar stroke is not exclusionary).
3.3.4
Removal of patients from therapy or assessment
3.3.4.1
Removal of individual patients
It is important to distinguish between premature study drug discontinuation and premature 
study discontinuation.
Patients can stop study drug for various reasons as described below however they should be 
encouraged to re-start study medication at the Investigator’s discretion and when he/she 
considers it safe to do so.  
Regardless of whether or not study drug continues to be taken, patients will continue to 
participate in regularly scheduled follow-up visits and assessments until the end of the trial.  
Patients not actively taking study drug are permitted to reduce their level of participation but 
are strongly encouraged to continue trial participation, contribute to end of study vital status 
collection and report OEs at minimum.
Data collected for all randomized patients will be used in the analysis. This includes 
randomized patients who never take study medications and patients that prematurely 
discontinue study drug.  Procedures to be followed for patients prematurely terminating the 
trial are detailed in Section 6.2.3.  Patients that withdraw from trial participation or study 
drug will not be replaced.  
Removal from study drug
If study drug is permanently stopped, patients should continue to attend scheduled study 
visits until the trial ends.  Refer to Section 6.2.2 for further details.
An individual patient is to be discontinued from study drug if the following occurs:

Development of an indication for antithrombotic therapy including: 
o
dual anti-platelet therapy (study drug can be restarted once dual antiplatelet 
therapy is no longer needed)
o
non-AF indication for anticoagulation (e.g. treatment of VTE)
o
Atrial fibrillation (with duration exceeding 6 minutes, either as single episode 
or cumulative time of several episodes recorded within 20 hours, or as per 
Investigator discretion), or atrial flutter


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
Patients who are found to have a CrCl <30mL/min during the course of the trial 
should have study drug temporarily discontinued (see Section 5.2.3 for calculation of 
CrCl and risks of taking DE with reduced renal function).  Labs can be repeated 
before stopping study drug if Investigator wishes to confirm initial lab result.  The 
patient will be permanently discontinued from study drug, unless CrCl recovers to 
30mL/min within seven days. A patient should also be permanently discontinued 
from study drug if CrCl drops <30mL/min on two different occasions during the trial.
During period of interruption, a patient can be treated per standard of care according 
Investigator’s discretion. Guidelines for transitioning to non-study antithrombotic 
medications are provided in Section 10.2.2.

Patient noncompliance with study drug administration (per Section 4.3)

If a patient becomes pregnant or a pregnancy is suspected during the trial the 
investigational drug will be stopped, the patient will be discontinued from treatment 
and the patient will be followed up through the end of the trial and until birth or 
otherwise termination of the pregnancy. For further information, including the process 
for follow-up on the outcome of the pregnancy please see Section 5.2.2.3. 

Withdrawal of consent
At the discretion of the Investigator/patient, an individual patient may be discontinued from 
study drug if:

The patient is no longer able to continue study drug for other medical reasons (e.g., 
surgery, AEs, other diseases or concomitant therapies)

In the opinion of the Investigator, continuation on the study drug is not in the patient’s 
best interest, if eligibility criteria are being violated, or if the patient fails to comply 
with the protocol (e.g. non-attendance at trial assessments, and reason to be recorded 
in the electronic Case Report Form (eCRF)) or if the patient develops a high 
propensity for falls where Investigator deems a patient’s potential risk for bleeding 
exceeds the potential benefits of study drug.

The patients elects to stop taking study drug
The date of last dose of study drug and reason for study drug discontinuation will be recorded 
on the eCRF. 
3.3.4.2
Discontinuation of the trial by the Sponsor
Boehringer Ingelheim reserves the right to discontinue the entire trial or at any individual site 
at any time. 
The following reasons are examples that may lead to discontinuation of some or all of the 
trial sites:
1. Failure to meet expected enrollment goals overall or at a particular trial site


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2. Emergence of any efficacy/safety information that could significantly affect continuation 
of the trial and/or invalidate the earlier positive benefit-risk assessment
3. Violation of GCP, the CTP, or the contract by a trial site or Investigator, disturbing the 
appropriate conduct of the trial.
4. Advice of the independent DMC, decision by an independent ethics committee
(IEC)/institutional review board (IRB) or Competent Authority (CA)
The Investigator/ the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason mentioned above).


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
4.1.1
Identity of BI investigational product and comparator product(s)
The investigational product DE, the comparator ASA and respective matching placebos will 
be supplied by Boehringer Ingelheim Pharma GmbH & Co. KG, Germany. The composition 
of these drugs capsules are as follows:
Table 4.1.1: 1 Dabigatran etexilate (Investigational drug)
____________________________________________________________
Substance: 
Dabigatran etexilate
_____________________________________________________________
Brand name: 
Pradaxa®
Pharmaceutical formulation: Capsule
Source: 
Boehringer Ingelheim Pharma GmbH & Co. KG, Germany
Unit strength: 
110 mg, 150 mg
Total Daily dose: 
220 mg or 300 mg
Route of administration: 
per os (oral) (p.o.)
Posology: 
1 capsule, b.i.d. (Section 4.1.4)
The main excipients of the dabigatran capsule include tartaric acid, acacia, hypromellose, 
dimeticone, talc, and hydroxylpropyl cellulose, HPMC (hydoxylpropylmethylcellulose) 
capsule shell consisting of titanium dioxide (E171) FD&C Yellow 6/Sunset Yellow (E110), 
FD&C Blue 2 /Indigo Carmine (E132) hypromellose, carrageenan and potassium chloride.
Table 4.1.1: 2
Placebo matching dabigatran 
__________________________________________________________
Substance: 
placebo matching dabigatran 150 mg
placebo matching dabigatran 110 mg
____________________________________________________________
Brand name:
not applicable
Pharmaceutical formulation: Capsule
Source: 
Boehringer Ingelheim Pharma GmbH & Co. KG, Germany
Unit strength: 
0 mg
Total Daily dose: 
not applicable
Route of administration: 
p.o.
Posology: 
1 capsule, b.i.d. (Section 4.1.4)


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Table 4.1.1: 3
Acetylsalicylic acid
_____________________________________________________________
Substance: 
Acetylsalicylic acid (immediate-release tablet)
_____________________________________________________________
Brand name: 
Acetylsalicylsäure (ASS) 100mg HEXAL
Pharmaceutical formulation: Tablet
Source: 
Hexal AG, Germany
Unit strength: 
100 mg
Total Daily dose: 
100 mg
Route of administration: 
p.o.
Posology: 
1 tablet, once daily (q.d)
Table 4.1.1: 4 
Placebo matching ASA
_____________________________________________________________
Substance:
placebo matching ASA (ASA-placebo)
_____________________________________________________________
Brand name: 
not applicable
Pharmaceutical formulation: Tablet
Source: 
Boehringer Ingelheim Pharma GmbH & Co. KG, Germany
Unit strength:
0 mg
Total Daily dose: 
not applicable
Route of administration: 
p.o.
Posology: 
1 tablet, once daily (q.d)
In general, the concomitant use of non-study ASA is prohibited with the exception of patients 
with CAD.  For patients with CAD, Investigators may (but are not required to) assign a 
blinded optional concomitant ASA kit (containing either ASA or placebo) via IRT. If the 
patient has been randomized to active DE, IRT will assign as optional concomitant ASA (100 
mg q.d.).  If the patient had been randomized to active ASA, IRT will assign the optional 
concomitant ASA-placebo (see Figure 4.1.1:1).
Table 4.1.1: 5
OPTIONAL ASA as co-medication
_____________________________________________________________
Substance: 
Acetylsalicylic acid (immediate-release tablet)
_____________________________________________________________
Brand name: 
Acetylsalicylsäure 100 mg HEXAL
Pharmaceutical formulation: Tablet
Source: 
Hexal AG, Germany
Unit strength: 
100 mg
Total Daily dose: 
100 mg
Route of administration: 
p.o.
Posology: 
1 tablet, once daily (q.d)


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Table 4.1.1: 6
Placebo matching OPTIONAL ASA as comedication
_____________________________________________________________
Substance: 
placebo matching ASA (ASA-placebo)
_____________________________________________________________
Brand name: 
not applicable
Pharmaceutical formulation: Tablet
Source: 
Boehringer Ingelheim Pharma GmbH & Co. KG, Germany
Unit strength:
0 mg
Total Daily dose:  
not applicable
Route of administration: 
p.o.
Posology: 
1 tablet, once daily (q.d)
Figure 4.1.1: 1 
Interactive Response Technology assignment of concomitant 
(optional) ASA or corresponding ASA placebo for patients with CAD
4.1.2
Method of assigning patients to treatment groups
Patient assignment to the treatment groups will be determined by IRT. Access to the 
randomisation code will be controlled and documented. All necessary instructions for using 
the IRT system will be described in a user guide/manual, a copy of which will be available in 
the ISF.


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Patients have an equal chance of being randomized to DE or ASA with an allocation ratio of 
1:1.  
At Visit 2, patients will be randomized and receive study medication for the first time.  If the 
patient is not randomized, a screen fail call will be made in the IRT System.  When patients 
return for the next scheduled visit (see Flow Chart), unused medication will be returned by 
the subject. Trial drug will be supplied on a per visit basis. Supply will be managed by IRT.
All study drug dispensed and returned to patients should be recorded by Investigator/designee 
on the Investigational Medicinal Product Accountability Forms. These original forms will be 
retained and the site and a copy filed in TMF.
4.1.3
Selection of doses in the trial
The doses of DE selected for this trial are the same as those used in RE-LY, the Phase III trial 
for SPAF. In RE-LY, a dose of DE 110 mg b.i.d. was shown to be comparable to warfarin 
(INR level 2.0–3.0) for preventing strokes and SE, and superior when considering major 
bleeding risk with a relative risk reduction of 20% (U09-3249-02). Moreover, there was an 
approximately 60% reduction in intracranial hemorrhage with both dosages of DE. 
The overarching goal related to this exposure level is to achieve superiority in efficacy over 
ASA with no clinically meaningful excess in bleeding with DE. To achieve this, the dosing 
instructions applied in this trial are intended to provide homogeneous exposure distribution 
among patients included into this trial. This means that patients at higher risk of bleeding (i.e. 
patients aged 75 years or older, or with moderate renal impairment) will receive the lower 
dose of 110 mg b.i.d. and will achieve an exposure comparable to those patients without these 
risk factors.
The average exposure across all patients (dabigatran trough levels) will range between the 
trough levels achieved with 110 mg b.i.d. (median of 66 ng/ml) in the RE-LY trial and the 
level obtained with 150 mg b.i.d. in RE-LY (median of 93 ng/ml): By utilizing the PK 
experience from RE-LY (U09-3249-02) and by considering patients characteristics such as 
age and renal function from a secondary stroke population included in the PRoFESS study 
(U08-3667-01), PK modeling has shown that the dosing algorithm in this study will result in 
a median of plasma trough levels of approximately 77 ng/mL. This exposure is expected to 
provide superior efficacy over the antiplatelet agent ASA with a comparable low rate of 
intracranial hemorrhage and the overall ability to deliver an optimal balance of efficacy and 
safety across the population in the trial. 
To obtain the targeted exposure, dabigatran dosing will be adjusted for age and renal 
function, as follows: Patients will be assigned to DE dose of 150 mg b.i.d., unless they are 75
years or older, or have a CrCl of ≥30 to < 50ml/min, in which case they will receive DE 110 
mg b.i.d. 
Patients assigned to DE, who initially qualify to receive 150 mg b.i.d., will be down-titrated 
to 110 mg b.i.d. if their CrCl deteriorates to ≥ 30 - < 50 mL/min, if they experience a GI 
bleed, or the patient becomes 75 years old during the course of the trial. The patient will be 


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asked to return their 150 mg medication and receive 110 mg at an unscheduled visit as soon 
as possible if their titration is due to drop in CrCl or GI bleed.  Patients who turn 75 years old 
during the trial will receive the 110 mg dose at their next scheduled visit.  Patients will only 
have the option to change the dose once, i.e. there will be no up-titration from 110 to 150 mg 
b.i.d. if renal function recovers.  
Using the characteristics of higher risk populations, modeling shows comparable exposure 
(median trough concentration of 89 ng/ml) in patients receiving DE 110 mg b.i.d. compared 
to patients without these risk factors receiving DE 150 mg b.i.d. (median trough 
concentration of 74 ng /ml) in this trial.  Therefore it is concluded that dose adjustment to DE
110 mg b.i.d. may optimize the risk-benefit profile in patients at higher risk of bleeding.
The 100 mg dose of ASA was selected based upon recommendations in current guidelines 
and because this dosage is widely available and acceptable to most clinicians around the 
world. Patients assigned to ASA will not change their ASA dose during the course of the 
trial.  
Because assignment of ASA vs. DE is blinded, all patients will have their DE down-titrated 
via IRT under the age, GI bleed or renal function conditions mentioned above.  It will be 
unknown if the DE kits are active or placebo.  
4.1.4
Drug assignment and administration of doses for each patient
Drug is dispensed by the Investigator, study coordinator, or pharmacist, depending on the 
study organization. IRT will be used to assign an appropriate active study drug and placebo to 
the patient. The site staff will be prompted to notify the IRT of all relevant information to 
identify patient as well as assign appropriate DE dose according to the algorithm (i.e. 
according to age, renal function and GI bleed that occurs during the course of the trial).
Study drug is dispensed every three months over the first year and every 6 months thereafter 
at regularly scheduled study visits (except the EOT and Final Visit).  Study drug kits will 
contain enough supply to last until the next visit plus some overage. 
Patients randomized to active treatment with DE will also receive an ASA placebo kit.  
Patients randomized to active treatment with ASA will also receive a DE placebo kit.
Patients will be instructed on the importance of taking both the active and placebo treatment
because they will not know which one is active versus placebo.  
Adjustments of DE dose can occur once per patient and will be managed within the IRT
system.  
Dabigatran etexilate capsules should be taken in the morning and in the evening, at the same 
time every day. The interval between doses should be as close to 12 hours as possible. If a 
dose of DE is not taken at the scheduled time, the dose should be taken as soon as possible on 
the same day; the missed dose should be skipped, if it cannot be taken at least 6 hours before 
the next scheduled dose. The next dose of DE should not be doubled to make up for a missed 
dose. If a dose of ASA or matching placebo is not taken at the scheduled time, the dose 


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should be taken as soon as possible on the same day; the missed dose should be skipped if it 
cannot be taken at the same day. For visits with pharmacokinetic trough sampling (Visit 1, 
Visit 3 and Visit 6 as outlined in the Flow Chart) patients should take that morning dose of 
trial medication at the study site (after the blood sample has been taken) to ensure the 
pharmacokinetic sample is taken at trough, 10:00-16:00 hours after the last drug intake and 
prior to the next drug intake.
Patients should be advised to take study medication with a full glass of water. Breaking or 
chewing of the tablets or capsules, or emptying the contents of the capsules is not permitted. 
The capsules and tablets should be swallowed as a whole and should not be dissolved in 
liquid. It is possible to take study medication with or without food. By taking study 
medication with food, dyspepsia-like side effects associated with DE may be reduced (U13-
3509-01). If dyspeptic symptoms remain, the Investigator should consider adding a proton 
pump-inhibitor or H2-blocker to the concomitant therapy of the patient.
Start of study treatment following the qualifying event of ESUS:
The decision about starting study medication after qualifying stroke is at the discretion of the 
Investigator. In general, study medication should be started as early as possible under 
consideration of the severity of the stroke and after ensuring that intracranial hemorrhage has 
been excluded. Recommendations on the earliest possible time point to start study medication 
are provided in Table 4.1.4: 1 (P12-02400).


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Table 4.1.4: 1
Recommendations on starting study medication after index event of 
stroke (mRS ≤3 at time of randomization) and for reintroduction of 
study treatment after recurrent stroke (mRS ≤3 at time of study 
medication restart)
Stroke Severity (at time of 
randomization / at time of study 
medication restart after recurrent 
stroke)
Earliest start of Study Medication after 
Stroke
Symptom resolution within 24 hours with 
evidence of brain damage by imaging
As soon as imaging has excluded a 
cerebral hemorrhage
Modified Rankin Scale = 1 or 2
3-5 days after most recent stroke onset1
Brain re-imaging is not required if starting 
study medication more than 10 days after 
index stroke.
Modified Rankin Scale = 3
Please take note:
This category includes patients with an initial 
Modified Rankin Scale of 4 at time of stroke, 
who have improved to a Modified Rankin 
Scale of 3.
Patients with Modified Rankin Scale of 4 at 
time of randomization are excluded. 
Patients with Modified Rankin Scale of 4 
cannot restart study medication unless their 
Modified Rankin Scale improves to 3.
5-7 days after most recent stroke onset1
Brain re-imaging is not required if starting 
study medication more than 10 days after 
index stroke.
1 If starting study medication within 10 days of most recent stroke in patients with mRS of 1, 2, or 3, re-imaging 
of the brain is required to rule out bleeding into the brain. Randomization in these patients should only occur 
after reimaging of the brain has been performed and eligibility has been confirmed. Hemorrhagic transformation 
of a primarily ischemic stroke may be included as per Investigator`s judgment. Sporadic microbleeds may be 
included as per Investigator`s judgment. As a general recommendation, a cerebral microbleed is considered to 
be in general ≤ 5mm, but sometimes up to 10 mm, in greatest diameter on gradient recalled echo (GRE), or T2*, 
MRI sequences. Microbleeds are incidental findings that do not constitute an exclusion criterion. In patients 
with hemorrhagic transformation or microbleeds, the Investigator may choose to delay the start of study 
medication. Any blood visualized on a CT will be classified as a macrobleed. In patients with macrobleeds, 
study medication should not be started.


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Treatment will continue until the end of the study if there is no reason to stop treatment 
earlier. The date of last dose of study drug will be recorded on the eCRF.  
Secondary stroke prevention treatment for patients after the completion of this trial is at the 
discretion of the Investigator or other treating physician.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
Trial medication will be identified by a medication code number.  Packaging and labelling 
will be otherwise identical.  Interactive Response Technology will be used to assign patients 
to treatment groups at the start of treatment (see Section 4.1.2) and for appropriate re-supply 
of medication to patients throughout the duration of the trial.  The IRT will also handle any 
required dose adjustments.
Colour, size and shape of the tablets and capsules (whether active or placebo) are identical 
(see Section 4.1.1 for actual sizes of each unit strength dose).  These measures will ensure 
that the medication blind will be maintained for both patient and Investigator throughout the 
trial. 
The randomisation schedule will be generated using validated software and will be verified 
by a statistician who is not involved in the trial.  Individuals involved in the conduct and 
assessments of the trial will remain blinded to the randomisation schedule until the entire 
database is locked.
Randomisation codes will be accessible for any authorised person at the study site via IRT.  
The codes should be broken only if knowledge of the patient’s treatment group is needed in 
order to provide appropriate medical care to that patient.  Refer to Section 4.1.5.2 for rules of 
breaking the code for an individual or for all patients.  The DMC will also be given access to 
unblinded patient information if required.
Refer to the DMC charter (available separately) for information about management of 
blinded information for the purposes of DMC review.
The randomization codes may be provided to bioanalytics (or designee) prior to last patient 
out (LPO) to allow them to exclude PK samples and assay validation samples taken from 
patients assigned to ASA from the these analyses. Bioanalytics (or designee) will not disclose 
the randomization code or the results of their measurements until the study is officially 
unblinded.
Due to the requirement to include unblinded information in suspected unexpected serious 
adverse reaction (SUSAR) reports, SUSAR reports will be blinded prior to distribution to 
sites and trial team to ensure that the BI personnel other than the drug safety representative 
remains blind to treatment allocation until after database lock.


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4.1.5.2
Procedures for emergency unblinding
The Investigator is instructed not to measure activated partial thromboplastin time (aPTT), 
thrombin time (TT), diluted thrombin time (dTT) and ecarin clotting time (ECT) unless there 
is an emergency or urgent intervention (see Section 4.2.1). 
If a patient experiences a clinical scenario resulting in a potentially unblinding coagulation 
test, it is preferable for another treating physician (not involved in the trial) to review lab 
results and manage the clinical scenario.  
An emergency code will be available via the IRT. This code may only be broken in 
emergency situations when the identity of the trial drug must be known to the Investigator in 
order to provide appropriate medical treatment or if required to assure safety of patients.  If 
the code for a patient is revealed, the Sponsor must be informed immediately and the patient 
must be permanently discontinued from study drug.  The reason for accessing the code must 
be documented on the appropriate eCRF page along with the date and the name of the person 
who broke the code.
4.1.6
Packaging, labeling, and re-supply
Investigational supplies will be available as trial medication kits. Each kit includes trial
medication sufficient for at least 90 days, packed as follows:

Four bottles, each containing 60 capsules DE 150 mg, 110 mg or matching placebo.

One blister package containing 120 tablets ASA 100 mg or matching placebo.
To enable adequate supply for 3 month visit intervals as scheduled during the first year, 
patients will receive one kit of DE (or placebo) and one blister package of ASA (or placebo)
at Visits 2, 3, 4 and 5.  Beginning at Visit 6 (Month 12), patients will receive two kits of DE
(or placebo) and two blister packages of ASA (or placebo) at each scheduled visit to ensure 
adequate supply for 6 month clinic visit intervals.  
The need for a patient to receive optional concomitant ASA will be determined by the 
Investigator and recorded in IRT. For patients with CAD who do require this, the optional 
ASA (or ASA placebo as appropriate) will also be assigned by the IRT according to the 
patient’s randomized treatment arm.  Optional concomitant ASA and ASA placebo will be 
packaged identically to each other but different from comparator ASA by label color to allow 
easy differentiation of supply while maintaining the blind.  They will be supplied as:

One blister package containing 120 tablets ASA 100 mg or matching placebo. (See 
Figure 4.1.1: 1).
For details of packaging and the description of the label, refer to the ISF.


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4.1.7
Storage conditions
Patients should be instructed to keep medication containers tightly closed and not to remove 
tablets/capsules from original package material until immediately prior to time of intake. It is 
not allowed to use medication from more than one DE kit at the same time.
Trial medication must be stored under the recommended storage conditions indicated on the 
label. A temperature log must be maintained by the site to make certain that the drug supplies 
are stored at the correct temperature. If the storage conditions are found to be outside the 
specified range, the Local Clinical Monitor (CML) for the study should be contacted 
immediately.
Trial medication must be stored securely at the study sites, out of reach of children and be 
protected from moisture and direct sunlight, e.g. in a locked cupboard or at a pharmacy. It 
may only be dispensed to trial patients fulfilling the inclusion and exclusion criteria by 
authorized study personnel as documented in the ISF. Receipt, usage, and return of the study 
medication must also be documented on the respective forms in the ISF.
All unused medication including bottles and outer boxes (empty or filled) must be either 
returned to the Sponsor, or, following written authorization from the Sponsor, may be 
destroyed at site. Receipt, usage and return must be documented on the respective forms.
Account must be given for any discrepancies.
4.1.8
Drug accountability
Drug supplies, which will be provided by the Sponsor, must be kept in a secure, limited
access storage area under the appropriate storage conditions defined by the Sponsor. A 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature.
The Investigator/Pharmacist/Investigational Drug Storage Manager will receive the
investigational drugs delivered by the Sponsor when the following requirements are fulfilled:

approval of the study protocol by the IRB / ethics committee,

availability of a signed and dated clinical trial contract between the Sponsor and the 
Head of Trial Centre,

approval/notification of the regulatory authority, e.g. CA, as required according to  
local regulations,

availability of the curriculum vitae of the principal Investigator,

availability of a signed and dated CTP including local signature page signed by PI, 

availability of the proof of a medical license for the principal Investigator (if 
applicable), 

signed financial disclosure of PI,

for USA, availability of the Form 1572.


