Conditions: Atrial Fibrillation Percutaneous Coronary Intervention
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 2725
Healthy volunteers: no

Brief summary:
The main objective of this study is to compare a Dual Antithrombotic Therapy (DAT) regimen of 110mg dabigatran etexilate b.i.d. plus clopidogrel or ticagrelor (110mg dabigatran etexilate (DE) DAT) and 150mg dabigatran etexilate b.i.d. plus clopidogrel or ticagrelor (150mg DE-DAT) with a Triple Antithrombotic Therapy (TAT) combination of warfarin plus clopidogrel or ticagrelor plus Aspirin (ASA) \<= 100mg once daily (warfarin-TAT) in patients with Atrial Fibrillation that undergo a PCI with stenting (elective or due to an Acute Coronary Syndrome).

The study aims to show non-inferiority of each dose of DE-DAT when compared to Warfarin-TAT in terms of safety. Safety will be determined by comparing the rates of bleeding events, assessed using the modified International Society of Thrombosis and Haemostasis classification of Major Bleeding and Clinically Relevant Non Major Bleeding Events.

Detailed description:

Arms:
arm 1: Patient to receive Dabigatran Etexilate 110mg twice a day (BID) arm 2: Patient to receive Dabigatran Etexilate 150mg twice a day (BID) arm 3: Warfarin doses to maintain INR

Interventions: intervention 1: Dabigatran Etexilate 110mg intervention 2: Warfarin 3mg intervention 3: Aspirin intervention 4: Dabigatran Etexilate 150mg intervention 5: Clopidogrel or Ticagrelor intervention 6: Clopidogrel or Ticagrelor intervention 7: Warfarin 5mg intervention 8: Clopidogrel or Ticagrelor intervention 9: Warfarin 1mg
Intervention descriptions: intervention 1: Active treatment intervention 2: Active comparator intervention 3: Active comparator intervention 4: Active treatment intervention 5: Active comparator intervention 6: Active comparator intervention 7: Active comparator intervention 8: Active comparator intervention 9: Active comparator

Protocol document:
Prot_000.pdf: 
Clinical Trial Protocol
Doc. No.: 
c02214385-09
EudraCT No.:
2013-003201-26
BI Trial No.:
1160.186
BI Investigational
Product(s):
Pradaxa®, dabigatran etexilate
Title:
A prospective Randomised, open label, blinded endpoint (PROBE) 
study to Evaluate DUAL antithrombotic therapy with dabigatran 
etexilate (110mg and 150mg b.i.d.) plus clopidogrel or ticagrelor vs. 
triple therapy strategy with warfarin (INR 2.0 – 3.0) plus clopidogrel or 
ticagrelor and aspirin in patients with non valvular atrial fibrillation 
(NVAF) that have undergone a percutaneous coronary intervention 
(PCI) with stenting
(RE-DUAL PCI)
Clinical Phase:
IIIb
Trial Clinical 
Monitor:
Phone:
Fax:
Co-ordinating 
Investigator:
Phone:
Fax:
Status:
Final Protocol (Revised Protocol (based on global Amendments 1, 2
and 3))
Version and Date:
Version:
4.0
         
Date: 21 July 2016
Page 1 of 150
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


Boehringer Ingelheim                                                                                                         21 Jul 2016
BI Trial No.: 1160.186
Doc. No.: c02214385-09                              Trial Protocol Version 4.0                           Page 2 of 150
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.
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 July 2016
  26 March 2014
1160.186
Title of trial:
A prospective Randomised, open label, blinded endpoint (PROBE) study to 
Evaluate DUAL antithrombotic therapy with dabigatran etexilate (110mg and 
150mg b.i.d.) plus clopidogrel or ticagrelor vs. triple therapy strategy with warfarin 
(INR 2.0 – 3.0) plus clopidogrel or ticagrelor and aspirin in patients with non 
valvular atrial fibrillation (NVAF) that have undergone a percutaneous coronary 
intervention (PCI) with stenting. (RE-DUAL PCI)
Co-ordinating 
Investigator:
Trial sites:
Multi-centre trial
Clinical phase:
IIIb
Objectives:
The main objective is to compare a dual antithrombotic regimen of 110mg dabigatran 
etexilate b.i.d. plus clopidogrel or ticagrelor (110mg DE-DAT) and 150mg dabigatran 
etexilate b.i.d. plus clopidogrel or ticagrelor (150mg DE-DAT) with a triple 
antithrombotic therapy (TAT) of warfarin plus clopidogrel or ticagrelor plus aspirin
(warfarin-TAT) in patients with non valvular atrial fibrillation (NVAF) that undergo a 
PCI with stenting. The study aims to show non-inferiority of each dose of DE-DAT 
when compared to Warfarin-TAT in terms of safety. Safety is determined by bleeding
events, assessed using the modified International Society of Thrombosis and 
Haemostasis (ISTH) classification of Major Bleeding and Clinically Relevant Non-
Major Bleeding Events (CRNMBE).
Methodology:
This is a prospective, randomised, open label, blinded endpoint (PROBE), active 
comparator (warfarin) trial. The study will employ a time to event analysis and all 
patients will remain on study treatment until the last patient entered has completed 
at least six months of treatment.
The patients will be stratified by age (<80 or ≥80 years old) and region (EU/ROW 
or USA).
No. of patients: 
total entered:
2502*


Boehringer Ingelheim                                                                                                         21 Jul 2016
BI Trial No.: 1160.186
Doc. No.: c02214385-09                              Trial Protocol Version 4.0                           Page 3 of 150
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.
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 July 2016
  26 March 2014
1160.186
each treatment:
834*
* These are approximations. As this is an event driven trial the actual number of 
patients entered may increase or decrease based on actual event rates. Sites will be 
notified when recruitment ends.
Diagnosis :
Patients with NVAF that undergo a successful PCI with stenting (elective or due to an 
acute coronary syndrome (ACS)).
Main criteria
for inclusion:
1.
Male or female patients aged ≥18 years
2.
Patients with NVAF that have been receiving oral anticoagulant treatment (either 
with warfarin, another VKA or other novel oral anticoagulant) or treatment naïve 
prior to PCI
3.
Patient with NVAF presenting with:

ACS that was successfully treated by PCI and stenting (either BMS or DES)
or

Stable Coronary Artery Disease with at least one lesion eligible for PCI that 
was successfully treated by elective PCI and stenting (either BMS or DES )
Test products:
Dabigatran etexilate 
dose:
110mg and 150mg (b.i.d.)
mode of admin.:
Oral
Comparator products: Warfarin
dose:
1mg, 3mg and 5mg
mode of admin.:
Oral
Duration of treatment:The minimum duration of study treatment is six months


Boehringer Ingelheim                                                                                                         21 Jul 2016
BI Trial No.: 1160.186
Doc. No.: c02214385-09                              Trial Protocol Version 4.0                           Page 4 of 150
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.
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 July 2016
  26 March 2014
1160.186
Criteria for efficacy:
The primary endpoint for this trial is a safety endpoint, please see below.
The secondary efficacy endpoints  (all time to first event) are:
A combined endpoint of thrombotic events or death (DTE: all death + MI + 
stroke/SE) and unplanned revascularisation by PCI/CABG
A combined endpoint of thrombotic events or death (DTE: all death + MI + 
stroke/SE)
Individual outcome events:

All death (Cardiovascular death, Non-cardiovascular death, 
Undetermined), 

MI

Stroke

SE 

Stent Thrombosis
Composite endpoint of death + MI + stroke
Unplanned revascularisation by PCI/CABG
Criteria for safety:
The primary endpoint for this trial is time to first ISTH Major or Clinically Relevant 
Non-Major Bleeding Event.
Statistical methods:
The stratified Cox proportional hazards regression model will be used to analyse time-
to-event endpoints. To control the Type I error rate at a one-sided 0.025 level, a 
hierarchical procedure for multiple testing will be used to test the safety 
hypotheses. Additional testing for safety and efficacy endpoints will also be included 
in this hierarchical procedure.


Boehringer Ingelheim
21 Jul 2016
BI Trial No.: 1160.186
Doc. No.: c02214385-09                                                                           Trial Protocol Version 4.0
Page 5 of 150
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.
FLOW CHART
Trial Periods
Screen
ing1
Random
isation1
Treatment
EOT2
Follow 
up3
Final 
Visit4
Visit
1
2
Baseline
3
4
5
6
7
85
9, 11 
10, 125
9706
980
990
Days since Randomisation
-5 to 0
0
Months since Randomisation
1
3
6
9
12
15
18, 24
21, 27
6-30
EOT + 
4 weeks
(+7 
days)
Time window (days)
0
7
14
14
14
14
14
14
14
Informed Consent7
X
Check Eligibility
X
X
Demographics
X
Medical History
X
Physical Examination
X8
X
Vital Signs (PR/BP)
X
X9
X
X
X
X
X
X
Weight
X
X
X
X
X
ECG10
X
X
X
X
X
Haematology Laboratory Evaluations11
X12
X
X
X
X
X
X
X
X
Chemistry Laboratory Evaluations11
X12
X
X
X
X
X
Creatinine Clearance13
X12
X
X
X
X
X
X
X
X
Pregnancy Test14
X
X
X
X
X
X
X
X
X


Boehringer Ingelheim
21 Jul 2016
BI Trial No.: 1160.186
Doc. No.: c02214385-09                                                                           Trial Protocol Version 4.0
Page 6 of 150
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.
Trial Periods
Screen
ing1
Random
isation1
Treatment
EOT2
Follow 
up3
Final 
Visit4
Visit
1
2
Baseline
3
4
5
6
7
85
9, 11 
10, 125
9706
980
990
Days since Randomisation
-5 to 0
0
Months since Randomisation
1
3
6
9
12
15
18, 24
21, 27
6-30
EOT + 
4 weeks
(+7 
days)
Time window (days)
0
7
14
14
14
14
14
14
14
Troponin11
X
X
INR/Warfarin dose adjustment15
X
every 2 weeks – monthly 16
Randomisation via IRT
X
Dispense Trial Medication
X
X
X
X
X
X
First Admin of Trial Medication
X17
Drug Accountability
X18
X
X
X
X
X
X
Bleeding Assessment
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant Therapy
X
X
X
X
X
X
X
X
X
X
X
X
X
Reporting of Outcome Events
In an expedited fashion – reporting timelines the same as for SAEs
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
Termination of Trial Medication
X19
End of Patient Participation
X20
X20


Boehringer Ingelheim
21 Jul 2016
BI Trial No.: 1160.186
Doc. No.: c02214385-09                                                                           Trial Protocol Version 4.0
Page 7 of 150
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.
1 Screening and randomisation will occur after successful PCI.
2 End of treatment (EOT) procedures to be completed by all patients at the time of study drug discontinuation.  For patients who discontinue early, the EOT visit should be 
performed instead of the scheduled trial visit at time of discontinuation.
3 For patients that complete all scheduled visits or discontinue treatment early, follow up visit to be conducted four weeks after EOT.  
4 For patients that discontinue treatment early, the final visit will take place at the time trial conclusion is declared.
5 To be conducted by telephone.
6 This event driven trial is expected to take place over 30 months, however, the trial can conclude earlier if an adequate number of events is reported sooner.  It can conclude later 
(or enrol additional patients) if more time is needed to observe the minimum number of required events. If it continues beyond 30 months, follow-up visits (with same 
assessments as required at visits 9 and 11) will occur every 6 months with telephone visits (with the same assessments as required at visits 10 and 12) in between.  At the time of 
trial conclusion (when adequate number of events were reported), all patients would be notified of study conclusion and have an EOT and follow up visit (patients that complete 
all scheduled visits) or final visit (premature treatment discontinuation) scheduled. Patients who discontinue study treatment early should continue to attend regularly scheduled 
visits.   Refer to (Section 6.2.2) for details on management of patients that wish to reduce study participation for any reason.  Collection of vital status and endpoints for all 
patients at the end of the trial is important and described in Section 6.2.3.
7 All patients must sign an informed consent form consistent with ICH-GCP guidelines prior to any trial-related procedures including screening tests.
8 Includes height at Visit 1.
9 If Visit 1 and Visit 2 occur within 24 hours then vital signs do not need to be repeated at Visit 2.
10 ECGs must be performed at baseline and every six months until EOT. If additional ECGs are performed during the course of the trial as part of patient normal care and 
demonstrate a change from baseline or a new pathology develops this should be documented in the eCRF. 
11 Standard safety lab panel (haematology and chemistry, including renal function and liver function tests (LFTs)) and troponin will be performed by the central laboratory at the 
visits indicated, except the screening visit. 
12 Will be performed locally, only those parameters required to verify eligibility are required at screening, standard of care local results taken within 7 days prior to screening can 
be used to verify eligibility.
13 Renal function: creatinine clearance (CrCl) will be calculated based on serum creatinine using the Cockcroft-Gault equation.


Boehringer Ingelheim
21 Jul 2016
BI Trial No.: 1160.186
Doc. No.: c02214385-09                                                                           Trial Protocol Version 4.0
Page 8 of 150
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.
14 Urine pregnancy test required for all women of child bearing potential. In addition women of child bearing potential will be supplied with pregnancy tests and instructed to 
perform pregnancy testing every 4 weeks. 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.
15 All patients will have a baseline INR. Follow-up INRs will be performed only in those patients randomised to warfarin. All INR measurements conducted locally.
16 At least two-weekly INR measurements for the first three months in patients who are commencing warfarin for the first time and monthly subsequently– all other patients at least 
monthly. More frequently if required.
17 Study drug should be administered  between 6 hours after sheath removal and preferably within 72 hours post PCI (refer to section 6.2.2), with haemostasis assured, however up 
to 120 hours post PCI is allowed.
18 Patients randomised to Warfarin only.
19 Patients switching to a non-study VKA from dabigatran etexilate may continue on study medication (dabigatran etexilate) after this visit for 2-3 days to assist bridging.
20 Patients that complete all scheduled visits will conclude participation at the follow up visit, patients who discontinue treatment early will conclude participation at the final visit.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 9 of 150
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.
TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................5
TABLE OF CONTENTS ...................................................................................9
ABBREVIATIONS.......................................................................................... 13
1.
INTRODUCTION.................................................................................... 16
1.1
MEDICAL BACKGROUND............................................................................16
1.2
DRUG PROFILE...............................................................................................19
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 24
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................24
2.2
TRIAL OBJECTIVES.......................................................................................24
2.3
BENEFIT - RISK ASSESSMENT ...................................................................25
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 29
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................29
3.1.1
Administrative structure of the trial...................................................31
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S).....................................................................................32
3.3
SELECTION OF TRIAL POPULATION ......................................................33
3.3.1
Main diagnosis for study entry............................................................33
3.3.2
Inclusion criteria...................................................................................33
3.3.3
Exclusion criteria ..................................................................................34
3.3.4
Removal of patients from therapy or assessments.............................36
3.3.4.1
Removal of individual patients................................................36
3.3.4.2
Discontinuation of the trial by the sponsor..............................37
4.
TREATMENTS........................................................................................ 39
4.1
TREATMENTS TO BE ADMINISTERED....................................................39
4.1.1
Identity of BI investigational product and comparator 
products .................................................................................................39
4.1.2
Method of assigning patients to treatment groups ............................40
4.1.3
Selection of doses in the trial................................................................41
4.1.4
Drug assignment and administration of doses for each patient .......41
4.1.5
Blinding and procedures for unblinding ............................................43
4.1.5.1
Blinding....................................................................................43


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 10 of 150
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.
4.1.5.2
Procedures for emergency unblinding .....................................43
4.1.6
Packaging, labelling, and re-supply ....................................................43
4.1.7
Storage conditions.................................................................................43
4.1.8
Drug accountability ..............................................................................44
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT....................................................................................................45
4.2.1
Rescue medication, emergency procedures, and additional 
treatments ..............................................................................................45
4.2.1.1
Major Bleeds............................................................................46
4.2.1.2
Minor Bleeds............................................................................47
4.2.1.3
Emergency and Elective Surgery.............................................48
4.2.1.4
Stroke.......................................................................................51
4.2.1.5
Acute Coronary Syndrome ......................................................52
4.2.1.6
Other Medical Intervention......................................................52
4.2.1.7
Overdose ..................................................................................53
4.2.2
Restrictions............................................................................................54
4.2.2.1
Restrictions regarding concomitant treatment .........................54
4.2.2.2
Restrictions on diet and life style.............................................55
4.3
TREATMENT COMPLIANCE.......................................................................56
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 58
5.1
EFFICACY.........................................................................................................58
5.1.1
Endpoints of efficacy.............................................................................58
5.1.2
Assessment of efficacy...........................................................................58
5.1.2.1
Death........................................................................................58
5.1.2.2
Myocardial infarction...............................................................59
5.1.2.3
Stroke.......................................................................................61
5.1.2.4
Systemic embolism..................................................................62
5.1.2.5
Stent Thrombosis .....................................................................62
5.1.2.6
Repeated revascularisation by PCI/CABG..............................63
5.2
SAFETY..............................................................................................................63
5.2.1
Endpoints of safety................................................................................63
5.2.2
Assessment of adverse events...............................................................64
5.2.2.1
Assessment of Bleeding events................................................64
5.2.2.2
Definitions of AEs ...................................................................67
5.2.2.3
Adverse event and serious adverse event reporting.................70
5.2.3 Assessment of safety laboratory parameters......................................71
5.2.4 Electrocardiogram................................................................................73
5.2.5
Assessment of other safety parameters...............................................73
5.2.5.1 Physical Examination...............................................................73
5.2.5.2
Vital Signs and Weight ...........................................................73


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 11 of 150
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.
5.3 OTHER....................................................................................................................74
5.3.1 Other endpoint(s).....................................................................................74
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................74
6.
INVESTIGATIONAL PLAN.................................................................. 75
6.1
VISIT SCHEDULE............................................................................................75
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................75
6.2.1
Screening and run-in period(s)............................................................75
6.2.1.1 Screening Visit (Visit 1).............................................................75
6.2.2
Treatment period(s)..............................................................................75
6.2.3
End of trial and follow-up period........................................................77
6.2.3.1 End of treatment.......................................................................77
6.2.3.2 Follow up visit .........................................................................77
6.2.3.3 Final Visit.................................................................................77
6.2.3.4 Vital Status and Outcome Event Collection ............................77
6.2.3.5 Withdrawal of consent .............................................................78
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 79
7.1
STATISTICAL DESIGN - MODEL................................................................79
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................79
7.3
PLANNED ANALYSES....................................................................................80
7.3.1
Primary analyses...................................................................................80
7.3.2
Secondary analyses ...............................................................................81
7.3.3
Safety analyses.......................................................................................81
7.3.4
Interim analyses ....................................................................................82
7.3.5
Pharmacokinetic analyses ....................................................................82
7.3.6
Pharmacodynamic analyses.................................................................82
7.3.7
Pharmacogenomic analyses..................................................................82
7.4
HANDLING OF MISSING DATA ..................................................................82
7.5
RANDOMISATION ..........................................................................................82
7.6
DETERMINATION OF SAMPLE SIZE ........................................................83
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 85
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................85
8.2
DATA QUALITY ASSURANCE .....................................................................87
8.3
RECORDS..........................................................................................................87
8.3.1
Source documents .................................................................................87
8.3.2
Direct access to source data and documents.......................................87


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 12 of 150
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.
8.3.3
Storage of records - Japan ...................................................................87
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE 
EVENTS..............................................................................................................88
8.4.1
Listedness...............................................................................................88
8.4.2
Expedited reporting to health authorities and IECs/IRBs................88
8.5
STATEMENT OF CONFIDENTIALITY.......................................................88
8.6
COMPLETION OF TRIAL..............................................................................88
8.7
PROTOCOL VIOLATIONS ............................................................................88
8.8
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT 
OF TRIAL RELATED INJURY......................................................................89
9.
REFERENCES......................................................................................... 90
9.1
PUBLISHED REFERENCES...........................................................................90
9.2
UNPUBLISHED REFERENCES.....................................................................96
10. APPENDICES .......................................................................................... 98
APPENDIX 10.1
STUDY DRUG START AND BRIDGING RULES ...........98
10.1.1 When to start dabigatran etexilate following treatment by 
other anticoagulants..............................................................................98
10.1.2 When to start warfarin following treatment by other 
anticoagulants or VKAs .......................................................................98
10.1.3 Bridging Therapy (e.g. for temporary interruptions of study 
drug due to interventions)....................................................................99
APPENDIX 10.2
SWITCHING FROM STUDY TREATMENT AT EOT.100
APPENDIX 10.3
DEFINITION OF DISABLING STROKE BY 
MODIFIED RANKIN SCALE .......................................................................101
APPENDIX 10.4
HANDLING OF OUTCOME EVENTS (BLEEDS AND 
MORTALITY / MORBIDITY EVENTS), SERIOUS ADVERSE 
EVENTS AND ADVERSE EVENTS.............................................................102
11. DESCRIPTION OF GLOBAL AMENDMENT(S)............................ 103


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 13 of 150
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.
ABBREVIATIONS
ACS
Acute Coronary Syndrome
AE
Adverse Event
AESI
Adverse Event of Special Interest
AF
Atrial Fibrillation
ALT
Alanine aminotransferase
aPTT
Activated Partial Thromboplastin Time
ASA
Aspirin
AST
Aspartate transaminase
AUC
Area under the Curve
BARC
Bleeding Academic Research Consortium
b.i.d.
Twice a day
BI
Boehringer Ingelheim
BMS
Bare Metal Stent
CABG
Coronary Artery Bypass Graft 
CI
Confidence Interval
CRA
Clinical Research Associate
CrCl
Creatinine Clearance
CRF
Case Report Form
CRNMBE
Clinically Relevant Non Major Bleeding Event
CT
Computed Tomography
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Cardiovascular
DAPT
Dual Antiplatelet Therapy
DAT
Dual Antithrombotic Therapy
DE
Dabigatran Etexilate
DES
Drug Eluting Stent
DILI
Drug Induced Liver Injury
DMC
Data Monitoring Committee
DTE
Death or Thrombotic Event
dTT
diluted Thrombin Time


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 14 of 150
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.
eCRF
Electronic Case Report Form
ECT
Ecarin Clotting Time
EOT
End of Treatment
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
GCP
Good Clinical Practice
GI
Gastrointestinal
HR
Hazard Ratio
IB
Investigator’s Brochure
IAC
Independent Adjudication Committee
IEC
Independent Ethics Committee
INR
International Normalised Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
ISTH
International Society of Thrombosis and Haemostasis
i.v.
Intravenous
LBBB
Left Bundle Branch Block
LFTs
Liver Function Tests
LMWH
Low Molecular Weight Heparin
MBE
Major Bleeding Event
MedDRA
Medical Dictionary for Drug Regulatory Activities
MI
Myocardial Infarction
MR
Magnetic Resonance
NVAF
Non Valvular Atrial Fibrillation
OPU
Operative Unit
OAC
Oral Anticoagulation 
OE
Outcome Event
p.o.
per os (oral)
PD
Pharmacodynamic
PCI
Percutaneous Coronary Intervention
P-gp 
P-glycoprotein


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 15 of 150
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.
PK
Pharmacokinetic
PPI
Proton Pump-Inhibitor
PROBE
Prospective, Randomised, Open Label trial with Blinded Endpoint
q.d.
quaque die (once a day)
RDC
Remote Data Capture
REP
Residual Effect Period
SAE
Serious Adverse Event
s.c.
Subcutaneous
SPAF
Stroke Prevention in Atrial Fibrillation 
SE
Systemic Embolism
SmPC
Summary of Product Characteristics
TAT
Triple Antithrombotic Therapy
TCM
Trial Clinical Monitor
TIMI
Thrombolysis In Myocardial Infarction
TSAP
Trial Statistical Analysis Plan
TT
Thrombin Time
TTR
Time in Therapeutic Range 
UA
Unstable Angina
UFH
Unfractionated Heparin
ULN
Upper Limit Normal 
URL
Upper Reference Limit
VKA
Vitamin K Antagonist


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 16 of 150
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.
1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
The current estimate of the prevalence of atrial fibrillation (AF) in the developed world is 
approximately 1.5–2% of the general population. The arrhythmia is associated with a five-
fold increase in the risk of stroke and a three-fold increase in the incidence of congestive 
heart failure and higher mortality. This arrhythmia is a major cardiovascular challenge in 
modern society and its medical, social and economic aspects are all set to worsen over the 
coming decades. Chronic anticoagulant treatment is mandatory in the great majority of the 
patients with AF [P10-14910, P12-11192]. 
Twenty to thirty percent of non valvular AF (NVAF) patients have concomitant coronary 
artery disease [R13-4127, P10-07397, P11-09369]. Revascularisation treatment by primary 
percutaneous coronary intervention (PCI) has reduced morbidity and mortality in patients 
with acute and chronic coronary artery disease [R13-4128, P13-11665, R13-4138]. 
Worldwide over 1,000,000 anticoagulated patients are candidates for a PCI each year [P10-
07397]. In patients undergoing PCI, the addition of clopidogrel to aspirin (ASA) reduces 
death, myocardial infarction (MI) and stroke [R13-4128, P13-11665, R13-4138]. Dual 
antiplatelet treatment with ASA and clopidogrel also reduces recurrences and the risk of stent 
thrombosis and is a routine treatment in patients undergoing PCI with stent regardless of 
indication [R13-4128, P13-11665, R13-4138]. Therefore, when patients with AF that are 
receiving anticoagulant treatment have to undergo a PCI with stenting, there is an indication 
for concomitant treatment with ASA and clopidogrel (triple antithrombotic therapy (TAT)) to 
prevent stent thrombosis [R13-4127, P10-07397, P11-09369]. 
Rigorous antithrombotic treatment invariably raises the risk of bleeding, adding to a poorer 
prognosis with an estimated five-fold mortality increase following MI. Major bleeding in 
patients with acute coronary syndromes (ACS) treated with an early invasive strategy confers 
an increased risk for both short-term and mid-term mortality [P11-09951, R13-4129, R13-
4130]. An acceptable bleeding risk while maintaining a lower ischaemic event rate is 
considered a must in the post-PCI setting [P10-07397, P11-09369, R13-4128, P13-11665, 
R13-4138, P11-09951, R13-4129].
In a large registry of patients undergoing PCI (CathPCI Registry - 386 688 procedures 
performed in the United States between 2004 and 2011), post procedural bleeding events 
were associated with increased risk of in-hospital mortality, with an estimated 12.1% of 
deaths related to bleeding complications [R13-4130]. It has been increasingly recognised that 
the adverse consequences of peri-procedural bleeding extends beyond the hospitalisation for 
the procedure and can continue for up to three years [P11-09951, R13-4129, R13-4130].
In patients with ACS or undergoing PCI, the presence of AF raises a therapeutic challenge 
because treatment with both anticoagulant and antiplatelet therapies is preferred to prevent 
stroke and further coronary events. In the absence of data derived from randomised clinical 
trials, the management of these patients remains unclear. An analysis of the patient 
subpopulation that was receiving warfarin at the time of hospital admission enrolled in 