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The Investigator/Pharmacist/Investigational Drug Storage Manager must maintain records of
the product’s delivery to the trial site, the inventory at the site, the use by each patient, and
the return to the Sponsor or alternative disposition of unused products.
These records will include dates, quantities, batch/serial numbers, expiry (‘use by’) dates, and
the unique code numbers assigned to the investigational products and trial patients. The
Investigator/pharmacist/investigational drug storage manager will maintain records that
document adequately that the patients were provided the doses specified by the CTP and 
reconcile all investigational products received from the Sponsor.
At the time of return to the Sponsor or appointed CRO; the Investigator/Pharmacist/
Investigational Drug Storage Manager must verify that all unused or partially used drug 
supplies have been returned by the patient and that no remaining supplies are in the 
Investigator’s possession.
For Japan:
The Investigator / pharmacist / investigational drug storage manager will receive the 
investigational drugs delivered by the Sponsor after IRB / ethics committee approval of the 
study and completion of a clinical trial contract between the Sponsor and the Head of Trial 
Centre.
The Investigator / pharmacist / investigational drug storage manager should return the unused 
and collected investigational drugs (including the empty boxes) to the Sponsor after 
unblinding the trial.
In case investigational drugs are returned before unblinding of the trial, the Investigator / 
pharmacist / investigational drug storage manager should seal the opened box (excluding 
empty boxes) for the patient, before returning the unused and collected investigational drugs 
(including the empty boxes) to the Sponsor.
When returning the investigational drugs, the Investigator / pharmacist / investigational drug 
storage manager should exercise utmost caution to assure that the Sponsor and other relevant 
trial staff members remain blinded to the patient’s name on the package (box or label) of the 
investigational drugs.
Upon completion of the trial, the Investigator / pharmacist / investigational storage manager 
submits to the Sponsor a copy of the investigational drug dispensing and return log. When 
submitting the copy, the Investigator / pharmacist / investigational drug storage manager 
should exercise caution to assure that the Sponsor and other relevant trial staff members 
remain blind to the patient’s name.


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4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT
Any additional concomitant therapy considered necessary for the patient’s welfare may be
given at the discretion of the Investigator, with the exception of those listed in Section 4.2.2.
Concomitant medications of interest (e.g. antithrombotic medications, medications to treat 
cardiovascular conditions, medications with potential interaction with dabigatran or ASA, 
treatments to manage bleeding) taken at randomization and throughout the conduct of the 
trial (including within 30 days of randomization) will be documented on the eCRF. 
Additionally, any treatments received for the index (qualifying) event of stroke will be 
recorded, including fibrinolytic, antiplatelet and anticoagulant medications.
The concomitant use of ASA up to 100 mg per day is discouraged, but not prohibited for 
patients with CAD. Patients requiring treatment with ASA for CAD can be included in the 
trial and can receive optional concomitant ASA 100 mg (or ASA 100 mg placebo) q.d. as 
concomitant medication.  See Section 4.1.1 and Section 4.1.6 for details.  
Certain concomitant therapies (e.g. fibrinolytics, anticoagulants) or surgery/intervention may 
require the temporary discontinuation of blinded DE and ASA. Study medication should be 
restarted as soon as safely possible, at the discretion of the Investigator. Following study drug 
discontinuation due to AEs (e.g. bleeds) the patient should be treated according to local 
clinical practice. After resolution of an AE, consideration should be given to resuming study 
medication at the assigned treatment and dose. In case of a temporary interruption, a restart of 
study medication is possible at the Investigator’s discretion. All study drug stop and restart 
dates will be recorded on the eCRF.
4.2.1
Rescue medication, emergency procedures, and additional treatment
The Investigator is responsible for ensuring that procedures and expertise are available to 
cope with medical emergencies that may occur during the study. In situations where there is 
an increased hemorrhagic risk (e.g. recent biopsy or major trauma, bacterial endocarditis),
close observation (looking for signs of bleeding or anemia) is generally required.
Recommendations on the management of study medication for invasive procedures or at the 
time of OEs are listed below. As study medication is blinded, the Investigator is asked to 
consider the individual bleeding risk of the patient and type of intervention and to weigh the 
risk of bleeding against the risk of thromboembolism associated with treatment interruption 
of either ASA or DE.  
Coagulation tests should not be performed in this trial to avoid unblinding. Investigators are 
discouraged to perform TT, dTT, aPTT or the ECT in this trial. Under certain exceptional 
circumstances, such as emergency procedures, stroke or life-threatening bleeding as 
described below, it may become necessary for patient management to perform a coagulation 
test.  Preferably, another treating physician (not involved in the trial) should review lab 
results and manage the clinical emergency scenario.  


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In the event that the identity of the trial drug must be known, see Section 4.1.5.2 for 
emergency unblinding.
For the latest information on DE, refer to the current version of the IB (U98-3208).
For specific guidance relating to ASA consult also the relevant Summary of Product 
Characteristics (SPC) of the HEXAL ASS 100 mg tablet (SPC - see Section 04 of the ISF).
Detailed information regarding the management of patients receiving study medication is 
provided below.
Elective Procedures
Preoperative Phase:
Some interventions in individual patients may be affected by the characteristics of ASA, 
others by DE. As study medication is blinded, the Investigator is asked to consider the type 
of intervention and individual bleeding risk of the patient and to weigh the risk of bleeding 
against the risk of thromboembolism associated with treatment interruption of assigned study 
drug. The impact of IRT-assigned optional ASA-co-medication should also be considered.
Serum creatinine should normally be checked 1-2 weeks before surgery and the CrCl should 
be calculated using the Cockroft-Gault formula (Section 5.2.3) and the impact on cessation of 
dabigatran must be considered in patients with reduced renal function.     
Where the Investigator becomes aware of a planned procedure/surgery, it is recommended 
that the study Investigator contact the treating surgeon.  Refer to Appendix 10.2 on 
transitioning to non-study medication in case bridging therapy is chosen.
Study drug assignment should not routinely be unblinded in preparation for an elective 
procedure.  Guidelines for stopping DE in advance of surgery are provided in Table 4.2.1: 1. 
These guidelines should in general be followed for all patients irrespective of their assigned 
study medication, unless the situation requires that the antiplatelet effect of ASA be 
completely resolved.  In that case, study drug should be stopped for approximately 7 days or 
longer depending on the type of intervention planned.
The following is a guide to the discontinuation of study medication before surgery taking 
renal function and additional risk factors into account. With elective procedures, timing of 
study medication stop and restart may depend on patient characteristics, type of intervention 
and type of study medication. Unless explicitly mentioned, the recommendations given for 
DE can also be applied to patients receiving ASA in the trial.


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Table 4.2.1: 1 
Recommendations on cessation of blinded study drug in relation to 
the timing of surgery – under special consideration of the 
pharmacokinetics of dabigatran
Renal function 
(CrCl, mL/min)1
Estimated half-
life in hours (for 
dabigatran)
Stop study drug before surgery3
High risk of bleeding2
Standard risk
>80
~13 
2 days before 
24 h before (2 doses)
≥50-80
~15 (12-18)
2-3 days before
1-2 days before
≥30 to <50
~18 (18-24)
4 days
at least 2 days (> 48 
hours)
<30
~27 (>24 )
> 5 days
2-5 days
1 CrCl can be estimated using serum creatinine by the Cockroft-Gault formula (see Section 5.2.3). Patients who develop 
CrCl <30mL/min during the course of the trial should have study medication temporarily stopped (see Section 3.3.4.1). For 
rules and prerequisites to restart DE treatment see Section 4.2.1.
2 In addition to renal function, high risk determinants of bleeding risk include type of surgery, advancing age, comorbidities 
(e.g. major cardiac, respiratory or liver disease), and concomitant use of antiplatelet therapy. The type of surgery associated 
with a high risk of bleeding includes but is not limited to cardiac surgery, neurosurgery, abdominal surgery or those 
involving a major organ. Other procedures such as spinal anesthesia may also require complete hemostatic function.
3 If the clinical situation requires that the antiplatelet effect of ASA should be completely resolved, study drug should be 
stopped for approximately 7 days or longer depending on the type of intervention planned.
During a temporary interruption, thrombosis prophylaxis therapy with commercial
antiplatelet(s) or a parenteral anticoagulant e.g. Low-molecular Weight Heparin (LMWH) or 
Unfractionated Heparin (UFH) (according to local practice) is at the discretion of the 
Investigator depending on duration of interruption, type of intervention and individual 
thromboembolic risk of the patient. See Appendix 10.2 for additional information related to 
initiation of thrombosis prophylaxis and switching back to study medication.
Emergency Procedures
In the case of emergency surgery, study medication should be discontinued (including IRT-
assigned optional ASA-co-medication).  If possible, surgery should be postponed until 12 
hours after the last oral intake of study drug.  
In an emergency event, a measure of anticoagulation may become necessary to manage the 
situation. A physician may consider using the TT, dTT, aPTT or the ECT. Coagulation times 
should be interpreted in relation to the timing of last drug intake of DE. In RE-LY, patients
receiving chronic therapy with dabigatran 150 mg bid, the median peak aPTT was 
approximately two-fold that of control. Twelve hours after the last dose (trough level), the 
median aPTT is approximately 1.5-fold that of control, with less than 10% of patients 
exhibiting two-fold increases in aPTT (P10-03790).  
An elevated TT or dTT should lead the clinician to consider delaying surgery. If the TT/dTT 
test is not available, an aPTT, though less precise than the TT, can be used.  A persistently 
prolonged TT or dTT in the absence of heparin, fibrin/fibrinogen degradation products (e.g. 
with disseminated coagulation activation, sepsis, severe inflammation, and other conditions) 


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or high concentrations of serum proteins (e.g. myeloma) suggests persistently elevated levels 
of dabigatran in the blood. 
If the condition is considered life threatening, consider reversal of anticoagulation as 
described under major bleeds. See Section 4.2.1- Overdose, for more information regarding 
the specific reversal agent for dabigatran. 
Refer also to Section 4.1.5.2 for Emergency Unblinding Procedures.  
ASA characteristics relevant in the context of surgery/intervention
The antiplatelet effect of ASA is present up to 7-10 days after medication cessation. 
Nonetheless, most interventions can be performed without an interruption of ASA therapy.
The type of surgery associated with a high risk of bleeding and which may preferably be 
performed after the antiplatelet effect of ASA has elapsed, includes but is not limited to 
cardiac surgery, neurosurgery, abdominal surgery or those involving a major organ. Other 
procedures such as spinal anesthesia may also require complete hemostatic function. It is at 
the discretion of the Investigator whether a complete resolution of the antiplatelet effect of 
ASA for a certain procedure is required. In this case, study medication (including IRT-
assigned optional ASA-co-medication) may have to be stopped for 7-10 days before the 
intervention and the risk of thromboembolism during this period must be weighed against the 
risk of bleeding. ASA does not lead to a prolongation of coagulation times such as aPTT, 
dTT, TT or ECT.
Dabigatran etexilate characteristics relevant in the context of surgery/intervention
Physicians may consider the following information regarding DE when patients need to 
undergo surgery or elective procedures.  Providing the patient has normal renal function, the 
onset of effect of dabigatran is within 1 hour of dosing and dabigatran has peak 
concentrations 2-3 hours after an oral dose.  Steady state is reached within 2-3 days.  
Plasma levels of dabigatran in steady state will vary across the population and are particularly
affected by renal function. Patients with renal dysfunction may have elevated concentrations
of dabigatran due to longer half-lives of active drug (see Table 4.2.1: 1). Serum creatinine 
should normally be checked 1-2 weeks before an elective surgery and the CrCl should be 
calculated using the Cockroft-Gault formula (Section 5.2.3). Patients with a CrCl <30mL/min 
during the course of this study should not be receiving study medication (Section 3.3.4.1). In 
patients where renal function is impaired or procedures undertaken which may temporarily 
compromise renal function, the impact on plasma levels of dabigatran must be considered.
The current version of the IB should be referenced for further information about DE (U98-
3208).
Post Procedural Period
Study medication will be initiated as soon as the patient is hemodynamically stable and 
hemostasis is achieved. If bridging medication has been used, please see Appendix 10.2.1 on 
how to switch back to study mediation after temporary interruption. 


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Spinal Anesthesia/Epidural Anesthesia/Lumbar Puncture
Procedures such as spinal anesthesia may require complete hemostatic function. See Table 
4.2.1: 1 for recommendations on when to stop DE before spinal/epidural anesthesia.
It is at the discretion of the Investigator whether a complete resolution of the antiplatelet 
effect of ASA is required for these types of procedures. Complete resolution of ASA 
antiplatelet effect would require a stop of study medication approximately 7-10 days.
The risk of spinal or epidural hematoma may be increased in cases of traumatic or repeated 
puncture and by the prolonged use of epidural catheters. After removal of a catheter, resume 
treatment with study medication after complete hemostasis is achieved, but at minimum an 
interval of at least 1 hour should elapse for all patients. These patients require frequent 
observation for neurological signs and symptoms of spinal or epidural hematoma.
Major Bleeds 
If a patient experiences a major bleed, the study medication should be stopped and the source
of bleeding investigated and treated. In an emergency bleeding situation, this may involve 
coagulation testing (aPTT, TT, dTT, ECT, platelet count as described above in Emergency 
Procedures), and possibly transfusion, diagnostic procedures and/or surgical hemostasis.
The recommendations given below are derived from guidelines to manage bleeding with DE,
however, with the exception of recommendations on the specific reversal agent for dabigatran, 
they can be applied to all patients in this trial irrespective of assigned study medication (i.e. 
DE or ASA).  
See section 4.2.1 Overdose, for more information regarding the specific reversal agent for 
dabigatran.  Since dabigatran is excreted predominantly by the renal route adequate diuresis 
must be maintained. Appropriate standard treatment, e.g. surgical hemostasis as indicated and
volume replacement should be undertaken as appropriate. In addition, consideration may be
given to the use of fresh frozen plasma (P10-03790). As protein binding is low, dabigatran is
dialyzable, however there is limited clinical experience in using dialysis in this setting.
Clearance of dabigatran by hemodialysis was investigated in patients with end-stage renal
disease. Dialysis was conducted with 700mL/min dialysate flow rate, four hour duration, a
blood flow rate of either 200mL/min or 350 - 390mL/min. This resulted in a removal of 50%
or 60% of free or total dabigatran concentrations, respectively. The amount of drug cleared
by dialysis is proportional to the blood flow rate (U11-1642-01). There is some experimental 
evidence to support the role of agents such as activated prothrombin complex concentrates 
(APCC) (e.g. Factor Eight Inhibitor Bypassing Activity (FEIBA)), recombinant Factor VIIa 
and three or four factor concentrates (factors II, IX and X with or without Factor VII) in 
reversing the anticoagulant activity of dabigatran. The usefulness in clinical settings has not 
yet been systematically demonstrated. Consideration should also be given to administration 
of platelet concentrates in cases where thrombocytopenia is present or where ASA (100 mg 
daily) has been assigned as co-medication. All symptomatic treatment has to be given 
according to the physician's judgment.


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A summary how to manage bleeding on DE is presented in Figure 4.2.1: 1. Unless explicitly 
mentioned, the recommendations given for DE can also be applied to patients receiving ASA 
in the trial.
Figure 4.2.1: 1 Management of bleeding
As study medication is blinded, the following characteristics of ASA should also be taken 
into consideration for the management of bleeding (adapted from P10-03790):
There is no specific reversal agent to counteract the antithrombotic activity of ASA. Since 
ASA is renally excreted adequate diuresis must be maintained. Alkalinization of the urine is a 
Minor bleeding1
Continue treatment, delay 
next dose, temporarily or 
permanently discontinue
treatment, as appropriate
• Symptomatic treatment
• Maintain adequate diuresis
• Mechanical compression2
• Surgical intervention2
• Fluid replacement and
  haemodynamic support2
• Blood product /platelet 
concentrate transfusion2
• Oral charcoal application2,3
(if dabigatran etexilate 
ingestion <2hr before)
• Haemodialysis 2, 3, 4
• Consideration of 
rFVIIa or APCC2, 3
• Delay next dose, temporarily 
or permanently discontinue  
treatment2
Patient with bleeding on dabigatran etexilate 
therapy 
Major or 
Life-threatening 
Bleeding1
1 for bleeding definitions see Section 5.2.2
2 when appropriate
3 recommendations based on limited clinical or non-clinical 
data only, limited or no experience in volunteers or patients
4 consider hemodialysis, especially if there also is acute renal 
failure.


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key concept in the management of salicylate overdose (see “Overdose” later within this 
section).
Re-administration of study medication after a major bleed
Re-administration of study medication (at the assigned dose) after the bleeding has resolved 
and hemostasis has been achieved, is at the discretion of the local Investigator. 
Minor Bleeds
If a patient experiences a minor bleed, study medication may be continued, interrupted 
temporarily or permanently discontinued, at the discretion of the Investigator. It is not a 
requirement however, that study drug is stopped in these cases. 
Stroke
Patients with documented or suspected stroke should be managed according to usual clinical
practice, which may include the use of fibrinolytic agents and mechanical clot removal. It is 
anticipated that in most cases study drug will be withheld until a CT or MRI scan has been 
obtained.
Ischemic stroke
For ischemic stroke, ASA and/or clopidogrel, or ASA/dipyridamole (the latter in lieu of
clopidogrel) may be administered as indicated according to usual clinical practice. Treatment 
with study drug can be continued at the discretion of the local Investigator, in the absence of 
evidence of bleeding. For recommendations on timing of restart of study medication see 
below in section “reintroduction of study treatment following a stroke”, see Table 4.1.4: 1.
Use of fibrinolytic agents for the treatment of acute ischemic stroke:
The use of fibrinolytic agents for the treatment of acute ischemic stroke may be considered if 
the patient presents with a TT, dTT, ECT, or (if TT, dTT or ECT are not available) an aPTT 
lab result not exceeding the ULN according to the local reference range.  Either TT or dTT, 
ECT (one of these parameters is preferred), or aPTT will be sufficient and the choice of the 
parameter will depend on local availability) (U11-1642-01).
Refer to Section 4.1.5.2 for Emergency Unblinding Procedures.  
Hemorrhagic Stroke
For hemorrhagic stroke or other intracranial bleeding, consultation with a coagulation expert
and a neurosurgeon is recommended.  See “Major Bleeds” earlier in this section for details 
relating to how to manage bleeding.


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In case of recurrent stroke during the trial, it is at the Investigator`s discretion whether study 
medication will be restarted or whether the patients will be switched to appropriate standard 
of care antithrombotic treatment.
Reintroduction of study treatment following a stroke (i.e. after recurrent stroke)
The decision about when to restart study medication following a recurrent stroke is at the 
discretion of the Investigator (with the exception of strokes with mRS of 4 or higher, where 
restart is not allowed, unless the patient improves to a mRS of 3). Table 4.1.4: 1 shows 
recommendations (P12-02400) on the earliest possible time point to start study medication.  
These recommendations in Table 4.1.4: 1 also apply to restarting study medication after 
recurrent stroke. Cerebral hemorrhage must be excluded before study drug is restarted. If
restarting study medication within 10 days of stroke in patients with mRS of 1, 2 or 3, re-
imaging is required to rule out bleeding into the brain (for details see footnote of Table 4.1.4:
1).
Acute Coronary Syndrome (ACS)
In patients with documented or suspected ACS, study drug should be temporarily
discontinued. 
Medication Management of ACS
ASA, clopidogrel and glycoprotein IIb/IIIa inhibitors may be administered according to usual 
clinical practice. However, the concomitant use of these treatments with study medication 
may increase the risk of bleeding.
For the use of heparins (UFH or LMWH) or other anticoagulants to manage ACS, the 
following guidance is provided for consideration:
Unfractionated or low-molecular-weight heparin should be withheld until the aPTT is less 
than 1.5 x ULN (upper limit of normal):

If the aPTT is between 1.2 and 1.5 x ULN, UF heparin may be commenced preferably 
without an intravenous loading dose and LMWH may be commenced at the usual 
therapeutic dose 

If the aPTT is above 1.5 times the ULN, it should be repeated every four hours until it 
falls below this level, after which heparin or other anticoagulation can be commenced.
Blinded study medication (either DE or ASA) can be restarted when clinically appropriate 
(generally ≥ 6 hours after a bolus administration of UFH or ≥ 12 hours after LMWH 
administration). See Appendix 10.2.1 for recommendations when to start study medication 
after treatment with parenteral anticoagulants.
Interventional / Surgical Management of ACS or stable CAD
Reperfusion with primary Percutaneous Coronary Intervention (PCI) is preferable over 
treatment with thrombolysis for patients who are anticoagulated with DE due to the increased


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risk for bleeding with concurrent use of thrombolytics and DE. During percutaneous coronary 
intervention, the activated clotting time (ACT) should be measured and heparin administered 
as needed according to usual practice.
If primary PCI is not available, the Investigator or treating physician may consider 
thrombolytic treatment. Thrombolytics should only be administered when the potential gains 
of reperfusion outweigh the potential risks of severe bleeding.  Particular consideration 
should be given to factors which further increase a patient’s risk for bleeding (i.e., elderly, 
reduced renal function).  If the physician elects to treat with thrombolytics, adjunctive 
treatment with UFH, or LMWH should be withheld until aPTT is <1.5 times control.
When coronary stent implantation is necessary, bare metal stents (BMS) should be preferred 
over drug-eluting stents to reduce the time of dual antiplatelet therapy due to stent 
implantation. Dual antiplatelet therapy will prompt withdrawal of trial-assigned treatment for 
the duration of dual antiplatelet therapy. The patient may return to study medication at any 
time once dual antiplatelets are no longer needed. Patients who permanently stop study 
medication will be followed-up until termination of the trial. 
When Coronary Artery Bypass Grafting (CABG) Surgery is clinically indicated, it should be 
delayed if possible until at least 12 hours after the last dose of study medication. Elective 
CABG surgery should be delayed if possible until at least two to three days after the last dose 
of DE, depending on the renal function of the patient (see Table 4.2.1: 1). Patients with renal 
dysfunction may have elevated concentrations of dabigatran due to longer half-lives of active 
drug (see Table 4.2.1: 1). If bypass surgery is to start during elevated plasma concentrations 
of DE there is an increased risk of bleeding. When preparing the patient for cardiopulmonary 
bypass, this should be taken into account. The procedure may be performed as usual, 
including the control of the anticoagulation levels using e.g. aPTT, ACT or TT 
measurements. For further advice on when to stop study medication before surgery see Table 
4.2.1: 1.
Overdose
Overdose may require discontinuation of study medication. 
As study medication is blinded, the following characteristics of both DE and ASA should
also be taken into consideration for the management of overdose:
Overdose with DE
Overdose following administration of DE may lead to hemorrhagic complications due to its 
PD properties. Suspected overdose with no clinical symptoms requires frequent observation 
for signs and symptoms of hematoma or overt bleeding. Symptomatic treatment includes the 
administration of fresh frozen plasma or fresh whole blood. In case of excessive bleeding, 
special measures to terminate bleeding (concentrates of coagulation factors II, VII, IX or X, 
or recombinant factor VII) may be indicated, although there is limited clinical data available 
to support the application of coagulation factors.  Consideration should also be given to 


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administration of platelet concentrates in cases where thrombocytopenia is present.  All 
symptomatic treatment has to be given according to the Investigator’s judgment.
For a summary how to manage bleeding on DE see Figure 4.2.1: 1.
In cases of suspected overdose it may be required to assess the anticoagulation status of a 
patient. To maintain the blind, the determination of anticoagulation status should only be 
performed in an emergency. In general, the risk of bleeding increases with increasing plasma 
level of dabigatran: An aPTT test may be useful to assist in determining an excess of 
anticoagulant activity, despite its limited sensitivity. An aPTT of greater than 2.0 – 3.0-fold 
of normal range at trough, i.e., when the next dose is due, is associated with a higher risk of 
bleeding (U11-1855-01). In such cases, the Investigator should consider delay in the next 
intake of study medication until the aPTT is < 1.5 fold of the ULN range.
Specific reversal agent to dabigatran
A specific reversal agent (idarucizumab) has been developed and is currently being reviewed 
for registration in various countries.  When clinically indicated and available, it can be given 
to a patient in the context of a clinical trial (e.g. BI trial 1321.3) or from commercial supply 
when it becomes approved.  If the specific reversal agent for dabigatran is given, information 
surrounding the clinical circumstances, treatment and clinical outcome will be collected on 
the CRF of the appropriate trials. 
Overdose with ASA 
Overdose (i.e. an intake of a dose of ≥ 3000 mg per day) following administration of ASA 
may lead to hemorrhagic complications due to its pharmacodynamic properties. Suspected 
overdose with no clinical symptoms requires frequent observation for signs and symptoms of 
hematoma or overt bleeding.  For further information on the management of overdose with 
ASA, refer to the SPC for Hexal ASS provided in the ISF. 
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
Corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) or anti-rheumatic agents in 
general should only be used if clinically indicated and benefits are expected to outweigh 
risks. These medications may increase the risk of gastrointestinal ulcers and gastrointestinal 
bleeding. 
The patients should be advised not to use over-the-counter medications containing additional 
ASA. In case of the need for pain relief, the use of acetaminophen, diclofenac or ibuprofen 
instead of ASA should be considered where appropriate. The use of these medications should 
be limited to the absolute minimum possible time period.
Patients with known need for long-term dual antiplatelet therapy at Visit 1 are excluded from 
the trial (see Section 3.3.3, exclusion criteria). 


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The following medications should not be taken concomitantly with study drug:

ASA (commercial drug /over the counter medications) is not allowed except in the 
case of CAD where it can be taken if dispensed through IRT as outlined in Section 
4.1.6. The use of IRT-assigned ASA should be limited to the absolute minimum 
possible time period and only if clinically indicated.

Clopidogrel, ticlopidine, ticagrelor, dipyridamole, dipyridamole+ASA, or prasugrel,
and any type of dual antiplatelet therapy

Vitamin K antagonists (e.g. warfarin, phenprocoumon, acenocoumarol), direct 
thrombin inhibitors, Factor Xa inhibitors (e.g. rivaroxaban, apixaban, and edoxaban),
or other oral anticoagulants

Fondaparinux, bivalirudin 

Treatment with systemic ketoconazole, itraconazole, posaconazole, cyclosporine, 
tacrolimus, or dronedarone.

Concomitant administration of the P-gp inducers rifampicin, St. John`s wort 
(Hypericum perforatum), carbamazepine, or phenytoin, which result in decreased 
dabigatran plasma concentrations.

Treatment with parenteral anticoagulants including but not limited to any heparins 
(UFH or LMWH), and heparinoids (e.g. danaparoid), with the following exceptions: 
o
Heparins or other alternate approved parenteral therapy for initial treatment of 
suspected VTE or ACS if maximum duration is not exceeding 72 hours (see 
Section 4.2.1).

Methotrexate ≥15 mg/week
The following medications should not be taken concomitantly with study drug except in 
clinical scenarios described within Section 4.2.1:

Fibrinolytic agents (see Section 4.2.1. for exception)

GPIIb/IIIa antagonists (e.g. abciximab, tirofiban) (see Section 4.2.1 for exception).
The following medications may potentiate or attenuate the effect of the study medication and 
may only be used, if expressly instructed by a physician to treat an underlying concomitant 
disease:

antidiabetics (e.g. sulphonylurea agents)

digoxin

methotrexate <15 mg/week

valproic acid


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
aldosterone antagonists (spironolactone and canrenoate)

loop diuretics (e.g. furosemide)

ACE inhibitors

uricosuric agents (e.g. probenecid, sulphinpyrazone)

selective serotonin re-uptake inhibitors (SSRI) or selective serotonin norepinephrine 
re-uptake inhibitors (SNRIs)
Please see Appendix 10.2.2 for guidance on thrombosis prophylaxis or temporary 
requirement for a parenteral anticoagulant, which requires a temporary stop of study 
medication.
Bleeding risk may be increased in patients concomitantly treated with selective serotonin re-
uptake inhibitors (SSRI) (U11-1642-01) or selective serotonin norepinephrine re-uptake 
inhibitors (SNRIs) (U12-1072-01).
Co-administration of oral anti-platelet (including ASA) and NSAID therapies increase the 
risk of bleeding (U09-3249-02). Specifically, with concomitant intake of antiplatelets or 
strong P-gp inhibitors in patients aged ≥75 years, the risk of major bleeding, including 
gastrointestinal bleeding, increases. 
In patients ≥75 years, or with previous gastritis, history of peptic ulcer disease or previous 
gastrointestinal bleeding, the Investigator should consider prescribing a proton-pump-
inhibitor (PPI) based on the local prescribing information while receiving NSAIDs/ASA.
A list of common P-gp inhibitors and P-gp inducers, which may affect plasma concentrations 
of dabigatran, will be provided in the ISF.
If bleeding is clinically suspected, appropriate measures such as testing for occult blood in
stool, or testing for a drop in hemoglobin is suggested (U12-1072-01).  Investigators should 
assess the benefit-risk of the concomitant use of drugs that can promote bleeding, e.g., 
NSAIDs, or corticosteroids and use them only when the benefits are thought to outweigh the 
risks.
Development of an Indication for Anticoagulant Therapy During Follow-Up
If a non-AF indication for anticoagulation is identified during the course of the trial (e.g. 
venous thromboembolism), trial-assigned therapy will be discontinued, and the patients will 
be switched to an appropriate anticoagulant, which will be determined and followed by the 
patient’s local physician. See Appendix 10.2.3 on how to transition from study drug to a non-
study antithrombotic treatment.  These patients should continue to attend regularly scheduled 
visits.
If AF is identified during follow-up and the duration of AF exceeds 6 minutes (either as 
single episode or cumulative time of several episodes within 20 hours), trial treatment must 
be discontinued (but the treatment assignment blind should not be broken), and the patient 
should be switched to standard of care treatment for stroke prevention in atrial fibrillation 


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(SPAF) (e.g. DE or other) according to local label recommendations. Shorter durations of AF
may result in discontinuation of assigned treatment at the Investigator`s discretion.   These 
patients should continue to attend regularly scheduled visits.
4.2.2.2
Restrictions on diet and life style
There are no specific dietary restrictions with DE or with ASA.
4.3
TREATMENT COMPLIANCE
Patients are requested to bring all remaining trial medication including empty package 
material with them to all visits.
Treatment compliance for capsules (DE or matching placebo) and tablets (ASA and matching
placebo) will be checked by the study staff at Visit 3 and all future visits, and will be 
recorded in the eCRF. The compliance check will be based on the number of capsules/tablets 
missing (i.e. actually taken) accountability log. 
Medication compliance should be ≥ 80% but ≤ 120%. If compliance does not meet this range, 
an explanation for this deviation should be given and recorded in the eCRF. Non-compliant 
patients should be advised about the importance of taking study medication strictly as
directed. If the investigator or staff detect compliance is out of range on two occasions, the 
Investigator should notify the Sponsor. Withdrawal from treatment may then be considered 
after discussion and agreement between Investigator and Sponsor.
Decisions about evaluability of patients will be made at the Blinded Report Planning Meeting 
(BRPM) and at the latest prior to database lock. 


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5.
VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY 
5.1.1
Endpoints of efficacy
The primary endpoint in this trial is time to first recurrent stroke (ischemic, hemorrhagic and 
unspecified).
The key secondary efficacy endpoints are (both time to event endpoints): 

Ischemic stroke 

Composite endpoint of nonfatal stroke, nonfatal MI and cardiovascular death
For statistical error probability considerations for key secondary endpoints, refer to 
Section 7.3.2.
Other Secondary efficacy endpoints (all time to event endpoints):

Disabling stroke (modified Rankin Scale ≥ 4, as determined 3 months after 
recurrent stroke)

All-cause death
 
 
 
 


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5.1.2
Assessment of efficacy
5.1.2.1
Recurrent stroke
Stroke is defined as an acute episode of focal or global neurological dysfunction caused by 
brain, spinal cord, or retinal vascular injury as a result of hemorrhage or infarction (!"# $
%&'%( !") $**"*).
Retinal arterial occlusion will be considered as a stroke if the ophthalmological examination 
has been performed and the opinion of the examining ophthalmologist agrees with such a 
diagnosis.  Other retinal vascular events (e.g. retinal venous occlusion, non-confirmed retinal 
arterial occlusion), will not be considered strokes.
Ischemic Stroke
+,-./01- ,2345/ 1, 6/718/6 9, 98 9-:2/ /;1,46/ 47 74-9< -/3/=39<( ,;189<( 43 3/2189<
6>,7:8-2148 
-9:,/6 => 18793-2148 
47 -/8239< 8/3?4:, ,>,2/0 21,,:/ @!"# $%&'%( !") $**"*AB
Hemorrhage may be a consequence of ischemic stroke. In this situation, the stroke is an 
ischemic stroke with hemorrhagic transformation and not a hemorrhagic stroke.
Hemorrhagic stroke
Hemorrhagic stroke is defined as an acute episode of focal or global cerebral or spinal 
dysfunction caused by intraparenchymal, intraventricular, or subarachnoid hemorrhage (!"# $
%&'%( !") $**"*). It does not include the hemorrhagic transformation of an ischemic stroke.
Undetermined Stroke
Undetermined stroke is defined as an acute episode of focal or global neurological
dysfunction caused by presumed brain, spinal cord, or retinal vascular injury as a result of 
hemorrhage or infarction but with insufficient information to allow categorization as 
ischemic or hemorrhagic stroke.
Fatal stroke
Fatal stroke is defined as death from any cause within 30 days of stroke. 
Severity of recurrent stroke 
Severity of recurrent stroke will be assessed by mRS at the onset of stroke and at 3 months 
after recurrent stroke, if this time frame falls anytime within the study participation (See 
Section 5.3.2 for definition of mRS).  Disabling stroke is defined as a stroke with mRS ≥4 at 
3 months.


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Stroke etiology 
Investigators are asked to further classify the type of stroke according to the five etiologic 
subtypes according to modified TOAST criteria, where possible: large-artery atherosclerosis, 
cardioembolism, small-artery occlusion (lacunar), acute stroke of other determined etiology,
cryptogenic stroke (R97-1235).  The category “ESUS” will also be collected.
5.1.2.2
Systemic embolism
Systemic embolism is an acute vascular occlusion of the extremities or any organ (kidneys, 
mesenteric arteries, spleen, or grafts) and must be documented by angiography, surgery, 
scintigraphy or autopsy.
5.1.2.3
Death
Death from any cause includes cardiovascular death, non-cardiovascular-death, and 
undetermined cause of death, as classified by adjudication:
Cardiovascular death 
Cardiovascular death includes death resulting from an acute MI, sudden cardiac death, death
due to heart failure (HF), death due to stroke, death due to cardiovascular (CV) procedures, 
death due to CV hemorrhage, and death due to other CV causes.
Non-cardiovascular death 
Non-cardiovascular death is defined as any death with a specific cause that is not thought to 
be cardiovascular in nature, as listed above. These are possible examples of non-CV causes of
death:
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
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
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Undetermined Cause of Death
Undetermined cause of death refers to a death not attributable to one of the above categories
of CV death or to a non-CV cause. Inability to classify the cause of death may be due to lack 
of information (e.g., the only available information is “patient died”) or when there is 
insufficient supporting information or detail to assign the cause of death. In general, most 
deaths should be classifiable as CV or non-CV, and therefore the use of this category of 
undetermined cause of death should apply to few patients only.
 
 
 
 
 
 
 
 
 


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5.1.2.6
Venous Thromboembolism
All VTEs should have objective verification by definitive diagnostic evaluation (e.g. 
Doppler/compression ultrasound (CUS), venography).
In case of death, autopsy is an additional way to confirm VTE.
Deep Vein Thrombosis
Deep Vein Thrombosis (DVT) is generally documented by one of the following:

Abnormal CUS

An intraluminal filling defect on venography

At autopsy
Pulmonary embolism 
Pulmonary embolism is generally documented by one of the following:

An intraluminal filling defect in segmental or more proximal branches on spiral CT 
scan

An intraluminal filling defect or an extension of an existing defect or a sudden cut-off 
of vessels more than 2.5 mm in diameter on the pulmonary angiogram

Perfusion defect of at least 75% of a segment with a local normal ventilation result 
(high-probability) on ventilation/perfusion lung scan (VPLS)

Inconclusive spiral CT, pulmonary angiography or lung scintigraphy with 
demonstration of DVT in the lower extremities by CUS or venography

At autopsy


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5.1.2.8
Cardiovascular hospitalization
Hospital admission with an overnight stay in hospital, covering at least 2 consecutive dates 
which occur after randomization and was not scheduled prior to randomization, categorized 
as cardiovascular if the primary reason for hospitalization is: 

Ischemic stroke 

Hemorrhagic stroke

Unspecified stroke

Transient cerebral Ischemic Attack

Venous Thromboembolism

Myocardial infarction or Unstable angina

Stable angina pectoris or atypical chest pain

Other atherosclerosis related (if not otherwise specified)

Cardiac and vascular surgery, including transcutaneous coronary, cerebrovascular or 
peripheral procedures

Cardiac rhythm abnormalities (supraventricular or ventricular)

Worsening congestive heart failure

Major bleeding (excluding hemorrhagic stroke)

Clinically relevant non-major bleeding

Blood pressure related (hypertension or hypotension)

Syncope
5.2
SAFETY
5.2.1 
Endpoint(s) of safety
The primary safety endpoint is time to first major bleed according to ISTH criteria (R05-
0344).
Secondary safety endpoints include:


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
Time to first intracranial hemorrhage

Time to life-threatening bleed

Fatal bleed

Time to any bleed (all severities)
5.2.2
Assessment of safety
5.2.2.1
Assessment of bleeding events
Patients should be carefully assessed for signs and symptoms of bleeding. Bleeding
definitions are provided below and will be classified as major or minor. Major bleeds will be 
further sub-classified as fatal, life-threatening and other major bleeds. Minor bleeds will be 
further sub-classified CRNMBEs and non-CRNMBEs.  The location of the bleeding
including the specific critical area or organ into which the bleeding occurred and whether or 
not it prolongs hospitalization will be recorded. 
Definition of Intracranial Hemorrhage
Intracranial hemorrhage comprises the subtypes of intracerebral bleeds, subdural bleeds, 
epidural bleeds and subarachnoid bleed and will be recorded in eCRF.  Microbleeds (for 
definition see below) do not qualify as ICH, except when they are symptomatic.

Definition of a microbleed:
A cerebral microbleed is in general ≤ 5mm, but sometimes up to 10 mm, in greatest diameter 
on gradient recalled echo (GRE), or T2*, MRI sequences (R15-2999). Any blood visualized 
on a CT will be classified as a macrobleed. Asymptomatic microbleeds are incidental 
findings that do not constitute an exclusion criterion.   Irrespective of size, any cerebral bleed 
that causes focal neurologic symptoms and/or signs does not constitute a microbleed, but will 
be reported as a stroke endpoint (hemorrhagic stroke) and bleeding event (intracerebral 
hemorrhage).
Definition of a Major Bleed
Major bleeds will be defined according to the ISTH definition of a major bleed, as follows 
(R05-0344).

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 associated with a reduction in hemoglobin of at least 2g/dL (1.24mmol/L), 
or leading to transfusion of two or more units of blood or packed cells1
and/or
                                                          
1 Bleeding should be overt and the hemoglobin drop should be considered to be due to and temporally related to the 
bleeding event.


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
Fatal bleed
Definition of a life-threatening bleed
Major bleeds are to be classified as life-threatening if they meet one or more of the following 
criteria:

Fatal, or symptomatic intracranial bleed; reduction in hemoglobin of at least 5g/dL; 
transfusion of at least four units of packed red blood cells, associated with 
hypotension requiring the use of i.v. inotropic agents; necessitated surgical 
intervention.
Definition of a fatal bleed
Fatal bleeding is defined as a bleeding event that the Independent Adjudication Committee
(IAC) determines is the primary cause of death or contributes directly to death.
Definition of a minor bleed
Minor bleeds are clinical bleeds that do not fulfill the criteria for major bleeds. Minor bleeds 
will be further divided to those that are CRNMBEs, and those that are not. 
Definition of a CRNMBE
A CRNMBE is a clinically overt bleed that does not meet the criteria for a major bleed but 
prompts a clinical response, in that it leads to at least one of the following: 

A hospital admission, 
or

A physician guided medical or surgical treatment for bleeding,
or

A physician guided change, interruption1 or discontinuation of study drug. 
Definition of a non-CRNMBE
Clinical bleeds that do not meet the criteria for a CRNMBE will be classified as a non-
CRNBE.
Any bleed
This is the sum of all major and minor bleeds. 
                                                          
1 Interruption of study drug (more than omitting one dose) due to the bleeding event.


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5.2.2.2
Definition of adverse events
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence, including an 
exacerbation of a pre-existing condition, in a patient in a clinical investigation who received a 
pharmaceutical product. The event does not necessarily have to have a causal relationship 
with this treatment.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which results in death, is immediately 
life-threatening, results in persistent or significant disability / incapacity, requires or prolongs 
patient hospitalization, is a congenital anomaly / birth defect, or is to be deemed serious for 
any other reason if it is an important medical event when based upon appropriate medical 
judgment which may jeopardize the patient and may require medical or surgical intervention 
to prevent one of the other outcomes listed in the above definitions.
Intensity of adverse event
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) which is/are easily tolerated
Moderate:
Enough discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of adverse event
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. Assessment of causal relationship should be recorded in the case report forms.
For Japan: The reason for the decision on causal relationship needs to be provided in the
eCRF.
Yes:
There is a reasonable causal relationship between the investigational product 
administered and the AE. 
No:
There is no reasonable causal relationship between the investigational product 
administered and the AE. 
If a SAE is reported from a still blinded trial, the causal relationship must be provided by the
Investigator for all potential trial drugs, i.e. dabigatran etexilate and ASA.


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Outcome Events
Since efficacy and safety endpoints are considered to be disease-related or are well-known 
side effects of anticoagulation. These events are considered OEs (OEs) and will not be 
reported as SAEs on the SAE form and consequently will not be reported in an expedited 
manner to the Competent Authorities. For handling of OEs, please see Appendix 10.4.          
A key objective of the independent DMC is to protect patient safety by monitoring the 
incidence and clinical relevance of safety data including outcome events, collected 
throughout the conduct of this study.
In addition, for the safety parameters of primary interest, namely any major bleeding event 
(see Section 5.2.2.1) and for the major mortality/morbidity clinical endpoints of interest (see 
Section 5.1.2), a blinded IAC will be in place with the responsibility to confirm and classify 
events as listed in Section 3.1.1.4.
Any Outcome Event (OE) that occurs prior to randomisation and fulfils the criteria of an SAE 
will be reported as SAE in the corresponding format and timelines; however, if the patient 
has been randomized, the events will not be reported as SAEs, but only entered in the eCRF 
as OEs. 
Outcome Events are therefore defined as follows:

Any bleeding including intracranial haemorrhage

All deaths 

All MIs

All strokes

All SE

All TIAs

All DVTs

All PEs 
The Investigator (or designee) will enter these OEs (even if they meet the criteria of an SAE) 
in the corresponding OE and AE pages in the eCRF in an expedited manner. A standard 
narrative1 and any required supporting documentation (including e.g. TEE, TTE, MRI, CT,
ECG examinations, or other) must also be provided to the DMC and IAC, as defined in their 
respective process documents. 
Worsening of the underlying disease or other pre-existing conditions
Worsening of the underlying disease or of other pre-existing conditions will be recorded as an 
(S)AE in the eCRF.
Changes in vital signs, ECG, physical examination, and laboratory test results
Changes in vital signs, ECG, physical examination and laboratory test results will be 
recorded as an (S)AE in the eCRF, if they are judged clinically relevant by the Investigator.
                                                          
1 A narrative will only be requested if needed


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Residual effect period (REP)
The residual effect period (REP) is the time period after the last dose administration of trial 
medication when measurable drug levels or PD effects are still likely to be present.                
Events occurring in the REP are handled as occurring on treatment. The residual effect Period
in this trial is defined as six days after last intake of administration of trial medication.
5.2.2.3 Adverse event and SAE reporting
Except where noted otherwise in Section 5.2.2.2, all SAEs occurring during the course of the 
clinical trial (i.e., from signing the informed consent onwards through the end of the follow-
up period) will be collected, documented and reported to the Sponsor by the Investigator on 
the appropriate eCRF pages and SAE reporting forms. Non-serious AEs medically related to 
the reported SAE must also be reported on the SAE form.
Reporting will be done according to the specific definitions and instructions detailed in the 
‘Adverse Event Reporting’ section of the ISF.
For each adverse event, the Investigator will provide at least the onset date, end date, 
intensity, treatment required, outcome, seriousness, and action taken with the investigational 
drug. The Investigator will determine the relationship of the investigational drug to all AEs as 
defined in Section 5.2.2.2. All events, irrespective of their seriousness, must include an 
assessment of its causal relationship to study medication made by the Investigator.
The Investigator does not need to actively monitor patients for new adverse events once the 
clinical trial has ended. However, if the Investigator becomes aware of an SAE that occurred 
after the end of the follow-up period, the Investigator should report it to the Sponsor if he
considers it related to BI investigational product.
The Investigator must report the following events by completing the SAE form and faxing it
immediately (within 24 hours or the next business day, whichever is shorter) to the Sponsor:

Serious Adverse Events

Non-serious AEs medically related to the SAE 
Always serious Adverse Events (AEs)
BI has set up a list of AEs which are defined to be always serious. The investigator can find 
the list of these “always serious” AEs via the RDC system. In order to support the 
Investigator with the identification of these “always serious” AEs, if the investigator reports a
non-serious AE which is identified to be serious per BI definition, a query will be raised. The 
Investigator must verify the description and seriousness of the event.  If the event description 
is correct, the item “serious” needs to be ticked and a completed SAE form has to be reported 
in expedited fashion following the same procedure as above. In Japan, this information must 
be also reported immediately to the head of the trial site.
The list of these AEs can be found via the remote data capture (RDC) system. 


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With receipt of further information to any of these events, a follow-up SAE report must be 
provided. All AEs, including those persisting after trial completion, must be followed up until 
resolution or the site confirms that no further information can be obtained.
The SAE form is to be forwarded to the defined unique entry point identified for the BI OPU 
(country-specific contact details will be provided in the Investigator Site File) or by using the 
electronic submission process. This immediate report is required irrespective of whether the 
investigational product has been administered or not and irrespective of causal relationship. It 
also applies if new information to existing SAEs or protocol-specified significant events 
becomes available.
Pregnancy
In rare cases, pregnancy might occur in clinical trials. Once a female subject has been 
enrolled into the clinical trial, after having taken study medication, the Investigator must 
report immediately any drug exposure during pregnancy to the Sponsor. Drug exposure 
during pregnancy has to be reported immediately (within 24 hours or next business day 
whichever is shorter) to the defined unique entry point for SAE forms of the respective BI 
OPU (country-specific contact details will be provided in the ISF). 
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up. In the absence of an (S)AE, only the Pregnancy Monitoring Form for Clinical 
Trials and not the SAE form is to be completed. The ISF will contain the Pregnancy 
Monitoring Form for Clinical Trials (Part A and Part B).
5.2.3
Assessment of safety laboratory parameters
An abbreviated hematology panel and chemistry panel including liver and renal function 
testing will be analyzed for safety at specific time-points throughout the trial by a certified 
central laboratory. With the exception of early randomization after index event of stroke (see 
below), all pre specified laboratory tests will be performed by a central laboratory. 
Exception: It is permitted to randomize patients based on local lab results in exceptional 
cases, specifically when the regular turnaround of central lab results would result in a delay 
of start of study medication early after index stroke event. If local lab results are used, 
central laboratory samples must also be collected from all patients to provide a baseline for 
the study.  This should preferably occur at Visit 1, however, it can alternatively be collected 
at Visit 2 prior to first study drug intake. Randomization based on central lab results is 
strongly encouraged and preferred. The central laboratory will provide the required materials 
for processing the samples, and will also provide instructions regarding centrifugation, 
processing, storage and shipment of samples (as outlined in a Laboratory Manual). Results of 
the central laboratory analyses will be uploaded directly into the trial database. In addition, 
the Investigator will receive a laboratory report for information on a per visit basis. Clinical
significance including any related comments will be entered directly in the eCRF.
If any of the results are judged as being clinically significant by the Investigator, the
Investigator should consider whether the result should be recorded as an AE. If deemed
necessary, laboratory parameters may be retested or followed as unscheduled tests.