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 17 of 150
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.
CRUSADE showed that current physician practices vary with regard to the perceived optimal 
antithrombotic strategy at time of hospital discharge [R13-4132]. Existing recommendations 
are based on small, single-centre, studies that mostly include patients treated with PCI with 
stent implantation. Overall, it has been concluded that further research is needed to guide 
patient care.  
Several retrospective analyses using patients that participated in observational registries and 
patient populations enrolled in clinical trials have assessed outcomes and have shown that 
there might be a potential benefit with the implementation of a dual antithrombotic therapy 
(DAT) regimen (anticoagulant plus clopidogrel) in comparison with a TAT regimen 
(anticoagulant plus clopidogrel plus ASA) in NVAF that have undergone PCI [R13-4133, 
R13-4134, P13-11669, P11-01097, R13-4135]. 
A nationwide registry in Denmark that comprised a total of 12,165 AF patients hospitalised 
with MI and/or undergoing PCI between 2001-2009 assessed the risk of MI, coronary death, 
ischaemic stroke and bleeding according to the antithrombotic treatment regimen. Within one 
year, MI or coronary death, ischaemic stroke and bleeding events occurred in 18.5%, 5.6%
and 6.3% of patients, respectively. Relative to triple therapy (oral anticoagulation (OAC) + 
ASA + clopidogrel), no increased risk of recurrent coronary events was seen for the dual 
regimens with OAC + clopidogrel, OAC + ASA, or ASA + clopidogrel. When compared to 
triple therapy, bleeding risk tends to be reduced (non-significantly reduced for OAC + 
clopidogrel and significantly reduced for dual therapy with OAC + ASA and ASA + 
clopidogrel) [R13-4136].
Since blockade of P2Y12 receptor-mediated signalling with clopidogrel is associated with 
greater platelet inhibitory effects than cyclooxygenase-1 inhibition with ASA and the 
established role that P2Y12 receptor blockade has on recurrent thrombotic events, clopidogrel 
might be expected to be more effective at reducing stent thrombosis, but with increased 
bleeding [P11-09369]. One small observational study observed a lower incidence of stent 
thrombosis with clopidogrel plus warfarin as compared with ASA plus warfarin [P11-09369].
Other retrospective reports and case-control studies of patients after coronary stenting with an 
indication for long-term OAC also found more favourable outcomes for clopidogrel than 
ASA in combination with OAC [R13-4136]. Significant differences in the rate of stent 
thrombosis have been reported between different antithrombotic drug combinations. The 
incidence of stent thrombosis has been reported to be higher in patients receiving a 
combination of warfarin plus ASA in comparison to a dual antiplatelet therapy (DAPT)
regimen, a DAT regimen of warfarin plus clopidogrel and a TAT regimen of warfarin plus 
clopidogrel plus ASA [R13-4136, P07-06963]. The rate of stroke has been observed to be 
higher in patients receiving a DAT regimen without anticoagulation [P07-06963]. 
The observations from the retrospective and case-control studies reinforce a concept that is 
well known and validated in prospective clinical trials; anticoagulant therapies are more 
beneficial for the prevention of thromboembolism in patients with AF and DAT regimens 
including a P2Y12 inhibitor are of greater benefit compared to dual antithrombotic regimens 
comprising warfarin plus ASA for the prevention of ischaemic events, including stent 
thrombosis, in patients undergoing PCI [P10-07397, P11-09369]. Recommendation of the 


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 18 of 150
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.
European and North American Consensus of using triple therapy for patients with recent MI 
and/or PCI and concurrent AF is established because of OAC being indicated for AF patients 
with stroke risk factors and DAT being indicated after ACS or PCI [P10-07397, P11-09369].
The WOEST results have been reflected in some of the recent guidelines for NVAF patients 
undergoing PCI with stenting [P14-05384, P14-12794, P16-02545] which recommend to 
consider the use of DAT in certain patients. Non randomised studies on triple therapy showed 
a protection from ischaemic events with no clear excess bleeding, compared to other 
regimens, but the studies all have limitations of being potentially underpowered, performed in 
single centre settings and only including patients after stent implantation [P10-07397, P11-
09369]. The main finding of the nationwide Danish registry was that in AF patients after 
MI/PCI, the combination of OAC plus clopidogrel is comparable with the recommended 
triple therapy in respect to the prevention of thromboembolic outcomes of MI/coronary death 
and ischaemic stroke while the risk of bleeding was similar [R13-4136]. Notably, the risk of 
all-cause mortality was similar between OAC plus clopidogrel and triple therapy but 
markedly increased for other therapies, namely, OAC plus ASA and DAPT therapy. No 
beneficial effect was evident for adding ASA to OAC plus clopidogrel treatment, which 
challenges current recommendations that favours triple therapy for this population. The data 
from the nationwide Danish registry is consistent with other retrospective reports and suggest 
that the favoured antiplatelet to be used in combination with OAC should be clopidogrel and
this combination may well be used in AF patients after recent MI and/or PCI [R13-4136, 
P07-06963].
A recently published small randomised controlled study (WOEST) [R13-4127], observed that 
bleeding and ischaemic event rates were lower in patients on DAT (warfarin + clopidogrel) 
compared to TAT (warfarin + clopidogrel + ASA). From previous experience it is also 
known that continued anticoagulation with warfarin during PCI procedures is associated with 
an increased risk of bleeding [P07-09550]. The WOEST study enrolled 573 patients
randomly assigned in a 1:1 ratio to receive oral anticoagulation  plus clopidogrel alone (DAT) 
or plus clopidogrel and aspirin (TAT). All patients were pretreated with a maintenance dose 
of 75mg clopidogrel per day for at least 5 days, a loading dose of 300mg clopidogrel at least 
24 hours before PCI, or a loading dose of 600mg clopidogrel at least 4 hours before PCI. A 
320mg loading dose of ASA was also given to patients who had not been taking ASA before 
the study. Study treatment was started promptly after randomisation. All patients received 75 
mg clopidogrel daily, and those in the TAT group were also given 80–100mg ASA daily.
One year follow up data were available for 279 (98.2%) patients assigned to receive DAT and 
284 (98.3%) assigned to receive TAT. Bleeding episodes were seen in 54 (19.4%) patients 
receiving dual therapy and in 126 (44.4%) receiving triple therapy hazard ratio (HR) 0.36, 
95% Confidence Interval (CI) 0.26–0.50, p<0·0001). In the dual-therapy group, six (2.2%) 
patients had multiple bleeding events, compared with 34 (12.0%) in the triple-therapy group. 
Eleven patients (3.9%) receiving dual therapy required at least one blood transfusion, 
compared with 27 (9.5%) patients in the triple-therapy group (odds ratio 0.39, 95% CI 0.17–
0.84, p=0.011). The combined secondary endpoint of death, MI, stroke, target-vessel 
revascularisation and stent thrombosis was reported in 31 (11.1%) patients in the DAT group 
and in 50 (17.6%) in the TAT group. After correction for imbalance in baseline 
characteristics, the HR remained similar (0.56, 95% CI 0.35–0.91). Seven patients (2.5%) in 
the DAT group and 18 (6.3%) in the TAT had died from any cause at 1 year [R13-4127]. 


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 19 of 150
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.
This study, however, was not powered for assessing efficacy and can only be considered 
hypothesis-generating.
As newer OACs (e.g. dabigatran etexilate, rivaroxaban, apixaban) are likely to replace 
vitamin K antagonists (VKA) in certain AF patients in the years to come, clinicians will soon 
face new treatment possibilities not explored in PCI clinical trials. In a RE-LY sub analysis 
focused on patients receiving concomitant antiplatelet therapy, dabigatran etexilate 110mg 
twice daily (b.i.d.) was non-inferior to warfarin in reducing stroke and systemic embolism
(SE), whether patients received antiplatelet therapy or not. There were fewer major bleeds 
than with warfarin in both dabigatran etexilate 110mg b.i.d. subgroups for patients who used 
antiplatelets and for patients who did not [P13-00071]. In the same sub-analysis, dabigatran 
etexilate 150mg b.i.d. reduced the primary outcome of stroke and SE in comparison with 
warfarin [P13-00071]. Dabigatran etexilate, would therefore be an attractive alternative to 
warfarin (as part of triple therapy), particularly used at a lower dose since it appears to have 
less bleeding without loss of efficacy [P11-09369]. Prospective clinical data concerning the 
possibility of implementing triple or DAT regimens with dabigatran etexilate and other new 
OACs addressing their efficacy and safety in patients undergoing PCI are needed [P11-
09369].
Newer P2Y12 inhibitors (e.g. ticagrelor, prasugrel) have also recently become available. Data 
is still lacking about both the concomitant use of ticagrelor with VKA or novel oral 
anticoagulant treatments and the potential use of ticagrelor as part of triple or dual 
antithrombotic therapy regimens [P11-09369]. The use of prasugrel is generally not 
recommended in patients ≥75 years of age because of the increased risk of fatal (1.0% 
prasugrel vs. 0.1% clopidogrel) and intracranial bleeding (0.8% prasugrel vs. 0.3% 
clopidogrel) and uncertain added benefit [P07-13246; R13-5262].
1.2
DRUG PROFILE
Dabigatran etexilate is the orally bioavailable prodrug of dabigatran, a novel, synthetic, direct 
thrombin inhibitor. Following oral administration dabigatran etexilate (prodrug) is rapidly 
converted to the active moiety dabigatran, which is a non-peptidic, highly potent, competitive 
and reversible inhibitor of thrombin [U06-1704, P08-12388].
The pharmacokinetic (PK) profile is characterised by peak plasma concentrations of 
dabigatran that occur approximately two hours after oral administration of the prodrug, a 
biexponential distribution phase and a terminal elimination half-life of 14-17 hours after 
multiple dose administration. Dabigatran maximum plasma concentrations and area under 
curve (AUC) increase in a dose proportional manner. PK steady state is reached by three days 
with b.i.d. dosing, pharmacodynamic (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. 
Dabigatran may be conjugated to form acylglucuronides, which are pharmacologically active. 
The absolute bioavailability of the current capsule formulation of dabigatran etexilate is 
approximately 6.5%.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 20 of 150
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.
In Phase I drug-drug interaction studies there was no significant influence of dabigatran 
etexilate 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 metabolised by the cytochrome P450 system and have no in 
vitro effects on human cytochrome P450 enzymes. There was, however, an effect on 
dabigatran etexilate 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. 
In a phase I study in young healthy male volunteers, the concomitant administration of 
dabigatran etexilate and clopidogrel resulted in no further prolongation of capillary bleeding 
times compared to clopidogrel monotherapy. In addition, dabigatran AUCτ,ss and Cmax,ss 
and the coagulation measures for dabigatran effect or the inhibition of platelet aggregation as 
measure of clopidogrel effect remained essentially unchanged comparing combined treatment 
and the respective mono-treatments. With a loading dose of 300mg or 600mg clopidogrel, 
dabigatran AUCτ,ss and Cmax,ss were increased by about 30-40 %. When comparing 
combined treatment and the respective mono-treatments, the coagulation measures for 
dabigatran’s effect (Activated Partial Thromboplastin Time (aPTT), Ecarin Clotting Time 
(ECT) and Thrombin Time (TT)) remained unchanged and inhibition of platelet aggregation, 
a measurement of clopidogrel’s effect, remained unchanged.
The potential for a PK interaction between ticagrelor and dabigatran was evaluated in a 
randomised, open-label, 2-period cross-over phase I study in 12 healthy male subjects (BI 
Trial No. 1160.141) [U12-2002]. In order to limit the potential bleeding risk to human 
volunteers, a low dose of 75mg dabigatran etexilate was administered either: alone in one 
trial period, or in combination with ticagrelor in a second period (i.e. one dabigatran etexilate
dose on Day 1 at the same time as a loading dose of ticagrelor (180mg) and the second time 
on Day 4 at the same time as ticagrelor after it had been dosed at 90mg b.i.d. over 3 
consecutive days with a goal of reaching steady state).
Co-administration of a loading dose of 180mg of ticagrelor on Day 1 with single dose of 
75mg dabigatran etexilate in study 1160.141 [U12-2002) resulted in a 1.73-fold (90% CI 1.18 
to 2.52) and 1.95-fold increase (90% CI1.26 to 3.00) in gMean AUC0-∞ and Cmax of total 
dabigatran, respectively. After further treatment with 90mg ticagrelor b.i.d. the increase of 
dabigatran gMean AUC0-∞ and Cmax after single oral administration of 75mg dabigatran 
etexilate on Day 4 were 1.46-fold (90% CI 1.00 to 2.12) and 1.56-fold (90% CI 1.02 to 2.38), 
respectively [U12-2002].
The interaction was further assessed under dabigatran steady state conditions in an open 
label, fixed sequence, multiple-dose, healthy volunteer study (BI study 1160.142 [U13-
2049]). Multiple doses of 110mg dabigatran etexilate b.i.d were given alone and in 
combination with ticagrelor (i.e. on Day 4 the morning dose of the 110mg dabigatran 
etexilate b.i.d treatment was given at the same time as a 180mg loading dose of ticagrelor) 
and the second time on Day 7 at the same time as ticagrelor after it had been dosed at 90mg
b.i.d. with a goal of reaching steady state (part 1). Further, the second part of the study 
investigated the effect of staggered administration of ticagrelor loading dose on dabigatran 


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 21 of 150
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.
exposure in steady state. The loading dose was given 2 hours after the morning dose of the 
110mg dabigatran etexilate b.i.d treatment.
Concomitant administration of the loading dose of 180mg ticagrelor at the same time as the 
morning dose of 110mg dabigatran etexilate b.i.d. increased the gMean (adjusted for 
treatment) total dabigatran AUCτ,ss 1.49-fold (90% CI 1.24 to 1.79) and Cmax,ss 1.65-fold (90% 
CI 1.34 to 2.03) compared with dabigatran etexilate given alone. Concomitant administration 
of the morning dose of 90mg ticagrelor b.i.d with the morning dose 110mg dabigatran 
etexilate increased the adjusted gMean total dabigatran AUCτ,ss 1.26-fold (90% CI 1.07 to 
1.49) and Cmax,ss 1.29-fold (90% CI 1.06 to 1.55) compared with dabigatran etexilate given 
alone. When the loading dose of 180mg ticagrelor was given 2 hours after the morning dose 
of 110mg dabigatran etexilate b.i.d gMean (adjusted for treatment) total dabigatran AUCτ,ss 
increased 1.27-fold (90% CI 1.08 to 1.49) and Cmax,ss 1.24-fold (90% CI 1.03 to 1.49) 
compared with dabigatran etexilate given alone [U13-2049].
The finding that ticagrelor increased dabigatran exposure is consistent with the hypothesis of 
P-gp inhibition by ticagrelor at the intestinal wall, which could have decreased the efflux of 
dabigatran etexilate into the gut and increased its absorption. With staggered intake of 
ticagrelor 2 hours after the intake of dabigatran etexilate the increase of dabigatran exposure 
observed after simultaneous administration of both drugs was reduced. This was most likely 
due to the fact that dabigatran absorption in the gut is complete after 2 hours. A similar 
reduction of PK interaction effects with staggered intake has also been observed for 
verapamil and dronedarone [U13-2049].
Administration of dabigatran etexilate (single or multiple doses) and the co-administration of 
dabigatran etexilate with the ticagrelor loading dose and the multiple-dose regimen of 
ticagrelor was safe, i.e. it did not cause bleeding in the healthy subjects included in the trials
1160.141 and 1160.142 [U13-2049].
In summary, a PK interaction between ticagrelor and dabigatran etexilate has been shown in 
drug-drug interaction trials examining a single- and multiple-dose applications of dabigatran 
etexilate (BI studies 1160.141, 1160.142) [U12-2002, U13-2049]. The magnitude of this PK
interaction under steady state conditions of dabigatran (i.e. in a clinically more relevant 
scenario) was lower when compared to conditions when the single dose of dabigatran 
etexilate was administered. Further, the interaction was also lower under the maintenance 
dose of ticagrelor or after a staggered intake of the ticagrelor loading dose (given 2 hours 
after dabigatran etexilate). The relative increase in dabigatran exposure under the various 
conditions presented above is expected to be of comparable magnitude when a dose of 150mg 
dabigatran etexilate is given, as dabigatran displays dose-proportional pharmacokinetics in 
healthy subjects and patients in the range of doses from 10 to 400mg [U12-2002, U13-2049].
The magnitude of PK interaction was dependent upon the dose administered. Under steady 
state conditions of dabigatran and ticagrelor, the plasma level increase of dabigatran was in 
the range (approx. +26-29%) of the P-gp inhibitor clarithromycin which is considered of no 
clinical safety concern. Similar increases can be seen when the loading dose of ticagrelor is 
given 2 hours after dabigatran etexilate intake. When the loading dose of ticagrelor is given at 
the same time as dabigatran etexilate, the increase of dabigatran was in the range (approx. 


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 22 of 150
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.
+50-65%) comparable to the increases of Pgp inhibitors such as amiodarone or quinidine. 
Similar to the concomitant administration of dabigatran etexilate with amiodarone or 
quinidine, a dose adjustment of dabigatran etexilate is considered not necessary when
ticagrelor treatment is initiated or given chronically [U12-2002, U13-2049].
It was demonstrated in the Phase III study, RE-LY (1160.26), that co-administration of P-gp 
inhibitors (such as amiodarone, quinidine and verapamil) in a long-term clinical trial setting 
had much smaller effects than those observed in Phase I studies, which were designed to 
show maximal possible PK effects. The greatest elevation of dabigatran exposure was 
observed for patients treated concomitantly with verapamil, who had on average a trough 
dabigatran plasma concentration increase of 16%. Concomitant administration of amiodarone 
or quinidine and dabigatran etexilate led to even smaller increases of plasma concentrations 
of dabigatran and did not appear to increase the relative risk of bleeding [U09-3249-02].
The PK and PD of dabigatran in subjects with normal renal function in comparison to 
subjects 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 (Creatinine Clearance (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. 
No influence of hepatic impairment on the absorption and bioconversion of dabigatran 
etexilate to the active form dabigatran and its excretion was observed comparing healthy 
subjects and subjects with moderate hepatic impairment (category B of the Child Pugh 
classification system) [P08-12388]. 
Dabigatran etexilate is registered for reducing the risk of stroke and SE in patients with 
NVAF. The RE-LY trial was a Phase III, prospective, randomised, open-label, multinational 
trial of stroke prevention in subjects with NVAF at risk of stroke. A total of 18,113 subjects 
were randomised to one of two blinded doses of dabigatran etexilate (110mg b.i.d. or 150mg 
b.i.d.) or to warfarin (target International Normalised Ratio (INR) 2.0-3.0) [U09-3249-02]. 
RE-LY demonstrated that dabigatran etexilate, 150mg b.i.d., was superior to warfarin for the 
prevention of stroke and SE in subjects with NVAF and at least one risk factor for stroke. 
Dabigatran 150mg also resulted in reductions of intracranial haemorrhage, total bleeding and 
vascular mortality. Dabigatran etexilate 110mg b.i.d. was non-inferior to warfarin for the 
primary endpoint of stroke and SE and reduced intracranial haemorrhage, major bleeding and 
total bleeding. 
Antiplatelet agents (ASA or clopidogrel) are known to increase bleeding. In RE-LY 
[U09-3249-02], the yearly major bleeding events (MBE) were about twice as high in subjects 
receiving additional ASA or clopidogrel, but this effect was similar to that observed when 
ASA or clopidogrel was administered with warfarin.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 23 of 150
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.
In an ACS setting, the RE-DEEM trial assessed the safety and indicators of efficacy of the 
novel oral direct thrombin inhibitor dabigatran etexilate in addition to DAPT (ASA plus 
clopidogrel). In this double-blind, placebo-controlled, dose-escalation trial of 1861 patients 
almost all patients (99.2%) received DAPT therapy with ASA and either clopidogrel or 
ticlopidine at baseline. Primary outcome was the composite of major or clinically relevant 
minor bleeding during the 6-month treatment period. Dabigatran etexilate, in addition to 
DAPT, was associated with a dose-dependent increase in bleeding events in patients with a 
recent MI. In addition, dabigatran etexilate 110mg b.i.d. and dabigatran etexilate 150mg b.i.d. 
were the doses associated with the lowest rate of the secondary composite ischaemic outcome 
compared to the lower doses that were tested (75mg b.i.d.; 50mg b.i.d.) and placebo [P11-
05772].
Please refer to the current version of the Investigator Brochure (IB) for dabigatran etexilate 
for additional information on drug-drug interaction studies, studies in special patient 
populations and completed Phase II/III trials.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 24 of 150
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.
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
There is uncertainty over the optimal antithrombotic management strategy for patients with 
NVAF undergoing PCI. The current treatment recommendations of TAT, comprising, VKA, 
clopidogrel and ASA [P10-07397, P11-09369] are based on limited data. There is increasing 
research to suggest that there might be a potential benefit with the implementation of a DAT 
regimen.
Dabigatran etexilate has been shown in the RE-LY trial in a NVAF setting at risk of stroke to 
be more effective than warfarin in the prevention of stroke and SE at a dose of 150mg b.i.d. 
and non-inferior to warfarin at a dose of 110mg b.i.d. With respect to bleeding risk, the 
150mg b.i.d. dabigatran etexilate dose was equivalent to warfarin, whilst the 110mg b.i.d 
dabigatran etexilate was seen to significantly reduce the risk of intracranial haemorrhage, 
major bleeding and total bleeding. 
Therefore the implementation of a DAT regimen with dabigatran etexilate (110mg b.i.d. or 
150mg b.i.d.) plus clopidogrel or ticagrelor is likely to provide clinical benefits compared 
with a warfarin TAT regimen that is considered the current standard of care.
The concomitant evaluation of the dabigatran etexilate 110mg b.i.d. and 150mg b.i.d. doses 
will define the benefit/risk of each dose compared with warfarin in this particular NVAF
patient subpopulation that have undergone PCI, that was not assessed in the RE-LY or RE-
DEEM trials, and will provide treatment guidance on the optimal antithrombotic therapy in 
these patients.
2.2
TRIAL OBJECTIVES
The main objective of this study is to compare a DAT regimen of 110mg dabigatran etexilate 
b.i.d. plus clopidogrel or ticagrelor (110mg DE-DAT) and 150mg dabigatran etexilate b.i.d. 
plus clopidogrel or ticagrelor (150mg DE-DAT) with a TAT combination of warfarin plus 
clopidogrel or ticagrelor plus ASA ≤ 100mg once daily (q.d.) (warfarin-TAT) in patients with 
NVAF that undergo a PCI with stenting (elective or due to an ACS). 
The study aims to show non-inferiority of each dose of DE-DAT when compared to 
Warfarin-TAT in terms of safety. Safety will be determined by comparing the rates of 
bleeding events, assessed using the modified International Society of Thrombosis and 
Haemostasis (ISTH) classification of Major Bleeding and CRNMBE.
See Section 5 for details of variables assessed.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 25 of 150
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.
2.3
BENEFIT - RISK ASSESSMENT
Anticoagulant therapies are more beneficial for prevention of thromboembolism in patients 
with AF and dual anti-platelet therapy regimens are of greater benefit compared to dual 
antithrombotic regimens comprising warfarin plus ASA for the prevention of ischaemic
events, including stent thrombosis, in patients undergoing PCI [P10-07397, P11-09369]. An 
acceptable bleeding risk while maintaining a lower ischaemic event rate is considered a must 
in the post-PCI setting [P10-07397, P11-09369, R13-4128, P13-11665, R13-4138, 
P11-09951]. 
The incidence of stent thrombosis averages 1–2% over the first year but is greatest in the first 
month regardless of the type of stent used. The rate slowly declines to less than 0.1%/ year 
after the first year for Bare Metals Stents (BMS) and 0.4–0.6%/year after the first year for the 
first generation Drug Eluting Stents (DES). Stent thrombosis is associated with a mortality of 
10–20% and a MI rate of 30–70% in those with early or late stent thrombosis. In the first 
year, however, meta-analyses of randomised trials have not shown any difference in stent 
thrombosis between BMS and DES with an incidence of 1.1% for DES versus 1.3% for 
BMS. The duration of DAPT, however, was shorter in these early studies and often only one 
month for BMS and less than six months for DES [P11-09369]. A number of studies in the 
1990s demonstrated that the most effective antithrombotic regimen to prevent stent 
thrombosis was DAPT with ASA and a thienopyridine. 
Therefore, a general principle guiding the use of TAT specified in the current guidelines is to 
choose a treatment strategy that is tailored to the individual patient, taking into consideration 
the anticipated risk of an adverse event (AE) particularly major bleeding. Although triple 
therapy including OAC, ASA and clopidogrel is recommended for AF patients with ACS 
and/or PCI, evidence stems from small observational studies of mostly single centre origin 
and American and European position documents categorise recommendations as Level of 
Evidence “C” [P10-07397, P11-09369]. Consequently, guidelines emphasise the need for 
individualisation of treatment in respect to careful assessment of each patient’s risk of 
thrombosis and bleeding to find the optimal balance between risk and benefit of treatment. A 
recent study showed that initiation of triple therapy is immediately associated with increased 
and persistent bleeding risk compared to OAC plus a single antiplatelet agent [R13-4135]. A 
recently communicated small randomised controlled study (WOEST) [R13-4127], observed 
that bleeding and ischaemic event rates were lower in patients on a DAT (warfarin + 
clopidogrel) compared to TAT (warfarin + clopidogrel + ASA). This study however, was not 
powered for assessing efficacy and can only be considered hypothesis-generating. The 
WOEST results have nevertheless been reflected in some of the recent guidelines for NVAF 
patients undergoing PCI with stenting [P14-05384, P14-12794, P16-02545] which 
recommend to consider the use of DAT in certain patients. However, data from clinical trials 
concerning the possibility of implementing DAT regimens with dabigatran etexilate and other 
new NOACs in this setting are needed.
Because many new agents have come on the market recently, there is a wide variety of 
possible strategies with regard to not only the number and type of agents but also the intensity 
of anticoagulation and duration of the combination treatment [P13-00072]. The new oral 
anticoagulants (dabigatran etexilate, rivaroxaban, apixaban, edoxaban) so far tested in clinical 


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 26 of 150
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.
trials have all shown non-inferiority compared with VKAs, consistently showing a lower rate 
of intracranial haemorrhage (RR 0.48 [0.39-0.59]; p < 0.001) [P13-16211, R13-5082]. On 
this basis, the European Society of Cardiology guideline now recommends them as broadly 
preferable to VKA in the vast majority of patients with NVAF, when used as studied in the 
clinical trials performed so far [P12-11192].
In RE-LY, there was a 60% reduction in intracranial haemorrhage with both doses of 
dabigatran etexilate [U09-3249-02]. In a RE-LY sub analysis focused on patients receiving 
concomitant antiplatelet therapy (mandatory concomitant treatment in patients that underwent 
a PCI), dabigatran etexilate 110mg b.i.d. was non inferior to warfarin in reducing stroke and 
SE, whether patients received antiplatelet therapy or not. There were fewer major bleeds than 
with warfarin in both dabigatran etexilate 110mg b.i.d. subgroups for patients who used 
antiplatelets and for patients who did not [P13-00071]. In the same sub-analysis, dabigatran 
etexilate 150mg b.i.d. reduced the primary outcome of stroke and SE in comparison with 
warfarin. Major bleeding with dabigatran etexilate 150mg b.i.d. was similar to warfarin 
regardless of antiplatelet use. 
Because the absolute bleeding risk on antiplatelet therapy was the lowest with the 110mg 
dose of dabigatran, regardless of the number of antiplatelet agents used, decreasing the dose 
of dabigatran from 150 to 110mg for the duration of additional antiplatelet therapy, especially 
in patients at high bleeding risk, seems to be reasonable. Because both doses are still 
associated with a lower risk of intracranial haemorrhage, however, continuing the 150mg 
twice-daily dose remains a defendable option, particularly in patients with relatively low 
bleeding risk and a high CHA2DS2-VASc score [P13-00072].
The implementation of a DAT regimen with dabigatran etexilate plus clopidogrel or 
ticagrelor is likely to provide clinical benefits compared with the warfarin TAT regimen that 
is considered the current standard of care for the prevention of thromboembolic and bleeding 
(ICH) complications in patients with NVAF following PCI. The potential benefit of 
dabigatran etexilate over warfarin is based on its more rapid onset and offset of action, the 
absence of a need for routine laboratory monitoring, its lack of drug-food interactions, its low 
drug-drug interaction potential and the superiority compared to warfarin demonstrated in 
patients with NVAF for the reduction of stroke and SE. A dual antithrombotic regimen with a 
NOAC is particularly appealing due to the potential benefit in terms of reduced risk of 
intracranial bleeding as well as due to the potential benefit of a reduced risk of major 
bleeding events in a post-PCI setting.
Dabigatran is eliminated primarily by the kidneys with urinary excretion accounting for 
approximately 80% of the dose administered intravenously. Treatment with dabigatran in 
patients with severe renal impairment (CrCl < 30 mL/min) is contraindicated and these 
patients will be excluded from participating in this trial. No dose adjustment is necessary in 
patients with mild renal impairment (CrCl 50 ≤ 80 mL/min) or moderate renal impairment 
(CrCl 30-50 mL/min). Close clinical surveillance is recommended in patients with renal 
impairment and CrCl will be monitored at every visit and followed up closely.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 27 of 150
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.
In all patients renal function will be assessed as follows:

Calculating the creatinine clearance (CrCl) prior to initiation of treatment with
dabigatran etexilate to exclude patients with severe renal impairment (i.e. CrCl < 30 
mL/min)

Renal function will also be assessed when a decline in renal function is suspected 
during treatment and as part of the routine follow up measures.
The method used to estimate renal function (CrCl in mL/min) during the clinical 
development of dabigatran etexilate was the Cockcroft-Gault method. This method is 
recommended, as indicated in the label, when assessing patients’ CrCl prior to and during 
dabigatran etexilate treatment.
Guidance on the management of patients who experience a haemorrhagic complication is 
provided in Section 4.2.1. 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 4.2.1.7 Overdose, for more 
information regarding the specific reversal agent for dabigatran.
It should be mentioned that no reliable clinical data are available in NVAF patients on the 
combined use of an oral anticoagulant with the new P2Y12 antagonists (prasugrel and
ticagrelor) either alone or with ASA. Therefore, dedicated prospective trials on this important 
clinical problem are definitely needed [P13-00072]. The proposed clinical trial will generate 
prospective data to evaluate or explore this important data gap.
The study will be conducted under the guidance of a Steering Committee and data will be 
scrutinised on an ongoing basis by an independent external data monitoring committee 
(DMC). The use of electronic data capture and a central laboratory should ensure quick 
turnaround times and up to date data for the independent DMC to provide an unbiased review 
of data. Additionally, all bleeds and thromboembolic events will be reviewed by an 
Independent Adjudication Committee (IAC); data will be provided in discrete patient packets, 
removing data which could potentially provide information on the patients drug assignment 
(INR values for example) in order to ensure the IAC review is conducted in a blinded 
fashion. For further details regarding the relevant committees please refer to Section 3.1.1.
For further details regarding the relevant considerations for the DMC please refer to Section 
7.3.4.
Based on the findings on the nonclinical studies with dabigatran etexilate conducted to date 
and in accordance with international regulatory guidelines, the inclusion of women of child
bearing potential in this study is justified. To minimise the risk of unintentional exposure of 
an embryo or foetus to the investigational drug, woman of child bearing potential must agree 
to the requirements for pregnancy testing and contraceptive methods described in this 
protocol.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 28 of 150
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.
Given the above considerations, the risk benefit assessment is considered favourable for the 
initiation and conduct of this trial.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 29 of 150
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.
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This is a prospective, randomised, open label, blinded endpoint (PROBE), active comparator 
trial and the clinical endpoints are being adjudicated by an IAC in a blinded fashion.
This trial is designed to test the safety in NVAF patients that have undergone a successful 
PCI (elective or due to ACS) with stenting and were treatment naïve or were receiving oral 
anticoagulant treatment (either with warfarin, another VKA or other novel oral anticoagulant)
before the procedure.
Patients will be consented and screened after undergoing a successful PCI. Randomisation 
will occur on local laboratory results taken at the screening visit or on standard of care local 
laboratory results taken within 7 days prior to screening; central laboratory samples must be 
taken at randomisation prior to first intake of study drug. Randomisation can occur up to 120
hours post PCI, however within 72 hours is preferable. Study drug should be administered
between 6 hours after sheath removal and preferably within 72 hours post PCI, with 
haemostasis assured, however up to 120 hours post PCI is allowed.
Patients aged < 80 years will be randomly assigned to 110mg dabigatran etexilate b.i.d., 
150mg dabigatran etexilate b.i.d. or warfarin in a 1:1:1 ratio for the duration of the trial. 
Patients aged ≥80 years will be randomly assigned depending on their geographical location: 

Patients aged ≥80 years in the USA will be assigned to 110mg dabigatran etexilate b.i.d., 
150mg dabigatran etexilate b.i.d. or warfarin in a 1:1:1 ratio

All other patients aged ≥80 years outside of the USA will be assigned to 110mg 
dabigatran etexilate or warfarin in a 1:1 ratio.
In addition to their randomised treatment:

All patients will receive either clopidogrel (75mg q.d.) or ticagrelor (90mg b.i.d), 
according to the local label, for at least 12 months after randomisation. Discontinuation of
clopidogrel or ticagrelor or switching to ASA (≤ 100mg q.d.) after 12 months of treatment 
is at the discretion of the Investigator

Patients randomised to receive warfarin will receive ASA (≤100mg q.d.) for either one 
month in patients with a bare metal stent BMS and for three months in patients with a 
DES.
For details of drug administration see Section 4.1.4.
The study plan is detailed in Figure 3.1: 1.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 30 of 150
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.
Figure 3.1: 1 
Study Plan
Prior to consent, the patient’s antithrombotic treatment (i.e. ASA and anticoagulant use 
before and during PCI, use of clopidogrel or ticagrelor loading dose) should be managed as 
per local standard of care. The screening period will consist of one visit (Visit 1). The 
patients will be randomised at Visit 2. Screening and randomisation can be conducted on the 
same day.  The treatment period will consist of between three and 10 visits (Visits 3-12). The 
trial is event driven and is designed to continue until approximately 500 patients with at least 
one MBE or CRNMBE (in total) occur. The last patient randomised will receive at least six 
months of treatment and patients recruited earlier remain in the study until the time point at 
which this last patient has reached at least six months. Any ongoing patient, at the time the 
required number of events is reached will be discontinued. Following completion of the 
treatment period, the patients will have a follow-up visit four weeks later. 
The visits scheduled at 15, 21 and 27 months (Visits 8, 10 and 12) are to be conducted by 
telephone. Collection of AEs, outcome events (OE) (including bleeding) and use of 
concomitant medication will be made.
Blood sampling for a standard chemistry safety panel (including renal function and Liver 
Function Tests (LFTs)) will be collected at Visits 1, 2, 3, 5, 7 and End of treatment (EOT). In 
addition, samples for standard haematology safety panel will be taken at all clinic visits. All 
Screening
Study Treatment
Follow up
Informed 
consent
R
One month
Minimum treatment duration 6 months
Dabigatran etexilate 110mg b.i.d. + clopidogrel or ticagrelor1
Dabigatran etexilate 150mg b.i.d. + clopidogrel or ticagrelor1
Randomisation can occur up to 120 hours post PCI, however within 72 hours is 
preferable. Study drug should be administered 6 hours after sheath removal 
preferably within 72 hours post PCI, however up to 120 hours post PCI is allowed
1 Clopidogrel or ticagrelor can be discontinued or switched to ASA (≤ 100mg q.d.) from 
Month 12 (Visit 7), at investigator discretion
2 ASA should be discontinued in patients randomised to receive warfarin at 1 month 
(BMS) or at 3 months (DES)
Patients aged ≥80 years outside of the US will only be randomised to dabigatran etexilate 
110mg b.i.d.  or Warfarin
Warfarin [INR 2.0-3.0] + clopidogrel or ticagrelor1 + ASA2


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 31 of 150
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.
blood measurements (with the exception of INR and screening labs) will be performed by a
central laboratory. 
For further study procedure details see Flow Chart.
The end of the trial is defined as “last patient out”, i.e. last visit completed by the last patient.
3.1.1
Administrative structure of the trial
An Executive Steering Committee, consisting of a small group of external experts and 
representatives from the Sponsor, will provide scientific leadership for the planning and 
conduct of the trial. A Steering Committee will also be formed, where in addition to these 
members, there will be representatives from every country participating in the trial. These 
committees will be chaired by the Coordinating Investigator. A charter describing the tasks 
and responsibilities of the Executive Steering Committee and Steering Committee will be 
developed. 
Overall organisation will be overseen by an Operations Committee, consisting of 
representatives of the Sponsor and Harvard Clinical Research Institute. The Operations 
Committee will oversee the conduct and execution of the trial, coordinate the agenda for the
Steering Committees and will be responsible for the day-to-day operations of the trial.
An independent DMC will monitor patient safety and the trial conduct. A detailed DMC 
charter will be written to govern the activities of this committee. The DMC analyses and 
operations will be formally separated from the Sponsor, the Investigators, the Steering 
Committees and the Operations Committee. All data (for both dabigatran etexilate and 
warfarin patients), both adjudicated and non-adjudicated will be reviewed by the DMC in an 
ongoing fashion.
An IAC will be established for the blinded adjudication of efficacy outcomes (e.g. death, 
stroke, MI, SE) as well as bleeding. An Adjudication Committee Charter, under which the 
principles of the PROBE design can be carried out, will govern their activities. The charter 
will provide detailed definitions of each endpoint and the processes by which adjudication 
will occur, including how blinding will be preserved.
The Coordinating Investigator is selected based on 
expertise in this therapeutic area and 
reputation for being a 
 in 
field.  
 will review and sign the clinical trial protocol 
(CTP) and relevant clinical trial report (CTR). 
Physicians (e.g. cardiologists, interventionalists) managing anticoagulation may be 
Investigators for this trial.
An Interactive Response Technology (IRT) will perform the randomisation of patients and 
ensure appropriate distribution of trial medication to trial sites during the course of the trial.
A central laboratory will perform all protocol specified blood analyses with the exception of 
INR and screening measurements.  


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 32 of 150
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.
All trial-related documents will be stored in the Clinical Trial Master File at each individual 
Boehringer Ingelheim (BI) Operative Unit (OPU) in accordance with standard operating 
procedures. 
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
TAT, comprising of VKA, clopidogrel and ASA, is the current standard treatment to prevent
post-PCI stent thrombosis and the recommendation by multiple international guidelines 
(consensus document of the European Society of Cardiology Working Group on Thrombosis 
that was endorsed by the European Heart Rhythm Association (EHRA) and the European 
Association of Percutaneous Cardiovascular Interventions (EAPCI) [P10-07397]; and the 
North American Consensus Document on Antithrombotic therapy in patients with AF
undergoing coronary stenting [P11-09369]). The WOEST results have been reflected in some 
of the recent guidelines for NVAF patients undergoing PCI with stenting [P14-05384, P14-
12794, P16-02545] which recommend to consider the use of DAT in certain patients. 
However, data from clinical trials concerning the possibility of implementing DAT regimens 
with dabigatran etexilate and other new NOACs in this setting are needed. 
Therefore, an active control group is required for any study in patients who have undergone
PCI with stenting. Warfarin, the most widely used VKA, was chosen as the active control in 
this study.
The trial is event driven; therefore all patients will remain in the trial until the required 
number of events have occurred. Individual patient participation will vary from 
approximately 6 months to 2.5 years or longer (estimated average duration 18 months).
Double-blind, double-dummy trials in anticoagulation have limitations due to potential 
unavoidable deviations from routine clinical procedures [R08-4453]. This trial will use the 
PROBE design. The PROBE approach has been used in several trials of anticoagulation 
comparing against VKAs, e.g. in patients with AF. 
The following procedures will be implemented to reduce the potential for bias in the 
reporting and assessment of primary and secondary events.
1. Clearly defined objective outcomes:
The primary and secondary outcomes of the study are clinically relevant events for which 
objective documentation will be obtained. Standard, widely accepted definitions are to be 
used that rely on objective documentation.
2. Blinded IAC:
All OEs will be adjudicated by blinded adjudication experts.  Blinding of all event 
documentation will be performed by trained specialists.  The role of the IAC will be to 
oversee and perform the blinded adjudication of all outcome events.  This Committee will 
report to the Executive Steering Committee and DMC.  
3. Bleeding Questionnaire:


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 33 of 150
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.
A questionnaire querying patients for signs and symptoms of bleeding will be 
administered at each visit.  The goal is to reduce the possibility of under-reporting of 
events.  All symptoms will be evaluated and if potentially consistent with an outcome 
event will be referred to the IAC.
4. Review of Data for Clinical Events:
Any AE that indicates potential loss of neurological function, such as unilateral weakness, 
loss of vision or sensory disturbance will trigger a request for more information from the 
centre for event adjudication if potentially consistent with an outcome event. Any 
decrease in haemoglobin of >2g/dL will be similarly investigated.
5. Data Handling:
Patients will be randomly allocated to the treatment arms via IRT. Wherever feasible, 
data management will be undertaken without knowledge of patient treatment allocation. 
Special procedures to handle data with the potential for unblinding, such as INRs, will be 
specified.  By treatment data tabulations will not be reviewed during the course of the 
trial and the data management personnel will not have access to the randomisation code.
By implementing these appropriate measures to avoid bias, the PROBE design is an 
acceptable [R14-0530] and preferred approach for this study.
3.3
SELECTION OF TRIAL POPULATION
In order to test the two combined efficacy-safety hypotheses in NVAF patients that have 
undergone a successful PCI, at least 834 patients per treatment group are estimated to be 
required (see Section 7.6).
Approximately 550 trial centres worldwide will participate in the trial. The enrolment target 
for each site is a minimum of one patient every two months. Enrolment will be competitive 
and the trial will be terminated when the total number of events has been observed, regardless 
of enrolment at individual centres. If enrolment is delayed, additional study centres 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.
3.3.1
Main diagnosis for study entry
3.3.2
Inclusion criteria
The patient must meet all the inclusion criteria:
1. Male or female patients aged 18 years
2. Patients with NVAF that have been receiving oral anticoagulant treatment (either with 
warfarin, another VKA or other novel oral anticoagulant), or were treatment naïve prior 
to PCI. AF may be paroxysmal, persistent or permanent, and not secondary to a 


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 34 of 150
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.
reversible disorder such as MI, pulmonary embolism, recent surgery, pericarditis or 
thyrotoxicosis, unless long term oral anticoagulation is planned
3. Patient presenting with:

An ACS (STEMI, NonSTEMI [NSTEMI] or unstable angina [UA]) that was 
successfully1 treated by PCI and stenting (either BMS or DES)
Or

Stable Coronary Artery Disease with at least one lesion eligible for PCI that was 
successfully1 treated by elective2 PCI and stenting (either BMS or DES)
4. The patient must be able to give informed consent in accordance with International
Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guidelines and local 
legislation and/or regulations.
3.3.3
Exclusion criteria
The patient must not meet any of the exclusion criteria:
1. Patients with a mechanical or biological heart valve prosthesis
2. Cardiogenic shock during current hospitalisation
3. Patients who have used fibrinolytic agents within 24 hours of randomisation that, in the 
opinion of the Investigator, will put the patient at high risk of bleeding 
4. Stroke within 1 month prior to screening visit
5. Patients, who in the opinion of the Investigator, have had major surgery within the month 
prior to screening
6. Patient has received an organ transplant or is on a waiting list for an organ transplant
7. History of intraocular, spinal, retroperitoneal or a traumatic intra-articular bleeding unless 
the causative factor has been permanently eliminated or repaired (e.g. by surgery)
8. Gastrointestinal (GI) haemorrhage within one month prior to screening, unless, in the 
opinion of the Investigator, the cause has been permanently eliminated (e.g. by surgery)
1  Successful treatment with PCI is defined as achievement of < 30 % residual diameter stenosis of the target 
lesion assessed by visual inspection or quantitative coronary angiography and no in-hospital major adverse 
cardiac events (MI or repeat coronary revascularisation of the target lesion).
2  Indication for elective PCI should be based upon the ACCF/SCAI/STS/AATS/AHA/ASNC [R14-1287] and 
ESC guidelines [P10-12773].


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 35 of 150
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.
9. Major bleeding episode (reduction in the haemoglobin level of at least 2g/dL, transfusion 
of at least two units of blood, or symptomatic bleeding in a critical area or organ) 
including life-threatening bleeding episode (symptomatic intracranial bleeding, bleeding 
with a decrease in the haemoglobin level of at least 5g/dL or bleeding requiring 
transfusion of at least 4 units of blood or inotropic agents or necessitating surgery) in one 
month prior to screening visit
10. Haemorrhagic disorder or bleeding diathesis (e.g. von Willebrand disease, haemophilia A 
or B or other hereditary bleeding disorder, history of spontaneous intra-articular bleeding, 
history of prolonged bleeding after surgery/intervention)
11. Anaemia (haemoglobin <10g/dL) or thrombocytopenia including heparin-induced
thrombocytopenia (platelet count <100 109/L) at screening (Visit 1)
12. Severe renal impairment (estimated CrCl calculated by Cockcroft-Gault equation) 
<30mL/min at screening (Visit 1)
13. Active liver disease as indicated by at least one of the following:

Prior and persistent alanine aminotransferase (ALT) or Aspartate transaminase 
(AST) or alkaline phosphatase (AP) >3 upper limit of normal (ULN)1

Known active hepatitis C

Known active hepatitis B 

Known active hepatitis A
14. Recent malignancy or radiation therapy (≤6 months) unless, in the opinion of the 
Investigator, the estimated life expectancy is greater than 36 months
15. Need for continued treatment with systemic ketoconazole, itraconazole, posaconazole, 
cyclosporine, tacrolimus, dronedarone, rifampicin, phenytoin, carbamazepine, St. John’s 
Wort. See Section 4.2.2
16. Patients who, in the Investigator’s opinion, need continuous treatment with Non-Steroidal 
Anti-Inflammatory Drugs (NSAIDs)
17. Patients with a known allergy to dabigatran etexilate or to the excipients used for the 
capsule of the drug
18. Patients with a known allergy to warfarin tablets or to the excipients
19. Patients who, in the Investigator’s opinion, should not be treated with OAC
20. Patients with a contraindication to clopidogrel, ticagrelor or ASA
                                                          
1 Clinical judgement of whether ALT/AST enzyme elevation is due to active liver disease or due to ACS, should 
be made by the Investigator following evaluation the of the clinical characteristics of the patient and the 
laboratory findings.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 36 of 150
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.
21. Pre-menopausal women (last menstruation ≤1 year prior to screening) who:

Are pregnant or breast feeding or 

Are not surgically sterile or 

Are of child bearing potential and not practising two acceptable methods of birth 
control, or do not plan to continue practising an acceptable method of birth control 
throughout the trial. Acceptable methods of birth control are 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, 
intrauterine device or intrauterine system, double-barrier method of contraception 
(condom and occlusive cap or condom and spermicidal agent), male sterilisation
and complete sexual abstinence (if acceptable by local authorities). Periodic 
abstinence is not an acceptable method of contraception.
22. Patients who have participated in another trial with an investigational drug or device 
within the past 30 days preceding the screening visit or are participating in another trial
(patients participating in an observational study only will not be excluded)
23. Patients not willing or able to comply with the protocol requirements or considered 
unreliable by the Investigator concerning the requirements for follow-up during the study 
and/or compliance with study drug administration, who have a life expectancy less than 
the expected duration of the trial due to concomitant disease, or who have any condition 
which in the opinion of the Investigator, would not allow safe participation in the study 
(e.g. drug addiction, alcohol abuse).
3.3.4
Removal of patients from therapy or assessments
3.3.4.1
Removal of individual patients
An individual patient is to be withdrawn from the trial if:

The patient withdraws consent, without the need to justify the decision
Treatment with study drugs should be discontinued if:

The patient needs to take concomitant drugs that interfere with the investigational 
product or other study medication(s)

The patient is no longer able to take trial medication for other medical reasons (e.g. 
surgery, AEs, or other diseases)

The patient is persistently noncompliant with study drug administration

If a patient becomes pregnant during the trial the investigational drug will be stopped, 
the patient will be discontinued from the trial medication and the patient will be 
followed up until birth or otherwise termination of the pregnancy. For further 


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 37 of 150
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.
information, including the process for follow-up on the outcome of the pregnancy 
please see Section 5.2.2.3.

Patients on dabigatran etexilate who are found to have a CrCl <30mL/min during the 
course of the trial, should have study medication stopped and a parenteral 
anticoagulant can be started according to local practice (see Appendix 10.1 for 
switching to a parenteral anticoagulant). CrCl laboratory testing should be repeated as 
soon as feasible, ideally within 48 hours. If this second measurement confirms a CrCl 
<30mL the patient should be permanently discontinued from dabigatran etexilate, 
unless the concomitant clinical condition is expected to allow recovery of the renal 
function within 7 days from the initial CrCl reduction. A patient should also be 
permanently discontinued from study drug, if CrCl drops to <30mL/min at two 
different occasions during the trial

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)

The patient elects to stop taking study drug (the patient should be encouraged to 
resume study drug per the protocol).
Patients who discontinue treatment prematurely will be followed up until the end of the study 
(for further details please see Sections 6.2.2 and 6.2.3).
Patients who drop out during the screening phase prior to randomisation (Visit 2) will be 
considered a screen failure. They have to be recorded as screen failures in the electronic Case 
Report Forms (eCRFs), along with the reason for failing screening, and no further follow-up 
is required. 
Patients who discontinue or withdraw from the study after randomisation (Visit 2) will be 
considered as “early discontinuations” and the reason for premature discontinuation must be 
recorded in the eCRFs. The data will be included in the trial database and will be reported. 
Patients who withdraw or discontinue from the trial after randomisation will not be replaced.
3.3.4.2
Discontinuation of the trial by the sponsor
BI reserves the right to discontinue the trial overall or at a particular trial site at any time for 
the following reasons:
1. Advice of the independent DMC, decision by an Independent Ethics Committee (IEC)
/Institutional Review Board /(IRB) or Competent Authority (CA)
2. Failure to meet expected enrolment goals overall or at a particular trial site
3. Emergence of any efficacy/safety information that could significantly affect continuation 
of the trial
4. Violation of GCP, the CTP, or the contract by a trial site or Investigator, disturbing the 
appropriate conduct of the trial.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 38 of 150
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.
The Investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the fourth reason).


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 39 of 150
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.
4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
4.1.1
Identity of BI investigational product and comparator products
The investigational product dabigatran etexilate and the comparator warfarin will be supplied 
by Boehringer Ingelheim Pharma GmbH & Co. KG, Germany. The composition of these 
drugs capsules are detailed in Table 4.1.1: 1 and Table 4.1.1:2.
Table 4.1.1: 1
Dabigatran etexilate (Investigational drug)
Substance:
Brand name:
Dabigatran etexilate
Pradaxa®
Pharmaceutical formulation:
Capsule
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG, Germany
Unit strength:
110mg and 150mg
Total Daily dose
220mg; 300mg
1 x 110mg capsule b.i.d. (total daily dose 220mg)
1 x 150mg capsule b.i.d. (total daily dose 300mg)
Route of administration:
p.o.
The main excipients of the dabigatran capsule include tartaric acid, acacia, hypromellose, 
dimeticone, talc, hydroxypropylcellulose, HPMC (hydroxylpropylmethylcellulose) 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.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 40 of 150
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.
Table 4.1.1: 2 
Warfarin (active comparator)
Substance:
Warfarin
Pharmaceutical formulation:
Tablet
Source:
Teva UK Limited, UK
Total Daily dose
1mg; 3mg; 5mg
As needed to maintain a target INR of 2.0- 3.0 (2.0-2.5 if 
feasible)
Route of administration:
p.o.
For easy identification warfarin tablet strengths will have a different colour label.
The warfarin sodium tablets are composed of lactose monohydrate, starch (pregelatinised, 
maize), dispersed erythrosine lake, sodium starch glycolate and magnesium stearate.
Patients will take the warfarin q.d.. The individual doses will be titrated without splitting of 
the tablet as needed to maintain a target INR of 2.0 - 3.0. If feasible, an INR of between 2.0 –
2.5 should be targeted. INR will be measured at least every two weeks for the first three 
months in patients newly commencing warfarin, otherwise at least every month throughout 
the study (more frequently immediately after initiation of warfarin therapy or if required, 
according to clinical judgement). 
All patients will also take clopidogrel (75mg q.d.) or ticagrelor (90mg b.i.d.) according to the 
local label for at least 12 months after randomisation (in addition to either dabigatran 
etexilate or warfarin). After 12 months of treatment the clopidogrel or ticagrelor can be 
discontinued or switched to ASA (≤ 100mg q.d.) at the discretion of the Investigator.
For patients randomised to receive warfarin:
Patients randomised to receive warfarin will receive ASA (≤ 100mg q.d.) for either one 
month in patients with a BMS and for three months in patients with a DES.
Warfarin and dabigatran etexilate supplies will be managed using the IRT system.
4.1.2
Method of assigning patients to treatment groups
Inclusion and exclusion criteria should be assessed at screening to ensure inclusion of eligible 
patients. After having signed the informed consent form, patients should complete the 
screening visit including specified procedures (see the Flow Chart).  
Eligible patients who meet all inclusion and none of the exclusion criteria at Visit 2 will be 
randomised to receive either dabigatran etexilate 110mg, dabigatran etexilate 150mg or 
warfarin (see Section 3.1). In addition, patients will be stratified by age (<80 or ≥80 years 


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 41 of 150
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.
old) and region (Europe (EU)/Rest of World (ROW) or USA). This stratification will be 
performed dynamically by the IRT.
The dose of warfarin for the patient will be adjusted to ensure the INR for the patient is 
maintained at a level of 2.0 – 3.0. If feasible, an INR of between 2.0 – 2.5 should be targeted.
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 will be described in a user guide/manual, a copy of which will be available in the 
ISF.
The IRT will assign the correct kit number for dabigatran etexilate for the patients at each 
time point, but for the warfarin patients, individual management will be by the Investigator. 
4.1.3
Selection of doses in the trial
The doses of dabigatran etexilate selected for this trial are the same as those used in RE-LY, 
the Phase III trial for stroke prevention in atrial fibrillation (SPAF).  In RE-LY, a dose of 
dabigatran etexilate 110mg b.i.d. was shown to be comparable to warfarin (INR level 2.0–
3.0) for preventing strokes and SE and superior (relative risk reduction of 20%) when 
considering major bleeding risk [U09-3249-02]. Moreover, there was an approximate 60% 
reduction in intracranial haemorrhage with both dosages of dabigatran etexilate. 
4.1.4
Drug assignment and administration of doses for each patient
Each patient will be randomised at Visit 2 to receive either dabigatran etexilate (110mg or 
150mg b.i.d.) or warfarin. The first dose of trial medication will be taken, between 6 hours 
after sheath removal and preferably within 72 hours post PCI, with haemostasis assured,
however up to 120 hours post PCI is allowed.
Patient randomised to receive dabigatran etexilate:
It is permitted for patients to receive bridging therapy with a parenteral anticoagulant 
according to local practice before switching to dabigatran etexilate. Dabigatran etexilate 
should be given 0-2 hours prior to the time that the next dose of parenteral anticoagulant 
would be due, or at the time of discontinuation in case of continuous treatment (e.g. 
intravenous (i.v.) unfractionated heparin (UFH)). See Appendix 10.1 for guidance how to 
switch from an anticoagulant to dabigatran etexilate.
Dabigatran etexilate capsules should be taken in the morning and in the evening (one at each 
timepoint), at the same time every day with a full glass of water. The capsules must not be 
crushed, nor opened and can be taken with or without food. If dyspeptic symptoms occur, the 
Investigator should consider adding a proton pump-inhibitor (PPI) or H2-blocker to the 
concomitant therapy of the patients. 
The interval between doses should be as close to 12 hours as possible. 
If a dose of dabigatran etexilate is missed for any reason, the forgotten dose may still be taken 
up to six hours prior to the next scheduled dose. From six hours prior to the next scheduled 