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Unscheduled tests should be performed by the Central Laboratory unless immediate results
are required for the patient’s safety.
Blood samples will be collected for the following tests in accordance with the visit Flow
Chart: 
Chemistry       
Hematology 
Other
ALT (SGPT)
Hemoglobin
PK
AST (SGOT)
Hematocrit
Biomarkers 
Alkaline Phosphatase
LDH
GGT
Platelet Count
Erythrocytes  
White Blood Cells
Assay Validation
Bilirubin, Total
Indirect Bilirubin*
Creatinine
Creatinine Clearance**
Sodium
Potassium
Urea
Total Protein
Albumin
* Indirect Bilirubin only reported if total bilirubin is elevated
** According to Cockcroft-Gault formula
In addition to the determination of creatinine clearance according to the Cockcroft-Gault 
formula, which represents the primary measure for renal function estimation, the glomerular 
filtration rate (GFR) will be assessed by Modification of Diet in Renal Disease (MDRD) and 
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations (R12-1392). 
GFR according to MDRD and CKD-EPI will not be used for dosing decisions in this trial.
Pregnancy testing
Women of child bearing potential must have a urine pregnancy test at screening, at each 
study visit in the clinic and at least 7 days after the EOT visit.  A urine dipstick test will be
given to the patient at the EOT visit for use by the patient at least 7 days after the EOT.  The 
patient will be asked to report the result to the site at the post treatment follow-up phone call.
Renal Function Measurements
Creatinine clearance (in mL/min) will be calculated based upon a single blood sample 
generally using the Cockcroft-Gault formula, as follows:


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For creatinine in micromol/L:
Males:
     (140-age) x weight (kg) x 1.23 
                               Creatinine [micromol/L]
Females:
0.85 x (140-age) x weight (kg) x 1.23 
        Creatinine [micromol/L]
For creatinine in mg/100 mL:
Males:
     (140-age (years)) x weight (kg) 
72 x serum creatinine (mg/100 mL)
Females:
0.85 x (140-age (years)) x weight (kg)
     72 x serum creatinine (mg/100 mL)
Creatinine Clearance value at Visit 1 and during the trial will determine the dose of DE (or 
placebo) assigned to the patient. Assignment of dabigatran dose (110 mg or 150 mg b.i.d.) is 
based upon renal function as measured by the CrCl (see Section 4.1.3 for details).  See 
Section 3.3.4.1 regarding rules for stopping study drug when CrCl falls below 30 mL/min.  
Investigators should be aware that patients with decreased renal function may experience a 
prolonged elimination of study drug (specifically dabigatran) and steady state levels could 
increase compared to a patient with normal renal function.  Such patients are therefore at 
increased risk for bleeding.  
For patients on study drug with borderline creatinine clearance, physicians should consider 
conducting (per standard of care) more frequent monitoring of creatinine clearance than 
required by this protocol to ensure that CrCl does not drop below 30 mL/min.
5.2.4
Electrocardiogram
A 12-lead ECG is collected at Visits 1, 6, 10 and at the EOT Visit. At all other Visits, a 12-
lead ECG should be performed if palpation of the pulse indicates irregular rhythm or 
symptoms of irregular pulse have been reported. If any ECGs are performed during the 
course of the trial as part of patient normal care and demonstrate a clinically relevant change 
from the previously recorded ECG or a newly developed pathology, this should be 
documented in the eCRF. 
Copies of all ECGs and reports form cardiac monitoring will be provided to the Sponsor’s 
designee.


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5.2.5
Assessment of other safety parameters
5.2.5.1 Full Physical Examination
A full physical examination will be completed on all patients at screening (Visit 1) and this 
will be repeated at the end of the study. The physical examination will include auscultation of 
cardiac sounds, which will be performed with the patient seated after having rested for at 
least five minutes. All clinically relevant abnormal findings at the screening visit will be 
recorded on the Medical History/Baseline Conditions eCRF page. New abnormal findings or 
worsening of baseline conditions detected at follow-up physical examinations will be 
recorded as AEs on the appropriate eCRF page. All AEs, including those persisting after trial 
completion must be followed up until they have resolved or have been sufficiently 
characterized. 
5.2.5.2
Vital Signs
Vital Signs will include seated SBP and DBP after 5 minutes in the sitting position and pulse 
rate (PR) in beats per minute.  For patients who cannot sit, supine BP is acceptable.  
Recording of vital signs also includes sitting heart rate with palpation of the pulse for one
minute.  A subsequent 12-lead ECG should be done if an irregular rhythm is detected or if the 
patient informs the Investigator about irregular heartbeats (see Section 5.2.4 above).  
 
 
 
 
 
 
 


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5.4
APPROPRIATENESS OF MEASUREMENTS
Efficacy endpoints
This study is powered for all strokes as the primary endpoint. Although the trial is not 
powered for other morbidity/mortality endpoints, it is appropriate to collect data on death, 
stroke, TIA, SE, VTE and MI.
Safety endpoints
The key safety endpoint in this trial is major bleeding, as categorized using the ISTH 
definition (which is very similar to that used in CURE (R02-1059), ESTEEM (R03-2266) and 
the Sponsor’s large phase III trial in the AF population, RE-LY (U09-3249-02). 
Classifications of bleeding events will be confirmed by the IAC and provided on an on-going 
basis to the DMC.  
 
 
 
 
 
 
 
 
 
 
 
                                                          
 


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Informed consent of all study patients will be obtained in compliance with ICH and GCP 
guidelines and the principles stipulated in the Declaration of Helsinki prior to any study 
related procedure.
The study will consist of three sequential periods, a Screening period of up to 14 days, a 
Treatment Period of approximately 6-36 months and a Follow up Period of one month.  The 
maximum treatment duration is expected to be 36 months, however, the trial can conclude 
earlier, if adequate number of events are reported sooner.  It can conclude later (or enroll 
additional patients) if more time is needed to observe the minimum number of required 
events.
The schedule for trial visits is summarised in the study Flow Chart including time windows
for study visits. All visit dates are calculated from the date of randomisation. In the event that 
visits are missed or out of sequence, subsequent visits will be planned according to the date 
of randomisation.
No protocol waivers will be given (e.g.  Sponsor will not grant permission to include a known 
ineligible patient). In the case of medical emergencies, prior approval from the Sponsor for 
protocol deviations (e.g. visit schedule) will not be required, but BI should be notified as soon 
as possible. The relevance of any such protocol deviation will be assessed prior to analysing 
the data.
The procedures to be conducted at each visit are provided in the Flow Chart and further 
described below.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening and run-in periods
The investigations outlined in Table 3.3.1: 1 are to be completed and documented per 
standard of care as a prerequisite to consideration for study participation.  (Note: a minimum 
of 20 hours cardiac monitoring is required for enrollment).  
Once ESUS is confirmed, a patient can be considered for eligibility and approached to assess 
their interest in volunteering as a participant in this trial. Written informed consent must be 
obtained prior to any study specific procedures.
The screening visit (see Flow Chart) will include review of medical history, demographics, 
inclusion/exclusion criteria, physical exam, vital signs (including BP and heart rate), ECG, 
urine pregnancy test for women of child-bearing potential who are not sterilized, safety 
laboratory tests collected according to central laboratory instructions, weight, and 
concomitant medications reviewed.  The MoCA test will also be performed. Modified Rankin 


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Scale/NIHSS will be determined and recorded. If the patient has a mRS >3 at time of 
qualifying stroke but the value improves to < 3 within 3 months (6 months for patients aged ≥ 
60 years plus additional risk factor), the patient can be considered for enrollment. A PK 
sample (and optional samples for biomarker assessment and assay validation for participating 
patients) will additionally be taken (this must occur prior to first intake of study drug).
All patients will have baseline blood samples sent to the central laboratory (preferably at 
Visit 1).  Randomization based on central lab results is strongly encouraged and preferred. 
However, local laboratory test results that have been collected within 14 days prior to 
randomization can also be used to verify eligibility (blood must additionally be collected and 
sent to central lab for analysis). In these exceptional cases it is permitted to randomize
patients based on local lab results. Local lab results must include at a minimum: hemoglobin, 
platelet count, creatinine, creatinine clearance, and LFTs (ALT (SGPT), AST (SGOT), AP, 
total bilirubin).
Detailed results of the required diagnostic imaging for the index stroke (from diagnostic 
evaluations specified in Table 3.3.1: 1) must be available in the source notes for all patients 
and in the case of recurrent stroke or death must also be provided to the Sponsor or Sponsor`s 
designee as part of the adjudication package.  All of the required diagnostic examinations
related to the index stroke must be completed prior to randomization.
Patients with mRS of 1, 2 or 3 at time of randomization who are scheduled for initiation of
study medication within 10 days of index event require repeat imaging of the brain to rule out 
bleeding into the brain (per Exclusion #6).  This repeat imaging must occur prior to 
randomization.
For sites participating in the Imaging substudy, brain images (i.e. CT, CT-angiography, MRI, 
MRI angiography, or other) related to the index stroke event and any imaging performed
during the trial (plus corresponding reports) must be provided to Sponsor’s designee where 
possible (see also Appendix 10.6).
6.2.2
Treatment periods
All tests for the visits in the treatment phase are detailed in the Flow Chart.
After eligibility has been confirmed and all Visit 1 procedures completed, Visit 2 can be 
conducted including randomization via IRT. IRT should not be called in advance of Visit 2, 
as randomization of a patient cannot be reversed.
At the start of Visit 2, it should be ensured that all Visit 1 procedures have been successfully 
completed within the past 14 days.
Randomization can occur as soon as patient eligibility is confirmed, and up to a maximum of 
3 months after the qualifying stroke (or 6 months in patients ≥ 60 years of age with one 
additional risk factor as noted in Inclusion Criterion 2b). Visit 2 procedures are outlined in 


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the Flow Chart and include randomization, collection of vital signs and recording of 
concomitant therapies of interest.  
Restricted medications as outlined in Section 4.2.2 will be stopped. Study medication will be 
dispensed and should be initiated as outlined in Section 4.1.4 and Table 4.1.4: 11.  AEs, 
SAEs and OEs (after randomization) will be collected as described in Section 5.1 and Section 
5.2.
Treatment visits will take place every three months during the first year of the trial and every 
six months thereafter (with interim telephone contacts between visits).
Unscheduled visits will be possible at any time, specifically in the first 3 months after 
treatment initiation, in order to check the safety of the patient including a potential worsening 
of renal function (CrCl). It is at the discretion of the investigator to perform an unscheduled 
visit including safety laboratory assessments, if deemed necessary.
Labs do not need to be drawn on the actual day of the visit.  They may be drawn earlier as 
long as it is within the visit window.
Heart rate must be checked at all follow-up visits by palpation of the pulse. If palpation of the 
pulse indicates irregular rhythm or symptoms of irregular pulse have been reported, a 12-
lead ECG must be done and additional cardiac monitoring may be performed at the 
Investigator`s discretion. If the pulse is normal and no symptoms are reported, a follow-up 
ECG is not necessary.
A 12-lead ECG should be performed at Visits 6 and 10. ECGs done per standard of care that
demonstrate a change compared to the previously recorded ECG or a newly developed 
pathology, should be recorded in the eCRF.  
Copies of all ECGs documented on the eCRF should be provided to the Sponsor’s designee. 
Additional cardiac monitoring (e.g. Holter-ECGs) may be performed at the discretion of the 
Investigator according to local standard of care. The results of these cardiac monitoring 
efforts will be documented in the CRF. Results obtained from implantable cardiac monitors 
will also be captured.
Permanent study drug discontinuation is only justified when clear, persistent 
contraindications arise or when the patient requests to be withdrawn from study drug, see 
Section 3.3.4.1.
All randomized patients must be followed up until the end of the study. Patients who 
discontinue treatment must continue to be followed up according to the visit schedule until 
the end of the study. At these visits collection of AEs, OEs (including bleeding) and use of 
concomitant medication of interest will be made. 
                                                          
1 As a reminder, if a patient has mRS of 1, 2 or 3 at time of randomization and study medication is to be started 
within 10 days of index event, repeat imaging is mandatory to rule out bleeding into the brain. Randomization 
should only occur after reimaging of the brain has been performed and eligibility has been confirmed.  Refer to 
Table 4.1.4: 1 for details.


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Patients that are not actively taking study drug may be less motivated to adhere to the study 
visit schedule.  Investigator and site staff should work to detect early signs of losing interest 
and readily present such patients (not actively taking study drug) with the following 
opportunities to encourage continued participation:

continue to attend regularly scheduled study visits until the trial ends

conduct only the final visit in person. All other visits would be done over the phone. 

conduct all remaining study visits over the phone 

discontinue participation in remaining trial activities but collect vital status and OEs at 
the end of the trial.

discontinue participation in remaining trial activities but permit collection of vital 
status at the end of the trial.
According to regulatory agencies’ recommendations, the Investigator should inform subjects 
that withdrawal of consent for follow-up will jeopardize the validity of the study. Therefore 
the patient will be asked to choose the most rigorous follow-up they are willing to comply 
with.
The site must make periodic documented attempts (at least every three months) to locate 
patients who are potentially lost to follow-up (LTFU). 
6.2.2.1
Interim Telephone Calls
After year one, interim telephone calls will be made to patients (at Visits 7, 9, 11 and 13).  
Phone calls will be scheduled 3 months after each regular office visit. During the phone calls, 
AEs, SAEs, and OEs will be collected and recorded in the eCRF.
6.2.3
End of trial and follow-up period
6.2.3.1
End of Treatment Visit
At the time that study drug is permanently stopped (whether this is done prematurely or due 
to the end of the trial), the EOT visit should be completed.  Study drug should be stopped and 
all unused study drug collected.  A 12-lead ECG should be performed.
The need to transition to non-study antithrombotic treatment should be determined by the 
clinical Investigator or treating physician taking current guidelines into consideration (see 
Appendix 10.2.3 for guidance on transition to a non-study antithrombotic medication). If the 
patient will be switched to ASA, the first dose of non-study ASA can be taken on the day the 
last dose of study drug was taken. Patients who continue study medication until the Final 
Visit must have EOT and Final Visit assessments done at the same visit. In these cases, it is 
expected that EOT and Final Visit eCRFs will be completed at the Final Visit. Refer to Flow
Chart for required assessments.  


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6.2.3.2
Final Visit 
Refer to Flow Chart for list of required assessments at the final visit. For patients that are on 
treatment at the end of the trial, the EOT and Final Visit assessments can be done at the same 
visit. The MoCA test will also be performed.
It will be documented whether the patient had received an implantable cardiac monitor for 
continuous cardiac monitoring during the course of this trial, including the results from this 
long-term cardiac monitoring.
6.2.3.3
Post Treatment Phone Call 
For all patients that stopped study drug at the Final Visit, a follow-up phone call will be 
conducted one month later.  During this call, concomitant medications of interest, AEs, SAEs 
and OEs during the 30 day period after last dose of study drug will be recorded in the eCRF.
Patients that permanently discontinued study drug within a month preceeding another
scheduled visit do not need to have this additional phone call. Their follow-up information, 
(inclusive of information about the month after their last dose of study drug) will be collected 
at their next scheduled visit. A urine dipstick pregnancy test performed by select patients (i.e. 
only in WOCBP) after the EOT with urine dipstick result to be reported back at Post 
Treatment phone visit.
6.2.3.4
Vital Status and Event Collection
It is important to record the vital status and adverse events -including Outcome Events- of all 
randomized patients at the end of the trial. It is critical that every randomized patient is 
followed until the end of the trial, even if study medication is never taken. If a patient does 
not attend the final visit for any reason, the site will contact them to assess their vital status, 
adverse events and OEs.   
If a site has difficulty contacting a patient at the end of the trial (or at any time during the 
trial), site staff should make reasonable attempts to contact the patient using different 
methods (e.g. phone, email, certified letter and/or other methods) until the patient is 
successfully contacted or the study ends.  In the absence of reaching the patient directly, 
alternative approaches which are allowable via local regulations and IRB/IEC should be used 
to establish vital status (at minimum) and incidence of recurrent stroke (where possible). It is 
good practice to specify in the informed consent form what processes are permitted by local 
regulations to establish vital status for patients that cannot be reached via phone for this visit 
(e.g. review of public databases, contacting primary care physician, contacting family
member, etc).
6.2.3.5
Withdrawal of consent 
Patients that discontinue medication and express desire to reduce degree of participation 
should be presented with alternative follow-up options as described in Section 6.2.2.  


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If a patient is not willing to continue in the trial and withdraws consent for any reason 
(without the need to justify the decision) prior to the end of the trial, an EOT Visit and Final 
Visit should be scheduled as soon as possible.  A 30 day follow-up phone call should also be 
conducted if the patient is agreeable.
In rare cases where patients withdraw consent from any further follow-up, no more data on 
their medical information will be requested directly from the patient.   Where permitted by 
local law, regulatory authorities and Ethics Committees, vital status information may be 
obtained via other means (e.g. medical records, public databases).


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
This is a prospective, multi-center, international, randomized, double blind, parallel-group 
study aiming to show superiority of DE over ASA as an active control in the prevention of 
recurrent stroke in patients with recent history of ESUS. Eligible patients will be randomized
to DE (110 or 150 mg b.i.d. dose – actual dose will be determined by algorithm which 
accounts for age and renal function) or ASA 100 mg once daily.
The primary outcome is time to any recurrent stroke (ischemic, hemorrhagic, or unspecified).  
Key secondary endpoints are time to first ischemic stroke, and time to the first occurrence in 
the composite endpoint of “nonfatal stroke, nonfatal MI, and cardiovascular death”.  
Multiplicity will be addressed using a list of hierarchical tests.
Time to event endpoints will be analyzed using the Cox model with covariates age, renal 
impairment, and stroke or TIA prior to index stroke (refer to Section 7.3.1 for details).
7.2
NULL AND ALTERNATIVE HYPOTHESES
The hypotheses for the primary and key secondary endpoints are:
Ho: HRDabigatran/ASA = 1
vs.
Ha: HR Dabigatran/ASA ≠ 1
Tests will be performed at the two-sided α = 0.05 level.
7.3
PLANNED ANALYSES
Two patient populations are defined:

The randomized set (RS) consists of all patients who were randomized, 
regardless of whether they took study medication.  The start date of the 
observation period for this population is the date of randomization.

The treated set (TS) consists of all patients who were treated with at least one 
dose of study medication.  The start date of the observation period for this 
population is the date of first intake of trial medication.
Two follow-up periods are defined:

Full follow-up: until the end of the trial, including all observed time on and off 
trial medication until the last known alive date (or date of death)

On-treatment: until the date of discontinuation of trial medication + 6 days
When composite endpoints are evaluated as survival endpoints, the time to first onset date of 
any of the events listed in the composite endpoint will be used as the date of the event. For 


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combined endpoints of nonfatal and fatal events the time to the first event is taken.  If the 
fatality is the first event, then the time to death (not the time to the event leading to death) is 
taken.
7.3.1
Primary analyses
The primary endpoint is time to first recurrent stroke (ischemic, hemorrhagic, or unspecified)
as determined by the adjudication committee.  It will be analyzed using the Cox proportional 
hazards regression model.  Covariates included in the model will be age (binary, < or ≥ 75 
years), renal impairment (binary; creatinine clearance < or ≥ 50 mL/min), and stroke or TIA 
prior to index stroke (binary, “yes” or “no”).
The primary analysis will be performed on the RS for the full follow-up period.  Patients who 
discontinue study medication will be followed until the end of the trial for OEs including 
vital status.  Patients who are lost to follow-up for vital status will be censored for the 
primary endpoint of recurrent stroke at the time of their last known alive date.
 
7.3.2
Secondary analyses
The key secondary efficacy endpoints are: 

Time to first ischemic stroke 

Time to first occurrence of nonfatal stroke, nonfatal MI, or cardiovascular 
death
Key secondary endpoints will be analyzed in a hierarchical manner to preserve the Type I 
error.  If the test for the primary endpoint is successful, then testing will continue for the first 
key secondary endpoint of time to ischemic stroke with two-sided α=0.05.  If this test is 
successful, then the second key secondary endpoint of time to nonfatal stroke, nonfatal MI, 
and cardiovascular death will be tested with two-sided α=0.05.  If at any point, the null 
hypotheses for the primary or key secondary endpoints cannot be rejected, formal testing will 
stop.
Other Secondary efficacy endpoints are listed in Section 5.1.1.  Key secondary and other 
secondary endpoints will be analyzed using the same Cox proportional hazards regression 
model (with covariates) as the primary endpoint.  All secondary analyses will be performed 
on the RS population for the full follow-up period.


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No multiplicity adjustments are planned for other secondary endpoints.  Nominal p-values 
will be reported for descriptive purposes.
 
 
 
 
 
7.3.3
Safety analyses
Analysis of all bleeding endpoints (as listed in Section 5.2.1) will be performed on the TS
population for the on-treatment period. The pre-specified bleeding endpoints will also be 
analyzed using the RS set as a sensitivity analysis and for publication purposes. 
Time to event endpoints will be analyzed using the same Cox proportional hazards regression 
model as the primary endpoint.  No multiplicity adjustments are planned for safety endpoints.  
Minor bleeds and CRNMBE will be presented using descriptive statistics.
Adverse events will be analyzed from the TS population.  AEs recorded prior to first intake 
of trial medication will be assigned to 'screening'. The REP is 6 days (refer to Section
5.2.2.2). All adverse events with an onset after the first dose of study medication up to a 
period of 6 days after the last dose of study medication will be assigned to the on-treatment 
period for evaluation. Those after the REP, but prior to the last per protocol contact will be 
assigned to 'post treatment", and those after the last per protocol contact will be assigned to 
‘post-study’. The same applies for planned measurements (e.g. vital signs or laboratory 
parameters) with the exception that measurements between start and last per protocol contact 
will be assignment to the corresponding treatment. These assignments including the 
corresponding time intervals will be defined in detail in the TSAP.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) coding dictionary. Standard BI summary tables and listings will be produced to 
compare the incidence of adverse events. 
Laboratory data will be analyzed both quantitatively as well as qualitatively.  The latter will 
be done via comparison of laboratory data to their reference ranges.  Values outside the 
reference range as well as values defined as clinically relevant will be highlighted in the 


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listings.  Treatment groups will be compared descriptively.  Even if randomization occurred 
based on local lab, Visit 1 results of the central laboratory analyses will be used for the 
analyses.
7.3.4
Interim analyses
No formal interim analyses are planned.  Refer to Section 3.1.1.3 for details about interim 
monitoring by the DMC.
A blinded sample size reassessment with the option to adjust the sample size will be 
performed by the Sponsor’s Trial Statistician based on continuous assessment of the 
enrollment rate and the OE rate. Using data from a previous recurrent stroke trial (PRoFESS), 
a projection of recurrent strokes will be created using a Kaplan-Meier plot. As blinded data 
from the present trial comes in, this projection will be refined to predict when the projected 
number of OEs will occur.  If the prediction is lower than expected, a decision will be made 
by the Executive Committee and Sponsor whether to increase the sample size, number of 
sites or extend the duration of the trial.  Final determination will occur no later than three 
months prior to discontinuation of enrollment.
 
 
 
 
 
 
 
 
 
 
 
 
7.4
HANDLING OF MISSING DATA
A major goal of the trial is to obtain virtually complete follow-up of vital status and all other 
OEs.  As mentioned in Section 7.3.1, all patients lost to follow-up will be treated as censored 
at the time of last known vital status.


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No missing data will be imputed for the primary and secondary time to event endpoints.
Regarding covariates for the Cox model, age and creatinine clearance are mandatory for trial 
entry, so these variables will not be missing.  If prior stroke or TIA data are missing, the 
patient will be assumed to have no stroke or TIA prior to index stroke (for the purpose of 
inclusion into the analysis only), thus no covariate data will be missing for purposes of 
analyzing the Cox model. 
 
 
7.5
RANDOMISATION
Patients will be randomized to a double-blind treatment arm in a 1:1 ratio. BI will arrange for 
the packaging and labeling of study medication.  The randomization list will be generated 
using a validated system using a pseudo random number generator so that the resulting 
treatment will be both reproducible and non-predictable.  The block size will be documented 
in the CTR.  Access to the codes will be controlled and documented.  
7.6
DETERMINATION OF SAMPLE SIZE
The expected yearly event rate for stroke in the ASA group of ~4.1% was informed by:

In the subset of patients with prior stroke/TIA in AVERROES the yearly event rates 
on ASA and apixaban were 8.3% and 2.5% respectively (R11-0578).

In the subset of patients with prior stroke/TIA in RE-LY the yearly event rates on 
warfarin, DE110 and DE150 were 2.8%, 2.1% and 2.3% respectively (P10-12861).

In PRoFESS the yearly event rates on Aggrenox® and clopidogrel in patients with 
stroke of undetermined source were 4.06% (U08-3667-01, and data on file).

Recurrence rates are in general higher early after the index event of stroke (i.e. over 
the first 3-6 months) and decline thereafter (U08-3667-01, and data on file).
To estimate the expected yearly event rate for stroke in this trial, data from a subset of 
PRoFESS patients with stroke of undetermined etiology (15.5% of patients in PRoFESS, 
mean age 66.7 y) was reviewed.  While the hazard of recurrent stroke was 4.1 on average, it 
was higher early after randomization (note that most patients had entered PRoFESS within 3 
months after the index stroke event, as it is planned for the majority of patients in this trial)
and decreased over time. The table below displays, for 6-month time intervals, the calculated 
yearly event rates observed in PRoFESS, the expected percentages of patients who enter the 
respective intervals (according to the planned recruitment schedule and the prospected length 
of this trial), and the expected number of events per interval assuming a 30% risk reduction 
favoring DE:


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Table: 7.6: 1
Estimated events per interval throughout the trial
Time since randomization
1 -  6 
months 
7 – 12 
months 
13-18 
months 
19 – 24 
months 
25 – 30 
months 
31 – 36 
months 
Total 
trial 
period
Yearly 
event rate
7.4% 
3.2% 
2.5% 
2.5% 
2.5% 
2.5% 
4.1%
Patients 
per 
interval 
100% 
90% 
70% 
50% 
30% 
10% 
100%
Events 
per 
interval*
193 
71 
42 
29 
16 
3 
353
* both treatment groups
Considering the decline of event rates over time, various patient population sizes were 
considered as shown in the table below. 
This review informed the estimation that 2.5 years recruitment, 3 years total observation of 
approximately 6000 patients with 353 events will give ~92% power if the risk reduction is 
30%.   
Table: 7.6: 2
Number of events and power required for varying hazard ratios and 
sample sizes
Hazard Ratio
Total sample size 
0.80
0.75
0.70
0.65
5000 patients 
311 / 50%
303 / 71%
294 / 86%
286 / 95%
6000 patients*
373 / 58%
363 / 78%
353 / 92%
343 / 98%
7000 patients 
435 / 64%
424 / 84%
412 / 95%
400 / 99%
8000 patients 
497 / 70%
484 / 89%
471 / 97%
457 / 99%
* These are approximations, as this is an event driven trial requiring 353 primary OEs to be reported to be 
sufficiently powered.  The actual number of patients entered may increase or decrease based upon actual event 
rate. As this is an event driven trial, the trial can conclude earlier, if adequate number of events reported sooner 
or later, if more events are needed. Sites will be notified when recruitment ends.  


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To protect against deviations from the assumption, the study will be event-driven and will be 
terminated when 353 OEs have been reported.
Regarding the impact of patients who develop AF during the study, the following additional 
information is given:

A rate of ~ 10% of AF detection is expected during the course of the trial 
(2.5 years recruitment, 3 years total observation).

Patients in whom AF is detected during the study need to be switched to standard of 
care antithrombotic treatment as considered appropriate by their Investigator), but will 
be observed until the end of the trial.

Treatment with an anticoagulant may reduce the event rate in the ASA arm and dilute 
the extent of risk reduction with DE.

Assuming a = the rate of new AF patients (switchers ), and further assuming that 
detection of AF is uniformly distributed across study length, then the observed hazard 
rate is: HR_obs = HR / (1- a/2·(1-HR)). With a 10% overall detection rate of AF, the 
HR increases from 0.70 to 0.711. See Table 7.6: 3.
Table 7.6: 3
Hazard ratio required taking undetected AF into account
Hazard Ratio
0.80
0.75
0.70
0.65
Rate of 
AF 
detection
10%
0.808
0.759
0.711
0.662
20%
0.816
0.769
0.722
0.674
30%
0.825
0.779
0.733
0.686
The slightly higher HR of 0.711 will have a limited impact on the power of the trial. For a 
risk reduction of 30% (in a total of 6000 patients) a power of 92% is achieved; the power will 
be 90% if the risk reduction is 29%.


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8. INFORMED CONSENT, DATA PROTECTION, TRIAL RECORDS
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonized Tripartite Guideline for 
GCP and relevant BI Standard Operating Procedures (SOPs). Standard medical care 
(prophylactic, diagnostic and therapeutic procedures) remains in the responsibility of the 
treating physician of the patient.
The Investigator should inform the Sponsor immediately of any urgent safety measures taken 
to protect the study patients against any immediate hazard, and also of any serious breaches 
of the protocol/ICH GCP. The rights of the Investigator and of the Sponsor with regard to 
publication of the results of this trial are described in the Investigator contract. As a general 
rule, no trial results should be published prior to finalization of the CTR.
The rights of the investigator and of the sponsor with regard to publication of the results of
this trial are described in the investigator contract. As a general rule, no trial results should be
published prior to finalisation of the Clinical Trial Report.
Insurance Cover: The terms and conditions of the insurance cover are made available to the 
Investigator and the patients via documentation in the ISF (where applicable).
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and
approved by the respective IRB / IEC and CA according to national and international 
regulations. The same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the Investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.
For Japan:  The Investigator must give a full explanation to trial patients including the items
listed below in association with the use of the patient information form, which is prepared
avoiding the use of technical terms and expressions. The patient is given sufficient time to
consider participation in the trial. The Investigator obtains written consent of the patient’s
own free will with the informed consent form after confirming that the patient understands the
contents. The Investigator must sign (or place a seal on) and date the informed consent form.
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.


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The following items need to be included:
1. That the clinical trial is aimed at testing.
2. Objectives of the trial.
3. The name, title, and address of the investigator to contact.
4. Trial procedures.
5. Anticipated benefits of the investigational products and anticipated disadvantages to 
the patient.
6. Matters concerning other therapeutic measures.
7. Duration of participation in the clinical trial.
8. That the patient may withdraw from the trial at any time.
9. That patient’s refusal of or withdrawal from participation in the trial does not cause 
any disadvantage to him or her.
10. That the monitors, the auditors, and the institutional review board are given access to the 
relevant source documents on condition that confidentiality of the patient is fully 
secured.
11. That privacy of the patient is kept.
12. The office of the medical institution to contact in the event of trial-related injury.
13. That necessary treatment is available to the patient in the event of trial-related injury.
14. Matters concerning compensation in the event of any trial-related injury.
15. The type of the IRB which is used for the reviews and deliberations on the matters
such as appropriateness of conducting the clinical trial, the matters to be reviewed and 
deliberated by each IRB, and other matters concerning the IRBs involved in the
clinical trial.
16. Other necessary matters concerning the clinical trial.
The patient must be informed that his/her personal trial-related data will be used by BI in 
accordance with the local data protection law. The level of disclosure must also be explained 
to the patient.
The patient must be informed that his / her medical records may be examined by authorized 
monitors (CML/Clinical Research Associate (CRA)) or Clinical Quality Assurance auditors 
appointed by BI, by appropriate IRB / IEC members, and by inspectors from regulatory 
authorities.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the Sponsor or 
Sponsor’s designees or by IRBs/IECs or by regulatory authorities. The quality assurance 
auditor will have access to all medical records, the Investigator’s trial-related files and 
correspondence, and the informed consent documentation of this clinical trial.
In order to ensure accurate, consistent, complete and reliable data the following measures will 
be taken:

Representatives from each site will have the opportunity to attend or review material 
from an Investigator Meeting at which trial processes will be discussed.


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
Central laboratory measurements are used for all blood samples (for exception see 
Section 5.2.3)

Centralized adjudication and assessment ensures a consist allocation of clinical 
endpoints

Regular onsite monitoring

Coding of concomitant medications is according to the WHO Drug Dictionary and 
coding of adverse events is according to the MedDRA dictionary.

O929 0989F/0/82 ;34-/6:3/, 24 /8,:3/ 2./ P:9<12> 47 2./ 6929 93/ 6/,-31=/6 18 6/291< 
18 2./ 2319< 6929 0989F/0/82 986 989<>,1, ;<98 @LOMQCA R.1-. 1, 9?91<9=</ 18 2./ 
JLMS

Steps to maintain the blind (refer to Section 4.1.5.1)
8.3
RECORDS
Electronic Case Report Forms for individual patients will be provided by the Sponsor, via 
remote data capture. See Section 4.1.5.2 for rules about emergency code breaks. For drug 
accountability, refer to Section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site.
Data entered in the eCRFs that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The Investigator may need 
to request previous medical records or transfer records, depending on the trial; current 
medical records must be available. Medical records must demonstrate eligibility.
For eCRFs all data must be derived from source documents.
In addition the following copies will need to be provided to the Sponsor:

Screening ECGs (including reports of cardiac monitoring) and ECGs with clinically 
relevant changes detected during the course of the study should be provided to the 
Sponsor`s designee.

For sites participating in the Imaging Substudy: Magnetic Resonance Image/CT 
reports and images for the index event of stroke, possible re-imaging done before 
randomization and any imaging related to recurrent stroke will be analyzed by the 
Sponsor`s designee. In addition MRIs (or CTs, if MRIs are not available) performed 


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during clinical routine (and corresponding reports) will be collected. (see Appendix 
10.6).

For events requiring adjudication (as noted in Section 3.1.1.4), supporting 
documentation and imaging (as needed and available) must be provided.

In the case of recurrent stroke or death detailed results of the required diagnostic 
imaging for the index stroke must also be provided as part of the adjudication 
package. 
8.3.2
Direct access to source data and documents
The Investigator / institution will permit trial-related monitoring, audits, IRB / IEC review 
and regulatory inspection, providing direct access to all related source data / documents. 
Electronic Case Report Forms and all source documents, including progress notes and copies 
of laboratory and medical test results must be available at all times for review by the 
Sponsor’s clinical trial monitor, auditor and inspection by health authorities (e.g. Food and 
Drug Administration (FDA)). The CRA / on site monitor and auditor may review all eCRFs, 
and written informed consents. The accuracy of the submitted data will be verified by 
reviewing the documents described in Section 8.3.1.
8.3.3
Storage of records
This section is only relevant to sites located in Japan only.
Storage period of records
Trial sites: 
The trial sites must retain the source documents and essential documents for a period defined 
by the Japanese GCP regulation and the Sponsor’s SOP.
Sponsor: 
The Sponsor must retain the essential documents according to the Sponsor’s SOPs.
When it is no longer necessary for the trial site to retain the source documents and essential 
documents, the Sponsor must notify the head of trial site.
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
8.4.1
Listedness
To fulfill the regulatory requirements for expedited safety reporting, the Sponsor evaluates 
whether a particular adverse event is "listed", i.e. is a known side effect of the drug or not. 
Therefore a unique reference document for the evaluation of listedness needs to be provided. 


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For DE this is the current version of the IB. For ASA this is the SPC of the HEXAL ASA 100 
mg tablet. The current versions of these reference documents are to be provided in the ISF. 
No AEs are classified as listed for matching placebo and study design.
8.4.2
Expedited reporting to health authorities and IECs/IRBs
Expedited reporting of SAEs, e.g. SUSARs, to health authorities and IECs/IRBs, will be done 
according to local regulatory requirements. Further details regarding this reporting procedure 
are provided in the ISF.
8.5
STATEMENT OF CONFIDENTIALITY
Individual patient medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the Sponsor’s
representatives, by the IRB / IEC and the regulatory authorities.  
8.6
COMPLETION OF TRIAL
When the trial is completed, the Investigator should inform the head of the trial site of the 
completion in writing, and the head of the trial site should promptly inform the IRB and 
Sponsor of the completion in writing.
The ethics committee (EC)/CA in each participating European Union (EU) member state, and 
where applicable, the respective authority as defined per local regulations for each other 
country, needs to be notified about the end of the trial (LPO, unless specified differently in 
Section 6.2.3 of the CTP) or early termination of the trial.  
8.7
PROTOCOL VIOLATIONS
For Japan: The Investigator or sub-Investigator should record all CTP violations. The 
Investigator should provide and submit the Sponsor and the head of the trial site the records 
of violations infringing the Japanese GCP or violations to eliminate an immediate hazard to 
trial patients and for other medically inevitable reasons.
8.8
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
TRIAL RELATED INJURY
For Japan: In the event of health injury associated with this trial, the Sponsor is responsible
for compensation based on the contract signed by the trial site.


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concomitant use of serotonin norepinehphrine reuptake inhibitors (SNRI). 
23 February 2012.
U13-3509-01
: RELY-ABLE long term multi-center 
extension of dabigatran treatment in patients with atrial fibrillation who 
completed the RE-LY trial and a cluster randomised trial to assess the 
effect of a knowledge translation intervention on patient outcomes. 
1160.71. 19 June 2013.


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10.
APPENDICES
APPENDIX 10.1
CHA2DS2-VASc Score
APPENDIX 10.2
STUDY DRUG START, THROMBOSIS PROPHYLAXIS AND 
TRANSITION TO NON-STUDY MEDICATION
      
APPENDIX 10.4
HANDLING OF OUTCOME EVENTS 
(BLEEDS AND MORTALITY/MORBIDITY EVENTS)
APPENDIX 10.5
NATIONAL INSTITUTE OF HEALTH STROKE SCORE
 


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10.1
CHA2DS2-VASC SCORE
The CHA2DS2-VASc score (P11-03557) is a refinement of CHADS2 score (Congestive heart 
failure, Hypertension, Age > 75, Diabetes, prior Stroke/TIA), which is a stroke risk score 
originally validated for and applicable to patients with atrial fibrillation. The CHA2DS2-
VASc score extends the CHADS2 score by assigning additional weight to the risk factor age 
and by including additional stroke risk factors, specifically vascular disease and gender, as 
displayed below in Table 10.1.1.  The maximum CHADS2 score is 6, whilst the maximum 
CHA2DS2-VASc score is 9. The higher the CHA2DS2-VASc score, the higher is the expected 
risk of thromboembolism (including stroke and SE, see Table 10.1.2)
Table 10.1.1
Components of the scoring system with the acronym CHA2DS2-VASc 
CHA2DS2-VASc Acronym
Score
Congestive heart failure/LV dysfunction
1
Hypertension
1
Aged ≥75 years
2
Diabetes mellitus
1
Stroke/TIA/TE
2
Vascular disease 
(prior MI, PAD, or aortic plaque)
1
Aged 65-74 years
1
Sex category (i.e. female sex*)
1
Maximum score
9
LV = left ventricular; MI = myocardial infarction; PAD = peripheral artery disease; 
TE = thromboembolism; TIA = transient ischemic attack. Based on R10-5332.
*Note that female gender only scores one point if the patient has at least one other risk factor, and does not 
score any points in isolation.


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Table 10.1.2
Stroke risk stratification with the CHA2DS2-VASc score
(according to R10-5332)
CHA2DS2-VASc Score
Thromboembolic Event Rate
during one year (%, 95% CI)1
0
0 (0-0)
1
0.6 (0.0-3.4)
2
1.6 (0.3-4.7)
3
3.9 (1.7-7.6)
4
1.9 (0.5-4.9)
5
3.2 (0.7-9.0)
6
3.6 (0.4-12.3)
7
8.0 (1.0-26.0)
8
11.1 (0.3-48.3)
9
100 (2.5-100)
1Based on initial validation cohort reported by Lip et al actual rates of stroke in contemporary cohorts may 
vary from these estimates (R10-5332).


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10.2  
STUDY DRUG START, THROMBOSIS PROPHYLAXIS AND 
TRANSITION TO NON-STUDY MEDICATION
10.2.1
When to start study drug following treatment with parenteral anticoagulants, 
Vitamin K antagonists, or antiplatelets
The following recommendations are provided for guidance only:
Parenteral anticoagulant pre-treatment (e.g. Heparins)
UFH or LMWH/injectable anticoagulant (if given) should be stopped prior to the first dose of 
study drug. Study drug should be initiated with the following suggested time windows:

Continuous UFH/other continuous i.v. anticoagulants: initiate study drug at the time 
the UFH/ other continuous i.v. anticoagulant is stopped 

Bolus of UFH: initiate study drug 6 hours after the bolus injection of UFH

Low-molecular Weight Heparin/other subcutaneous (s.c.) injectable anticoagulants: 
initiate study drug 0-2 hours prior to the time that the next dose of the LMWH/other 
s.c. injectable anticoagulant would be due.
Vitamin K antagonists (VKAs)

The Vitamin K antagonist should be stopped. Study medication can be given as soon 
as the INR is < 2.0.
Antiplatelet pre-treatment
(i.e. ASA, clopidogrel, ticlopidine, prasugrel, ticagrelor, dipyridamole, dipyridamole+ASA,
at any labeled maintenance dosage)

Non-study antiplatelets should be stopped prior to the first dose of study drug. Study 
drug can be initiated at any time-point after discontinuation of the non-study 
antiplatelet, with one exception: After a loading dose of ticagrelor, clopidogrel or 
prasugrel has been taken, a minimum of 2 hours should elapse before the first dose of 
study medication can be given. 
Please note that ASA (commercial drug/over the counter medication) ticagrelor, 
clopidogrel, dypyridamole, dypyridamole+ASA and prasugrel are restricted 
medications and may not be taken during treatment with study drug.  (Note: optional 
concomitant ASA assigned by IRT may be given, see Section 4.1.1).
10.2.2
Thrombosis prophylaxis or temporary requirement for parenteral 
anticoagulant or antiplatelet(s)
Immobilization or intervention may require temporary thrombosis prophylaxis with e.g. UFH 
or LMWH or antiplatelet(s). Certain interventions may require the use of parenteral 
anticoagulants.


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The following rules should apply, if thrombosis prophylaxis/parenteral anticoagulants are 
considered temporarily necessary by the Investigator:

Temporarily stop study medication.  It is recommended to wait 12 hours after the last 
dose of study medication before switching to a parenteral anticoagulant (e.g. UFH, 
LMWH).  Antiplatelet(s) can be started at any time after last dose of study drug.
The period of thrombosis prophylaxis should be kept to a minimum. For recommendations 
how to switch back to study drug (DE or ASA) see Section 10.2.1.
10.2.3
Transition to non-study antithrombotic treatment with early study drug 
discontinuation or at the end of the trial
Patients actively taking study drug at their final treatment visit and patients who stop study 
medication early may need to switch to a non-study antithrombotic treatment at the 
Investigator`s discretion. The following recommendations are provided for guidance only

If the non-study treatment will be antiplatelet agent(s), this medication can be initiated 
at any time-point after last intake of study medication.

If the non-study treatment will be DE or another NOAC (such as rivaroxaban, 
apixaban or edoxaban), the first dose of DE (or other NOAC) should be taken at the 
time that the next dose of study medication would have been due.  

If the non-study treatment is a Vitamin K antagonist, the starting time of the VKA 
should be adjusted according to the patient´s CrCl as follows:

CrCl ≥ 50 mL/min: start VKA 3 days before discontinuing study drug

CrCl ≥ 30-< 50 mL/min: start VKA 2 days before discontinuing study drug


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.
 
 
 
 
.
:
 
 
 
 
 
 
 
 
 
 
.
 
 
 
 
 
 
 


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Is the AE an Outcome Event?
Yes
Outcome Event
-
Bleed
-
Death
-
Myocardial infarction
-
TIA
-
Stroke
-
Systemic embolism
-
Deep vein thrombosis
-
Pulmonary embolism
1. Complete e-CRF 
pages 
2. Complete and 
upload outcome 
event narrative1 / 
supporting 
documentation
AE
SAE
(That is deemed not an outcome event–
but satisfies one or more of the 
following):
1.
results in death
2.
immediately life threatening
3.
persistent or significant 
disability/incapacity
4.
requires patient hospitalisation
5.
prolongs patient hospitalisation
6.
congenital anomaly/birth defect
7.
other comparable medical 
criteria (specify under 
description)
Yes
1. Completion of 
SAE form 
2. Record event on 
AE eCRF page 
(code as serious)
No
No
Is the AE an SAE?
Report on AE eCRF page
Did the Outcome Event
start before randomisation?
No
Yes
10.4
HANDLING OF OUTCOME EVENTS (BLEEDS AND 
MORTALITY/MORBIDITY EVENTS)
Figure 10.4.1 Hierarchical algorithm of reporting Events
1A narrative will only be requested if needed


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10.5
NATIONAL INSTITUTE OF HEALTH STROKE SCALE
1a.Level of consciousness
0
Alert
1
Not alert, but arousable with minimal stimulation
2
Not alert, requires repeated stimulation to attend
3
Coma
1b. Ask patient the month and 
their age
0
Answers both correctly
1
Answers one correctly
2
Both incorrect
1c.Ask patient to open/close 
eyes and form/release fist
0
Obeys both correctly
1
Obeys one correctly
2
Both incorrect
2.Best gaze (only 
horizontal eye movements)
0
Normal
1
Partial gaze palsy
2
Forced gaze deviation
3. Visual field testing
0
No visual field loss
1
Partial hemianopsia
2
Complete hemianopsia
3
Bilateral hemianopsia (blind, incl. Cortical blindness)
4. Facial paresis (Ask 
patient to show teeth or raise 
eyebrows and close eyes 
tightly)
0
Normal symmetrical movement
1
Minor paralysis (flattened nasolabial fold, asymmetry on
2
Partial paralysis (total or near total paralysis of lower face)
3
Complete paralysis of one or both sides (absence of facial movement in the 
upper and lower face)
5a.Motor Function 
- right arm
0
Normal (extends arm 90º or 45º for 10 sec without drift)
1
Drift
2
Some effort against gravity
3
No effort against gravity
4
No movement
9
Untestable (joint fused or limb amputated)
5b. Motor 
Function - left arm
0
Normal (extends arm 90º or 45º for 10 sec without drift)
1
Drift
2
Some effort against gravity
3
No effort against gravity
4
No movement
9
Untestable (joint fused or limb amputated)
6a. Motor Function 
-right leg
0
Normal (holds leg in 30º position for 5 sec without drift)
1
Drift
2
Some effort against gravity
3
No effort against gravity
4
No movement
9
Untestable (joint fused or limb amputated)
6b. Motor 
Function -left leg
0
Normal (holds leg in 30º position for 5 sec without drift)
1
Drift
2
Some effort against gravity
3
No effort against gravity
4
No movement
9
Untestable (joint fused or limb amputated)
7. Limb ataxia
0
No ataxia
1
Present in one limb
2
Present in two limbs
8. Sensory (use pinprick to test 
arms, legs trunk and face, 
compare side to side)
0
Normal
1
Mild to moderate decrease in sensation
2
Severe to total sensory loss


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9. Best language (describe 
picture, name items)
0
No aphasia
1
Mild to moderate aphasia
2
Severe aphasia
3
Mute
10. Dysarthria (read several 
words)
0
Normal articulation
1
Mild to moderate slurring of words
2
Near unintelligible or unable to speak
9
Intubated or other physical barrier
11. Extinction and inattention
(use visual double stimulation
or sensory double stimulation)
0
Normal
1
Inattention or extinction to bilateral simultaneous stimulation in one of the 
sensory modalities
2
Severe hemi-inattention or hemi-inattention to more than one modality


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
This is the revised protocol.
GLOBAL AMENDMENT 1
Number of global amendment
1
Date of CTP revision
06AUG 2015
EudraCT number
2013-003444-24
BI Trial number
1160.189
BI Investigational Product(s)
Dabigatran etexilate
Title of protocol
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)
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB/IEC/ Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Synopsis
Description of change
Clarified change in lower age limit from 50 years 
to 18 years. 
CTP revision date added
Timing of follow-up MOCA was also clarified as 
follows:
Change in cognitive status from Visit 1 to end of 


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Number of global amendment
1
treatment (EOT) Final Visit in all patients who 
are still on study medication at year 2 (or longer)
as assessed by Montreal Cognitive Assessment 
(MoCA) questionnaire
Rationale for change
Rationale for these changes is described below.
Section to be changed
Flowchart Footnote 1
Description of change
Text was revised as follows: 
It is preferred randomization to occur as soon as 
possible after confirming eligibility but up to 14 
days after signing informed consent is permitted.  
Informed consent will be signed any time before 
screening procedures.   
Rationale for change
To clarify timing of consent does not need to be 
within 14 days of randomization. 
Section to be changed
Flowchart
Description of change
“Submission of documentation for central 
evaluation of ESUS” for Visit 2 was added to the 
flowchart 
Rationale for change
This will serve as clarification for sites that a 
copy of records of diagnostic pathway 
examinations should be made and sent for central 
collection
Section to be changed
Flowchart, 3.3.2, 6.2.2, 6.2.3.2
Description of change
CARDIAC MONITORING DURING THE 
TRIAL
“Documentation of Cardiac Monitoring” has been 
added to the flowchart for visits 1-6, 8, 10, 12, 
EOT, and FINAL VISIT.     
The following text was also added to flowchart 
footnote 8: 
“Additional cardiac monitoring (e.g. Holter-
ECGs) may be performed at the discretion of the 
Investigator according to local standard of care. 
Where this is done, the results of these cardiac 
monitoring efforts will be documented in the 
eCRF.”
Section 3.3.2 Inclusion 4 Footnote 4 previously 
stated:


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Number of global amendment
1
“If there is an increased risk of AF and the 
Investigator determines extended ECG 
monitoring is warranted, cardiac monitoring for 
more than 24 hours is acceptable, but all 
monitoring efforts must be completed prior to 
randomization.  Cardiac telemetry is not 
sufficient, unless the data of telemetry had been 
recorded and summarized results are available.” 
Section 3.3.2 Inclusion 4 Footnote 4 now states: 
“Cardiac telemetry is not sufficient, unless the 
data of telemetry had been recorded and 
summarized results are available.  Cardiac 
monitoring efforts (beyond minimum required per 
Inclusion 4) may continue after randomization at 
the Investigator or a treating physician’s 
discretion.   All cardiac monitoring data and 
findings collected during the trial will be recorded 
in the eCRF.”
Section 6.2.2 had the following text added:
Additional cardiac monitoring (e.g. Holter-ECGs) 
may be performed at the discretion of the 
Investigator according to local standard of care. 
The results of these cardiac monitoring efforts 
will be documented in the CRF. Results obtained 
from implantable cardiac monitors will also be 
captured.
Section 6.2.3.2 was updated as follows: 
It will be documented whether the patient had 
received an implantable cardiac monitor for 
continuous cardiac monitoring during the course 
of this trial, including the results from this long-
term cardiac monitoring.
Rationale for change
This was added to clarify that medical chart 
review of cardiac monitoring efforts done as part 
of clinical routine throughout the trial.  This 
should be documented on the CRF.  The degree of 
monitoring efforts during the trial is expected to 
impact the amount of AF detected during the trial.  
There is no agreement on the optimal amount of 
cardiac monitoring that should be done in ESUS 
patients to detect AF. The recording of cardiac 


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Number of global amendment
1
monitoring results will deliver an answer on the 
percentage of patients who develop AF.
Section to be changed
3.3.3, Exclusion 7
Description of change
7a) Major23 surgery
Rationale for change
There was an error in the footnote numbering.  
This was corrected to align with the appropriate 
footnote.
Section to be changed
Flowchart, 6.2.1, 8.3.1, 10, Appendix 10.6
Description of change
BRAIN IMAGING SUBMISSION REMOVED 
FROM MAIN STUDY AND SUBSTUDY 
INTRODUCED
In the original protocol, all sites were required to 
submit brain images (CT/MRI) conducted during 
trial conduct (including those performed as part of 
patient standard care) for central review.  In the 
revised protocol, only sites that volunteer for the 
substudy are required to submit brain images 
(CT/MRI).  MRIs are required to be submitted by 
substudy sites, if available.  CTs will be submitted 
only in cases where MRIs are not available.
Flowchart was changed from: 
Submission  of all brain images (CT/MRI)
conducted during trial conduct (including those 
performed as part of patient standard care22
To: 
Imaging Substudy: Submission  of brain images 
(CT/MRI) conducted during trial conduct 
(including those performed as part of patient 
standard care)22
Flowchart footnote 21 was revised as follows: 
For endpoint events which require adjudication as 
per Section 3.1.1.4., copies of relevant source 
documentation (e.g. imaging reports) should be 
collected and submitted. For recurrent stroke, this 
should include copies of images performed and 
their corresponding reports.
Flowchart footnote 22 was revised as follows: 
For sites that participate in the imaging substudy:
Evaluation of brain images will include CT and/or


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Number of global amendment
1
MRI imaging analysis of index stroke, recurrent 
stroke and any repeat imaging done to initiate 
study drug.  It will also include the collection of 
MRI images performed per standard of care 
during the course of this trial (i.e. not 
done/repeated specifically for this trial). CTs 
and/or MRIs (and corresponding reports) will be 
forwarded to the Sponsor`s designee for imaging 
analyses (see Appendix 10.6).
Section 6.2.1 was updated as follows: 
For sites participating in the Imaging substudy,
All Bbrain images (i.e. CT, CT-angiography, 
MRI, MRI angiography, or other) related to the 
index stroke event and any imaging performed 
during the trial (plus corresponding reports) must 
be provided to Sponsor’s designee where possible
(see also Appendix 10.6).
Section 8.3.1 was updated as follows: 
For sites participating in the Imaging Substudy:
Magnetic Resonance Image/CT reports and 
images for the index event of stroke, possible re-
imaging done before randomization and any 
imaging related to recurrent stroke will be 
analyzed by the Sponsor`s designee. In addition 
MRIs (or CTs, if MRIs are not available)
performed during clinical routine (and 
corresponding reports) will be collected. (see 
Appendix 10.6). 
Section 10 was updated as follows: 
Appendix 10.6 SUBSTUDY: NEUROIMAGING 
ANALYSES OF INDEX EVENT AND 
RECURRENT STROKE
Appendix 10.6 title was changed as follows: 
SUBSTUDY: NEUROIMAGING ANALYSES 
OF INDEX EVENT AND RECURRENT 
STROKE
Appendix 10.6 was changed as follows:
This sub study will be conducted in selected sites, 


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Number of global amendment
1
which show an interest in participating.  
Evaluation of brain images will include CT and 
MRI imaging analysis of index event (including 
possible repeat imaging, i.e. before randomization 
to study drug) and recurrent stroke. It will also 
include the collection of MRI images (or CT 
images, if MRI images are not available)
performed per standard of care during the course 
of this trial…
… All patients entered into the study at all 
selected sites choosing to participate should be 
included in the analysis of index and recurrent 
stroke images, providing that the transfer of 
images to the Sponsor’s designee is technically 
feasible….
Some of the goals of the analysis of index and 
recurrent stroke images have been changed as 
follows: 

to identify silent strokes  (as judged by the 
Investigator) at Visit 1 and during study 
conduct (using MRI images performed per 
standard of care, or alternatively CT 
images, if MRI  images are not 
available)… 
… Index and recurrent stroke images and their 
corresponding reports, made as part of patient 
clinical routine or during the course of the trial
(i.e. CT and MRI images, with or without 
vascular imaging) will need to be provided to the 
Sponsor`s designee.
Rationale for change
Investigators have indicated that the complexity 
of this study is impairing recruitment. In order to 
keep the study feasible to recruit, some changes 
are being made: 
- collection of brain images will be from a portion 
of voluntary sites instead of all sites 
-the assessment of silent stroke will be judged by 
the Investigator instead of a central reviewer  
There is no change to collection of brain imaging 
reports.  All sites will continue to submit these 
reports for index stroke and recurrent stroke for 
central review of index stroke and adjudication of 
recurrent stroke 


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Number of global amendment
1
Section to be changed
Flowchart, 5.2.3, 6.2.1, 6.2.2
Description of change
LOCAL  LAB CLARIFICATIONS 
Three changes are described here related to 
collection of labs: 
1) An “(X)”10 was added to the flowchart for 
Safety laboratory tests at Visit 2.  An 
“(X)”11 was added to the flowchart for PK
tests at Visit 2.  This clarifies that central 
lab samples can still be collected at Visit 2 
prior to medication intake in case it was 
not drawn at Visit 1.  
2) Local labs taken within 14 days of 
randomisation (instead of 3 days) can be 
used for eligibility.  
3) Follow-up lab samples (including safety, 
PK, assay validation and biomarker 
samples) can also be collected prior to the 
study visit.
Flowchart Footnote 10 text was revised to include 
new text as follows:
…Local labs (within 14 days of randomisation)
can be used to verify eligibility (in addition to 
collection of central labs) where it is necessary to 
avoid delaying the initiation of study drug.  Refer 
to Section 5.2.3 for calculation of Creatinine 
Clearance (CrCl) and Section 4.1.3 for 
information about dose changes based upon CrCl 
value. Central labs must also be collected from all 
patients to provide a baseline for the study.  This 
should preferably occur at Visit 1, however, it can 
alternatively be collected at Visit 2 prior to first 
study drug intake.  Follow-up safety labs do not 
need to be drawn on the actual day of the visit.  
They may be drawn earlier as long as it is within 
the visit time window.
In flowchart footnote 11, the following changes 
were made: 
In flowchart footnote 11, the following changes 


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Number of global amendment
1
were made regarding PK samples:
Pharmacokinetic (PK) samples (for HPLC-
MS/MS measurement) at trough to be 
drawn at Visit 1, Visit 3 and Visit 6. The 
Visit 1 baseline sample must be taken 
prior to first intake of study medication. 
This should preferably occur at Visit 1, 
however, it can alternatively be collected 
at Visit 2 prior to first study drug intake.
The PK blood samples for the dabigatran 
plasma concentration measurements must 
be taken when the dabigatran plasma 
concentration is at trough levels (last drug
intake must have occurred 10:00–16:00 
hours before blood sampling). Therefore, 
for these visits, patients should take the 
trial medication at the study site (after the 
PK blood sample has been taken) to 
ensure the PK sample is taken at trough, 
10:00–16:00 hours after the last drug 
intake and prior to the next drug intake.  
Follow-up PK may be drawn anytime 
within the visit time window.
The following text was added to Flowchart 
footnote 12: 
Follow-up biomarker may be drawn anytime 
within the visit time window
The following text was added to Flowchart 
footnote 13:
Follow-up assay validation samples may be 
drawn anytime within the visit time window.
Section 5.2.3 was updated as follows: 
If local lab results are used, central laboratory 
samples must also be collected from all patients to 
provide a baseline for the study.  This should 
preferably occur at Visit 1, however, it can 
alternatively be collected at Visit 2 prior to first 
study drug intake. Visit 1 samples should 
additionally be collected and sent to the central 
lab.
Section 6.2.1 was updated as follows: 
All patients will have baseline blood samples sent 
to the central laboratory (preferably at Visit 1).  


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Number of global amendment
1
Randomization based on central lab results is 
strongly encouraged and preferred. However, 
local laboratory test results that have been 
collected within 14 3 days prior to randomization 
can also be used to verify eligibility (blood must 
additionally be collected and sent to central lab 
for analysis).
Section 6.2.2 was updated with the following new 
text: 
Labs do not need to be drawn on the actual day of 
the visit.  They may be drawn earlier as long as it 
is within the visit window. 
Rationale for change
This change allows for local labs to be used with 
the same flexibility as central labs.  This is 
particularly helpful when recent local labs reports 
are already available.
Collecting labs ahead of the visit is preferred by 
some investigators to allow them to review study 
results on the day of the visit.  This flexibility is 
also applicable to PK, biomarker and assay 
validation samples to avoid multiple blood draws 
for the patient.
Section to be changed
Flowchart, 5.1.1, 5.1.2.7, 5.3.2, 6.2.3.2, 7.3.2.1
Description of change
MOCA ASSESSMENTS 
Timing of MOCA follow-up was changed in the 
flowchart. Previously, it was at Visit 1 and Visit 
10 for patients still on treatment, now it is at Visit 
1 and Final Visit for all patients regardless of 
treatment status.  
Flowchart footnote 15 was revised as follows: 
The follow-up  MoCA assessment  is only
required for all patients (regardless of 
study drug status) still on study 
medication at Visit 10 (or later). For these 
patients, there needs to be one final 
assessment of the MoCA test at their End 
of Treatment Final visit.
Section 5.1.1 was updated as follows: 
Further efficacy endpoint are…: 


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-…..Change in cognitive status from Visit 1 to 
Final Visit EOT in all patients who are still on 
study medication at year 2 (or longer) as assessed 
by MoCA questionnaire
Section 5.1.2.7 was updated as follows: 
The MoCA questionnaire to assess cognitive 
status will be performed in all patients at Visit 1
and at the Final Visit. A follow-up MoCA 
assessment is required for patients still on study 
medication at Visit 10 or later (i.e. 24 months 
after randomization, or later). In these patients, 
there needs to be one final assessment of the 
MoCA test at their End of Treatment (EOT) visit 
(i.e. 
at 
the 
time-point 
of 
study 
drug 
discontinuation or shortly thereafter).
Section 5.3.2 was updated as follows: 
The MoCA test (R13-4024) will be used to 
assess cognitive status at Visit 1 and in patients 
who are still taking study medication at the Final
Visit 10 or later (i.e. at least 24 months after 
randomization, or later). In these patients, there 
needs to be one final assessment of the MoCA 
test at their End of Treatment (EOT) visit (i.e. at 
the time-point of study drug discontinuation or 
shortly thereafter). The MoCA questionnaire will 
be performed in countries where a validated 
translation is available.
Section 6.2.3.2 was updated as follows: 
Refer to Flow Chart for list of required 
assessments at the final visit. For a patients that 
are on treatment at the end of the trial, the EOT 
and Final Visit assessments can be done at the 
same visit. The MoCA test will also be 
performed.
Section 7.3.2.1 was updated as follows: 
Change in MoCA scores from Visit 1 to EOT 
final visit will be analyzed using Analysis of 
covariance (ANCOVA) with fixed effects of 
treatment, Visit 1 MoCA, and country. The 
percentage of patients with cognitive impairment 
(defined by MoCA < 26) at Visit 1 and EOT final 


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visit will be presented as descriptive statistics.
All time-to-event further efficacy analyses will be 
performed on the RS population for the full 
follow-up period. MoCA analyses will be 
performed on the TS for the on-treatment period.
Rationale for change
MoCA follow-up will be performed in all patients 
irrespective of study drug continuation status to 
allow for a full analysis of MoCA (and in order to 
also cover e.g. patients who stopped medication 
due to recurrent stroke)
Section to be changed
Abbreviations
Description of change
Abbreviations for CKD-EPI and CK-MB were 
switched
Rationale for change
This was a correction
Section to be changed
1.1
Description of change
The novel oral anticoagulant (NOAC) dabigatran 
etexilate (DE) has been demonstrated to be 
effective against cardioembolic stroke related to 
AF with significantly reduced risk of intracranial 
hemorrhage compared to warfarin.
Rationale for change
The abbreviation DE has been clarified.
Section to be changed
1.1
Description of change
The following text was added to provide 
explanation for early study drug start in this 
study: 
Patients are at highest risk of recurrent stroke in 
the first days after index stroke as demonstrated 
by the CHANCE trial (R15-2975).  The RE-
SPECT ESUS study will assess the effectiveness 
and safety of DE versus ASA with study 
medication started early during this high risk 
period.  Providing cerebral hemorrhage is ruled 
out, study drug can be started as early as one day 
after index stroke. For details on recommended 
earliest study drug start according to stroke 
severity, refer to Table 4.1.4:  1.
Rationale for change
There is not a standard guideline for when to start 
treatment after stroke.  Guidance is provided for 
the earliest study drug start within this clinical 


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trial (see Table 4.1.4: 1).  The rationale for 
starting study drug soon after stoke is clarified 
here for common understanding.   
Section to be changed
2.3, 4.2.1
Description of change
REVERSAL AGENT DATA COLLECTION
“Antidote” was changed to “ specific reversal 
agent” in Section 2.3 and 4.2
Section 2.3 was revised as follows: 
There is currently no specific treatment (specific 
reversal agent) available to reverse the 
anticoagulant effects of dabigatran should a life-
threatening bleeding arise. Standard management 
for bleeding (such as transfusion of blood 
products, etc.) needs to be applied as described in 
Section 4.2.1 and in Figure 4.2.1: 1.   A specific 
reversal agent (idarucizumab) has been developed 
and is currently being reviewed for registration in 
various countries.  When clinically indicated and 
available, it can be given to a patient in the 
context of a clinical trial (e.g. BI trial 1321.3) or 
from commercial supply when it becomes 
approved.  See section 4.2.1 Overdose, for more 
information regarding the specific reversal agent 
for dabigatran.    
Text was added to Section 4.2.1 Emergency 
Procedures as follows: 
See section 4.2.1- Overdose, for more information 
regarding the specific reversal agent for 
dabigatran.  
Section 4.2.1 Major Bleeds was revised as 
follows: 
The recommendations given below are derived 
from guidelines to manage bleeding with DE, 
however, with the exception of recommendations 
on the specific reversal agent for dabigatran, they 
can be applied to all patients in this trial 
irrespective of assigned study medication (i.e. DE 
or ASA).  
There is currently no specific antidote to 


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counteract the antithrombotic activity of 
dabigatran.  See section 4.2.1 Overdose, for more 
information regarding the specific reversal agent 
for dabigatran.  
Text was removed from Section 4.2.1 Overdose 
with DE as follows: 
To date, there is no specific reversal agent to 
counteract the antithrombotic activity of 
dabigatran, although there is one in development 
(P13-05131)
A section was added to Section 4.2.1 as follows:
Specific reversal agent to dabigatran
A specific reversal agent (idarucizumab) has been 
developed and is currently being reviewed for 
registration in various countries.  When clinically 
indicated and available, it can be given to a 
patient in the context of a clinical trial (e.g. BI 
trial 1321.3) or from commercial supply when it 
becomes approved.  If the specific reversal agent 
for dabigatran is given, information surrounding 
the clinical circumstances, treatment and clinical 
outcome will be collected on the CRF of the 
appropriate trials.
Rationale for change
To clarify terminology and allow collection of 
information regarding use of the reversal agent.
Section to be changed
3.3
Description of change
RESCREENING
The following text was added to Section 3.3 at the 
bottom:
If a patient is deemed ineligible for a reason 
which later resolves and all eligibility criteria can 
be met (e.g. time since an exclusionary event), 
patients can be rescreened up to one time 
provided it is still within 3 months since index 
stroke (within 6 months for select patients).  
Patients cannot be re-screened if any of the 
following exclusions were met:  # 4, 7e, 8, 9, 19, 
20, or 21; during the initial screening.  
Rationale for change
To explicitly clarify that rescreening of patients is 
permitted, if they become eligible within the 


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allowed time window since index stroke (up to 3 
months before randomization, or up to 6 months 
before randomization in patients that are ≥60 
years plus at least one additional risk factor for 
recurrent stroke- see stroke risk factors a-f as 
outlined in Inclusion 1).
Section to be changed
3.3
Description of change
# of countries increased from approximately 35 to 
40
Section 3.3 was updated as follows: 
An estimated 6,000 patients will be randomized at 
approximately 550 sites in approximately 35 40
countries.
Rationale for change
There is a potential to conduct the study in 
additional countries.
Section to be changed
Table 3.3.1: 1, Section 3.3.2 Inclusion 4, 3.3.4.1, 
4.2.2.1, 6.2.1  
Description of change
MINIMUM AMOUNT OF CARDIAC 
MONITORING REQUIRED FOR ENTRY
A minimum of 20 hours (instead of 24 hours) of 
cardiac monitoring is required to rule out atrial 
fibrillation prior to study entry.   Additionally, it 
is clarified that cardiac monitoring with 
interruption is acceptable within the boundaries 
described in the protocol.
Table 3.3.1: 1 Step 4 was updated as follows: 
4. Cardiac monitoring for ≥20 24 hours with 
automated rhythm detection
Table 3.3.1: 1 footnote 2 has new text: 
Eligible patients can be enrolled with a minimum 
of 20 hours of cardiac monitoring completed and 
results demonstrate < 6 min AF.  Cardiac 
monitoring with interruption is acceptable, if the 
total recording time of at least 20 hours is 
completed within the same hospital stay or within 
consecutive 10 days.
Section 3.3.2 Inclusion 4 was updated as follows: 
As evidenced by cardiac monitoring for ≥ 20 24


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hours with automated rhythm detection, there is 
absence of AF > 6 minutes in duration (within a 
20 24 hour period, either as single episode or 
cumulative time of multiple episodes). 
Section 3.3.4.1 was updated as follows: 
(An individual patient is to be discontinued from 
study drug if the following occurs…): Atrial 
fibrillation (with duration exceeding 6 minutes, 
either as single episode or cumulative time of 
several episodes recorded within 20 24 hours, or 
as per Investigator discretion), or atrial flutter
Section 4.2.2.1 was updated as follows: 
If AF is identified during follow-up and the 
duration of AF exceeds 6 minutes (either as single 
episode or cumulative time of several episodes
within 20 24 hours), trial treatment must be 
discontinued (but the treatment assignment blind 
should not be broken), and the patient should be 
switched to standard of care treatment for stroke 
prevention in atrial fibrillation (SPAF) (e.g. DE or 
other) according to local label recommendations.
Section 6.2.1 was updated as follows: 
The investigations outlined in Table 3.3.1: 1 are 
to be completed and documented per standard of 
care as a prerequisite to consideration for study 
participation.  (Note: a minimum of 20 hours 
cardiac monitoring is required for enrollment).  
Rationale for change
During the early part of trial conduct, it was 
realized that in clinical practice what is referred to 
as a “24 hour” holter monitor does not necessarily 
mean that the holter device would be connected to 
the patient for a full 24 hour time period.  20 
hours more reasonably reflects routine clinical 
practice and it is considered the minimum 
required monitoring time needed to rule out AF.
Section to be changed
3.3.2 Inclusion criterion 1
Description of change
MINIMUM AGE FOR ENTRY 
3.3.2 Inclusion criterion 1 was updated to allow 
enrollment of patients as young as 18 years old 


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(instead of 50).  The change is as follows: 
Age 18 50 -59 years
Rationale for change
To allow enrollment of younger patients that have 
ESUS. 
Assuming 10% of patients enrolled under the age 
of 50 would have reduced recurrent stroke rate of 
2.1% (compared to 4.1% for all other patients), 
power calculations estimate that the length of the 
trial may have to be increased by 6 weeks to 
observe the 353 recurrent strokes, if all estimates 
are correct. Because of the potential 
impreciseness of these estimates and the fact that 
the actual number of recurrent strokes will be 
actively monitored, it is not necessary to change 
the estimated length of the trial at this time.
Section to be changed
Section 3.3.2 Inclusion criterion 2  
Description of change
REFORMATING OF INCLUSION 2
Section 3.3.2 Inclusion criterion 2 was revised as
follows:
2) 2a) Acute Ischemic stroke with an 
anatomically appropriate a brain lesion 
visualized by neuroimaging (either brain CT1
or MRI). The visualized stroke is a non-
lacunar infarct , i.e. 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.  See 
Exclusion 21 for definition of lacunar stroke.
2b) The index stroke It must have occurred 
either:
a.
up to 3 months before randomization 
(mRS ≤3 at randomization)
OR
b. 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 (see stroke risk factors 


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a - f as outlined in Inclusion 1).  
Rationale for change
Dividing Inclusion criterion 2 into 2a and 2b 
clarifies there are two prerequisites that must be 
met.  2a (to describe eligible infarct size, location) 
and 2b (to define time since ESUS).  Reference to 
inclusion criteria 2b was also updated in 6.2.2.
Inclusion criterion 2 is amended to clarify that 
non-lacunar strokes in certain other locations of 
the brain (e.g. brain stem) do not need to meet 
size requirements outlined for exclusively 
subcortical infarcts.
A reference to new Exclusion 21 (definition of 
lacunar stroke) is also provided.
Section to be changed
3.3.2 Inclusion criterion 3 
Description of change
The following text was added to footnote 3:
Cases with acute full artery occlusion deemed by 
Investigator to be of embolic origin are allowed.
Rationale for change
To allow for inclusion of certain patients with full 
occlusion due to an embolus of unknown origin 
(e.g. in cases where imaging done prior to ESUS
index stroke demonstrated absence of relevant 
large vessel disease and no occlusion or the 
occlusion appears embolic in nature). This change 
is in line with the embolic source concept of the 
study.
Section to be changed
3.3.2 Exclusion criterion 6, Table 4.1.4: 1, 5.2.2.1
Description of change
MICROBLEED DEFINED
Exclusion criterion 6 footnote 2 was updated as 
follows: 
A hemorrhagic transformation of a primarily 
ischemic stroke may be included as per 
Investigator`s judgment. Sporadic microbleeds 
may be included as per Investigator`s judgment. 
As a general recommendation, a cerebral 
microbleed is considered to be < 0.5 cm ≤ 5mm, 
but sometimes up to 10mm, in greatest diameter 
on gradient recalled echo (GRE), or T2*, MRI 
sequences. MRI (criteria may vary depending on 
MRI imaging modalities). Any blood visualized 


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on a CT will be classified as a macrobleed. A 
macrobleed is an exclusion criterion for the trial.
Table 4.1.4: 1 Foot note 1 was updated as 
follows: 
… Sporadic microbleeds may be included as per 
Investigator`s judgment. As a general 
recommendation, a cerebral microbleed is 
considered to be in general ≤ 5mm, but 
sometimes up to 10 mm, in greatest diameter on 
gradient recalled echo (GRE), or T2*, MRI 
sequences. Microbleeds are incidental findings 
that do not constitute an exclusion criterion. < 0.5 
cm in greatest diameter on gradient recalled echo 
(GRE) MRI (criteria may vary depending on MRI 
imaging modalities). In patients with hemorrhagic 
transformation or microbleeds, the Investigator 
may choose to delay the start of study medication. 
Any blood visualized on a CT will be classified as 
a macrobleed.  In patients with macrobleeds, 
study medication should not be started.
Section 5.2.2.1 was updated as follows: 
Intracranial hemorrhage comprises the subtypes 
of intracerebral bleeds, subdural bleeds, epidural 
bleeds and subarachnoid bleed and will be 
recorded in eCRF.  Microbleeds (for definition 
see below) do not qualify as ICH, except when 
they are symptomatic.