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 42 of 150
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.
dose on, the “missed” dose should be omitted. A double dose to make up for missed 
individual doses must not be taken.
Any patient that decides to discontinue study medication should be considered for a switch to 
an appropriate (non-study) anticoagulant according to local practice. For patients receiving 
dabigatran etexilate, continuation of study drug for 2-3 days to assist bridging may be 
appropriate. For recommendations on how to switch from dabigatran etexilate to other 
anticoagulants see Appendix 10.2).
Patient randomised to receive warfarin:
Anticoagulant bridging therapy (according to local practice) is at the discretion of the 
Investigator (see Appendix 10.1).
Warfarin compliance will be monitored by means of the INR rather than by pill counts as it is 
a more accurate and biologic measure of pharmacodynamic effect than pill counts. Warfarin 
patients will usually be managed by their Investigator. However, Investigators will also be 
able to assign INR monitoring to a local anticoagulation clinic. All dose adjustment will be 
done according to usual clinical practice. The Investigator will be responsible for reporting 
INR results and the dose of warfarin prescribed. 
For patients initiating warfarin, INR should be measured at least every two weeks for the first 
three months to obtain target INR as soon as possible and to avoid over- or under-dosing.
Thereafter, minimum acceptable intervals for INR measurements are every month. More 
frequent INR measurements will be done as necessary at the discretion of each Investigator or 
anticoagulation clinic. 
To aid Investigators, a validated normogram, will be provided which will indicate 
recommended dose changes and INR re-testing times for different INR values. This 
normogram requires more frequent INR monitoring after out-of-range INR values have 
occurred. 
Numerous factors, alone or in combination, may influence the patient’s response to 
anticoagulants. Thus to ensure adequate control it is recommended that additional INR 
measures are done when other medications are initiated, discontinued or taken irregularly 
and/or diet changes. All patients should be educated about potential interactions with other 
medications, herbal preparations and foods and about the importance of monitoring. INR 
measurements can be performed independently from the scheduled study visits (see Flow 
Chart and Section 6), however all available INR values should be entered into the eCRF. It is 
critical to obtain the best possible level of INR control.
Regular study treatment will be completed with the last dose of trial medication being taken
on the evening before or the morning of the EOT visit. If the trial medication is to be 
terminated the patient should switch to an appropriate (non study) anticoagulant according to 
the local practices. 
For recommendations on switch from dabigatran etexilate and study warfarin to other 
anticoagulants see Appendix 10.2.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 43 of 150
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.
Clopidogrel or ticagrelor
All patients will also receive clopidogrel or ticagrelor for at least 12 months following 
randomisation. The decision as to whether the patient should receive clopidogrel or ticagrelor
is at the discretion of the Investigator. This background medication will not be provided as 
part of the clinical trial supplies, unless required by local laws and regulations.
ASA:
Patients who require ASA treatment as detailed in Section 4.1.1 will also receive ASA 
(≤100mg per day). This background medication will not be provided as part of the clinical 
trial supplies, unless required by local laws and regulations.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
This is an open-label trial; treatment allocation to the Investigators and patients will not be 
concealed throughout the study. The eCRF will contain information on randomised treatment. 
Trial medication will be identified by a medication code number. Despite the trial being open 
label, all activities conducted by the trial team will be performed in a blinded manner until 
database lock.
For justification of the PROBE design chosen for this study see Section 3.2.
4.1.5.2
Procedures for emergency unblinding
Not applicable.
4.1.6
Packaging, labelling, and re-supply
Dabigatran etexilate will be provided in kits. Each kit will contain four bottles that each 
contains 60 capsules of either 110mg or 150mg dabigatran etexilate. The number of kits 
provided to the patient will vary depending on the time between visits. 
Patients on warfarin will receive the required combination of 1mg, 3mg and 5mg tablets in 
bottles or blister packs according to their actual needs as defined by the measured INR value. 
Each warfarin bottle will contain 66 tablets. Each blister pack will contain 70 tablets. 
Warfarin supplies should be checked at each visit to ensure the patient has sufficient quantity 
and that expiry dates will not be compromised prior to the next clinic visit.
Supply and re-supply will be managed by the IRT.  
For details of packaging and the description of the label, refer to the ISF.
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 dabigatran etexilate kit at the same time. 


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 44 of 150
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.
Trial medication must be stored under the recommended storage conditions indicated on the 
label. A temperature log must be maintained by the Investigator / pharmacist / investigational 
drug storage manager 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 process 
outlined in the ISF should be followed.
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 
authorised 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, blisters and outer boxes (empty or filled) must be 
either returned to the Sponsor, or, following written authorisation 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
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 / IEC,

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. competent authority,

availability of the curriculum vitae of the Principal Investigator,

availability of a signed and dated CTP or immediately imminent signing of the CTP
(in exceptional cases, medication could already be sent to the site, before its activation 
via IRT)

availability of the proof of a medical licence for the Principal Investigator, if 
applicable

For USA, availability of the Form 1572.
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 product(s). 
These records will include dates, quantities, batch/serial numbers, expiry (‘use by’) dates and
the unique code numbers assigned to the investigational product(s) 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 product(s) received from the sponsor. 
At the time of return to the sponsor, the Investigator / pharmacist / investigational drug 
storage manager must verify that all unused or partially used drug supplies have been 
returned by the clinical trial patient and that no remaining supplies are in the Investigator’s 
possession.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 45 of 150
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.
For non-investigational medicinal products (NIMPs), a system allowing traceability will be 
implemented (please refer to Section 4.2.1 for the definition of a NIMP in this trial). This will 
include the following:
- documentation of intake of the NIMP in the source data (e.g. name of NIMP, how much and 
when it was taken [but no unit count will be necessary])
- documentation of intake of NIMP in the eCRF.
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT
Any additional drugs considered necessary for the patient’s welfare may be given at the 
discretion of the Investigator and with due consideration of the information provided below.
Comprehensive details of concomitant medication of special interest (e.g. antiplatelet 
medication, parenteral anticoagulant, thrombolytic agent, GPIIb/IIIa antagonist, VKA, 
therapies for bleeding management, novel direct oral anticoagulant) administered to the 
patient from 30 days prior to Informed Consent until the patient completes follow-up should 
be recorded in the eCRF. Abbreviated information will be collected for any other 
concomitant therapy.
Certain concomitant therapies (e.g. fibrinolytics, anticoagulants other than warfarin/ 
dabigatran etexilate) or surgery/intervention may require the temporary discontinuation of 
warfarin or dabigatran etexilate. Study medication should be restarted as soon as safely 
possible. In case of a temporary interruption, bridging therapy with a parenteral anticoagulant 
is allowed at the discretion of the Investigator (see Appendix 10.1 for guidance on bridging 
therapy). 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 dose.
The concomitant administration of PPIs is strongly recommended in patients without clinical 
contraindications for those agents, to reduce the risk of GI bleeding. In patients receiving
clopidogrel, PPIs that do not interact with the CYP2C19 (lanzoprazole, pantoprazole, etc.)
should be used.
4.2.1
Rescue medication, emergency procedures, and additional treatments
In this trial clopidogrel, ticagrelor and ASA are considered a NIMP. This means that in the 
event of a serious adverse event (SAE), the Investigator will assess the causal relationship of 
the SAE to the NIMP. Further details regarding SAE reporting can be found in Section 
5.2.2.3.
The Investigator is responsible for ensuring that procedures and expertise are available to 
cope with medical emergencies that may occur during the study.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 46 of 150
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.
4.2.1.1
Major Bleeds
Dabigatran Etexilate Treated Group:
If a patient experiences  major bleeding, the study medication should be temporarily stopped 
and the source of bleeding investigated and treated. This will generally involve coagulation 
testing (e.g. aPTT, TT, ECT), platelet count, and possibly transfusion, diagnostic procedures
and/or surgical haemostasis.
The recommendations given below are derived from guidelines to manage bleeding with 
dabigatran etexilate. See Section 4.2.1.7 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 haemostasis 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, P13-06400]. As protein binding is low, 
dabigatran is dialysable, however there is limited clinical experience in using dialysis in this 
setting. Clearance of dabigatran by haemodialysis 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. There is some experimental 
evidence to support the role of agents such as activated prothrombin complex concentrates 
(APCC, e.g. 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 long acting antiplatelet drugs have been used. All 
symptomatic treatment will be given according to the treating physician's judgement. 
Re-administration of study medication (at the same dose as before) after the bleeding has 
resolved and haemostasis has been achieved, is at the discretion of the Investigator. In the 
case of a temporary stop of dabigatran etexilate bridging therapy with a parenteral 
anticoagulant with e.g. UFH or LMWH (according to local practice) is at the discretion of the 
Investigator. See Appendix 10.1 for additional information related to bridging.
A summary of how to manage bleedings on dabigatran etexilate is presented in 
Figure 4.2.1.1: 1.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 47 of 150
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.
Figure 4.2.1.1: 1 
Management of bleeding on dabigatran therapy [P10-03790]
Warfarin Treated Group:
If a patient experiences a major bleed warfarin should be temporarily stopped. The 
anticoagulant effect of VKAs can be reversed with vitamin K, prothrombin complex 
concentrates and/or fresh frozen plasma. Re-administration of warfarin after the bleeding has 
resolved and haemostasis has been achieved is at the discretion of the Investigator. Bridging 
therapy, e.g. UFH until the INR has returned back to the target range, is at the discretion of 
the Investigator (see Appendix 10.1).
4.2.1.2
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 be stopped in these cases.
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)
• Haemodialysis2, 3
• Consideration of rFVIIa or APCC2,3
•
Delay next dose, temporarily or permanently 
discontinue  treatment2
• Administration of reversal agent4
Patient with bleeding on dabigatran etexilate 
therapy 
Major or Life-threatening 
Bleeding1,
1  for bleeding definitions see Section 5
2 when appropriate
3 recommendations based on limited clinical or non-
clinical data only, limited or no experience in 
volunteers or patients
4  see Section 4.2.1.7 Overdose, for more information 
regarding the specific reversal agent for dabigatran


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 48 of 150
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.
4.2.1.3
Emergency and Elective Surgery
Dabigatran Etexilate Treated Group:
Preoperative Phase:
Emergency Surgery
In the case of emergency surgery, study medication should be discontinued.  If possible, 
surgery should be postponed until 12 hours, or longer in case of renal failure, 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 or diluted TT (where available), activated 
partial thromboplastin time (aPTT) or the ECT.  For further details on results of coagulation 
times expected with dabigatran, see section on elective surgery below.
See Section 4.2.1.7 Overdose, for more information regarding the specific reversal agent for
dabigatran.
Elective Surgery
Physicians may consider the following information regarding dabigatran etexilate 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 4.2.1.3: 1]. Serum creatinine 
should normally be checked 1-2 weeks before surgery and the CrCl should be calculated 
using the Cockcroft-Gault formula (Section 5.2.3). Patients with a CrCl <30mL/min during 
the course of this study should not be receiving study medication (see Section 3.3.4.1). 
The following is a guide to the discontinuation of dabigatran etexilate (under special 
consideration of the half-life of dabigatran depending on renal function) before surgery taking 
renal function and additional risk factors into account. In patients with normal renal function, 
discontinuation of two doses of dabigatran etexilate will decrease plasma levels to 
approximately 25% of steady state trough levels and discontinuation of four doses will 
decrease dabigatran plasma levels to approximately 5-10% of steady-state trough levels.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 49 of 150
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.
Table 4.2.1.3: 1 
Recommendations on cessation of study drug in relation to the timing 
of major surgery  
Renal function 
(CrCl, 
mL/min)1
Estimated half-
life if on 
dabigatran
etexilate
Stop study dabigatran etexilate before surgery
High Risk of 
bleeding2
Standard Risk
80
~ 13 hours
2 days before
24h prior (2 doses)
50 to <80
~ 15 (12-18) hours
2-3 days before
1-2 days before
30 to <50
~18 (18-24) hours
4 days before
At least 2 days (>48 hours)
<30
~ 27 (>24) hours
>5 days before
2-5 days
1 CrCl can be estimated using serum creatinine by the Cockcroft-Gault formula (see Section 5.2.3). Patients who develop 
CrCl <30mL/min during the course of the trial should have study medication stopped (see Section 3.3.4.1). 
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 anaesthesia may also require complete haemostatic 
function.  
In patients at high risk of bleeding, including those in whom severe renal dysfunction may 
occur in the course of the trial (<30mL/min CrCl), an elevated thrombin clotting time (TT) or 
diluted thrombin time ((dTT); only in countries where this assay is approved)) 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 TT/dTT should be performed 6-12 hours before 
elective surgery and a normal result as defined by the local lab should be obtained before a 
patient undergoes surgery. A persistently prolonged thrombin time (TT or dTT) in the 
absence of heparin, fibrin/fibrinogen degradation products (e.g. with disseminated 
coagulation activation, sepsis, severe inflammation and other conditions) or high 
concentrations of serum proteins (e.g. myeloma) suggests persistently elevated levels of 
dabigatran in the blood.
In patients receiving chronic therapy with dabigatran etexilate 110mg b.i.d., the median peak 
aPTT is approximately 57 sec [U09-3249-02]. Assuming the baseline range of normal is 
between 22 to 40 sec (aPTT assay as used in RE-LY) this peak aPTT prolongation 
corresponds to approximately 2 times control [U11-1855-01]. Twelve hours after the last 
dose, the median aPTT is approx. 1.7 times control [U09-3249-02], (median trough aPTT 
prolongation for patients receiving 110mg BID in RE-LY: 48 sec) given adequate renal 
function, with less than 10% of patients exceeding 2.4 times control [U11-1855-01,U09-
3249-02], (90th percentile trough aPTT prolongation for patients receiving 110mg b.i.d. in 
RE-LY: 69 sec). ECT shows a close linear correlation with the plasma concentrations of 
direct thrombin inhibitors, including dabigatran. Median ECT ratios over baseline of 
approx.1.8 at trough and 2.5 [U11-1855-01] at peak, have been observed after intake of 
dabigatran etexilate 110mg b.i.d. Coagulation times should be interpreted in relation to the 
timing of last drug intake of study medication (peak versus trough dabigatran levels). The 


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 50 of 150
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.
current version of the IB should be referenced for further information about dabigatran 
etexilate.
Post Procedural Period:
With the exception of cardiac surgery, dabigatran etexilate will be initiated as soon as the 
patient is haemodynamically stable and haemostasis is achieved. If oral medication is not 
feasible, bridging therapy with i.v. or subcutaneous (s.c.) UFH or s.c. Low Molecular Weight 
Heparin (LMWH) should be considered at the discretion of the Investigator (see Appendix 
10.1).
Note:  In patients where renal function is impaired or procedures undertaken which may
temporarily compromise renal function, a serum creatinine should be performed and CrCl 
calculated based on the Cockcroft-Gault formula. In patients receiving dabigatran etexilate, if 
CrCl drops to <30mL/min during the course of the study, study medication should be stopped 
and bridging therapy may be considered. Study drug dabigatran etexilate can be re-started if 
CrCl recovers to 30mL/min within seven days; otherwise it should be permanently 
discontinued for the duration of the trial and the patient followed until the trial completes. A 
patient should also be permanently discontinued from study drug, if CrCl drops to 
<30mL/min at two different occasions during the trial. See Section 3.3.4.1.   
WarfarinTreated Group:
Preoperative Phase:
Bridging therapy with a parenteral anticoagulant should be considered depending on the 
length of study drug interruption. Bridging therapy is at the discretion of the Investigator and 
can be performed according to local practice (see Appendix 10.1 for guidance). 
Post Procedural Period:
Anticoagulation can be started as soon as clinically feasible with i.v. (unfractionated) or s.c. 
LMWH and simultaneously with study warfarin until the INR is ≥2.0. Parenteral bridging 
therapy should be stopped when target INR is achieved (see Appendix 10.1 for guidance). 
Spinal Anaesthesia/Epidural Anaesthesia/Lumbar Puncture
Dabigatran and Warfarin Treated Group:
Procedures such as spinal anaesthesia may require complete haemostatic function. See Table 
4.2.1.3: 1 for recommendations on when to stop dabigatran before spinal/epidural 
anaesthesia. For patients randomised to Warfarin, INR measurements should be performed to 
ensure that coagulation is under control.
The risk of spinal or epidural haematoma 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 haemostasis is achieved, but at minimum an 
interval of at least one hour should elapse for all patients. These patients require frequent 
observation for neurological signs and symptoms of spinal or epidural haematoma.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 51 of 150
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.
4.2.1.4
Stroke
Patients with documented or suspected stroke should be managed according to usual clinical 
practice. It is anticipated that in most cases study drug will be withheld until a computed 
tomography (CT) or magnetic resonance (MR) imaging scan has been obtained. 
Ischaemic stroke:
For ischaemic stroke, ASA and/or clopidogrel, or ASA/dipyridamole (the latter in lieu of 
clopidogrel) may be administered as indicated according to usual clinical practice. 
Anticoagulation with the study drug can be continued at the discretion of the local 
Investigator, in the absence of evidence of bleeding [P13-06400].
Fibrinolytics may be considered for ischaemic stroke, if a normal aPTT, ECT or TT test is 
obtained for patients receiving dabigatran etexilate, or if the INR is ≤ 1.7 in patients receiving 
warfarin.
Haemorrhagic stroke:
For haemorrhagic stroke or other intracranial bleeding, consultation with a coagulation expert 
and a neurosurgeon is recommended. 
See Section 4.2.1.1 and Figure 4.2.1.1: 1 for details relating to how to manage bleeding on 
dabigatran etexilate or warfarin.
Reintroduction of study treatment following a stroke:
Dabigatran Etexilate Treated Group:
The decision about restarting dabigatran etexilate following a stroke is at the discretion of the 
Investigator. The following recommendations on when to restart dabigatran etexilate are 
provided for guidance only. 
Table 4.2.1.4: 1 
Recommendations on restarting dabigatran etexilate following a 
stroke [P12-02400]
Stroke Severity 
Restart of Dabigatran etexilate
TIA 
as soon as imaging has excluded a 
cerebral haemorrhage
Mild Stroke 
3-5 days after stroke onset 
Moderate Stroke 
5-7 days after stroke onset 
Severe Stroke
2 weeks after stroke onset


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 52 of 150
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.
Warfarin Treated Group:
The decision about restarting study warfarin following a stroke and its exact timing is at the 
discretion of the Investigator.
4.2.1.5
Acute Coronary Syndrome
In patients with documented or suspected ACS, study drug should be temporarily 
discontinued if other anticoagulants (e.g. UFH) are deemed necessary. ASA, clopidogrel and 
glycoprotein IIb/IIIa inhibitors may be administered according to usual clinical practice.
Dabigatran Etexilate Treated Group:
In patients receiving dabigatran etexilate, unfractionated or low-molecular-weight heparin 
should be withheld until at least 12 hours have passed since the last dose of dabigatran 
etexilate or the aPTT is less than 1.5 x ULN.

If the aPTT is between 1.2 and 1.5 x ULN, UFH may be commenced with or without 
a loading dose at the discretion of the physician and LMWH may be commenced at 
the usual therapeutic dose (without an i.v. loading 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.
Warfarin Treated Group:
Unfractionated or low-molecular-weight heparin (or other anticoagulants) may be 
administered in warfarin treated patients according to usual clinical practice.
4.2.1.6
Other Medical Intervention
Percutaneous Coronary Intervention (PCI): 
Dabigatran etexilate should be discontinued in advance and bridging anticoagulation 
administered according to local practice. ASA, clopidogrel or ticagrelor use is permitted 
according to usual clinical practice.
For patients randomised to Warfarin, refer to Section 4.2.1.3.
Study medication can be reintroduced between 6 hours after sheath removal with haemostasis 
assured, as considered appropriate by the Investigator.
Coronary Artery Bypass Graft (CABG) Surgery:
Dabigatran etexilate should be discontinued in advance and bridging anticoagulation 
administered according to local practice. Usual priming therapies for cardiovascular surgical 
procedures are allowed.  Patients with renal dysfunction may have elevated concentrations of 
dabigatran due to longer half-lives of active drug (see Table 4.2.1.3: 1). If bypass surgery is 
to start during elevated plasma concentrations of dabigatran etexilate 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 dTT/TT measurements. For further advice on 


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 53 of 150
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.
emergency and elective cardiac surgery see Section 4.2.1.3 and corresponding 
Table 4.2.1.3: 1.
For patients randomised to Warfarin, refer to Section 4.2.1.3.
Cardioversion:
!" #$%&% 
'( ) *%%+ 
",& -. 
/)&+',0%&(',* +1&'*2 #$% (#1+34 #$% 5)#'%*# 6'77 8% 9)'*#)'*%+ ,* #$% 
/1&&%*# 
(#1+3 +&12 1*7%(( '* #$% :1+29%*# ," #$% !*0%(#'2)#,&)*,#$%& )55&,)/$ '( +%%9%+ 
*%/%(()&3;
Other Minor Procedures:
In the case of other elective procedures or minor surgery, dabigatran etexilate can be 
continued until 24 hours before the procedure. 
For patients randomised to Warfarin, refer to Section 4.2.1.3.
Reintroduction following medical intervention:
Dabigatran etexilate can be re-commenced at the cessation of parenteral anticoagulant 
treatment according to the same regimen as at randomisation, provided clinically indicated 
and in accordance with the recommendations in Appendix 10.1.
For patients randomised to Warfarin, refer to Section 4.2.1.3.
4.2.1.7
Overdose
Overdose following administration of dabigatran etexilate may lead to haemorrhagic 
complications due to its pharmacodynamic properties. In cases of suspected overdose it may 
be advisable to assess the anticoagulation status of a patient. A TT measure with the 
calibrated Hemoclot® thrombin inhibitor assay indicating a dabigatran plasma concentration 
of >200ng/mL (approximately >65 seconds) prior to the next drug intake after 150mg twice-
daily dosing (trough measure, i.e. 10-16 hours after the last drug intake) may be associated 
with an increased risk of bleeding. An aPTT test may be useful to assist in determining an 
excess of anticoagulant activity, despite its limited sensitivity. An aPTT > 2-fold ULN at 
trough, i.e. when the next dose is due, may be associated with a higher risk of bleeding.
For a summary how to manage bleeding events on dabigatran etexilate see also Section 
4.2.1.1 and corresponding Figure 4.2.1.1: 1.
Specific reversal agent to dabigatran
A specific reversal agent (idarucizumab) has been developed and is currently available in 
many countries and being reviewed for registration in various other 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 eCRF of the appropriate trials.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 54 of 150
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.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
Corticosteroids or NSAIDs may be used if clinically indicated according to current treatment 
guidelines but it is strongly recommended to avoid these if possible. It should be noted that 
the use of any of these agents with warfarin or dabigatran etexilate is likely to increase the 
risk of bleeding. 
The following treatments should not be taken during the active treatment phase of the trial:
1. Treatment with ticlopidine or prasugrel
2. Fibrinolytic agents (see Section 4.2.1.4 for exception)
3. GPIIb/IIIa antagonists (e.g. abciximab, tirofiban)
4. Treatment with systemic ketoconazole, itraconazole, posaconazole, cyclosporine, 
tacrolimus, dronedarone and rifampicin, phenytoin, carbamazepine or St. John’s Wort
5. Diypyridamole, rivaroxaban, apixaban and edoxaban, or other oral anticoagulants (e.g. 
VKAs)
6. ASA - except where specified in the protocol for patients randomised to the warfarin arm
or in both treatment arms after 12 months of treatment if clopidogrel or ticagrelor is
switched to ASA (≤ 100mg q.d.) at Investigator discretion. The patients should be 
advised to not use additional ASA-containing over-the-counter medications.
The Investigator is alerted to the use of concomitant administration of moderate to strong P-
gp inhibitors (e.g. such as amiodarone, verapamil, quinidine, nelfinavir, posaconazole, 
ritonavir, saquinavir and tipranavir+ritonavir or lopinavir+ritonavir) or P-gp inducers in this 
study due to a potential risk of higher or lower plasma levels of dabigatran and consequent 
exaggerated or reduced pharmacodynamic effect of dabigatran etexilate (notably bleeding 
risk). Concomitant use of such drugs is not prohibited in this study per se (except for 
treatment with ketoconazole, itraconazole, posaconazole, cyclosporine, tacrolimus 
dronedarone, rifampicin, phenytoin, carbamazepine or St. John’s Wort), but should be used 
with caution or, at Investigator discretion, switched to a suitable alternative. 
In the RE-LY study, patients treated concomitantly with verapamil had on average at trough 
and two hours post-dose dabigatran plasma concentrations increased by only 16% and 20%, 
respectively. Accordingly, the annualised bleeding rates in patients who had used verapamil 
at least once together with warfarin, dabigatran etexilate 110mg b.i.d. or 150mg b.i.d. were 
3.33%, 3.09% and 3.92%, respectively. If verapamil is initiated during the course of this trial
in a patient randomised to receive dabigatran etexilate 150mg b.i.d, consideration to separate 
the timing of administration of dabigatran etexilate and verapamil should be given. 


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 55 of 150
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.
If dabigatran etexilate is given at least two hours before verapamil for the first three days, the 
increase of dabigatran exposure will be reduced compared to taking verapamil and dabigatran 
etexilate at the same time-point.
In the RE-LY study, concomitant administration of amiodarone or quinidine and dabigatran 
etexilate did not increase the relative risk of bleeding compared to patients on warfarin and 
amiodarone or quinidine. Therefore, no dose adjustment of dabigatran etexilate is considered 
necessary in this study for patients receiving amiodarone or quinidine as co-medications.
The strong P-gp inducer rifampicin (and potentially also carbamazepine, phenytoin or St. 
John’s Wort) is associated with a potential risk of lower plasma levels of dabigatran (in a 
Phase I trial rifampicin decreased total dabigatran peak plasma concentration and total 
exposure (AUC) by 65.5% and 67%, respectively) and consequent reduced 
pharmacodynamic effect of dabigatran etexilate (notably increased thromboembolic risk) and 
should therefore not be taken during the course of this trial.
A list of common P-gp inhibitors will be provided in the ISF.
The concomitant use of dabigatran etexilate with the following treatments has not been 
studied and may increase the risk of bleeding: UFHs (except at doses necessary to maintain 
patency of central venous or arterial catheter) and heparin derivatives, low molecular weight 
heparins (LMWH), fondaparinux, desirudin, thrombolytic agents, GPIIb/IIIa receptor 
antagonists, ticlopidine, dextran, sulfinpyrazone, rivaroxaban, apixaban, edoxaban, prasugrel, 
direct thrombin inhibitors, VKAs and the P-gp inhibitors itraconazole, tacrolismus, 
cyclosporine, ritonavir, tipranavir, nelfinavir and saquinavir.
Bleeding risk may be increased in patients concomitantly treated with selective serotonin re-
uptake inhibitors (U11-1642-01) or selective serotonin norepinephrine re-uptake inhibitors 
(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 GI
bleeding, increases. 
If bleeding is clinically suspected, appropriate measures such as testing for occult blood in 
stool, or testing for a drop in haemoglobin is suggested (U12-1072-01).  Investigators should 
assess the benefit-risk of the concomitant use of drugs that can promote bleeding, e.g., 
NSAIDs, corticosteroids and ASA, other anticoagulants and use them only when the benefits 
are thought to outweigh the risks.
4.2.2.2
Restrictions on diet and life style
Dabigatran etexilate can be taken with or without food. There are no specific dietary 
restrictions with dabigatran etexilate, whereas patients randomised to VKA need to follow 
dietary instructions regarding their vitamin K intake. They must also be aware of the potential 
risk of over- or under dosing with changes of co-medications (e.g. use of antibiotics) or 
concomitant diseases (e.g. diarrhoea).