Definition of a microbleed:
A cerebral microbleed is in general ≤ 5mm, but 
sometimes up to 10 mm, in greatest diameter on 
gradient recalled echo (GRE), or T2*, MRI 
sequences (R15-2999). Any blood visualized on a 
CT will be classified as a macrobleed. 
Asymptomatic microbleeds are incidental 
findings that do not constitute an exclusion 
criterion.   Irrespective of size, any cerebral bleed 
that causes focal neurologic symptoms and/or 
signs does not constitute a microbleed, but will be 
reported as a stroke endpoint (hemorrhagic 
stroke) and bleeding event (intracerebral 


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hemorrhage).
Rationale for change
Definition added for cerebral microbleeds for 
common implementation as it relates to eligibility 
and reporting of outcome events, specifically 
intracranial hemorrhage.
Clarification added that asymptomatic 
microbleeds do not qualify as intracranial 
hemorrhage.
Section to be changed
3.3.3 Exclusion criterion 7e
Description of change
3.3.3 Exclusion criterion 7e was revised as 
follows: 
platelet count < 100,000/ml <100 x10^3/µl at 
screening  
Rationale for change
Correction of units
Section to be changed
3.3.3 Exclusion criterion 7h
Description of change
Exclusion criterion 7h was added as follows: 
7h) Any history of intracranial aneurysm (unless 
it was permanently resolved with either clipping 
or coiling at least one year prior to the study 
entry).  
Rationale for change
This exclusion criterion was added to exclude 
patients at high risk for future intracranial 
hemorrhage.
Section to be changed
3.3.3 Exclusion criterion 8
Description of change
Clarification to state that patients with history of 
symptomatic non-traumatic intracranial 
hemorrhage could be eligible if the Investigator 
deems patient is not at risk for recurrent ICH.
Exclusion criterion 8 was revised as follows: 
8. History of symptomatic nontraumatic 
intracranial hemorrhage with risk of recurrence 
according to Investigator judgment.
Rationale for change
If according to the Investigator`s judgment the 
risk for recurrent ICH is not increased despite a 
history of symptomatic non-traumatic intracranial 
hemorrhage, there is no safety reason to exclude 
the patient.   
Section to be changed
3.3.3 Exclusion 15
Description of change
Exclusion 15 was revised as follows: 


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Women of childbearing potential must be ready 
and able to use highly effective methods of birth 
control per ICH M3 (R2) (R15-5904) that result 
in a low failure rate of less than 1% per year when 
used consistently and correctly.  A list of 
contraception methods meeting these criteria is 
provided in the patient information.  Acceptable 
methods of birth control include a) complete 
sexual abstinence, b) intra uterine devices/systems 
(IUDs/IUSs), c) oral or parenteral (patch, 
injection, implant) hormonal contraception, which 
has been used continuously for at least one month 
prior to the first dose of study medication, d) 
condom and occlusive cap (diaphragm or cervical 
caps) or condom with spermicidal agent  (also 
referred to as double barrier methods), or e) male 
sterilization (with the appropriate post-vasectomy 
documentation of the absence of sperm in the 
ejaculate. If this method is chosen, WOBCP must 
attest that they are in a monogamous 
relationship).
Rationale for change
To align the protocol with the ICH M3 (R2) 
guideline (R15-5904) regarding highly effective 
methods of birth control and with the company’s 
latest guidance on contraception in Clinical 
Trials.
Section to be changed
3.3.3 Exclusion criterion 16
Description of change
Clarification to make clear how past involvement 
in a clinical trial can impact eligibility.
Exclusion criterion 16 was updated as follows: 
Patients who participated in another trial within 
14 days prior to screening.  Patients with residual 
effect from another investigational product 
remaining at time of screening.  Patients who 
have participated in another trial with an 
investigational drug or device within the past 14 
days preceding the screening visit or are 
participating in another trial assuming no clinical 
effect from the investigational drug or device 
used in the previous study remains.  Patients 
participating in a purely observational study will 
not be excluded.


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Rationale for change
Clarification was necessary to guide Investigators 
on the eligibility of patients previously or 
currently involved in other studies (including 
observational studies) for better understanding
Section to be changed
3.3.3 Exclusion criterion 17
Description of change
New text was added as follows:
Patients considered unreliable by the Investigator 
concerning the requirements for follow-up during 
the study or at the end of the study (e.g. not able 
to comply with regular medication intake)
Rationale for change
Clarified that if a patient was not able to comply 
with regular medication intake, they would not be 
eligible to avoid enrolling patients where 
noncompliance with study drug intake could be 
foreseen by the Investigator. Regular study 
medication intake is considered a prerequisite for 
overall compliance, trial follow-up and 
completion.
Section to be changed
3.3.3 Exclusion criterion 18, 3.3.4.1
Description of change
Exclusion criterion 18 was updated as follows: 
Any condition the Investigator believes would not 
allow safe participation in the study, e.g. other 
neurological condition that would complicate 
assessment of outcomes (e.g. severe dementia, 
high propensity for falls where Investigator deems 
a patient’s potential risk for bleeding exceeds the 
potential benefits of study drug).
3.3.4.1 was updated as follows: 
At the discretion of the Investigator/patient, an 
individual patient may be discontinued from study 
drug if….in the opinion of the Investigator, 
continuation on the study drug is not in the 
patient’s best interest, if eligibility criteria are 
being violated, or if the patient fails to comply 
with the protocol (e.g. non-attendance at trial 
assessments, and reason to be recorded in the 
electronic Case Report Form (eCRF)) or if the 
patient develops a high propensity for falls where 
Investigator deems a patient’s potential risk for 
bleeding exceeds the potential benefits of study 
drug.


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Rationale for change
To clarify that the Investigator should consider 
the potential risks associated with falls prior to 
inclusion of the patient.   A patient could be 
excluded if they had a high propensity for falls 
where Investigator deems a patient’s potential risk 
for bleeding exceeds the potential benefits of 
study drug.  If this risk develops during the trial 
for a patient on study drug, the Investigator can 
stop study drug if they deem it appropriate.
Section to be changed
3.3.3 Exclusion criterion 21, Table 1.1: 1
Description of change
LACUNAR STROKE DEFINED
Exclusion criterion 21 was added as follows: 
Lacunar stroke.  Lacunar infarcts of restricted size 
in the deep parts of the brain in the territories of 
small penetrating arteries. They are absent from 
the cerebral and cerebellar cortex. On brain CT 
and MR images they are <1.5 cm in largest 
diameter or <2.0 cm if measured on MRI 
diffusion sequences. In several pathological 
studies, sites of predilection included the 
lenticular nucleus, thalamus, central white matter, 
internal capsule, centrum ovale, corpus callosum, 
basis pontis, and, rarely, the cerebellum, midbrain 
and medulla. Infarcts <1.5 cm in largest diameter, 
or <2.0 cm if measured on MRI diffusion 
sequences, in the dorsal or lateral areas of the 
brainstem, in the territory of circumferential, 
rather than deep penetrating, arteries are not 
lacunar infarcts.  (note: history of lacunar stroke 
is not exclusionary).
Table 1.1: 1 footnote 2 was revised as follows: 
Lacunar defined as subcortical infarct  ≤1.5 cm 
(≤ 2.0 cm on MRI diffusion-weighted images) in 
largest dimension, and in the distribution of the 
small, penetrating cerebral arteries; visualization 
by CT usually requires delayed imaging > 24-48 
hours after stroke onset.  is defined in Section 
3.3.3 exclusion criterion 21
Rationale for change
To clearly provide a definition of lacunar stroke.  
Index strokes must meet ESUS criteria (part of 


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which requires the stroke be non-lacunar).  
However, this also clarifies that a history of a 
lacunar stroke (other than ESUS stroke) is not 
exclusionary.
Section to be changed
3.3.4.1
Description of change
A statement was added: 
Guidelines for transitioning to non-study 
antithrombotic medications are provided in 
Section 10.2.2.
Rationale for change
To clarify that additional information can be 
referenced in case study drug needs to be stopped 
for patients who have reduced renal function
Section to be changed
4.1.1
Description of change
“Concomitant use of ASA is at the discretion of 
the Investigator” was removed.
Rationale for change
Correction to original protocol: Concomitant use 
of ASA is not allowed while taking study drug 
except for patients with CAD and where blinded 
ASA is dispensed by IRT.
Section to be changed
4.1.4
Description of change
Text was changed as follows: 
Breaking or chewing of the tablets or capsules, or 
emptying the contents of the capsules is not
recommended permitted.
Rationale for change
This correction was to clarify that breaking or 
study medication is not permitted.
Section to be changed
Table 4.1.4: 1 revised, 4.2.1, Table 4.2.1: 2 was 
removed, 6.2.1, 6.2.2
Description of change
STARTING/RESTARTING STUDY DRUG 
AFTER STROKE - reformatted
Table 4.1.4: 1 was entitled Recommendations on 
starting study medication after index event of 
stroke (mRS ≤3 at time of randomization) 
Table 4.2.1: 2 was entitled Recommendations on 
re-starting study medication following a stroke 


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during the trial 
Tables 4.1.4: 1 and 4.2.1: 2 have been combined
into Table 4.1.4: 1 which is now named: 
Recommendations on starting study medication 
after index event of stroke (mRS ≤ 3 at time of 
randomization) and for reintroduction of study 
treatment after recurrent stroke (mRS ≤ 3 at time 
of study medication restart)
Table 4.1.4: 1 first column is now updated to
Header of left column updated as follows: 
Stroke Severity (at time of stroke randomization / 
at time of study medication restart after recurrent 
stroke)
Row for Modified Rankin Scale = 3 updated with 
this additional text:
Please take note:
This category includes patients with an initial 
Modified Rankin Scale of 4 at time of stroke, who 
have improved to a Modified Rankin Scale of 3.
Patients with Modified Rankin Scale of 4 at time 
of randomization are excluded. 
Patients with Modified Rankin Scale of 4 cannot 
restart study medication unless their Modified 
Rankin Scale improves to 3.
Header of right column updated as follows: 
Earliest start of Study Medication after Index 
Event Stroke
Row for MRS 1 or 2 was updated as follows: 
3-5 days after most recent stroke onset
Row for MRS 3 was updated as follows: 
5-7 days after most recent stroke onset
Table 4.1.4: 1 Footnote 1 was also updated as 
follows: 
If starting study medication within 10 days of 


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index most recent stroke in patients with mRS of 
1,2, or 3, re-imaging of the brain is required to 
rule out bleeding into the brain....
Section 4.2.1 text was revised as follows: 
Reintroduction of study treatment following a 
stroke (i.e. after recurrent stroke)
The decision about when to restart study 
medication following a recurrent stroke is at the 
discretion of the Investigator (with the exception 
of strokes with mRS of 4 or higher, where restart 
is not allowed, unless the patient improves to a 
mRS of 3). Table 4.1.4: 1 4.2.1:2 shows 
recommendations (P12-02400) on the earliest 
possible time point to restart start study 
medication.  These recommendations in Table 
4.1.4:1 also apply to restarting study medication 
after recurrent stroke.  Cerebral hemorrhage must 
be excluded before study drug is restarted. If 
restarting study medication within 10 days of 
stroke in patients with mRS of 1, 2 or 3, re-
imaging is required to rule out bleeding into the 
brain (for details see footnote of Table 4.1.4:1
4.2.1:2).
Table 4.2.1:2 was removed from this section as 
noted above.
Section 6.2.1 text was revised as follows: 
Patients with mRS of 1,2 or 3 at time of 
randomization who are scheduled for initiation of 
study medication within 10 days of index event 
require repeat imaging of the brain to rule out 
bleeding into the brain (per Exclusion #6).  This 
repeat imaging must occur prior to randomization.
Section 6.2.2 was revised as follows (some text 
was moved into a footnote): 
Restricted medications as outlined in Section 
4.2.2 will be stopped. Study medication will be 
dispensed and should be initiated as outlined in 
Section 4.1.4 and Table 4.1.4:11.   As a reminder, 
if a patient has mRS of 1,2 or 3 and study 
medication is to be started within 10 days of 


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index event, repeat imaging is mandatory to rule 
out bleeding into the brain. Randomization should 
only occur after reimaging of the brain has been
performed and eligibility has been confirmed.
AEs, SAEs and OEs (after randomization) will be 
collected as described in Section 5.1 and Section 
5.2.
Footnote 1 was added: As a reminder, if a patient 
has mRS of 1,2 or 3 at time of randomization and 
study medication is to be started within 10 days of 
index event, repeat imaging is mandatory to rule 
out bleeding into the brain. Randomization should 
only occur after reimaging of the brain has been 
performed and eligibility has been confirmed.  
Refer to Table 4.1.4:1 for details.
Rationale for change
The two tables were combined into one table 
within Section 4.2.1 as recommendations on 
medication start after index stroke versus 
recurrent stroke are essentially the same. 
Clarification was added for patients with a mRS
of 4. 
Section to be changed
4.1.5.2
Description of change
Text was revised as follows: 
An emergency code will be available to the 
Investigator/pharmacist/investigational drug 
storage manager via the IRT.
Rationale for change
The unblinding module will be available to the 
appropriate user type within IRT.  
Section to be changed
4.2.1
Description of change
The following text was added regarding 
Management of an elective procedure in the 
perioperative phase: 
Where the Investigator becomes aware of a 
planned procedure/surgery, it is recommended 
that the study investigator contact the treating 
surgeon.  Refer to Appendix 10.2 on transitioning 
to non-study medication in case bridging therapy 
is chosen.
Rationale for change
To provide further guidance to the Investigator to 
facilitate a planned intervention of the patient.


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Section to be changed
4.2.1, 10.2.2, 10.2.3
Description of change
The following text in Section 4.2.1 was revised 
regarding Management of an elective procedure 
in the perioperative phase: 
During a temporary interruption, thrombosis 
prophylaxis therapy with commercial
antiplatelet(s) or a parenteral anticoagulant e.g. 
Low-molecular Weight Heparin (LMWH) or 
Unfractionated Heparin (UFH) (according to local 
practice) is at the discretion of the Investigator 
depending on duration of interruption, type of 
intervention and individual thromboembolic risk 
of the patient.
Section 10.2.2 Title was revised as follows: 
Thrombosis prophylaxis or temporary 
requirement for parenteral anticoagulant or 
antiplatelet(s)
Section 10.2.2 was revised as follows: 
Immobilization or intervention may require 
temporary thrombosis prophylaxis with e.g. UFH 
or LMWH or antiplatelet(s). Certain interventions 
may require the use of parenteral anticoagulants.
The following rules should apply, if thrombosis 
prophylaxis/parenteral anticoagulants are 
considered temporarily necessary by the 
Investigator:

Temporarily stop study medication.  It is
recommended to wait 12 hours after the 
last dose of study medication before 
switching to a parenteral anticoagulant 
(e.g. UFH, LMWH).  Antiplatelet(s) can 
be started at any time after last dose of 
study drug
Section 10.2.3 was revised as follows: 

If the non-study treatment will be an
antiplatelet agent(s), this medication can 
be initiated at any time-point after last 
intake of study medication.
Rationale for change
To clarify that non-study antiplatelet(s) can be 


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used while not taking study drug
Section to be changed
4.2.1
Description of change
The section describing management of stroke was 
changed as follows: 
Patients with documented or suspected stroke 
should be managed according to usual clinical 
practice, which may include the use of fibrinolytic 
agents and mechanical clot removal.
Rationale for change
Mechanical clot removal was added as a patient 
management strategy for patients with stroke.  It 
is increasingly used in stroke patients
Section to be changed
4.2.2.1
Description of change
Text was added as follows: 
In patients ≥75 years, or with previous gastritis, 
history of peptic ulcer disease or previous 
gastrointestinal bleeding, the Investigator should 
consider prescribing a proton-pump-inhibitor 
(PPI) based on the local prescribing information 
while receiving NSAIDs/ASA.
Rationale for change
Concomitant use of PPIs should be considered in 
select patients at highest risk of GI bleeding to 
potentially protect them from future GI bleeds.  
The decision to use PPIs remains at the discretion 
of the Investigator.
Section to be changed
5.2.2.2
Description of change
Section 5.2.2.2 was updated as follows: 
In addition, for the safety parameters of primary 
interest, namely any major bleeding event (see 
Section 5.2.2.1) and for the major 
mortality/morbidity clinical endpoints of interest 
(see Section 5.1.2), a blinded IAC will be in place 
with the responsibility to confirm and classify 
events as listed in Section 3.1.1.4.
Rationale for change
Clarify verbiage to make clear that major bleeds 
are adjudicated (but not minor bleeds).
Section to be changed
5.5.2
Description of change
The following text was added to Section 5.5.2: 


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The PK samples will be discarded not later than 3 
years following availability of the final CTR (or 
as dictated by local requirements).
Rationale for change
Clarify storage of PK samples
Section to be changed
5.6.2.1
Description of change
Section 5.6.2.1 was updated as follows: 
Blood samples of about 5 mL will be collected in 
glass tubes for biomarker analyses.
Rationale for change
This is a correction to the original protocol.
Section to be changed
5.8, 7.3.5
Description of change
CHANGES TO PK ANALYSIS
Text from Section 5.8 has been revised as 
follows:
Not applicable.
The relationship between dabigatran trough 
plasma concentrations with safety (bleeding) and 
efficacy events (stroke/ischemic stroke) may be 
explored in case the number of events will suffice 
for a scientifically sound analysis. Details will be 
outlined in the Trial Statistical Analysis Plan 
(TSAP).
Section 7.3.5 was revised as follows:
…Trough plasma concentrations of total 
dabigatran will also be displayed for certain 
demographic subgroups (e.g. sex, age, race, body 
weight, Body Mass Index (BMI), creatinine 
clearance) categorized by the occurrence of pre-
specified events (primary endpoint: first recurrent 
stroke, secondary endpoint: first MBE), and 
displayed by use of relevant medication (e.g. P-
glycoprotein inhibitors) at the time of sampling.
Details on further subgroup analyses will be 
specified in the TSAP….
…Non-compartmental PK analyses will not be 
performed. Trough concentrations may be subject 
to PopPK analysis using the final model derived 
on data from AF patients in RE-LY (U10-2017-


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01) to evaluate the applicability of the RE-LY 
model to this patient population. Results of this 
analysis will be reported separately.
Rationale for change
Analysis of the PK-PD relationship special PK 
analyses and of a population PK analysis has been 
removed.  This will streamline the data analysis 
processes.
Section to be changed
6.2.1, 8.3.1
Description of change
INDEX SOURCE DOCUMENT COLLECTION
Section 6.2.1 was updated as follows: 
Detailed results of the required diagnostic 
imaging for the index stroke (see from diagnostic 
evaluations specified in Table 3.3.1:1) must be 
provided to the Sponsor or Sponsor`s designee 
including the required reports of brain imaging, 
echocardiography, cardiac rhythm monitoring, a 
12-lead ECG and vascular imaging. All of the 
required diagnostic examinations related to the 
index stroke, including extended cardiac 
monitoring (if deemed warranted by the 
investigator) must be completed prior to 
randomization.  
Section 8.3.1 was updated as follows: 
All other Examination reports supporting the 
diagnosis of index ESUS, i.e. reports of the 
required examinations, including 
echocardiography, cardiac rhythm monitoring and 
vascular imaging such as imaging of the 
extracranial and intracranial arteries supplying the 
area of brain ischemia (either catheter 
angiography, MRI angiography, computed 
tomographic angiography, or cervical plus TCD 
ultrasonography) must be provided to the 
Sponsor`s designee. Copies of 12 lead ECG 
reports done as part of the clinical routine at the 
time of index stroke need not be submitted.  
Rationale for change
Protocol language surrounding collection of 
documentation for central index source document 
review has been modified to reduce specificity.  


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For example, at this time, copies of 12-lead ECGs 
are not required to be collected, as a baseline 
ECG is part of the Visit 1 procedures.
Section to be changed
9.1
Description of change
The following references were added in Section 9 
and referenced where appropriate within protocol: 
R15-0010 (added to section 5.1.2.1, 5.1.2.4, 
5.1.2.5)
R15-2975 (added to section 1.1)
R15-2999 (added to section 5.2.2.1)
R15-5904 (added to Section 3.3.3)
Rationale for change
To update protocol to reflect latest literature
Section to be changed
Appendix 10.5
Description of change
National Institute of Health Stroke Score changed 
to National Institute of Health Stroke Scale
Rationale for change
Correction of terminology


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GLOBAL AMENDMENT 2
Number of global amendment
2
Date of CTP revision
21 Apr 2016
EudraCT number
2013-003444-24
BI Trial number
1160.189
BI Investigational Product(s)
Dabigatran etexilate
Title of protocol
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)
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB/IEC/ Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Title Page
Description of change
Change of Trial Clinical Monitor name and 
contact details 
Rationale for change
To reflect change of Trial Clinical Monitor and to 
provide current contact details.


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2
Section to be changed
FLOW CHART
Description of change
Deletion of visit 2 procedure “submission of 
documentation for central evaluation of ESUS”.
Rationale for change
To simplify and optimize logistics of the trial and 
reduce operational complexity, central source data 
reassessment processes is cancelled. This change 
is related to data collection only and does neither 
affect patients` safety nor the integrity of the 
overall study. Removal of this data collection 
portal will optimize the feasibility of the trial.
Section to be changed
6.2.1. Screening and run-in periods
Description of change
Detailed results of the required diagnostic 
imaging for the index stroke (from diagnostic 
evaluations specified in Table 3.3.1: 1) must be 
provided to the Sponsor or Sponsor`s designee.
Changed to:
Detailed results of the required diagnostic 
imaging for the index stroke (from diagnostic 
evaluations specified in Table 3.3.1: 1) must be 
available in the source notes for all patients and in 
the case of recurrent stroke or death must also be 
provided to the Sponsor or Sponsor`s designee as 
part of the adjudication package.
Rationale for change
To simplify and optimize logistics of the trial and
reduce operational complexity, central source data 
reassessment processes is cancelled. This change 
is related to data collection only and does neither 
affect patients` safety nor the integrity of the 
overall study. Removal of this data collection 
portal will optimize the feasibility of the trial.
Section to be changed
7.3.1. Primary analyses
Description of change
Sensitivity analyze that includes only patients 
whose ESUS diagnosis was confirmed by central 
source data reassessment performed by Sponsor`s 
designee is removed.
Rationale for change
Not applicable due to cancellation of central 
source data reassessment.


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Section to be changed
8.3.1. Source documents
Description of change
Following text deleted:

Examination reports supporting the diagnosis 
of index ESUS, i.e. reports of the required 
examinations, including echocardiography, 
cardiac rhythm monitoring and vascular 
imaging such as imaging of the extracranial 
and intracranial arteries supplying the area of 
brain ischemia (either catheter angiography, 
MRI angiography, computed tomographic 
angiography, or cervical plus TCD 
ultrasonography) must be provided to the 
Sponsor`s designee. Copies of 12 lead ECG 
reports done as part of the clinical routine at 
the time of index stroke need not be 
submitted.
Following text added instead:

In the case of recurrent stroke or death 
detailed results of the required diagnostic 
imaging for the index stroke must also be 
provided as part of the adjudication package.
Rationale for change
To simplify and optimize logistics of the trial and 
reduce operational complexity central source data 
reassessment processes is cancelled. This change 
is related to data collection only and does neither 
affect patients` safety nor the integrity of the 
overall study. Removal of this data collection
portal will optimize the feasibility of the trial.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02244185
4.0
clinical-trial-protocol-version-03
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)
Author-Trial Clinical Monitor
21 Apr 2016 14:06 CEST
Author-Trial Clinical
Pharmacokineticist
21 Apr 2016 14:10 CEST
Approval-Therapeutic Area 
21 Apr 2016 14:20 CEST
Approval-Team Member Medicine
21 Apr 2016 15:36 CEST
Author-Trial Statistician
26 Apr 2016 16:34 CEST
Verification-Paper Signature
Completion
26 Apr 2016 16:53 CEST


Boehringer Ingelheim 
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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02244185
4.0

SAP_000.pdf: 
TITLE PAGE
ABCD
Trial Statistical Analysis Plan
c02583764-04
BI Trial No.:
1160.189
Title:
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)
Including Protocol Amendment 1 <1160.189>-protocol-amendment-1 
[c02244185-02] and Protocol Amendment 2 <1160.189>-protocol-
amendment-2 [c02244185-04]
Investigational 
Product:
Pradaxa®, Dabigatran etexilate
Responsible trial 
statistician:
Phone
Fax:
Date of statistical 
analysis plan:
10 APRIL 2018 REVISED
Version:
Revised
Page 1 of 25
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2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
1.
TABLE OF CONTENTS ......................................................................2
LIST OF TABLES ..............................................................................................3
2.
LIST OF ABBREVIATIONS ...............................................................4
3.
INTRODUCTION..................................................................................6
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ......7
5.
ENDPOINTS ..........................................................................................9
5.1
PRIMARY ENDPOINT ......................................................................................9
5.2
SECONDARY ENDPOINTS..............................................................................9
5.2.1
Key secondary endpoints................................................................................9
5.2.2
(Other) Secondary endpoints .........................................................................9
5.4
OTHER VARIABLES.........................................................................................9
6.
GENERAL ANALYSIS DEFINITIONS...........................................10
6.1
TREATMENTS..................................................................................................10
6.2
IMPORTANT PROTOCOL VIOLATIONS ..................................................11
6.3
PATIENT SETS ANALYSED..........................................................................12
.................................................................................................13
6.5
POOLING OF CENTRES ................................................................................14
6.6
HANDLING OF MISSING DATA AND OUTLIERS ...................................14
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ..................15
6.8
CALCULATION OF TIME TO EVENT........................................................16
7.
PLANNED ANALYSIS.......................................................................17
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS........17
7.2
CONCOMITANT DISEASES AND MEDICATION ....................................17
7.3
TREATMENT COMPLIANCE .......................................................................18
7.4
PRIMARY ENDPOINTS..................................................................................18
7.5
SECONDARY ENDPOINTS............................................................................18
7.5.1
Key secondary endpoints..............................................................................18
7.5.2
(Other) Secondary endpoints .......................................................................19
..............................................................................19
7.7
EXTENT OF EXPOSURE................................................................................20
7.8
SAFETY ANALYSIS.........................................................................................20
7.8.1
Adverse events ...............................................................................................21
7.8.2
Laboratory data.............................................................................................22
7.8.3
Vital signs.......................................................................................................22
7.8.4
ECG ................................................................................................................22
7.8.5
Others .............................................................................................................22
8.
REFERENCES.....................................................................................23
...............................................................24
10.
HISTORY TABLE...............................................................................25


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LIST OF TABLES
Table 6.2: 1
Important protocol violations..........................................................................11
Table 6.3: 1
Patient sets analysed........................................................................................13
Table 6.7: 1
Visit schedule ..................................................................................................15
Table 10: 1
History table ....................................................................................................25


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse event
ASA
Acetylsalicylic Acid
BRPM
Blinded report planning meeting
CTC
Common Terminology Criteria  
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DE
Dabigatran etexilate
DM&SM
Boehringer Ingelheim Data Management and Statistics Manual
DRA
Drug Regulatory Affairs
DMG
Dictionary Maintenance Group
EMA
European Medicines Agency 
FAS
Full analysis set
ICH
International Conference on Harmonisation
IPV
Important protocol violation
LOCF
Last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
MoCA
Montreal Cognitive Assessment
MQRM
Medical Quality Review Meeting
mRS
Modified Rankin Scale
O*C
Oracle Clinical
PK
Pharmacokinetics
PPS
Per protocol set
PSTAT
Project Statistician
PT
Preferred term
PV
Protocol violation
Q1
Lower quartile
Q3
Upper quartile
RS
Randomized set
SA
Statistical analysis
SD
Standard deviation


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Term
Definition / description
SMQ
Standardised MedDRA query
SOC
System organ class
TCM
Trial Clinical Monitor
TESS
Treatment emergent signs and symptoms 
TOC
Table of contents
TMW
Trial Medical Writer
TS
Treated set
TSAP
Trial statistical analysis plan


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3.
INTRODUCTION
As per ICH E9 [1], the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This TSAP assumes familiarity with the Clinical Trial Protocol (CTP), including Protocol 
Amendments. In particular, the TSAP is based on the planned analysis specification as 
written in CTP Section 7 “Statistical Methods and Determination of Sample Size”. Therefore, 
TSAP readers may consult the CTP for more background information on the study, e.g., on 
study objectives, study design and population, treatments, definition of measurements and 
variables, planning of sample size, randomization.
This TSAP does not cover the planned analyses by the Data Monitoring Committee (DMC).  
A separate DMC TSAP will be produced for this purpose.
This document is developed by using “TSAP annotations” [2]. SAS® Version 9.4 (or later 
version) will be used for all analyses.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
Changes added to the TSAP since the protocol are:
 

Addition of Screened Set to the Patients sets analysed (see Section 6.3)

Missing data rules for National Institutes of Health stroke scale (NIHSS), baseline 
creatinine clearance, modified Rankin Scale, and disabling stroke were added (see 
Section 6.6)
 
 
 
 
 
 
 
Additional changes added to the TSAP as a result of Amendment 1 are:
 
 
 

Important protocol violation (IPV) clarified, separating atrial fibrillation > 6 minutes 
and cardiac monitoring < 20 hours into distinct IPVs (A1.1, A1.2) (see Table 6.2: 1)

ECG analyses were modified based on changes to data collection (see Section 7.8.4) 


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Additional changes added to the TSAP as a result of Amendment 2 are:
 
Additional changes added to the TSAP as a result of local Japanese Amendment are:

Clarification that in Japan, the criteria for major bleed includes transfusion of 4.5 
units or more of blood (text added to Section 5.4 that includes those details, but does 
not change original protocol definition of major bleeds)


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
The primary endpoint, as defined in the CTP, Section 5.1, is time to first recurrent stroke 
(ischemic, hemorrhagic and unspecified). 
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
The key secondary efficacy endpoints are (both time to event endpoints): 

Ischemic stroke 

Composite endpoint of non-fatal stroke, non-fatal MI and cardiovascular death
5.2.2
(Other) Secondary endpoints
Other Secondary efficacy endpoints (all time to event endpoints):

Disabling stroke (modified Rankin Scale ≥ 4, as determined 3 months after recurrent 
stroke)

All-cause death
 
5.4
OTHER VARIABLES
Safety endpoints will be used as defined in the CTP, Section 5.2.1.
Major bleeds will be defined according to the ISTH definition of a major bleed, as follows
(R05-0344).

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 associated with a reduction in hemoglobin of at least 2g/dL (1.24mmol/L),
or leading to transfusion of two or more units of blood or packed cells (equivalent to 
4.5 or more units in Japan) (Bleeding should be overt and the hemoglobin drop should 
considered to be due to and temporally related to the bleeding event)
and/or

Fatal bleed


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
Treatment periods are the on-treatment period, defined to start on the first day of treatment 
and end on the last day of study medication intake plus 6 days or date of death, if earlier, and 
the post-treatment period, defined to start 7 days after last intake of randomized study drug 
and end on the date of trial completion, or death, whichever comes first.  If no data indicating 
that the patient is alive are recorded after the last day of study medication intake plus 6 days, 
then there is no post-treatment period.  The screening period is defined as the date of 
informed consent until the day before first intake of study medication.
Patients will be analyzed in the treatment group as randomized regardless of treatment 
misallocations.  Randomized treatment groups are dabigatran etexilate (merged group of both 
110 mg and 150 mg) and acetylsalicylic acid (ASA).  
Additional treatment comparisons using baseline assigned dose (DE 110, DE 150, ASA) will 
be analyzed for primary and secondary efficacy endpoints (and components) plus 
 
 Safety endpoints will also be compared by baseline assigned dose
(DE 110, DE 150, ASA). These analyses will be descriptive and will include the main safety 
endpoint major bleeding, as well as life-threatening, fatal, any bleed, intracranial hemorrhage, 
  Descriptive statistics will be 
used for these analyses because these dose groups are not randomized.


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6.2
IMPORTANT PROTOCOL VIOLATIONS
Table 6.2: 1 contains important protocol violations that will be listed in the clinical trial 
report.
Table 6.2: 1
Important protocol violations
Category/
Code
Description
Example/Comment
Excluded 
from
A
Entrance criteria not met
A1.1
Atrial fibrillation duration > 6 minutes 
AFib duration > 6 minutes
None
A1.2
Cardiac monitoring < 20 hours
Cardiac monitoring < 20 
hours
None
A2.1
Conditions not consistent with diagnosis of ESUS
Inclusion criteria 2A, 3 
(IN2A, IN3), Exclusion 
criterion 1,2,4,5,21 (EX1, 
EX2, EX4, EX5, EX21), 
and IN2 (programmed for 
patients without ESUS) 
None
A2.2
Any indication that requires treatment with 
anticoagulant
EX3
None
A2.3
Primary intracerebral hemorrhage on qualifying 
neuroimaging
EX6
None
A2.4
Conditions associated with risk of bleeding
EX7, EX7A
None
A2.5
History of symptomatic intracranial hemorrhage 
EX8, EX8A
None
A2.6
Renal impairment; CrCL<30mL/min
EX9
None
A2.7
History of hypersensitivity to dabigatran or ASA
EX10
None
A2.8
Participation in another trial with investigational drug 
or device within past 14 days
EX16, EX16A
None
A2.9
Conditions that would not allow safe trial participation 
EX18, EX18A
None
A2.10
Active liver disease
EX19
None
A2.11
Severe glucose-6-phosphate dehydrogenase deficiency
EX20
None
A2.12
Previous participation (receipt of randomized 
treatment) in this trial
Manual PV
None
B
Informed consent
B1
Informed consent not available/not done
Informed consent date 
missing
All
B2
Informed consent too late
Informed consent date was 
after Visit 1 date
None


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Table 6.2: 1 (continued)
Important protocol violations
Category/
Code
Description
Example/Comment
Excluded 
from
C
Trial medication and randomization
C1
Incorrect trial medication taken
Medication kit assigned 
not matching treatment 
patient was randomized to 
(cross-treatment) and/or 
not matching IVRS 
assignment
None
C2
Randomization not followed
Date of first trial 
medication before date of 
randomization
None
C3.1
Treatment not interrupted when required
Study drug not interrupted
when AF diagnosed or 
CrCL < 30 mL/min
None
C3.2
Non-compliance
Cumulative compliance 
<80% or >120% (see 
Section 7.3)
None
C4
Medication code broken inappropriately
Manual PV
None
C5
Incorrect dose adjustment (on wrong medication > 50% 
of the time)
Patient on incorrect dose 
according to age, renal 
criteria, in-trial GI bleed
None
D
Concomitant medication
D2
Prohibited medication use
See CTP Section 4.2.2.1
None
6.3
PATIENT SETS ANALYSED

Screened set (SCR):
This patient set includes all patients who signed informed consent and completed at 
least some screening procedures.

Randomized set (RS)
This patient set includes all randomized patients, whether treated or not.

Treated set (TS):
This patient set includes all patients who were documented to have taken at least one 
dose of investigational treatment. The start date of the observation period for this 
analysis set is the date of first intake of trial medication.
The final decision as to whether a patient is included in or excluded from each analysis set 
will be taken before database lock in a blinded manner and will be documented in the minutes 
of the Blinded Report Planning Meeting (BRPM) or Database Lock Meeting.
Analyses will be performed as outlined in Table 6.3: 1.


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Table 6.3: 1
Patient sets analysed
Patient set
Class of endpoint
Screened set
Randomized 
set
Treated set
Primary endpoints 
X
S1
Secondary 
 
 endpoints 
X
Safety endpoints 
S1
X
Patient disposition
X
1 S=Sensitivity analyses (see Section 7.4 and 7.8)
Two analysis periods are defined:

Full follow-up: from date of randomization until the date of last contact (see Section 
6.8), including all observed time on and off trial medication

On-treatment: from the date of first treatment intake until the date of discontinuation 
of trial medication + 6 days (or death, if death occurs earlier)


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6.5
POOLING OF CENTRES
This section is not applicable because centre/country is not included in the statistical model.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
For each time to event analysis, patients who do not experience the assessed outcome will be 
censored.
Missing or incomplete AE dates are imputed according to BI standards (see “Handling of 
missing and incomplete AE dates”) [3].  The same philosophy will be applied to missing or 
incomplete outcome event dates, index qualifying stroke date, concomitant medication dates 
(where applicable), and dates of temporary study medication discontinuation and restart, and 
trial completion date.


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If prior 
 is missing, it will be assumed that the patient did not have previous 
when used as a baseline covariate in the Cox model.  If baseline creatinine 
clearance is missing, then the first on-treatment creatinine clearance will be used as a baseline 
covariate in the Cox model (and if there is no creatinine clearance in the database, then 
creatinine clearance ≥ 50 will be used as covariate in the model).
 
 
For NIHSS –if the score on any item is 9 or the ataxia item is missing, default these items to 
“0” (best case).  Otherwise, for patients with up to 2 items missing, the worst case score for 
that item is imputed.  For patients with 3 or more items missing, a total score will not be 
calculated and the NIHSS will be considered missing.
 
  
 
Other missing and incomplete data will not be imputed.  
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
The planned study period will include 14 visits conducted at Screening, Randomization 
(Day 0, i.e., baseline), and every 3 months thereafter during the first year.  After year one, 
planned visits will be every 6 months starting month 18 with telephone follow ups at months 
15, 21, 27 and 33.  
If the trial is extended, planned visits will be extended at 3 month intervals.  If a patient stops
medication before the end of the trial, visits should still be made to the clinic (or by 
telephone).  For patients that permanently stop study drug and choose not to continue visits, 
vital status will be checked during the trial closeout.
Table 6.7: 1
Visit schedule
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Month
-
0
3
6
9
12
15
18
21
24
27
30
33
36


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The actual number of visits that a patient will have depends on when the patient started the 
trial.  
Time windows will not be used.  Most analyses are collected in real time (e.g., time to death).  
Variables that are collected at visits will be analyzed by planned time point.
A patient will be considered to have completed follow-up if he/she has a date of last contact 
during the end of trial period, defined as within six months of the date of Last Patient Out.
6.8
CALCULATION OF TIME TO EVENT
The calculations of time to events and the time that patients without an event were in the 
study (under risk) are done according to procedures described in this section.
Date of randomization
The day of randomization is the reference for all RS analyses, regardless of when (or if) 
treatment started.
Date of event
For one-time events, like death, the date of event reported on the event case report form 
(CRF) will be used. For events with multiple episodes, such as MI and recurrent stroke, the 
onset date of the first episode will be used. For composite outcome, the onset date of the first
occurring component will be used.
Date of last contact
This is determined as the latest date among the trial completion date (from CRF), last clinic 
visit/phone call, assessment date or last known alive date from the vital status CRF, and the 
maximum of the start dates of all adverse events. If a patient dies, then the date of death is
the date of last contact.
Survival time for full follow-up analyses
For those with an event, the survival time is calculated as:
<date of event> - <date of randomization> + 1
For those patients without an event, the survival time is calculated as:
<date of last contact> - <date of randomization> + 1
Survival time for on-treatment analyses
For those with an event, the survival time is calculated as:
<date of event> - <treatment start date> + 1
For those without an event, the survival time is calculated as:
<min (date of last administration of trial medication + 6, date of last contact)> -
<treatment start date> + 1


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7.
PLANNED ANALYSIS
For End-Of-Text (EoT) tables, the set of summary statistics is: N / Mean / SD / Min / Median 
/ Max. 
For tables that are provided for endpoints with some extreme data, median, quartiles and 
percentiles should be preferred to mean, standard deviation, minimum and maximum.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group (unless otherwise specified, all patients in the respective patient 
set whether they have non-missing values or not). Percentages will be rounded to one decimal 
place. The category missing will be displayed only if there are actually missing values.
When composite endpoints are evaluated as survival endpoints, the time to first onset date of 
any of the events listed in the composite endpoint will be used as the date of the event.  For 
combined endpoints of non-fatal and fatal events, the time to the first event is taken.  If the 
fatality is the first event, then the time to death (not the time to the event leading to death) is 
taken.  For example, if a patient has a stroke at study day 100 and subsequently dies due to 
stroke (as adjudicated) on day 110. For the combined endpoint “Non-fatal stroke, non-fatal 
MI, CV death” the day of event would be day 110.  In the analysis of stroke this patients 
enters the analysis with day 100; in an analysis of fatal stroke this patient should also be 
included with day 100. However in an analysis of CV death the relevant day is day 110.
 
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics by treatment group (and total) are planned for this section of the 
report.
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report.  The frequency [N (%)] 
of patients with different concomitant diseases (baseline conditions) will be presented.
Concomitant medications of special interest will be collected for the following categories:  
antiplatelet medications, thrombolytic agents (fibrinolytics), novel direct oral anticoagulants, 
parenteral anticoagulants, vitamin K antagonists, GPIIb/IIIa antagonists, therapies for 
bleeding management.  These medications will be classified using the World Health 
Organization (WHO) dictionary.


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The remainder of concomitant medications will be collected by tickbox.  All concomitant 
medications will be summarized according to category and displayed by treatment using 
descriptive statistics [N, (%)].  Separate tables for baseline, on-treatment, and post-treatment 
will be presented.  Concomitant therapy during the treatment period will be indicated as used 
if used for at least one day during the treatment period (from the first on-treatment visit 
through termination of trial medication visit).  A separate post-treatment display will be 
generated summarizing use from the end of treatment until last patient contact.
7.3
TREATMENT COMPLIANCE
Descriptive statistics, N / Mean / SD / 1st percentile / Q1 (lower quartile) / Median / Q3 
(upper quartile) / 99th percentile / N missing, for patient mean compliance will be presented 
together with the N (%) of patients with compliance < 80%, between 80 and 120% and > 
120%.  Compliance percentage for each patient is based on cumulative compliance per 
patient (e.g., by taking average of each visit and weighting by the number of days between 
visits.
7.4
PRIMARY ENDPOINTS
The primary endpoint of time to first recurrent stroke (ischemic, hemorrhagic, or unspecified) 
as determined by the adjudication committee will be analyzed using the Cox proportional 
hazards regression model.  Covariates included in the model will be age (binary, < or ≥ 
75 years old), renal impairment (binary; creatinine clearance < or ≥ 50 mL/min), and stroke 
or TIA prior to index stroke (binary, “yes” or “no”).
The primary analysis will be performed on the RS for the full follow-up period.  Patients who 
discontinue study medication will be followed until the end of the trial for OEs including 
vital status.  Patients who are lost to follow-up for vital status will be censored for the 
primary endpoint of recurrent stroke at the date of last contact (see Section 6.8).
The hypotheses for the primary (and key secondary endpoints) are:
Ho: HRDabigatran/ASA = 1
vs.
Ha: HR Dabigatran/ASA ≠ 1
Tests will be performed at the two-sided α = 0.05 level.
 
 
 
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
Key secondary endpoints will be analyzed in a hierarchical manner to preserve the Type I 
error.  If the test for the primary endpoint is successful, then testing will continue for the first 


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key secondary endpoint of time to ischemic stroke with two-sided α=0.05.  If this test is 
statistically significant, then the second key secondary endpoint of time to non-fatal stroke, 
non-fatal MI, and cardiovascular death will be tested with two-sided α=0.05.  If at any point, 
the null hypotheses for the primary or key secondary endpoints cannot be rejected, formal 
testing will stop.
Key secondary endpoints will be analyzed using the same Cox proportional hazards 
regression model (with covariates) as the primary endpoint.  All secondary analyses as 
determined by the adjudication committee will be performed on the RS for the full follow-up 
period.
No multiplicity adjustments are planned for other secondary endpoints.  Nominal p-values 
will be reported for descriptive purposes.
7.5.2
(Other) Secondary endpoints
Other secondary endpoints will be analyzed using the same Cox proportional hazards 
regression model (with covariates) as the primary endpoint.  All secondary analyses will be 
performed on the RS for the full follow-up period.
No multiplicity adjustments are planned for other secondary endpoints.  Nominal p-values 
will be reported for descriptive purposes.


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7.7
EXTENT OF EXPOSURE
Extent of exposure to trial medication within the study will be displayed by treatment to the 
extent that data were collected for the TS.  Both descriptive statistics and categorization by 
exposure intervals (e.g., cumulative exposure intervals <1, 1 - <3, 3 - <6, 6 - <12, 12 - <18, 
18 - < 24, 24 - < 30, 30 - < 36 months, >36 months, if applicable) will be used.
Extent of observation time (defined as: date of randomization to date of last contact) will be 
summarized similarly.  The same intervals will be used except for combining the first three 
intervals into 0-6 months.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the treated set as randomized. 
The primary safety endpoint is time to first major bleed.  


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Secondary safety endpoints are: 

Time to first intracranial hemorrhage

Time to life-threatening bleed

Time to fatal bleed

Time to first bleed (all severities)
Further safety endpoints are:
  
 
 
 
Only investigator-determined major and potentially major bleeds are adjudicated.  Bleeding 
endpoints (as determined by the adjudication committee) that will be analyzed are: major 
bleeds, intracranial hemorrhage, life-threatening and fatal bleeds.  
 
 Time to event endpoints will be analyzed 
using the same Cox proportional hazards regression model as the primary endpoint.  No 
multiplicity adjustments are planned for safety endpoints.
7.8.1
Adverse events
Analyses of adverse events will be descriptive in nature. All analyses of AEs will be based on 
the number of patients with AEs and NOT on the number of AEs.
Furthermore, for analysis of AE attributes such as duration, severity, etc. multiple AE
occurrence data on the CRF, will be collapsed into AE episodes provided that all of the 
following applies:
•
The same MedDRA lowest level term was reported for the occurrences
•
The occurrences were time-overlapping or time-adjacent (time-adjacency of 
2 occurrences is given if the second occurrence started on the same day or on the day after the 
end of the first occurrence)
•
Treatment did not change between the onset of the occurrences OR treatment changed 
between the onset of the occurrences, but no deterioration was observed for the later 
occurrence
For further details on summarization of AE data, please refer to the guideline 'Handling and 
summarization of adverse event data for clinical trial reports and integrated summaries' [5].


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The analysis of adverse events will be based on the concept of treatment emergent adverse 
events. That means that all adverse events occurring between first drug intake until 6 days 
after last drug intake will be assigned to the randomized treatment. All adverse events 
occurring before first drug intake will be assigned to ‘screening’ and all adverse events 
occurring after last drug intake + 6 days will be assigned to ‘post-treatment’ (for listings 
only). For details on the treatment definition, see Section 6.1. In general, adverse events 
attributed to ‘Screening’ or ‘Post-treatment’ will be listed only.
An overall summary of adverse events will be presented. 
Frequencies [N (%)] of patients with adverse events will be summarised by treatment, 
primary system organ class and preferred term (using MedDRA). Separate tables will be 
provided for patients with serious adverse events. 
The system organ classes will be sorted according to the standard sort order specified by 
EMA, preferred terms will be sorted by frequency (within system organ class).
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards [6].
7.8.3
Vital signs
Only descriptive statistics are planned for this section of the report.
7.8.4
ECG
ECGs will be evaluated centrally by an external vendor.  Summary statistics will be displayed 
at baseline. Additional summaries will be produced for patients who have abnormal ECG 
findings at baseline or during the study period.
7.8.5
Others
Duration of cardiac monitoring performed during the course of the trial and the observed 
duration of atrial fibrillation (from this monitoring) will be summarized using descriptive 
statistics.


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8.
REFERENCES
1
CPMP/ICH/363/96: “Statistical Principles for Clinical Trials”, ICH Guideline 
Topic E9; Note For Guidance on Statistical Principles for Clinical Trials, current 
version.
2
001-MCG-160_RD-01: "TSAP annotations", current version; IDEA for CON.
3
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current 
version; IDEA for CON.
4
001-MCS-36-472_RD-01: "Noncompartmental
Pharmacokinetic/Pharmacodynamic Analyses of Clinical Studies", current version; 
IDEA for CON.
5
001-MCG-156: "Handling and summarisation of adverse event data for clinical 
trial reports and integrated summaries", current version; IDEA for CON.
6
001-MCG-157: "Display and Analysis of Laboratory Data", current version, IDEA 
for CON.


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10.
HISTORY TABLE
This is a revised TSAP including the following modifications to the final TSAP.
Table 10: 1
History table
Version 
Date
(DD-MMM-YY)
Author
Sections changed
Brief description of change
Final
29-JUL-14
None
This is the final TSAP without any 
modification.
Revised
14-NOV-14
6.2, 6.3, 
 
Table 6.2: 1 (Important PVs) inserted. 
Revised
11-AUG-15
4, 6.2, 6.3, 
 6.6, 
 7.8.5
Section 6.6 missing data rules added 
for NIHSS.
Other changes due to Amendment 1 are
summarized in Section 4.
Revised
10-APR-18
2, 4, 5.1, 
 
 
6.1, 6.2, 6.3, 
 
6.6, 6.7, 6.8, 7.3, 
7.4, 7.5.1,
7.7,
7.8, 7.8.4
Section 6.8 added to specify time to 
event calculation rules.  Rule to define 
full follow-up added to Section 6.7.
Additional changes in 5.1, 
 6.1, 6.3, 
 7.3, 7.5.1, 
 7.7, 7.8 are wording 
clarifications.