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 56 of 150
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.
4.3
TREATMENT COMPLIANCE
Patients are requested to bring all remaining trial medication including empty package 
material with them when attending visits.
Dabigatran Etexilate:
Based on capsule counts, treatment compliance will be calculated as the number of capsules 
taken, divided by the number of capsules which should have been taken according to the 
scheduled period, multiplied by 100. 
Doses taken on the current visit day will be excluded from the count and doses taken on the 
previous visit day will be included in the count.
Treatment compliance (%) =
Number of tablets actually taken 100
     Number of tablets which should have been taken1
A patient will be considered as non-compliant if the number of doses taken is not between 
80-120% of the expected number of doses. If compliance does not meet this range the patient 
should be asked to provide an explanation and re-informed about the purpose and conduct of 
the trial. Non-compliance should be discussed with BI.
General principles regarding the evaluability of non-compliant patients are outlined in 
Section 7.3. Decisions about evaluability of patients will be made at the Blinded2 Report 
Planning Meeting (BRPM) and at the latest prior to database lock. 
Warfarin:
Warfarin compliance will be monitored by means of the INR rather than by pill counts as it is
a more accurate and biologic measure of pharmacodynamic effect than pill counts. 
Investigators will be able to assign INR monitoring to a clinic outside the investigational site 
and dose adjustments will be made according to usual clinical practice. However, the 
Investigator will be responsible for reporting INR results, dose management of the patient 
and drug accountability of the warfarin prescribed. Patients must have the INR measured at 
least every two weeks for first three months, when commencing warfarin for the first time, 
otherwise at least monthly measurement are required. More frequent INR measurements may
be done as necessary at the discretion of each Investigator or anticoagulation clinic. To aid 
Investigators, a validated nomogram, will be provided in the ISF, which will indicate 
recommended dose changes and INR re-testing times for different INR values. This 
nomogram requires more frequent INR monitoring after out-of-range INR values have 
occurred.
The quality of warfarin therapy for each patient will be assessed by reporting the number of 
INR values within the indicated therapeutic target range (2.0 – 3.0 and 2.0 – 2.5) as well as 
those above and below this range. The Rosendaal method [R08-1695] will be used to 
evaluate the percentage of time that a patient’s INR is in range (i.e. time in therapeutic range
                                                          
1 The number of tablets which should have been taken should take into account any temporary interruptions in study drug
2 Despite the trial being open label, the trial team will be blinded during medical quality review.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 57 of 150
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.
(TTR)). For each calendar month, the mean of all INR values will be reported. This will be 
calculated for each patient, for each centre, for each country and for the whole study. The 
mean percentage of time of INR in range will be calculated for each centre and each country 
during the trial conduct to monitor the INR control. The percentage of time of INR in range 
for each country and for the trial will be reported at study end. 
Analyses from clinical trial data for SPAF have identified a minimum threshold of TTR of at 
least 60%, below which warfarin may be considered as no more effective than DAPT [P07-
02268]. The goal for the study is that the INR control should be at least as good as that 
achieved for anticoagulation in the historical control studies. The mean TTR [INR 2.0-3.0] 
for warfarin in RE-LY was 64% (median 67%) [U09-3249-02].


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 58 of 150
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.
5.
VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY 
5.1.1
Endpoints of efficacy
The primary endpoint for this trial is a safety endpoint. See section 5.2.1. There are no 
primary efficacy endpoints. 
The secondary efficacy endpoints (all time to first event) are:
1. A combined endpoint of thrombotic events or death (DTE: all death + MI + stroke/SE)
and unplanned revascularisation by PCI/CABG
2. A combined endpoint of thrombotic events or death (DTE: all death + MI + stroke/SE)
3. Individual outcome events:

All death 
o
Cardiovascular death
o
Non-cardiovascular death
o
Undetermined

MI

Stroke

SE

Stent thrombosis
4. Composite endpoint of death + MI + stroke 
5. Unplanned revascularisation by PCI/CABG
See Section 7.3.1 for details of the analyses.
5.1.2
Assessment of efficacy
These endpoints will be adjudicated by the IAC using criteria outlined in its charter 
governing the adjudication process. 
5.1.2.1
Death
Death from any cause includes cardiovascular death, non-cardiovascular-death and
undetermined cause of death, as classified by adjudication [R13-4874, R15-0010].
Cardiovascular death 
Cardiovascular (CV) death '*/71+%( +%)#$ &%(17#'*2 
"&,9 )* )/1#% <!4 (1++%* /)&+')/ +%)#$4 
+%)#$ +1% #, $%)&# 
")'71&%
4 +%)#$ +1% #, (#&,=%4 +%)#$ +1% #,
.> 5&,/%+1&%(4 
+%)#$ +1% #, .> 
$)%9,&&$)2%)*+ +%)#$ +1% #, ,#$%& 
.> /)1(%(;


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 59 of 150
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.
Non-cardiovascular death 
?,* @.>
+%)#$ '( +%"'*%+ 
)( )*3 +%)#$ 6'#$ ) (5%/'"'/ /)1(% #$)# '( *,# #$,12$# #, 8%
/)&+',0)(/17)& '* *)#1&%4 
)( 7'(#%+ )8,0%; A$%(%)&% 5,(('87% %B)957%( ," *,* @.> /)1(%( ,"
+%)#$C

Pulmonary

Renal

Gastrointestinal

Hepatobiliary

Pancreatic

Infection (includes sepsis)

Inflammatory (e.g., Systemic Inflammatory Response Syndrome (SIRS) / Immune

(including autoimmune)

Haemorrhage that is neither cardiovascular bleeding or a stroke 

Non-CV procedure or surgery

Trauma

Suicide

Non-prescription drug reaction or overdose

Prescription drug reaction or overdose

Neurological (non-cardiovascular)

Malignancy

Other non-CV (to be specified)
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.
Further details on death classification will be specified in the adjudication charter.
5.1.2.2
Myocardial infarction
Criteria for acute MI [R13-4872]:
The term acute MI should be used when there is evidence of myocardial necrosis in a clinical 
setting consistent with acute myocardial ischaemia.
Under these conditions any one of the following criteria meets the diagnosis for MI:


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 60 of 150
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.

Detection of a rise and/or fall of cardiac biomarker values [preferably cardiac troponin 
(cTn)] with at least one value above the 99th percentile upper reference limit (URL) and 
with at least one of the following:
-
Symptoms of ischaemia
-
New or presumed new significant ST-segment–T wave (ST–T) changes or new 
left bundle branch block (LBBB)
-
Development of pathological Q waves in the ECG
-
Imaging evidence of new loss of viable myocardium or new regional wall motion 
abnormality
-
Identification of an intracoronary thrombus by angiography or autopsy

Cardiac death with symptoms suggestive of myocardial ischaemia and presumed new  
ischaemic ECG changes or new LBBB, but death occurred before cardiac biomarkers 
were obtained, or before cardiac biomarker values would be increased

PCI related MI is arbitrarily defined by elevation of cTn values > 5 x 99th percentile URL 
in patients with normal baseline values (≤99th percentile URL) or a rise of cTn values 
≥20% if the baseline values are elevated and are stable or falling. In addition, either (i) 
symptoms suggestive of myocardial ischaemia or (ii) new ischaemic ECG changes or (iii) 
angiographic findings consistent with a procedural complication or (iv) imaging 
demonstration of new loss of viable myocardium or new regional wall motion 
abnormality are required

Stent thrombosis associated with MI when detected by coronary angiography or autopsy 
in the setting of myocardial ischaemia and with a rise and/or fall of cardiac biomarker 
values with at least one value above the 99th percentile URL

CABG related MI is arbitrarily defined by elevation of cardiac biomarker values (>10 x 
99th percentile URL) in patients with normal baseline cTn values (≤99th percentile 
URL). In addition, either (i) new pathological Q waves or new LBBB, or (ii) 
angiographic documented new graft or new native coronary artery occlusion, or (iii) 
imaging evidence of new loss of viable myocardium or new regional wall motion 
abnormality.
Criteria for fatal MI
Death due to Acute MI refers to a death by any cardiovascular mechanism (e.g., arrhythmia, 
sudden death, heart failure, stroke, pulmonary embolus, peripheral arterial disease) ≤ 30 days 
after a MI related to the immediate consequences of the MI, such as progressive heart failure 
or recalcitrant arrhythmia. Acute MI (for criteria see above) should be verified to the extent 
possible by the diagnostic criteria outlined for acute MI or by autopsy findings showing 
recent MI or recent coronary thrombosis. Death resulting from a procedure to treat a MI (e.g.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 61 of 150
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.
PCI, CABG), or to treat a complication resulting from MI, should also be considered death 
due to acute MI [R15-0010].
Silent MI
Silent myocardial infarction will be retrospectively diagnosed by the appearance of
significant new Q-waves on an ECG performed after randomisation. In such cases, the date of 
the event is recorded as the midpoint between the ECG with new Q-waves and the prior
normal ECG.
Criteria for prior MI [R13-4872]:
Any one of the following criteria meets the diagnosis for prior MI:

Pathological Q waves with or without symptoms in the absence of non-ischaemic causes

Imaging evidence of a region of loss of viable myocardium that is thinned and fails to 
contract, in the absence of a non-ischaemic cause

Pathological findings of a prior MI.
5.1.2.3
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 haemorrhage or infarction [DEF@
GHIG4 R15-0010J.
Ischaemic Stroke
Ischaemic stroke is defined as an acute episode of focal cerebral, spinal, or retinal 
dysfunction caused by infarction of central nervous system tissue. Haemorrhage may be a 
consequence of ischaemic stroke. In this situation, the stroke is an ischaemic stroke with 
haemorrhagic transformation and not a haemorrhagic stroke.
Haemorrhagic stroke 
Haemorrhagic stroke is defined as an acute episode of focal or global cerebral or spinal 
dysfunction caused by intraparenchymal, intraventricular, or subarachnoid haemorrhage.
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 
haemorrhage or infarction but with insufficient information to allow categorisation as 
ischaemic or haemorrhagic stroke.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 62 of 150
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.
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 modified Rankin Scale (mRS) at the onset of 
stroke and at 3 months after recurrent stroke, if this time frame falls anytime within the study 
participation. Disabling stroke is defined as a stroke with mRS ≥4 at 3 months (see Appendix 
10.3 for definition of mRS). 
5.1.2.4
Systemic embolism 
SE is an acute vascular occlusion of the extremities or any organ (kidneys, mesenteric 
arteries, spleen, retina or grafts) and must be documented by angiography, surgery, 
scintigraphy or autopsy.
5.1.2.5
Stent Thrombosis
There will be three categories of evidence to define stent thrombosis:
1. Definite Stent Thrombosis
A definite stent thrombosis is considered to have occurred by either angiographic or 
pathological confirmation [R13-4874, R15-0010]:

Angiographic confirmation of stent thrombosis1

The presence of a thrombus2 that originates in the stent or in the segment 5 mm
proximal or distal to the stent and presence of at least 1 of the following criteria
within a 48-hour time window:
o
Acute onset of ischaemic symptoms at rest
o
New ischaemic ECG changes that suggest acute ischaemia
o
Typical rise and fall in cardiac biomarkers (refer to definition of 
spontaneous MI)
o
Non-occlusive thrombus
Intracoronary thrombus is defined as a (spheric, ovoid, or irregular) non-
calcified filling defect or lucency surrounded by contrast material (on 3 sides 
or within a coronary stenosis) seen in multiple projections, or persistence of 
                                                          
1 The incidental angiographic documentation of stent occlusion in the absence of clinical signs or symptoms is not 
considered a confirmed stent thrombosis (silent occlusion).
2 Intracoronary thrombus


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 63 of 150
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.
contrast material within the lumen, or a visible embolization of intraluminal 
material downstream
o
Occlusive thrombus
Thrombolysis In Myocardial Infarction (TIMI) 0 or TIMI 1 intrastent or 
proximal to a stent up to the most adjacent proximal side branch or main 
branch (if originates from the side branch). 

Pathological Confirmation of Stent Thrombosis
Evidence of recent thrombus within the stent determined at autopsy or via examination of
tissue retrieved following thrombectomy.
2. Probable Stent Thrombosis
Clinical definition of probable stent thrombosis is considered to have occurred after
intracoronary stenting in the following cases:

Any unexplained death within the first 30 days

Irrespective of the time after the index procedure, any MI that is related to 
documented acute ischaemia in the territory of the implanted stent without 
angiographic confirmation of stent thrombosis and in the absence of any other 
obvious cause
3. Possible Stent Thrombosis
Clinical definition of possible stent thrombosis is considered to have occurred with any 
unexplained death from 30 days after intracoronary stenting until end of trial follow-up.
5.1.2.6
Repeated revascularisation by PCI/CABG
Repeated revascularisation due to objectively documented recurrent ischaemia, stent 
thrombosis or ACS. Unplanned revascularisation is any repeated revascularisation not 
planned prior to informed consent. These cases will undergo adjudication for confirmation of 
whether the event was unplanned, the type of procedure, the indication and if it is a target 
lesion revascularisation.
All details of documentation required for adjudication will be provided in the ISF.  
5.2
SAFETY
5.2.1
Endpoints of safety
The primary endpoint for this trial is time to first ISTH MBE or CRNMBE. For definition of 
CRNMBE see section 5.2.2.1.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 64 of 150
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.
Other safety endpoints are:
1. Major bleeding (ISTH)
2. CRNMBE (for definition see section 5.2.2.1)
3. Clinically relevant bleeding measured using the following definitions:

Bleeding Academic Research Consortium (BARC) ≥3

TIMI group - Major and Minor
4. Minor and total bleeding (ISTH, BARC and TIMI)
5. Intracranial haemorrhage
5.2.2
Assessment of adverse events
5.2.2.1
Assessment of Bleeding events
Patients should be carefully assessed for signs and symptoms of bleeding. Bleeding will be 
classified as major, Clinically Relevant Non Major Bleeding Event (CRNMBE) or minor. 
Major bleeds will be further sub classified as life-threatening and other major bleeds. The 
location of the bleeding including the specific critical area or organ into which the bleeding 
occurred and whether or not it prolongs hospitalisation will be recorded. The following 
definitions are specified for bleeds:
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 haemoglobin of at least 2g/dL (1.24mmol/L), or 
leading to transfusion of two or more units of blood or packed cells1
and/or

Fatal bleed
Definition of a CRNMBE
A clinically relevant non-major bleeding event is a clinically overt bleed that does not meet 
                                                          
1 Bleeding should be overt and the haemoglobin drop should be considered to be due to and temporally related to the 
bleeding event.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 65 of 150
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.
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 for bleeding
or

A physician guided medical or surgical treatment for bleeding
or

A physician guided change, interruption1 or discontinuation of study drug.
Definition of a minor bleed
Minor bleeds are clinical bleeds that do not fulfil the criteria for major bleeds. Minor bleeds 
will be further divided to those that are CRNMBE, (see above) and those that are not. 
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 haemoglobin of at least 5g/dL; 
transfusion of at least four units of blood or packed cells, associated with hypotension 
requiring the use of i.v. inotropic agents; necessitated surgical intervention.
Definition of intracranial haemorrhage (ICH)
Intracranial haemorrhage (ICH) comprises the subtypes of intracerebral bleeds, subdural 
bleeds, epidural bleeds and subarachnoid bleeds and will be recorded.
Definition of a fatal bleeding
Fatal bleeding is defined as a bleeding event that the IAC determines is the primary cause of 
death or contributes directly to death.
Total bleeds
This is the sum of all major and minor bleeds. 
In addition to the specified primary definition to be used for major bleeds in this trial 
(according to ISTH criteria, see above), components of the further bleeding definitions will 
be prospectively collected.  It will be the responsibility of the IAC to categorise investigator-
reported bleeding events according to the following pre-specified secondary classifications: 

BARC (R13-4065, R13-4066) 

TIMI (P07-10190)
TIMI Classification of Bleeding
                                                          
1 Interruption of study drug (more than omitting one dose) due to the bleeding event.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 66 of 150
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.
The TIMI definition of bleeding uses four categories: major, minor, minimal and none, with 
definitions of the first three as follows:

Major
Intracranial haemorrhage or a ≥ 5g/dL decrease in haemoglobin concentration or a ≥15% 
absolute decrease in haematocrit

Minor
Observed blood loss: ≥ 3g/dL decrease in haemoglobin concentration or ≥ 10% decrease 
in haematocrit. 
No observed blood loss: ≥ 4g/dL decrease in haemoglobin concentration or a ≥ 12% 
decrease in haematocrit

Minimal
Any clinically overt sign of haemorrhage (including imaging) associated with a < 3g/dL 
decrease in haemoglobin concentration or < 9% decrease in haematocrit.
BARC Definition for Bleeding1
Type 0: no bleeding
Type 1: bleeding that is not actionable and does not cause the patient to seek unscheduled 
performance of studies, hospitalisation, or treatment by a healthcare professional; may 
include episodes leading to self-discontinuation of medical therapy by the patient without 
consulting a healthcare professional
Type 2: any overt, actionable sign of haemorrhage (e.g., more bleeding than would be 
expected for a clinical circumstance, including bleeding found by imaging alone) that does 
not fit the criteria for type 3, 4, or 5 but does meet at least one of the following criteria: (1) 
requiring nonsurgical, medical intervention by a healthcare professional, (2) leading to 
hospitalisation or increased level of care, or (3) prompting evaluation
Type 3:

Type 3a
-
Overt bleeding plus haemoglobin drop of 3 to < 5 g/dL* (provided haemoglobin 
drop is related to bleed)
-
Any transfusion with overt bleeding
                                                          
1 Footnotes to BARC definition:
CABG indicates coronary artery bypass graft. Platelet transfusions should be recorded and reported but are not included in 
these definitions until further information is obtained about the relationship to outcomes. If a CABG-related bleed is not 
adjudicated as at least a type 3 severity event, it will be classified as not a bleeding event. If a bleeding event occurs with a 
clear temporal relationship to CABG (i.e., within a 48-h time frame) but does not meet type 4 severity criteria, it will be 
classified as not a bleeding event.
*Corrected for transfusion (1 U packed red blood cells or 1 U whole blood = 1 g/dL haemoglobin).
†Cell saver products are not counted.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 67 of 150
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.

Type 3b
-
Overt bleeding plus haemoglobin drop ≥ 5 g/dL* (provided haemoglobin drop is 
related to bleed)
-
Cardiac tamponade
-
Bleeding requiring surgical intervention for control (excluding 
dental/nasal/skin/haemorrhoid)
-
Bleeding requiring i.v. vasoactive agents

Type 3c
-
Intracranial haemorrhage (does not include microbleeds or haemorrhagic
-
transformation, does include intraspinal)
-
Subcategories confirmed by autopsy or imaging or lumbar puncture
-
Intraocular bleed compromising vision
Type 4: CABG-related bleeding

Perioperative intracranial bleeding within 48 hour

Reoperation after closure of sternotomy for the purpose of controlling bleeding

Transfusion of ≥ 5 U whole blood or packed red blood cells within a 48-hour period†1

Chest tube output ≥ 2L within a 24-hour period
Type 5: fatal bleeding

Type 5a
-
Probable fatal bleeding; no autopsy or imaging confirmation but clinically 
suspicious

Type 5b
-
Definite fatal bleeding; overt bleeding or autopsy or imaging confirmation
The protocol specified study definitions will be used by the Adjudication Committee as 
outlined in its Charter governing the adjudication process. 
5.2.2.2
Definitions of AEs
AE
                                                          
1 Footnotes to BARC definition:
CABG indicates coronary artery bypass graft. Platelet transfusions should be recorded and reported but are not included in 
these definitions until further information is obtained about the relationship to outcomes. If a CABG-related bleed is not 
adjudicated as at least a type 3 severity event, it will be classified as not a bleeding event. If a bleeding event occurs with a 
clear temporal relationship to CABG (i.e., within a 48-hour time frame) but does not meet type 4 severity criteria, it will be 
classified as not a bleeding event.
*Corrected for transfusion (1 U packed red blood cells or 1 U whole blood = 1 g/dL haemoglobin).
†Cell saver products are not counted.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 68 of 150
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.
An 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.
SAE
An 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 hospitalisation, 
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 judgement which may 
jeopardise the patient and may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definitions.
Intensity of AE
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. 
Outcome Events
Since efficacy and safety endpoints can also be SAEs, they can be treated as disease-related. 
These events 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 remit of the independent DMC is to protect patient safety by monitoring the incidence 
and clinical relevance of safety data collected throughout the conduct of this study.  
In addition, for the safety parameters of primary interest, namely any bleeding event (see 
Section 5.2.2.1) and for the major mortality/morbidity clinical endpoints of interest (see 


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 69 of 150
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.
Section 5.2.2.2 and Section 5.1.2), a blinded IAC will be in place with the responsibility to 
confirm and classify all such events.  
Any OE that occurs prior to randomisation and fulfils the criteria of an SAE will be reported 
in the standard expedited fashion as an SAE; however, if the patient has been randomised, 
these events will not be reported as SAEs, but entered in the eCRF as OEs.  
OEs are therefore defined as follows:

Any bleed

All deaths 

All MIs

All strokes

All SE

All TIAs

All stent thromboses
The Investigator (or designee) will enter these OEs (even if they meet the criteria of an SAE) 
in the corresponding pages in the eCRF within 24 hours of awareness, as well as providing 
any defined supporting documentation (including imaging e.g. MR, CT, angiography). This 
will be provided by the Sponsor to the DMC and IAC, as defined in their respective charter. 
This procedure is defined in more detail in Appendix 10.4.
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.
Protocol-specified Adverse Events of Special Interest (AESI)
No AESIs are defined for this trial.
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 


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 70 of 150
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.
occurring in the REP are handled as occurring on treatment. The residual effect period is 
defined as 6 days after last intake of trial medication.
5.2.2.3
Adverse event and serious adverse event reporting
Except where noted in Section 5.2.2.2, all AEs, serious and non-serious, occurring during the 
course of the clinical trial (i.e., from signing the informed consent onwards through the 
observational phase) will be collected, documented and reported to the sponsor by the 
Investigator on the appropriate eCRFs / SAE reporting forms. Reporting will be done 
according to the specific definitions and instructions detailed in the ‘Adverse Event 
Reporting’ section of the ISF. 
For each AE, 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 a causal 
relationship assessment made by the Investigator.
The Investigator also has the responsibility to report any AEs occurring in the four weeks
after a patient completes the trial. Any AEs reported to the sponsor during this phase must be 
documented in the safety database.
The Investigator does not need to actively monitor patients for AEs once the clinical trial has 
ended. However, if the Investigator becomes aware of an SAE that occurred after the patient 
has completed the clinical trial (including the REP and follow-up period), the Investigator
should report it to the sponsor if the Investigator considers it relevant to BI investigational 
product.
The Investigator must report the following events via fax immediately (within 24 hours or the 
next business day, whichever is shorter) to the sponsor: SAEs and non-serious AEs relevant
to the SAE.
BI has set up a list of AEs which are defined to be always serious. In order to support the 
Investigator with the identification of these “always serious AEs”, if a non-serious AE is 
identified to be serious per BI definition and does not meet the definition of an OE, 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 an SAE 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.
With receipt of any further information to these events, a follow-up SAE report has to 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 ISF). This immediate report is 


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 71 of 150
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.
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). Congenital anomalies are always 
considered to be SAEs.
5.2.3 Assessment of safety laboratory parameters
Blood samples will be taken at the screening visit for those parameters required to verify 
eligibility (haemoglobin, platelets, ALT and / or AST, AP and creatinine (the latter to 
calculate CrCl according to the Cockcroft-Gault formula)) and will be analysed by a local 
laboratory. If standard of care local blood results are available, taken within 7 days prior to 
screening, these can be used to verify eligibility. From Visit 2 (randomisation) onwards, an 
abbreviated haematology panel and chemistry panel including liver and renal function testing 
(defined in Table 5.2.3:1) will be analysed by the central laboratory at the specific time points 
indicated in the flowchart. Central laboratory samples must be taken at the randomisation
visit, prior to first intake of study medication.
The central laboratory will provide the required materials for processing the samples (except 
INRs and local testing at screening) 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. 
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.
Unscheduled tests should be performed by the Central Laboratory unless immediate results
are required for the patient’s safety.
All blood samples can be taken in a non-fasting condition.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 72 of 150
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.
Table 5.2.3:1 Safety laboratory parameters
Chemistry
Haematology 
ALT (SGPT)
Erythrocyte
AST (SGOT)
Haemoglobin
Alkaline Phosphatase
Haematocrit
Bilirubin total, fractionated if increased
Platelet Count
GGT
WBC
LDH
Albumin
Creatinine
Creatinine Clearance*
Glucose
Potassium
Sodium
Total Protein
Urea
                               * According to Cockcroft-Gault formula
Pregnancy Testing
A urine pregnancy test will be performed locally on all women of child bearing potential at 
all clinic visits. In additional women of child bearing potential will be supplied with 
pregnancy tests and instructed to perform pregnancy testing every 4 weeks. Urine pregnancy 
tests will be provided. 
Renal Function Measurements
CrCl will be calculated using the Cockcroft-Gault formula, as follows:

For creatinine in Mol/L:
(140-age [years]) weight [kg] x 1.23 (0.85 if female)
serum creatinine [Mol/L]

For creatinine in mg/dL:
(140-age [years]) weight [kg] (0.85 if female)
72 serum creatinine [mg/dL]
Please refer to Section 3.3.4.1 for guidance if a patient’s CrCl is <30mL/min. 


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 73 of 150
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.
5.2.4 Electrocardiogram
All ECGs will be collected on standardised devices and stored at a central digital database
provided by a central ECG service. At each visit as indicated in the Flow Chart a 12-lead 
ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded. The ECGs will be evaluated by 
the Investigator or a designate for immediate investigation or treatment. In addition, the 
central ECG vendor will provide manual reading results which will be communicated to the 
Investigator for 
 further judgment and will be stored in the central database of the vendor. 
Additional ECGs recorded outside the Investigator's facilities may be collected by the 
Investigator and transferred to the central database for safety reasons.
Upon receipt of an alert from the ECG vendor, the Investigator or designate is expected to 
review, sign and date the findings, record their clinical judgement in the source documents. 
Agreement with the findings should result in a reported OE or (S)AE, if judged to be 
clinically relevant. If the Investigator does not agree with the ECG reviewer’s findings, a note 
should be made in the source regarding the review of the alert. Clinically relevant changes in 
the ECG will be reported as AEs. 
5.2.5
Assessment of other safety parameters
5.2.5.1 
Physical Examination
A cardiovascular focused physical examination will be performed by medical qualified 
personnel according to the flowchart. Documentation of and findings from the physical 
examination, must be part of the source documents available at the site. All 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 the EOT 
physical examinations will be recorded as AEs on the appropriate eCRF page, if judged 
clinically relevant by the investigator. In the event that clinically relevant findings are 
observed in the physical examination at the end of treatment, the patient should be followed 
by the Investigator until resolution of the event, or an agreement has been made with the 
Sponsor that follow-up is sufficient on that patient.
5.2.5.2
Vital Signs and Weight
BP and PR will be performed at every visit after resting for at least five minutes. For each 
patient, all BP recordings shall be made using the same type of instrument (i.e. manual BP 
recording vs. automatic digital vital signs monitor) on the same arm. Weight will be 
measured at the visits indicated in the flow chart in order to calculate CrCl according to 
Cockcroft-Gault. Any new clinically relevant findings that are identified will be reported as 
AEs.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 74 of 150
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.
5.3 OTHER
5.3.1 Other endpoint(s)
Transient Ischaemic Attacks will be collected and adjudicated. TIA is defined as a transient 
episode of focal neurological dysfunction caused by brain, spinal cord, or retinal ischaemia, 
without acute infarction [R13-4874, R15-0010]. All details of documentation required will be 
provided in the ISF. 
5.4
APPROPRIATENESS OF MEASUREMENTS
The primary endpoint for this study is a safety endpoint using the ISTH definition for major 
bleeding and CRNMBEs which are similar endpoints to those used in other contemporary 
clinical trials in the same setting (ClinicalTrials.gov: NCT01830543 and NCT02415400).
In order to allow bleeding incidence in this trial, to be compared to published data with other 
antithrombotic combinations, key components of the BARC bleeding classifications will be 
prospectively collected. Classifications of bleeding events (to various different scales and 
major/minor) will be confirmed by the IAC and provided on an on-going basis to the DMC.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 75 of 150
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.
6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
The study will consist of three sequential periods, Screening/Baseline Period of up to 5 days, 
a Treatment Period of up to approximately 30 months and a Follow up Period of four weeks. 
The maximum treatment duration is expected to be 30 months, however, the trial can 
conclude earlier, if adequate number of events are reported sooner or it can conclude later (or 
enrol 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 (Day 1). 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 (i.e. no permission can be granted by the Sponsor 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 (i.e. constituting a 
protocol violation) will be assessed prior to analysing the data.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
No study procedures may be initiated prior to the patient signing the informed consent in 
compliance with ICH-GCP and local legislation.
6.2.1
Screening and run-in period(s)
6.2.1.1 Screening Visit (Visit 1)
Screening will be performed after successful PCI. All tests as detailed in the Flow Chart must 
be performed. 
Screened patients should be registered in IRT. Only patients meeting the study criteria will be 
randomised. Patients who fail screening will not be followed up. Patients who fail screening 
should be registered as a screen failure in IRT.
6.2.2
Treatment period(s)
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 done, Visit 2 can be conducted 
including randomisation via IRT. Screening and randomisation can be on the same day, 
depending on the availability of the screening laboratory results.
Randomisation can occur immediately after successful screening and up to 120 hours post 
PCI, however, randomisation within 72 hours is preferable. The first dose of trial medication 


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 76 of 150
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.
will be taken between 6 hours after sheath removal and preferably within 72 hours post PCI
(end of intervention i.e. when the last catheter used for PCI is removed), with haemostasis 
assured, however randomisation up to 120 hours post PCI is allowed.
Treatment visits will take place approximately every three months for the first 12 months of 
treatment and every six months thereafter.  After month 12, phone calls will be conducted in 
between regular clinic visits.  These calls are designed to encourage accurate and timely 
event reporting and continued engagement of patients.  
As this is an OE driven trial, patients will remain in the treatment period until the necessary 
number of OEs is reached. 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 patients who discontinue treatment 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 (as indicated in the Flow Chart) ECGs will 
be performed and the collection of AEs, OEs (including completion of the bleeding
questionnaire) and use of concomitant medication will be made.
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 permit collection of 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.
The patient will be asked to choose the most rigorous follow-up they are willing to comply 
with.
For patients who withdraw consent no more data on their medical information will be 
requested, see Section 3.3.4.1. 
The site must make periodic documented attempts (approximately every three months) to 
locate patients who are lost to follow up. 


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 77 of 150
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.
6.2.3
End of trial and follow-up period
6.2.3.1 End of treatment
All patients will remain on study treatment until the last patient entered has completed at least 
six months of treatment.  Based on the number of OEs, the operations committee will declare 
the end of the trial date and ask that all patients be brought in for their end of trial visit within 
a certain time period, which will be communicated by the trial team.
The EOT visit should take place for all patients when they discontinue study drug.
Patients who discontinue the study medication early should be registered as “withdrawn” and 
patients who complete the full treatment period should be registered as completed in the IRT.
After termination of study drug the patient should be switched to an appropriate non study 
anticoagulant and antiplatelet regimen (if required) according to the local practices. See 
Appendix 10.2.
Assessments should be performed as mentioned in the Flow Chart.
6.2.3.2
Follow up visit
All patients should have a follow-up visit performed four weeks after EOT. During this visit, 
concomitant medications, AEs, SAEs and OEs (including signs and symptoms of bleeding)
during the 4 week period after last dose of study drug will be collected. 
Patients who discontinue the study medication early should return to their original visit 
schedule after this follow up visit (see Section 6.2.2).
6.2.3.3
Final Visit 
The final visit will be conducted in all patients who discontinue study treatment early at the 
time the trial conclusion is declared. Assessments will be done according to the flowchart. 
6.2.3.4
Vital Status and Outcome Event Collection
It is important to record the vital status and OEs of all randomised patients at the end of the 
trial. 
If a site has difficulty contacting a patient at the end of the trial, site staff should make a 
minimum of three documented attempts to contact the patient using different methods (i.e. 
phone, email, certified letter, other).  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 thrombotic events and major bleeds 
(where possible).


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 78 of 150
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.
6.2.3.5
Withdrawal of consent 
Patients that discontinue medication and express desire to reduce their degree of participation 
should be presented with a reduced follow-up option as described in Section 6.2.2.  
If the patient is not willing to continue in the trial and withdraws consent refer to Section 
3.3.4.1. 


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 79 of 150
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.
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
This is a prospective, randomised, open label, blinded endpoint (PROBE), active comparator 
trial and the clinical endpoints are being adjudicated by an IAC in a blinded fashion. The 
study will employ a time to first event analysis (using a stratified Cox proportional hazards 
regression model) and it is assumed that all patients will remain on study treatment until the 
last patient entered has completed at least six months of treatment (up to an anticipated 
maximum duration of approximately 30 months for the first patient entered).  The trial will be 
monitored by an independent DMC.
This study is designed to test a safety hypothesis in NVAF patients that have undergone a 
successful PCI (elective or due to ACS) with stenting and were treatment naïve or were 
receiving oral anticoagulant treatment (either with warfarin, another VKA or other novel oral 
anticoagulant) before the procedure.
The primary outcome is stated in Section 5.2.1.
1. ISTH MBE and CRNMBE
7.2
NULL AND ALTERNATIVE HYPOTHESES
Two safety hypotheses (110mg Dabigatran Etexilate (DE-DAT) vs. warfarin-TAT and 
150mg DE-DAT vs. warfarin-TAT) will be tested:
1. 110mg DE-DAT is non-inferior to warfarin-TAT with respect to MBE/CRNMBE 
over the duration of the trial
2. 150mg DE-DAT is non-inferior to warfarin-TAT with respect to MBE/CRNMBE 
over the duration of the trial.
To control the Type I error rate at a one-sided 0.025 level, a hierarchical procedure for 
multiple testing will be used to test the above hypotheses. Additional testing for safety and 
efficacy endpoints will also be included in this hierarchical procedure. The following 
hierarchical procedure will be applied:
Step 1 – Non-inferiority of 110mg DE-DAT to warfarin-TAT in MBE/CRNMBE is met at 
the one-sided 0.025 level of significance
Step 2 – Non-inferiority of 150mg DE-DAT to warfarin-TAT in MBE/CRNMBE is met at 
the one-sided 0.025 level of significance
Step 3 – Non inferiority of 150mg DE-DAT and 110mg DE-DAT combined to warfarin-TAT 
in DTE and unplanned revascularisation by PCI/CABG is met at the one-sided 0.025 level of 
significance


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 80 of 150
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.
Step 4 –Superiority of 110mg DE-DAT to warfarin-TAT in MBE/CRNMBE is met at the 
one-sided 0.025 level of significance
Step 5 – Non inferiority of 150mg DE-DAT and 110mg DE-DAT combined to warfarin-TAT 
in DTE is met at the one-sided 0.025 level of significance
Step 6 – Superiority of 150mg DE-DAT to warfarin-TAT in MBE/CRNMBE is met at the 
one-sided 0.025 level of significance
If any of the steps above fail to meet statistical significance, the testing procedure will stop at 
that step and subsequent tests will not be performed.
The Non-Inferiority (NI) margin used for MBE/CRNMBE will be 1.38 (on the relative HR 
scale).  See Section 7.6 for a clinical justification of this margin.  The upper bound of the 
Wald confidence interval (CI) of the HR of DE-DAT vs. warfarin-TAT (one-sided 97.5%) 
will be compared to this NI margin for the NI testing.
7.3
PLANNED ANALYSES
7.3.1
Primary analyses
The primary endpoint (measured from date of randomisation to end of observation period) is:

Time to first MBE/CRNMBE
as determined by the IAC.  It will be analysed using the stratified Cox proportional hazards 
regression model including factors for age (<80 or ≥80 years old) and treatment arm (110mg 
DE-DAT vs warfarin-TAT and 150mg DE-DAT vs warfarin-TAT). Models will be fitted for 
each comparison separately.
The primary analysis will be performed under the intention-to-treat framework on the full 
analysis set of patients (FAS) that includes all randomised patients (regardless of whether 
they have received treatment).  Patients who discontinue study medication will be followed 
until the end of the trial.  Patients who are lost to follow-up for vital status will be censored 
for the primary endpoint at the time of their last known vital status.  All patients will be 
analysed according to the treatment arm to which they were randomised.
For the comparison of 110mg DE-DAT vs warfarin-TAT, patients of all ages and 
geographical regions will be included.  For the comparison of 150mg DE-DAT vs warfarin-
TAT, patients from the EU/ROW who are ≥80 years old will be excluded from the warfarin-
TAT arm (as patients who are ≥80 years old from the EU/ROW are not randomised to 150mg 
DE-DAT).
The robustness of the primary analysis will be assessed by an on-treatment analysis.  This on-
treatment analysis will only count events that occur while a patient is taking study medication 
(including the REP of 6 days – see Section 5.2.2.2).  It will also analyse patients by the actual 
treatment that was being taken while the event occurred.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 81 of 150
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.
In addition, a sensitivity analysis will be performed that censors patients who switch from 
dabigatran to non-study warfarin or from study warfarin to non-study NOAC, at the time of 
the switch. The proportional hazards assumption will be investigated.
Kaplan-Meier curves will also be presented.
Subgroup analyses are planned and will be specified in the Trial Statistical Analysis Plan 
(TSAP).
7.3.2
Secondary analyses
Secondary efficacy endpoints (all time to first event, measured from date of randomisation to 
end of observation period) are:

A combined endpoint of thrombotic events or death (DTE: all death + MI + stroke/SE)
and unplanned revascularisation by PCI /CABG

A combined endpoint of thrombotic events or death (DTE: all death + MI + stroke/SE)

All death 
o
Cardiovascular death
o
Non-cardiovascular death
o
Undetermined

MI

Stroke

SE

Stent thrombosis

Composite of death + MI + stroke

Unplanned revascularisation by PCI /CABG
Time to first event endpoints will be analysed using the same methods as for the primary 
endpoint.  No multiplicity adjustments are planned for secondary endpoints (apart from those 
mentioned in the hierarchy, see Section 7.2).  Nominal one-sided p-values will be reported 
for descriptive purposes.
All secondary analyses will be performed on the FAS. The robustness of these analyses will 
be assessed by on-treatment analyses (see Section 7.3.1). 
TIA (further endpoint, see Section 5.3.1) will be analysed using the same approaches as 
above.
7.3.3
Safety analyses
Safety endpoints are defined in Section 5.2.1.
These endpoints will be analysed using the same methods as the primary endpoints.  No 
multiplicity adjustments are planned for safety endpoints (apart from those mentioned in the 
hierarchy, see Section 7.2).


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 82 of 150
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.
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 AEs. All AEs with an onset after the first dose of study medication 
up to the end of the REP of 6 days (see Section 5.2.2.2) after the last dose of study 
medication will be assigned to the treatment period for evaluation. Other adverse events will 
be assigned either to the screening or post study period as appropriate.
On-treatment analyses will be performed for AEs.
7.3.4
Interim analyses
No interim analysis is planned, but blinded sample size re-calculations may be performed.  
The conduct of the trial will be monitored by a DMC. The DMC will hold regular meetings to 
monitor imbalance in endpoints, with the focus on MBE/CRNMBE. The DMC’s objectives 
and working practices are documented in the DMC charter. 
The DMC may recommend terminating the study at any time for DE-DAT safety concerns.  
Further details will be included in the DMC charter.
The DMC will have unblinded safety reviews every 2 months.
7.3.5
Pharmacokinetic analyses
Not applicable.
7.3.6
Pharmacodynamic analyses
Not applicable.
7.3.7
Pharmacogenomic analyses
Not applicable.
7.4
HANDLING OF MISSING DATA
A major goal of the trial is to obtain virtually complete follow-up of vital status.  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.
The CTR will contain a summary of the number and proportion of patients with (and without) 
complete follow-up of vital status in each treatment group.
Partial dates will be imputed for the primary and secondary endpoints.  Specific imputation 
rules will be documented in the TSAP.
7.5
RANDOMISATION
Patients aged <80 years old will be randomly assigned to 110mg DE-DAT, 150mg DE-DAT 
or warfarin-TAT in a 1:1:1 ratio for the duration of the trial. 


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 83 of 150
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.
Patients aged ≥80 years old will be randomly assigned depending on their geographical 
region: 

Patients aged ≥80 years old in the USA will be assigned to 110mg DE-DAT, 150mg DE-
DAT or warfarin-TAT in a 1:1:1 ratio

All other patients aged ≥80 years old (i.e. EU/ROW) will be assigned to 110mg DE-DAT 
or warfarin-TAT in a 1:1 ratio.
Patients will be randomised in permuted blocks, dynamically stratified by age (<80 or ≥80 
years old) and region (EU/ROW or USA) using an IRT.  Dynamic stratification allocates 
blocks of randomisation numbers according to the strata of the first randomised patient within 
that block.  For example, if the first patient randomised to the first block is <80 years old and 
from the USA, other randomisation numbers within this block will only be allocated to 
patients <80 years old from the USA (until there are no more randomisation numbers left to 
allocate within this block).  BI will arrange for the packaging and labelling of study 
medication. The randomisation list will be generated using a validated system and 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
This is an event-driven trial where it is assumed that the first patient recruited into the study 
will be followed up for a maximum of approximately 30 months and the last patient recruited 
into the trial will be followed up for a minimum of 6 months. It is assumed that patient 
accrual will be approximately uniform over the 24 month recruiting period.
The proportion of patients with at least one MBE/CRNMBE at one year is estimated to be 
14% based on current blinded trial data.
A relative NI margin for the original co-primary endpoint (DTE) was chosen in analogy to 
recent SPAF trials with primary endpoints of stroke/SE, where 1.38 was used by the FDA for 
ximelagatran, apixaban, rivaroxaban and dabigatran to preserve at least 50% of the relative 
reduction (on the log scale) in the risk associated with warfarin in six previous (historical), 
randomised, controlled trials. See publication by Jackson K, Gersh BJ, Stockbridge N, et al. 
[R08-2662]. The same NI margin has been applied to MBE/CRNMBE as it was considered 
the most clinically relevant available reference in the absence of any other type of data.
The overall sample size is driven by the non-inferiority comparison of  MBE/CRNMBE 
between 110mg DE-DAT or 150mg DE-DAT and warfarin-TAT.  With alpha=0.025 (one-
sided) and 14% of patients with at least one event at one year, 334 patients with at least one 
MBE/CRNMBE in each pair of treatment groups (i.e. 167 patients with MBE/CRNMBE per 
treatment group) are required to achieve 83.6% power for this endpoint, yielding a final 
sample size estimated at 834 patients in each treatment group (i.e. 2502 randomised patients 
in total). Therefore approximately 500 patients with at least one MBE/CRNMBE are required 
in total across the three treatment groups.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 84 of 150
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.
As described in Section 7.3.1, for the comparison of 150mg DE-DAT vs warfarin-TAT, 
patients from the EU/ROW who are ≥80 years old will be excluded from the warfarin-TAT 
arm (as patients who are ≥80 years old from the EU/ROW are not randomised to 150mg DE-
DAT).  The actual number of patients entered may increase or decrease based upon actual 
event rates. As this is an event-driven trial, the trial can conclude earlier, if an adequate 
number of events are reported sooner or later, if more events are needed. Because the last 
patient entered must be followed up for a minimum of 6 months and to avoid accruing too 
many events, recruitment will need to be stopped before the required number of events are 
observed.  Blinded event rates will be monitored closely by BI (and the Executive Steering 
Committee) to predict the time at which recruitment should be stopped.  Sites will be notified 
when recruitment ends.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 85 of 150
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.
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 Harmonised 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 subjects against any immediate hazard and also of any serious breaches of 
the protocol/ICH GCP and in Japan, the Japanese GCP regulations (Ministry of Health and 
Welfare Ordinance No. 28, March 27, 1997).
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.
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 competent authority (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. The following items need to be 
included:


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 86 of 150
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.
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 authorised 
the Local Clinical Monitors or Clinical Research Associate (CRA) or Clinical Quality 
Assurance auditors appointed by Boehringer Ingelheim, by appropriate IRB / IEC members
and by inspectors from regulatory authorities.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 87 of 150
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.
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.
8.3
RECORDS
eCRFs for individual patients will be provided by the sponsor, via RDC. 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; also current
medical records must be available.
For eCRFs all data must be derived from source documents.
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. 
eCRFs 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. FDA). The CRA / on site monitor 
and auditor may review all eCRFs and written informed consents. An adaptive approach to 
clinical trial monitoring that directs monitoring focus and activities to the evolving areas of 
greatest risk which have the most potential to impact subject safety and data quality will be 
utilised. The accuracy of the data will be verified by reviewing the documents described in 
Section 8.3.1.
8.3.3
Storage of records - Japan
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 sites to retain the source documents and the 
essential documents, the Sponsor must notify the head of trial site.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 88 of 150
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.
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
8.4.1
Listedness
To fulfil the regulatory requirements for expedited safety reporting, the sponsor evaluates 
whether a particular AE 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. For
dabigatran etexilate this is the current version of the IB (U98-3208). For the comparator
(Warfarin) this is the current UK Summary of Product Characteristics (SmPC). The current 
versions of these reference documents are to be provided in the ISF. For the NIMPs the 
reference documents are the UK SmPC for ticagrelor, the UK SmPC for clopidogrel and the 
US Package Insert for ASA. No AEs are classified as listed for study design or invasive 
procedures.
8.4.2
Expedited reporting to health authorities and IECs/IRBs
Expedited reporting of serious adverse events, e.g. suspected unexpected serious adverse 
reactions (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, i.e. the CA.
8.6
COMPLETION OF TRIAL
For Japan: 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 EC/competent authority in each participating EU member state needs to be notified about 
the end of the trial (last patient/patient out, 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 
subjects and for other medically inevitable reasons.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 89 of 150
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.
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.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 90 of 150
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.
9.
REFERENCES
9.1
PUBLISHED REFERENCES
P05-11198
Benjamini Y, Hochberg Y Controlling the false discovery rate: a practical and 
powerful approach to multiple testing. J R Stat Soc (B) 57 (1), 289 - 300 
(1995)
P07-02268
White HD, Gruber M, Feyzi J, Kaatz S, Tse HF, Husted S, Albers GW. 
Comparison of outcomes among patients randomized to warfarin therapy 
according to anticoagulant control: results from SPORTIF III und V. Arch 
Intern Med 2007, 167: 239 – 245
P07-06963
Karjalainen PP, Porela P, Ylitalo A, Vikman S, et al. Safety and efficacy of 
combined antiplatelet-warfarin therapy after coronary stenting. Eur Heart J 
2007, 28: 726–732
P07-09550
Leon MB, Baim DS, Popma JJ, et al. A clinical trial comparing three 
antithrombotic-drug regimens after coronary-artery stenting. Stent 
Anticoagulation Restenosis Study Investigators. N Engl J Med 1998; 
339:1665-1671
P07-10190
Rao SV, Eikelboom JA, Granger CB, Harrington RA, Califf RM, Bassand JP
Bleeding and blood transfusion issues in patients with non-ST-segment 
elevation acute coronary syndromes. Eur Heart J 2007; 28 (10), 1193 - 1204 
P07-13246
Prasugrel versus Clopidogrel in Patients with Acute Coronary Syndromes. 
Wiviott SD, Braunwald E, McCabe CH, Montalescot G, et al. N Engl J Med 
2007;357:2001-15.
P08-12388
Stangier J, Staehle H, Rathgen K, Roth W, Shakeri-Nejad K. 
Pharmacokinetics and pharmacodynamics of dabigatran etexilate, an oral 
direct thrombin inhibitor, are not affected by moderate hepatic impairment. J 
Clin Pharmacol 2008, 48: 1411-1419 
P09-11669
Connolly SJ, Ezekowitz MD, Salim Yusuf S, et al. Dabigatran versus 
Warfarin in Patients with Atrial Fibrillation. N Engl J Med 2009; 361:1139-
1151
P10-03790
van Ryn J, Stangier J, Haertter S, Liesenfeld KH, Wienen W, Feuring M, 
Clemens A. Dabigatran etexilate - a novel, reversible, oral direct thrombin 
inhibitor: interpretation of coagulation assays and reversal of anticoagulant 
activity. Thromb Haemost 2010, 103: 1116 – 1127
P10-07397
Lip GYH, Huber K, Andreotti F, et al. Antithrombotic management of atrial 
fibrillation patients presenting with acute coronary syndrome and/or 
undergoing coronary stenting: executive summary—a Consensus Document of 
the European Society of Cardiology Working Group on Thrombosis, endorsed 


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 91 of 150
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.
by the European Heart Rhythm Association (EHRA) and the European 
Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart 
J 2010, 31: 1311–1318
P10-12773 
Wijns W, et al. Guidelines on myocardial revascularization: the Task Force on 
Myocardial Revascularization of the European Society of Cardiology (ESC) 
and the European Association for Cardio-Thoracic Surgery (EACTS): 
developed with the special contribution of the European Association for 
Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 2010, 31 
(20), 2501 - 2555 
P10-14910
Wann LS, Curtis AB, January CT, Ellenbogen KA, Lowe JE, Estes NAM 3rd, 
Page RL, Ezekowitz MD, Slotwiner DJ, Jackman WM, Stevenson WG, Tracy 
CM, writing on behalf of the 2006 ACC/AHA/ESC Guidelines for the 
Management of Patients With Atrial Fibrillation Writing Committee. 2011 
ACCF/AHA/HRS focused update on the management of patients with atrial 
fibrillation (updating the 2006 guideline): a report of the American College of 
Cardiology Foundation/American Heart Association Task Force on Practice 
Guidelines. Circulation. 2011;123:104 –123 
P11-01097
Fisher M, Loscalzo J. The Perils of Combination Antithrombotic Therapy and 
Potential Resolutions. Circulation. 2011;123:232-235
P11-05772
Oldgren J, Budaj A, Granger CB, et al. Dabigatran vs. placebo in patients with 
acute coronary syndromes on dual antiplatelet therapy: a randomized, double-
blind, phase II trial. Eur Heart J 2011, 32: 2781–2789
P11-09369
Faxon DP, Eikelboom JW, Berger PB, et al. Consensus Document: 
Antithrombotic therapy in patients with atrial fibrillation undergoing coronary 
stenting: A North-American perspective Thromb Haemost 2011; 106: 571–
584
P11-09951
Steg PG, Huber K, Andreotti F, et al. Bleeding in acute coronary syndromes 
and percutaneous coronary interventions: position paper by the Working 
Group on Thrombosis of the European Society of Cardiology. Eur Heart J 
2011; 32: 1854-1864
P12-02400
Huisman MV, Lip GYH, Diener HC, Brueckmann M, van Ryn J, Clemens A. 
Dabigatran etexilate for stroke prevention in patients with atrial fibrillation: 
resolving uncertainties in routine practice. Thromb Haemost 2012, 107: 838 -
847
P12-11192
Camm AJ, Lip GYH, De Caterina R, Savelieva I, Atar D, Hohnloser SH, 
Hindricks G, Kirchhof P. 2012 focused update of the ESC Guidelines for the 
management of atrial fibrillation. An update of the 2010 ESC Guidelines for 
the management of atrial fibrillation Developed with the special contribution 
of the European Heart Rhythm Association. Eur Heart J 2012, 33: 2719–2747 


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 92 of 150
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.
P13-00071
Dans AL, Connolly SJ, Wallentin L, et al. Concomitant Use of Antiplatelet 
Therapy with Dabigatran or Warfarin in the Randomized Evaluation of Long-
Term Anticoagulation Therapy (RE-LY) Trial. Circulation 2013; 127: 634-
640
P13-00072
Sinnaeve PR, Van de Werf F. Do Ingredients Make the Difference? Finding 
the Best Cocktail of an Anticoagulant with Antiplatelets. Circulation 2013; 
127: 566-568
P13-06400
Heidbuchel H, Verhamme P, Alings M, Antz M, et al. European Heart 
Rhythm Association Practical Guide on the use of new oral anticoagulants in 
patients with non-valvular atrial fibrillation. Europace 2013, 15: 625–651
P13-11665
Jneid H, Anderson JL, Wright RS, Adams CD, Bridges CR, Casey DE Jr, 
Ettinger SM, Fesmire FM, Ganiats TG, Lincoff AM, Peterson ED, Philippides 
GJ, Theroux P, Wenger NK, Zidar JP. 2012 ACCF/AHA focused update of 
the guideline for the management of patients with unstable angina/non–ST-
elevation myocardial infarction (updating the 2007 guideline and replacing the 
2011 focused update): a report of the American College of Cardiology 
Foundation/American Heart Association Task Force on Practice Guidelines. J 
Am Coll Cardiol 2012; 60: 645–681 
P13-11669
Verheugt FWA. Triple antithrombotic therapy after coronary stenting in the 
elderly with atrial fibrillation: Necessary or too hazardous? Am Heart J 
2012;163: 531-534
P13-16211
Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and 
safety of new oral anticoagulants with warfarin in patients with atrial 
fibrillation: a meta-analysis of randomised trials. Lancet; 383: 955–62 (2014)
P14-02938 
Caldeira D, Barra M, Santos AT, Abreu D de, Pinto FJ, Ferreira JJ, Costa J. 
Risk of drug-induced liver injury with the new oral anticoagulants: systematic 
review and meta-analysis. Heart 2014;100:550-556.
P14-05384
January CT, Wann LS, Alpert JS, Calkins H, Cleveland JC, Cigarroa JE, Conti 
JB, Ellinor PT, Ezekowitz MD, Field ME, Murray KT, Sacco RL, Stevenson 
WG, Tchou PJ, Tracy CM, Yancy CW. 2014 AHA/ACC/HRS guideline for 
the management of patients with atrial fibrillation: a report of the American 
College of Cardiology/American Heart Association Task Force on Practice 
Guidelines and the Heart Rhythm Society: developed in collaboration with the 
Society of Thoracic Surgeons. J Am Coll Cardiol, 64(21):2246-2280 (2014)
P14-12794
Lip GYH, Windecker S, Huber K, Kirchhof P, Marin F, Berg JM ten, 
Haeusler KG, Boriani G, Capodanno D, Gilard M, Zeymer U, Lane D. 
Management of antithrombotic therapy in atrial fibrillation patients presenting 
with acute coronary syndrome and/or undergoing percutaneous coronary or 
valve interventions: a joint consensus document of the European Society of 
Cardiology Working Group on Thrombosis, European Heart Rhythm 


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 93 of 150
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.
Association (EHRA), European Association of Percutaneous Cardiovascular 
Interventions (EAPCI) and European Association of Acute Cardiac Care 
(ACCA) endorsed by the Heart Rhythm Society (HRS) and Asia-Pacific Heart 
Rhythm Society (APHRS). Eur Heart J, 35(45):3155-79 (2014)
P16-02545
Windecker S, et al, 2014ESC/EACTS guidelines on myocardial 
revascularization: the Task Force on Myocardial Revascularization of the 
European Society of Cardiology (ESC) and the European Association for 
Cardio-Thoracic Surgery (EACTS): developed with the special contribution of 
the European Association of Percutaneous Cardiovascular Interventions 
(EAPCI). Eur Heart J 35, 2541 - 2619 (2014)
R02-1059 
Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK, CURE Trial 
Investigators. Effects of clopidogrel in addition to aspirin in patients with 
acute coronary syndromes without ST-segment elevation. N Engl J Med 345 
(7), 494 - 502 (2001)
R03-2266
Wallentin L, Wilcox RG, Weaver WD, Emanuelsson H, Goodvin A, Nystrom 
P, Bylock A, ESTEEM Investigators. Oral ximelagatran for secondary 
prophylaxis after myocardial infarction: the ESTEEM randomised controlled 
trial. Lancet 362 (9386), 789 - 797 (2003)
R05-0344 
Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the 
Scientific and Standardization Committee of the International Society on 
Thrombosis and Haemostasis, Definition of major bleeding in clinical
investigations of antihemostatic medicinal products in non-surgical patients. J 
Thromb Haemost 3, 692 - 694 (2005)
R08-1695
Rosendaal FR, Cannegieter SC, Meer FJM van der, Briet E. A method to 
determine the optimal intensity of oral anticoagulant therapy. Thromb 
Haemost 1993, 69: 236 – 239 investigations of antihemostatic medicinal 
products in non-surgical patients. J Thromb Haemost 3, 692 - 694 (2005)
R08-2662
Jackson K, Gersh BJ, Stockbridge N, et al. Antithrombotic drug development 
for atrial fibrillation: proceedings, Washington, DC, July 25-27, 2005. Am 
Heart J 2008;155:829-40
R08-4453
Bueller HR, Halperin JL, Bounameaux H, Prins M. Double-blind studies are 
not always optimum for evaluation of a novel therapy: the case of new 
anticoagulants. J Thromb Haemost 2008, 6: 227 – 229
R13-4065
Hicks KA, Stockbridge NL, Targum SL, Temple RJ. Bleeding Academic 
Research Consortium consensus report: the Food and Drug Administration 
perspective. Circulation 2011, 123 (23), 2664 - 2665
R13-4066
Mehran R, Rao SV, Bhatt DL, Gibson CM, Caixeta A, Eikelboom J, Kaul S, 
Wiviott SD, Menon V, Nikolsky E, Serebruany V, Valgimigli M, Vranckx P, 
Taggart D, Sabik JF, Cutlip DE, Krucoff MW, Ohman EM, Steg PG, White H. 


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 94 of 150
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.
Standardized bleeding definitions for cardiovascular clinical trials: a 
consensus report from the Bleeding Academic Research Consortium. 
Circulation 2011, 123 (23), 2736 - 2747
R13-4127
DeWilde W, Oirbans T, Verheugt FWA, et al. Use of clopidogel with or 
without aspirin in patients taking oral anticoagulant therapy and undergoing 
percutaneous coronary intervention: an open-label, randomised, controlled 
trial (WOEST). Lancet 2013; 381: 1107–15
R13-4128
Levine GN, Bates ER, Blankenship JC, Bailey SR, Bittl JA, Cercek B, 
Chambers CE, Ellis SG, Guyton RA, Hollenberg SM, Khot UN, Lange RA, 
Mauri L, Mehran R, Moussa ID, Mukherjee D, Nallamothu BK, Ting HH. 
2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention: 
executive summary: a report of the American College of Cardiology 
Foundation/American Heart Association Task Force on Practice Guidelines 
and the Society for Cardiovascular Angiography and Interventions. 
Circulation 2011; 124: 2574–2609
R13-4129
Suh J-W, Mehran R, Claessen BE, et al. Impact of In-Hospital Major Bleeding 
on Late Clinical Outcomes After Primary Percutaneous Coronary Intervention 
in Acute Myocardial Infarction. The HORIZONS-AMI (Harmonizing 
Outcomes With Revascularization and Stents in Acute Myocardial Infarction) 
Trial. J Am Coll Cardiol 2011;58: 1750–6
R13-4130
Chhatriwalla AK, Amin AP, Kennedy KF, et al. Association Between 
Bleeding Events and In-hospital Mortality After Percutaneous Coronary 
Intervention. JAMA 2013; 309: 1022-1029
R13-4132
Wang TY, Robinson LA, BS, Ou F-S, et al. Discharge antithrombotic 
strategies among patients with acute coronary syndrome previously on 
warfarin anticoagulation: Physician practice in the CRUSADE registry. Am 
Heart J 2008;155: 361-368
R13-4133
Nikolsky E, Mehran R, Dangas GD, et al. Outcomes of Patients Treated With 
Triple Antithrombotic Therapy After Primary Percutaneous Coronary 
Intervention for ST-Elevation Myocardial Infarction (from the Harmonizing 
Outcomes With Revascularization and Stents in Acute Myocardial Infarction 
[HORIZONS-AMI] Trial). Am J Cardiol 2012;109: 831– 838
R13-4134
Andrade JG, Deyell MW, Khoo C, et al. Risk of Bleeding on Triple 
Antithrombotic Therapy After Percutaneous Coronary Intervention Stenting 
A Systematic Review and Meta-analysis. Can J Cardiol 2013; 29: 204-212
R13-4135
Lamberts M, Olesen JB, Ruwald MH,et al. Bleeding After Initiation of 
Multiple Antithrombotic Drugs, Including Triple Therapy, in Atrial 
Fibrillation Patients Following Myocardial Infarction and Coronary 
Intervention. A Nationwide Cohort Study. Circulation. 2012;126:1185-1193


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 95 of 150
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.
R13-4136
Lamberts M, Gislason GH, Olesen JB, et al. Oral Anticoagulation and 
Antiplatelets in Atrial Fibrillation Patients After Myocardial Infarction and 
Coronary Intervention. J Am Coll Cardiol 2013; 62: 981–989
R13-4138
O’Gara PT, Kushner FG, Ascheim DD, Casey DE Jr, Chung MK, de Lemos 
JA, Ettinger SM, Fang JC, Fesmire FM, Franklin BA, Granger CB, Krumholz 
HM, Linderbaum JA, Morrow DA, Newby LK, Ornato JP, Ou N, Radford MJ, 
Tamis-Holland JE, Tommaso CL, Tracy CM, Woo YJ, Zhao DX. 2013 
ACCF/AHA guideline for the management of ST-elevation myocardial 
infarction: executive summary: a report of the American College of 
Cardiology Foundation/American Heart Association Task Force on Practice 
Guidelines. J Am Coll Cardiol 2013; 61: 485–510
R13-4178
Slutsky AS, Lavery JV. Data Safety and Monitoring Boards. N Engl J Med 
2004, 350: 1143-1147
R13-4872
Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD; the 
Writing Group on behalf of the Joint ESC/ACCF/AHA/WHF Task Force for 
the Universal Definition of Myocardial Infarction. Third universal definition 
of myocardial infarction. Circulation 2012; 126: 2020–2035
R13-4874
Hicks KA, Hung HMJ, Mahaffey KW, Mehran R, Nissen SE, Stockbridge 
NL, Targum SL, Temple R. Standardized Definitions for Cardiovascular and 
Stroke End point events in clinical trials (draft definitions for testing 
November 9, 2012)
R13-5082
Giugliano RP, et al, ENGAGE AF-TIMI 48 Investigators Edoxaban versus 
warfarin in patients with atrial fibrillation. N Engl J Med, (2013);369:2093-
104
R13-5262
Effient PI (Effient® is a registered trademark of Eli Lilly and Company). 
Initial U.S. Approval: 2009. Revised: 11/2013
R14-0530 
European Medicines Agency (EMA): Guideline on clinical investigation of 
medicinal products for prevention of stroke and systemic embolic events in 
patients with non-valvular atrial fibrillation. EMA/CHMP/623942/2013
R14-1287
Coronary Revascularization Writing Group, Technical Panel, Appropriate Use 
Criteria Task Force, ACCF/SCAI/STS/AATS/AHA/ASNC/HFSA/SCCT 2012 
Appropriate Use Criteria for Coronary Revascularization Focused Update. J 
Am Coll Cardiol 2012. 59(9) 857–81
R15-0010 
Hicks KA, Tcheng JE, Bozkurt B, Chaitman BR, Cutlip DE, Farb A, Fonarow
GC, Jacobs JP, Jaff MR, Lichtman JH, Limacher MC, Mahaffey KW, Mehran
R, Nissen SE, Smith EE, Targum SL. 2014 ACC/AHA Key data elements and
definitions for cardiovascular endpoint events in clinical trials: a report of the
American College of Cardiology/American Heart Association Task Force on


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 96 of 150
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.
Clinical Data Standards (Writing Committee to Develop Cardiovascular
Endpoints Data Standards). Circulation. 2015;132:302-361
R97-0643
Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. 
Biometrika 1983. 70(3):659-663
R97-2418
O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. 
Biometrics 1979. 35:549-556
9.2
UNPUBLISHED REFERENCES
U98-3208
. Dabigatran 
investigator’s brochure (current version – see ISF)
U06-1704
. Pharmacokinetics, pharmacodynamics, 
safety and tolerability of 150mg dabigatran etexilate p.o. in patients with 
different degrees of renal impairment in comparison to subjects with normal 
renal function in a monocentric, open, parallel-group trial (1160.23). 09 
November 2006
U09-3249-02
. Clinical trial report RE-LY 
(1160.26). 05 January 2011
U11-1642-01
 Amendment to 
Pradaxa ® CCDS after approval of dabigatran etexilate for SPAF in US and 
EU Amendment to Pradaxa ® CCDS concerning the use of fibrinolytic agents 
for acute ischemic stroke and the simultaneous use of ticagrelor (plus ASA), 
selective serotonin re-uptake inhibitors or dronedarone (Multaq®). 23 
September 2011
U11-1855-01 
 Clinical Overview 
Statement Pradaxa Hard Capsules 75mg, 110mg, 150mg Prescriber Guide 
Reference Document – Derivation of limits in coagulation tests as given in 
Pradaxa prescriber guides for SPAF and VTEp. 15 July 2011.
U12-1072-01 
 COS CCDS Update  elderly and bleeding. Additional 
wording for Pradaxa® Company Core Data Sheet (CCDS) regarding the risk 
of bleeding in the elderly and the concomitant use of serotonin norepinephrine 
reuptake inhibitors (SNRI). 24 February 2012.
U12-2002 
. Investigation of 
pharmacodynamic effects of dabigatran and ticagrelor (Part 1 and 2, open, 
non-randomised, 2 parallel groups) and assessment of ticagrelor interaction 
potential with dabigatran (Part 3, open, randomised, two-period cross-over) in 
healthy male subjects. 1160.141. 02. November 2012.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 97 of 150
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.
U13-2049
: Investigation of drug-drug 
interaction of dabigatran and ticagrelor under steady state conditions in 
healthy male subjects. (1160.142).


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 98 of 150
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.
10.
APPENDICES
APPENDIX 10.1
STUDY DRUG START AND BRIDGING RULES
10.1.1
When to start dabigatran etexilate following treatment by other anticoagulants
Heparins
UFH or LMWH/injectable anticoagulant (if given) should be stopped prior to the first dose of 
dabigatran etexilate. Dabigatran etexilate should be initiated with the following suggested 
time windows:

UFH/other continuous i.v. anticoagulants: initiate dabigatran etexilate at the time the 
UFH/other continuous i.v. anticoagulant is stopped 

LMWH/other s.c. injectable anticoagulants: initiate dabigatran etexilate 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
Patients already on VKA, should start dabigatran etexilate once the INR is <2.0. If the INR is 
≥2.0, study medication can be dispensed but the patient will be instructed not to start it until 
notified. Follow-up INR testing will be performed in 1-2 day intervals until INR falls below 
2.0, at which time the patient will be instructed to start taking the study medication.
Novel Oral Antiocagulants
Patients taking apixaban, edoxaban,rivaroxaban or dabigatran etexilate can be initiated at the 
time the next dose of the novel oral anticoagulant would have been due. As there is no 
clinical experience for switching from other novel oral anticoagulants to dabigatran etexilate, 
the decision must be taken based on clinical considerations and recommendations [P13-
06400].
10.1.2
When to start warfarin following treatment by other anticoagulants or VKAs 
Parenteral anticoagulants
Warfarin can be initiated at the same time as the patient is taking parenteral anticoagulants 
(for recommendations on how to dose warfarin see the nomogram provided in the ISF). 
Parenteral bridging therapy (e.g. UFH, LMWH) should be stopped when target INR is 
achieved.
Vitamin K antagonists
For recommendations on how to switch a patient from another VKA to warfarin and for 
maintenance of warfarin therapy see the nomogram provided in the ISF.
Novel Oral Anticoagulants
An overlapping therapy with both novel oral anticoagulant and warfarin should not be 
performed for patients randomised to warfarin. It is recommended to use bridging therapy 
with a parenteral anticoagulant instead while initiating warfarin. 


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 99 of 150
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.
The novel oral anticoagulant should be discontinued and the parenteral anticoagulant should 
be started at the time of the next scheduled dose of the novel oral anticoagulant (in line with
the respective novel oral anticoagulant label). 
10.1.3
Bridging Therapy (e.g. for temporary interruptions of study drug due to 
interventions)
The use of bridging therapy depends on the thomboembolic risk status of the patient and the 
length of the planned interruption. It is at the discretion of the investigator whether to use a 
parenteral anticoagulant for bridging purposes or not. 
Due to the short off- and onset of action, the majority of interventions in patients receiving 
dabigatran etexilate may not require the use of bridging therapy. If bridging therapy is 
deemed necessary for patients in the dabigatran etexilate arm, it is recommended to wait 12 
hours after the last dose before switching from dabigatran etexilate to a parenteral 
anticoagulant.
Patients in the warfarin arm should be treated at the discretion of the investigator. In general, 
a parenteral anticoagulant may be considered when the INR is below the target INR. For 
recommendations how to switch back to study drug (dabigatran etexilate or warfarin) see 
Sections 10.1.1 and 10.1.2.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 100 of 150
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.
APPENDIX 10.2
SWITCHING FROM STUDY TREATMENT AT EOT
At the end of the study or if a patient discontinues early, continued anticoagulant therapy will 
usually be required because the patients has NVAF. 
Investigators should plan for each subject’s transition to standard of care taking into 
consideration the individual patient’s risk profile and previous experience with non-study 
VKA. 
As patients have different risk profiles, optimal approaches might differ between patients and 
not all possible approaches are described below. 
OPTION 1:
STARTING WARFARIN PRIOR TO DABIGATRAN ETEXILATE 
DISCONTINUATION
Start warfarin at the EOT visit and continue on dabigatran etexilate for 2-3 days after the 
EOT visit1. In patients with CrCl >50mL/min who discontinue dabigatran but still require 
anticoagulation, dabigatran should be continued for three more days. For patients with 
moderate renal dysfunction (CrCl ≥30 to <50mL/min), as measured in the visit before EOT, 
dabigatran can be stopped after two days of concomitant VKA.
Many physicians will want to see warfarin naïve patients before starting warfarin. There is no 
special need to measure the CrCl before starting warfarin. If the INR is checked on the day of 
the EOT visit, Investigators should recognise that the presence of dabigatran could elevate the 
INR. Because dabigatran etexilate can increase the INR, the INR will better reflect warfarin’s 
effect only after dabigatran etexilate has been stopped for at least 24 hours.
OPTION 2:
BRIDGING WITH LMWH
Patient comes in on the day of the EOT visit, dabigatran etexilate is stopped and non-study 
VKA is started. LMWH can be used to bridge the patient until the INR becomes therapeutic. 
The LMWH can be started 12 hours after the last dose of dabigatran etexilate. This approach 
is an alternative to Option 1 described above. 
The decision to use bridging therapy is at the discretion of the investigator (see Appendix 
10.1).
Please consult local guidelines for the starting dose of the respective VKA. 
Although there are large differences in the plasma half-lives of the various VKAs in clinical 
use, apart from the selection of the starting dose, the half-life of the VKA will have no impact 
on the transition from dabigatran etexilate. 
                                                          
1 The date of final intake of dabigatran etexilate must be documented in the eCRF.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 101 of 150
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.
APPENDIX 10.3
DEFINITION OF DISABLING STROKE BY MODIFIED 
RANKIN SCALE
Grade 0: 
no symptoms at all
Grade 1: 
no significant disability despite symptoms;
able to carry out all usual duties and activities
Grade 2: 
slight disability:
unable to carry out all previous activities but able to look after own affairs 
without assistance
Grade 3: 
moderate disability:
requiring some help but able to walk without assistance
Grade 4: 
moderate severe disability:
unable to walk without assistance and unable to attend to own bodily needs 
without assistance
Grade 5: 
severe disability: 
bedridden, incontinent and requiring constant nursing care and attention.
Grade 6: 
dead


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 102 of 150
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.
APPENDIX 10.4
HANDLING OF OUTCOME EVENTS (BLEEDS AND 
MORTALITY / MORBIDITY EVENTS), SERIOUS ADVERSE 
EVENTS AND ADVERSE EVENTS
1A narrative will only be requested if needed
Figure 10.4: 1
Hierarchical algorithm for reporting OEs, SAEs and AE.
Is the AE an Outcome Event?
Yes
Outcome Event
-
Bleed
-
Death
-
MI
-
TIA
-
Stroke
-
Systemic embolism
-
Stent thrombosis
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


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 103 of 150
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.
11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
16 September 2015
EudraCT number
2013-003201-26
BI Trial number
1160.186
BI Investigational Product(s)
Pradaxa®, dabigatran etexilate
Title of protocol
A prospective Randomised, open label, blinded 
endpoint (PROBE) study to Evaluate DUAL
antithrombotic therapy with dabigatran etexilate 
(110mg and 150mg b.i.d.) plus clopidogrel or 
ticagrelor vs. triple therapy strategy with warfarin 
(INR 2.0 – 3.0) plus clopidogrel or ticagrelor and 
aspirin in patients with non valvular atrial 
fibrillation (NVAF) that have undergone a 
percutaneous coronary intervention (PCI) with 
stenting
(RE-DUAL PCI)
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
Cover Page Fax number
Description of change
Fax:
  
Has been changed to
Fax:
  


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 104 of 150
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.
Number of global amendment
1
Rationale for change
To reflect update of fax number
Section to be changed
Flow Chart
Description of change
Visit 1 visit window updated from:
-3 to 0 days
To 
-5 to 0 days
Rationale for change
To facilitate patient recruitment and to operationally 
simplify where possible.
Section to be changed
Flow Chart
Description of change
Physical examination
Footnote added at Visit 1:
Includes height at Visit 1
Subsequent footnotes have been re-numbered.
Rationale for change
To add clarity that height is part of the physical 
examination at Visit 1
Section to be changed
Flow Chart
Description of change
Vital Signs (PR/BP)
Footnote added at Visit 2:
If Visit 1 and Visit 2 occur within 24 hours then 
vital signs do not need to be repeated at Visit 2
Subsequent footnotes have been re-numbered.
Rationale for change
To clarify that no additional vital sign measurement 
is needed when Visit 1 and Visit 2 both occur within 
24 hours
Section to be changed
Flow Chart
Description of change
INR/Warfarin dose adjustment13


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 105 of 150
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.
Number of global amendment
1
every 2 - 4 weeks14
Has been changed to:
every 2 weeks – monthly14
Rationale for change
To be consistent with section 4 of the protocol.
Section to be changed
Flow Chart
Description of change
Footnote 12 (previously footnote 10)
Will be performed locally, only those parameters 
required to verify eligibility are required at 
screening.
Has been changed to:
Will be performed locally, only those parameters 
required to verify eligibility are required at 
screening, standard of care local results taken 
within 7 days prior to screening can be used to 
verify eligibility.
Rationale for change
To minimise blood samples that need to be taken
from patient and the use of standard of care local 
laboratory results taken within 7 days prior to 
screening is considered acceptable. 
Section to be changed
Flow Chart
Description of change
Footnote 17 (previously footnote 15)
Study drug should be administered between 6 hours 
after sheath removal and up to 72 hours post PCI, 
with haemostasis assured.
Has been changed to:
Study drug should be administered between 6 hours 
after sheath removal and preferably within 72 
hours post PCI (refer to section 6.2.2), with 
haemostasis assured, however up to 120 hours post 
PCI is allowed.
Rationale for change
To facilitate patient recruitment and to operationally 
simplify where possible.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 106 of 150
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.
Number of global amendment
1
Section to be changed
Flow Chart
Description of change
Drug Accountability
Footnote added at Visit 3:
Patients randomised to Warfarin only
Rationale for change
Clarification. At Visit 2 patients randomised to 
Dabigatran receive a 3 month kit, therefore drug 
accountability does not need to be performed at 
Visit 3 for patients randomised to dabigatran 
etexilate.
Section to be changed
1.1 Medical Background
Description of change
The bold text below has been added:
A recently published small randomised controlled 
study (WOEST) [R13-4127], observed that bleeding 
and ischaemic event rates were lower in patients on 
DAT (warfarin + clopidogrel) compared to TAT 
(warfarin + clopidogrel + ASA). From previous 
experience it is also known that continued 
anticoagulation with warfarin during PCI procedures 
is associated with an increased risk of bleeding 
[P07-09550]. The WOEST study enrolled 573 
patients randomly assigned in a 1:1 ratio to 
receive oral anticoagulation plus clopidogrel 
alone (DAT) or plus clopidogrel and aspirin 
(TAT). All patients were pretreated with a 
maintenance dose of 75mg clopidogrel per day 
for at least 5 days, a loading dose of 300mg 
clopidogrel at least 24 hours before PCI, or a 
loading dose of 600mg clopidogrel at least 4 
hours before PCI. A 320mg loading dose of ASA 
was also given to patients who had not been 
taking ASA before the study. Study treatment 
was started promptly after randomisation.  All 
patients received 75mg clopidogrel daily, and 
those in the TAT group were also given 80–100 
mg ASA daily.  
Rationale for change
To provide details in relation to the pre-PCI 
antithrombotic regimens used in the WOEST study.
Section to be changed
2.3 Benefit – Risk Assessment


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 107 of 150
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.
Number of global amendment
1
Description of change
Excessive anticoagulation may require interruption 
of dabigatran treatment. There is currently no 
specific antidote to dabigatran available on the 
market. Guidance on the management of patients 
who experience a haemorrhagic complication is 
provided in Section 4.2.1.
Has been changed to:
Guidance on the management of patients who 
experience a haemorrhagic complication is provided 
in Section 4.2.1. 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.
Rationale for change
To clarify terminology and allow collection of
information regarding use of the reversal agent if 
administered to patient.
Section to be changed
2.3 Benefit – Risk Assessment
Description of change
The following text has been deleted
Although rare, a potential for drug-induced liver 
injury is under constant surveillance by sponsors 
and regulators. Therefore, this study requires timely 
detection, evaluation and follow-up of laboratory 
alterations of selected liver laboratory parameters to 
ensure patients´ safety.
Rationale for change
See rationale for change in section 5.2.2.2
Definitions of AEs
Section to be changed
3.1
Overall Trial Design And Plan
Description of change
Patients will be consented and screened after 
undergoing a successful PCI. Randomisation will 
occur on local laboratory results taken at the 
screening visit; however central laboratory samples 
must be taken at randomisation prior to first intake 
of study drug. Randomisation can occur up to 72 


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 108 of 150
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.
Number of global amendment
1
hours post PCI. Study drug should be administered 
between 6 hours after sheath removal and up to 72 
hours post PCI, with haemostasis assured.
Has been changed to:
Patients will be consented and screened after 
undergoing a successful PCI. Randomisation will 
occur on local laboratory results taken at the 
screening visit or on standard of care local 
laboratory results taken within 7 days prior to 
screening; central laboratory samples must be taken 
at randomisation prior to first intake of study drug.
Randomisation can occur up to 120 hours post PCI, 
however within 72 hours is preferable. Study drug 
should be administered between 6 hours after sheath 
removal and preferably within 72 hours post PCI, 
with haemostasis assured, however up to 120 hours
post PCI is allowed.
Rationale for change
To minimise blood samples that need to be taken
from patient and the use of standard of care local 
laboratory results taken within 7 days prior to 
screening is considered acceptable. 
To facilitate patient recruitment and to operationally 
simplify where possible. 
Section to be changed
3.1
Overall Trial Design And Plan
Description of change
In addition to their randomised treatment:

All patients will receive either clopidogrel 
(75mg q.d.) or ticagrelor (90mg b.i.d), according 
to the local label, for at least 12 months after 
randomisation. Discontinuation of clopidogrel or 
ticagrelor after 12 months of treatment is at the 
discretion of the Investigator
Has been changed to:
In addition to their randomised treatment:

All patients will receive either clopidogrel 
(75mg q.d.) or ticagrelor (90mg b.i.d), according 
to the local label, for at least 12 months after 
randomisation. Discontinuation of clopidogrel or 


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 109 of 150
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.
Number of global amendment
1
ticagrelor or switching to ASA (≤ 100mg q.d.)
after 12 months of treatment is at the discretion 
of the Investigator
Figure 3.1: 1. also updated to reflect this change and 
increase of time window for randomisation to 120 
hours.
Rationale for change
To allow the switch of antiplatelet therapy 
(clopidogrel or ticagrelor to ASA) after month 12 as 
per Investigator discretion.
Section to be changed
3.1
Overall Trial Design And Plan
Description of change
The screening period will consist of one visit (Visit 
1). The patients will be randomised at Visit 2. 
Has been changed to:
Prior to consent the patient’s antithrombotic 
treatment (i.e. ASA use during PCI, use of 
clopidogrel loading dose) should be managed as 
per local standard of care. The screening period 
will consist of one visit (Visit 1). The patients will 
be randomised at Visit 2. 
Rationale for change
To clarify that before consent the patient should be 
treated per local standard of care.
Section to be changed
3.3.2 Inclusion Criteria
Description of change
Inclusion 2 
Patients with NVAF that have been receiving oral 
anticoagulant treatment (either with warfarin, 
another VKA or other novel oral anticoagulant), or 
were treatment naïve prior to PCI. AF may be 
paroxysmal, persistent or permanent, but must not 
be secondary to a reversible disorder such as MI, 
pulmonary embolism, recent surgery, pericarditis or 
thyrotoxicosis
Has been changed to:
Patients with NVAF that have been receiving oral 
anticoagulant treatment (either with warfarin, 
another VKA or other novel oral anticoagulant), or 
were treatment naïve prior to PCI. AF may be 
paroxysmal, persistent or permanent, and not


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 110 of 150
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.
Number of global amendment
1
secondary to a reversible disorder such as MI, 
pulmonary embolism, recent surgery, pericarditis or 
thyrotoxicosis, unless long term oral 
anticoagulation is planned
Rationale for change
To allow inclusion of patients who are a candidate 
for long term oral anticoagulation.
Section to be changed
3.3.3 Exclusion Criteria 
Description of change
Footnote added to exclusion 13:
Active liver disease as indicated by at least one of 
the following:

Prior and persistent alanine aminotransferase 
(ALT) or Aspartate transaminase (AST) or
alkaline phosphatase (AP) >3 upper limit of 
normal (ULN)1

Known active hepatitis C

Known active hepatitis B 

Known active hepatitis A
1 Clinical judgement of whether ALT/AST 
enzyme elevation is due to active liver disease or 
due to ACS, should be made by the Investigator 
following evaluation of the clinical characteristics 
of the patient and the laboratory findings.
Rationale for change
To provide clarification to exclusion criterion 14 in 
relation to active liver disease.
Section to be changed
3.3.3 Exclusion Criteria
Description of change
Exclusion 15: 
Need for continued treatment with systemic 
ketoconazole, itraconazole, posaconazole, 
cyclosporine, tacrolimus, dronedarone, rifampicin, 
phenytoin, carbamazepine, St. John’s Wort or any 
cytotoxic/myelosuppresive therapy.
Has been changed to:
Need for continued treatment with systemic 
ketoconazole, itraconazole, posaconazole, 
cyclosporine, tacrolimus, dronedarone, rifampicin, 
phenytoin, carbamazepine, St. John’s Wort.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 111 of 150
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.
Number of global amendment
1
Rationale for change
Cytotoxic/myelosuppresive  therapies are not 
contraindicated for patients receiving dabigatran 
etexilate or warfarin. Therefore patients on 
cytotoxic/myelosuppresive therapy do not need to 
be excluded. 
Section to be changed
4.1.1
Identity of BI investigational product and 
comparator products
Description of change
All patients will also take clopidogrel (75mg q.d.) or 
ticagrelor (90mg b.i.d.) according to the local label 
for at least 12 months after randomisation (in 
addition to either dabigatran etexilate or warfarin). 
Discontinuation of clopidogrel or ticagrelor after 12 
months of treatment is at the discretion of the 
Investigator.
Has been changed to:
All patients will also take clopidogrel (75mg q.d.) or 
ticagrelor (90mg b.i.d.) according to the local label 
for at least 12 months after randomisation (in 
addition to either dabigatran etexilate or warfarin). 
After 12 months of treatment the clopidogrel or 
ticagrelor can be discontinued or switched to 
ASA (≤ 100mg q.d.) at the discretion of the 
Investigator.
Rationale for change
To allow the stop or switch of antiplatelet therapy 
(clopidogrel or ticagrelor; switch to ASA) after 
month 12 as per Investigator discretion.
Section to be changed
4.1.4
Drug assignment and administration of doses 
for each patient
Description of change
Each patient will be randomised at Visit 2 to receive 
either dabigatran etexilate (110mg or 150mg b.i.d.) 
or warfarin. The first dose of trial medication will be 
taken, between 6 hours after sheath removal and up 
to 72 hours post PCI, with haemostasis assured.
Has been changed to:
Each patient will be randomised at Visit 2 to receive 
either dabigatran etexilate (110mg or 150mg b.i.d.) 
or warfarin. The first dose of trial medication will be 
taken, between 6 hours after sheath removal and 


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 112 of 150
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.
Number of global amendment
1
preferably within 72 hours post PCI, with 
haemostasis assured, however up to 120 hours post 
PCI is allowed.
Rationale for change
To facilitate patient recruitment and to operationally 
simplify where possible.
Section to be changed
4.1.4
Drug assignment and administration of doses 
for each patient
Description of change
The following text has been changed under “Patient 
randomised to receive dabigatran etexilate”:
It is permitted for patients to receive bridging 
therapy with a parenteral anticoagulant according to 
local practice before switching to dabigatran 
etexilate. Dabigatran etexilate should be given 0-2 
hours prior to the time that the next dose of 
parenteral anticoagulant would be due, or at the time 
of discontinuation in case of continuous treatment 
(e.g. intravenous (i.v.) unfractionated heparin 
(UFH)). See Appendix 10.2 for guidance how to 
switch from a parenteral anticoagulant to dabigatran 
etexilate.
Has been changed to:
It is permitted for patients to receive bridging 
therapy with a parenteral anticoagulant according to 
local practice before switching to dabigatran 
etexilate. Dabigatran etexilate should be given 0-2 
hours prior to the time that the next dose of 
parenteral anticoagulant would be due, or at the time 
of discontinuation in case of continuous treatment 
(e.g. intravenous (i.v.) unfractionated heparin 
(UFH)). See Appendix 10.1 for guidance how to 
switch from an anticoagulant to dabigatran etexilate.
Rationale for change
Guidance updated to cover switch from oral 
anticoagulant aswell as parenteral anticoagulant. 
Appendices re-numbered due to removal of clinical 
evaluation of liver injury – see rationale for change 
to section 5.2.2.2 Definitions of AEs.
Section to be changed
4.1.6
Packaging, labelling, and re-supply
Description of change
Patients on warfarin will receive the required 
combination of 1mg, 3mg and 5mg tablets in bottles 


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 113 of 150
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.
Number of global amendment
1
according to their actual needs as defined by the 
measured INR value. Each warfarin bottle will 
contain 66 tablets.
Has been changed to:
Patients on warfarin will receive the required 
combination of 1mg, 3mg and 5mg tablets in bottles 
according to their actual needs as defined by the 
measured INR value. Each warfarin bottle will 
contain 66 tablets. Warfarin bottles should be 
checked at each visit to ensure the patient has 
sufficient supplies and that expiry dates will not 
be compromised prior to the next clinic visit.
Rationale for change
To facilitate medication compliance checks and 
ensure appropriate trial supplies available to patient
Section to be changed
4.2 Concomitant Therapy, Restrictions, and Rescue 
Treatment
Description of change
Details of concomitant medication administered to 
the patient during the course of the study should be 
recorded in the eCRF. This includes all concomitant 
therapies from time of patient informed consent 
until the patient completes follow-up. In addition, at 
the Screening Visit, information regarding specific 
drugs (e.g. antithrombotic medication, medications 
with a potential drug-drug interaction with 
dabigatran etexilate (P-gp inhibitors and inducers)), 
administered in the 30 days prior to Informed 
Consent will be recorded.
Has been changed to:
Comprehensive details of concomitant 
medication of special interest (e.g. antiplatelet 
medication, parenteral anticoagulant, 
thrombolytic agent, GPIIb/IIIa antagonist, VKA, 
therapies for bleeding management, novel direct 
oral anticoagulant) administered to the patient 
from 30 days prior to informed consent until the 
patient completes follow-up should be recorded 
in the eCRF. Abbreviated information will be 
collected for any other concomitant therapy.
Rationale for change
Clarification in relation to recording of concomitant 
therapy.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 114 of 150
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.
Number of global amendment
1
Section to be changed
4.2.1.1 Major Bleeds
Description of change
There is no specific antidote currently available on 
the market to counteract the antithrombotic activity 
of dabigatran etexilate.
Has been changed to:
The recommendations given below are derived 
from guidelines to manage bleeding with 
dabigatran etexilate. See section 4.2.1.7 
Overdose, for more information regarding the 
specific reversal agent for dabigatran.
Rationale for change
To clarify that the recommendations apply to the 
management of bleeding with dabigatran etexilate 
treatment and to introduce the reversal agent for 
dabigatran. 
Section to be changed
4.2.1.3 Emergency and Elective Surgery
Description of change
The following text has been added:
See section 4.2.1.7- Overdose, for more 
information regarding the specific reversal agent 
for dabigatran.
Rationale for change
To allow collection of information regarding use of 
the reversal agent.
Section to be changed
4.2.1.6 Other Medical Intervention
Description of change
Percutaneous Coronary Intervention (PCI): 
…… 
Study medication can be reintroduced between 6 
hours after sheath removal and up to 72 hours post 
PCI with haemostasis assured.
Has been updated to say:
Percutaneous Coronary Intervention (PCI): 
…… 
Study medication can be reintroduced between 6 
hours after sheath removal with haemostasis 
assured, as considered appropriate by the 
Investigator.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 115 of 150
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.
Number of global amendment
1
Rationale for change
To allow Investigator’s medical discretion when to 
re-introduce study medication.
Section to be changed
4.2.1.7 Overdose
Description of change
The following text has been added:
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
4.2.2.1 Restrictions regarding concomitant treatment
Description of change
ASA >100mg per day, corticosteroids, or NSAIDs 
may be used if clinically indicated according to 
current treatment guidelines but it is strongly 
recommended to avoid these if possible. The 
patients should be advised to not use additional 
ASA-containing over-the-counter medications on a 
regular basis.  It should, however, be noted that the 
use of any of these agents with warfarin or 
dabigatran etexilate is likely to increase the risk of 
bleeding. 
Has been changed to:
Corticosteroids or NSAIDs may be used if clinically 
indicated according to current treatment guidelines 
but it is strongly recommended to avoid these if 
possible. It should be noted that the use of any of 
these agents with warfarin or dabigatran etexilate is 
likely to increase the risk of bleeding. 
Additional text added to section –


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 116 of 150
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.
Number of global amendment
1
The following treatments should not be taken during 
the active treatment phase of the trial:
1. ………..
6.  ASA - except where specified in the protocol 
for patients randomised to the warfarin arm or 
in both treatment arms after 12 months of 
treatment if clopidogrel or ticagrelor is switched
to ASA (≤ 100mg q.d.) at Investigator discretion.
The patients should be advised to not use 
additional ASA-containing over-the-counter 
medications.
Rationale for change
Clarification of the restrictions of ASA use in order 
to comply with the clinical trial objectives.
Section to be changed
5.1.2.1 Death
5.1.2.3 Stroke
5.1.2.5 Stent Thrombosis
5.3.1 Other endpoints
Description of change
Inclusion of reference R15-0010
Rationale for change
Updated publication released. However, the 
endpoint definitions within these sections of the 
protocol are not affected.
Section to be changed
5.1.2.2 Myocardial infarction
Description of change
The following definitions have been added:
Criteria for fatal MI
Death due to Acute MI refers to a death by any 
cardiovascular mechanism (e.g., arrhythmia, 
sudden death, heart failure, stroke, pulmonary 
embolus, peripheral arterial disease) ≤ 30 days 
after a MI related to the immediate consequences 
of the MI, such as progressive heart failure or 
recalcitrant arrhythmia. Acute MI (for criteria 
see above) should be verified to the extent 
possible by the diagnostic criteria outlined for 
acute MI or by autopsy findings showing recent 
MI or recent coronary thrombosis. Death 
resulting from a procedure to treat a MI (eg PCI, 
CABG), or to treat a complication resulting from 
MI, should also be considered death due to acute 


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 117 of 150
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.
Number of global amendment
1
MI (R15-0010).
Silent MI
Silent myocardial infarction will be 
retrospectively diagnosed by the appearance of 
significant new Q-waves on an ECG performed 
after randomisation. In such cases, the date of 
the event is recorded as the midpoint between the 
ECG with new Q-waves and the prior normal 
ECG.
Rationale for change
Sub classifications of MI that were not previously 
included.
Section to be changed
5.1.2.3 Stroke
Description of change
The following definition has been added:
Fatal stroke
Fatal stroke is defined as death from any cause 
within 30 days of stroke.
Rationale for change
Additional definition not previously included in 
error.
Section to be changed
5.1.2.3 Stroke
Description of change
Severity of recurrent stroke
Severity of recurrent stroke will be assessed by 
modified Rankin Scale (mRS) at the onset of stroke 
and at 3 months after recurrent stroke, if this time 
frame falls anytime within the study participation. 
(see Appendix 10.4 for definition). 
Has been changed to:
Severity of recurrent stroke will be assessed by 
modified Rankin Scale (mRS) at the onset of stroke 
and at 3 months after recurrent stroke, if this time 
frame falls anytime within the study participation. 
Disabling stroke is defined as a stroke with mRS 
≥4 at 3 months (see Appendix 10.3 for definition of 
mRS). 
Rationale for change
Additional definition not previously included in 
error. Appendices re-numbered due to removal of 
clinical evaluation of liver injury - for rationale refer 


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 118 of 150
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.
Number of global amendment
1
to update made to section 5.2.2.2 Definitions of 
AEs.
Section to be changed
5.2.2.2 Definitions of AEs
Description of change
Protocol-specified Adverse Events of Special 
Interest (AESI)
The following are considered as Protocol-specified 
Adverse Events of Special Interest:

Hepatic injury defined by an elevation of AST 
and/or ALT >3 fold ULN combined with an 
elevation of total bilirubin >2 fold ULN 
measured in the same blood draw sample.
Patients showing these lab abnormalities need to be 
followed up according to Appendix 10.1 of this CTP
and the Drug Induced Liver Injury (DILI) checklist 
provided in the eCRF and the ISF.
Protocol-specified AESIs are to be reported by the 
Investigator to the Sponsor in an expedited manner 
(within 24 hours of awareness) similar to Serious 
Adverse Events, even if they do not meet any of the 
seriousness criteria. For details please see Section 
5.2.2.3.
Has been changed to:
Protocol-specified Adverse Events of Special 
Interest (AESI)
No AESIs are defined for this trial.
Rationale for change
DILI monitoring is no longer considered necessary 
for dabigatran etexilate at this advanced stage of 
development for the following reasons:
During the clinical development of the product, 
extensive DILI monitoring had been conducted. 
Extensive data available from clinical trials 
conducted so far in different indications with 
close to 30,000 patients exposed to dabigatran in 
clinical trials has not evidenced risk of 
hepatoxicity (U98-3208). In fact, data of liver 
enzymes from the pivotal trials during and post-


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 119 of 150
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.
Number of global amendment
1
treatment did not indicate that administration of 
dabigatran etexilate is associated with 
hepatotoxicity. Independent of the indication,
there does not appear to be any dose response 
effect in the frequency of occurrence of liver 
enzyme (ALT/AST) elevations with dabigatran 
etexilate . Also, a recently published systematic 
review and meta-analysis concluded that the 
NOACs (dabigatran etexilate, rivaroxaban, 
apixaban, darexaban, edoxaban) were not 
associated with an increased risk of DILI (P14-
02938).
Post-marketing experience from over 4 million 
patient-years over a period of more than 6 years 
has not evidenced signs of hepatotoxicity. The 
evaluation of BI cumulative data collected since 
market introduction has not evidenced any risk of 
severe liver injury/hepatotoxicity associated with 
the use of dabigatran etexilate.
Removal of DILI monitoring is not contradicting 
FDA requirements for assessing the potential for 
a drug to cause severe liver injury, which in 
general applies to premarketing clinical 
evaluation (FDA Guidance for Industry: “Drug-
Induced Liver Injury) and this assessment has 
already been extensively done for dabigatran.
Additionally, a DMC will be regularly 
monitoring and evaluating the safety of the 
patients included in the study and will be able to 
make recommendations based on the available 
data.
Section to be changed
5.2.2.3 Adverse event and serious adverse event 
reporting
Description of change
The Investigator must report the following events 
via fax immediately (within 24 hours or the next 
business day, whichever is shorter) to the sponsor: 
SAEs, AESIs and non-serious AEs relevant to the 
SAE or AESI.
Has been changed to:
The Investigator must report the following events 


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 120 of 150
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.
Number of global amendment
1
via fax immediately (within 24 hours or the next 
business day, whichever is shorter) to the sponsor: 
SAEs and non-serious AEs relevant to the SAE.
Rationale for change
Removal of AESI. For rationale refer to update 
made to section 5.2.2.2 Definitions of AEs.
Section to be changed
5.2.3 Assessment of safety laboratory parameters
Description of change
Blood samples will be taken at the screening visit 
for those parameters required to verify eligibility 
and will be analysed by a local laboratory
Has been changed to
Blood samples will be taken at the screening visit 
for those parameters required to verify eligibility 
(haemoglobin, platelets, ALT and / or AST, AP 
and creatinine (the latter to calculate CrCl
according to the Cockcroft-Gault formula)) and 
will be analysed by a local laboratory. If standard 
of carelaboratory blood results are available, 
taken within 7 days prior to screening, these can 
be used to verify eligibility.
Rationale for change
To provide clarification of laboratory parameters 
needed to verify eligibility and to minimise blood 
samples that need to be taken from patient. The use 
of standard of care local laboratory results taken 
within 7 days prior to screening is considered 
acceptable. 
Section to be changed
5.2.3 Assessment of safety laboratory parameters
Description of change
Pregnancy Testing
………Urine pregnancy tests will be provided by 
the central laboratory. 
Has been changed to:
Pregnancy Testing
…….. Urine pregnancy tests will be provided.
Rationale for change
It is not possible for the central laboratory to provide 
urine pregnancy testing kits for home testing in all 
countries therefore these tests will be sourced 
locally in all countries except the USA.
Section to be changed
5.2.3 Assessment of safety laboratory parameters


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 121 of 150
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.
Number of global amendment
1
Description of change
Renal Function Measurements
CrCl will be calculated using the Cockcroft-Gault 
formula, as follows:
For creatinine in Mol/L:
(140-age [years]) weight [kg] x 1.23 (0.85 if female) 
serum creatinine [Mol/L]
Has been changed to
Renal Function Measurements
CrCl will be calculated using the Cockcroft-Gault 
formula, as follows:
For creatinine in Mol/L:
(140-age [years]) weight [kg] x 1.23 (0.85 if female)
                serum creatinine [Mol/L]
Rationale for change
Correction to formatting
Section to be changed
5.2.5.1 Full Physical Examination
Description of change
5.2.5.1 Full Physical Examination
A complete physical examination will be performed 
by the Investigator according to the flowchart. 
Has been updated to:
5.2.5.1 Physical Examination
A cardiovascular focused physical examination 
will be performed by medical qualified personnel
according to the flowchart.
Rationale for change
To operationally simplify the study procedures and 
focus the physical examination to the relevant organ 
system.
Section to be changed
6.1 Visit Schedule
Description of change
The study will consist of three sequential periods, 
Screening/Baseline Period of up to 3 days, a 
Treatment Period of up to approximately 30 months
and a Follow up Period of four weeks.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 122 of 150
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.
Number of global amendment
1
Has been updated to:
The study will consist of three sequential periods, 
Screening/Baseline Period of up to 5 days, a 
Treatment Period of up to approximately 30 months
and a Follow up Period of four weeks.
Rationale for change
To facilitate patient recruitment and to operationally 
simplify where possible.
Section to be changed
6.2.2
Treatment period(s)
Description of change
Randomisation can occur immediately after 
successful screening and up to 72 hours post PCI. 
The first dose of trial medication will be taken
between 6 hours after sheath removal and up to 72 
hours post PCI (end of intervention), with 
haemostasis assured.
Has been changed to:
Randomisation can occur immediately after 
successful screening and up to 120 hours post PCI
however, randomisation within 72 hours is 
preferable. The first dose of trial medication will be 
taken between 6 hours after sheath removal and
preferably within 72 hours post PCI (end of 
intervention i.e. when the last catheter used for 
PCI is removed), with haemostasis assured,
however, randomisation up to 120 hours post 
PCI is allowed.
Rationale for change
To facilitate patient recruitment and to operationally 
simplify where possible.
Section to be changed
6.2.2 Treatment period(s)
Description of change
All patients who discontinue treatment 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 ECGs will be performed 
and the collection of AEs, OEs (including 
completion of the bleeding questionnaire) and use of 
concomitant medication will be made. 
Has been changed to:


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 123 of 150
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.
Number of global amendment
1
All patients who discontinue treatment 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 (as indicated in the Flow 
Chart) ECGs will be performed and the collection 
of AEs, OEs (including completion of the bleeding 
questionnaire) and use of concomitant medication 
will be made. 
Rationale for change
To provide guidance on the tests and assessments to 
be conducted for patients that discontinue study 
medication but are to be followed up to end of 
study.
Section to be changed
7.3.4
Interim analyses
Description of change
The DMC may choose to recommend capping the 
110mg DE-DAT arm at the interim analysis stage if 
DTE or MBE event rates are different in patients 
who are ≥80 years old.
Has been changed to:
The DMC may choose to recommend capping the 
110mg DE-DAT arm at the interim analysis stage if 
the DTE or MBE event rates were to differ 
significantly from the trial assumptions and/or 
the anticipated event rates.
Rationale for change
To reflect the responsibilities of the DMC and not 
limit their remit
Section to be changed
Section 9 References
Description of change
1) Reference P14-02938 added
2) References P13-12832, R11-2774, R13-4131, 
R13-4137, R13-4177, R13-5264 removed.
3) Reference  R05-0344  updated to:
Schulman S, Kearon C, Subcommittee on Control of 
Anticoagulation of the Scientific and Standardization 
Committee of the International Society on 
Thrombosis and Haemostasis, Definition of major 
bleeding in clinical investigations of antihemostatic 
medicinal products in non-surgical patients. J 


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 124 of 150
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.
Number of global amendment
1
Thromb Haemost 3, 692 - 694 (2005)
4) Reference R15-0010 added
Rationale for change
1) Addition of new reference as result of AESI / 
DILI removal
2) Removal of references included in error that are 
not referenced within the protocol
3) Correction 
4) Updated publication added
Section to be changed
Section 10 Appendices
Description of change
Appendix 10.1 Clinical Evaluation of Liver Injury 
has been removed and subsequent appendices have 
been re-numbered. 
Rationale for change
See rationale specified in section 5.2.2.2 Definitions 
of AEs
Section to be changed
Section 10.1.1 (Formerly Section 10.2.1)
Description of change
Section heading re named from:
When to start dabigatran etexilate following 
treatment by parenteral anticoagulants
to:
When to start dabigatran etexilate following 
treatment by other anticoagulants
And the following text has been added:
Vitamin K antagonists
Patients already on VKA, should start 
dabigatran etexilate once the INR is <2.0. If the 
INR is ≥2.0, study medication can be dispensed 
but the patient will be instructed not to start it 
until notified. Follow-up INR testing will be 
performed in 1-2 day intervals until INR falls 
below 2.0, at which time the patient will be 
instructed to start taking the study medication.
Novel Oral Antiocagulants
Patients taking apixaban, edoxaban or 


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 125 of 150
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.
Number of global amendment
1
rivaroxaban, dabigatran etexilate can be initiated 
at the time the next dose of the novel oral 
anticoagulant would have been due. As there is 
no clinical experience for switching from other 
novel oral anticoagulants to dabigatran etexilate, 
the decision must be taken based on clinical 
considerations and recommendations [P13-
06400].
Rationale for change
Guidance updated to cover switch from oral 
anticoagulant aswell as parenteral anticoagulant.
Section to be changed
Section 10.1.2 (Formerly Section 10.2.2)
Description of change
Section heading re named from 
When to start warfarin following treatment by
parenteral anticoagulants or VKAs
to:
When to start warfarin following treatment by other
anticoagulants or VKAs
And the following text has been added:
Novel Oral Anticoagulants
An overlapping therapy with both novel oral 
anticoagulant and warfarin should not be
performed for patients randomised to warfarin. 
It is recommended to use bridging therapy with a 
parenteral anticoagulant instead while initiating 
warfarin. 
The novel oral anticoagulant should be 
discontinued and the parenteral anticoagulant 
should be started at the time of the next 
scheduled dose of the novel oral anticoagulant (in 
line with the respective novel oral anticoagulant
label).
Rationale for change
Guidance updated to cover switch from novel oral 
anticoagulant aswell as parenteral anticoagulant.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 126 of 150
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.
Number of global amendment
2
Date of CTP revision
05 April 2016
EudraCT number
2013-003201-26
BI Trial number
1160.186
BI Investigational Product(s)
Pradaxa®, dabigatran etexilate
Title of protocol
A prospective Randomised, open label, blinded 
endpoint (PROBE) study to Evaluate DUAL 
antithrombotic therapy with dabigatran etexilate 
(110mg and 150mg b.i.d.) plus clopidogrel or 
ticagrelor vs. triple therapy strategy with warfarin 
(INR 2.0 – 3.0) plus clopidogrel or ticagrelor and 
aspirin in patients with non valvular atrial 
fibrillation (NVAF) that have undergone a 
percutaneous coronary intervention (PCI) with 
stenting
(RE-DUAL PCI)
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
Clinical Trial Protocol Synopsis Objectives
Description of change
The study aims to show non-inferiority of both 
doses of DE-DAT when compared to Warfarin-TAT 
in efficacy and safety. Efficacy will be determined 
by comparing a composite event rate of death, MI, 
stroke and systemic embolism (SE). Safety will be 
determined by comparing the rates of clinically 
relevant bleeding, assessed using the modified 
International Society of Thrombosis and 


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 127 of 150
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.
Number of global amendment
2
Haemostasis (ISTH) major classification.
Has been changed to:
The study aims to show non-inferiority of each dose
of DE-DAT when compared to Warfarin-TAT in 
terms of safety. Safety is determined by bleeding 
events, assessed using the modified International 
Society of Thrombosis and Haemostasis (ISTH) 
classification of Major Bleeding and Clinically 
Relevant Non-Major Bleeding Events 
(CRNMBE).
Rationale for change
The study has been progressing behind schedule due 
to many reasons (e.g. patients previously treated 
with NOACs not willing to be randomised to 
warfarin, patients with co-morbidities not qualifying 
for the study). Although, a recent protocol 
amendment 1 (dated 16-Sep-2015) included some 
measures to facilitate recruitment (e.g. expanding 
the time-window for study drug administration, 
simplifying laboratory requirements for selection of 
patients), these changes alone are not considered to 
be  sufficient to achieve the original required 
number of patients (8,520) in the planned timeline. 
Thus, the study design needed to be revised and will 
now focus on safety. It will be powered to test the 
non-inferiority of each of the dabigatran etexilate 
doses (110mg and 150 mg bid) in a dual 
antithrombotic regimen versus warfarin in a triple 
antithrombotic regimen in respect to bleeding events 
(time to first ISTH major bleeding or clinically 
relevant non-major bleeding event). Efficacy 
parameters (e.g. all death, myocardial infarction, 
stroke/systemic embolism), including the original 
co-primary endpoints (DTE), will now be evaluated 
as secondary endpoints. The adoption of a safety 
primary endpoint is similar to other contemporary 
clinical trials in the same setting.
Section to be changed
Clinical Trial Protocol Synopsis total entered and 
each treatment
Description of change
Total entered:
8520


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 128 of 150
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.
Number of global amendment
2
Has been changed to:
2502
Each treatment:
2840
Has been changed to:
834
Rationale for change
See rationale for first change, sample size 
calculations now based on revised study design 
focusing on safety. 
Section to be changed
Clinical Trial Protocol Synopsis Criteria for 
Efficacy
Description of change
The dual primary endpoints are a composite 
endpoint of efficacy and a safety endpoint: 
1. Time to death or first thrombotic event (all 
death, MI, stroke/SE) 
2. Time to first major bleed (ISTH major)
Has been changed to:
The primary endpoint for this trial is a safety 
endpoint, please see below. 
The secondary efficacy endpoints  (all time to first 
event) are:

A combined endpoint of thrombotic events 
or death (DTE: all death + MI + 
stroke/SE) and unplanned 
revascularisation by PCI/CABG

A combined endpoint of thrombotic events 
or death (DTE: all death + MI + 
stroke/SE)

Individual outcome events:
o
All death (Cardiovascular death, 
Non-cardiovascular death, 
Undetermined), 
o
MI
o
Stroke


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 129 of 150
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.
Number of global amendment
2
o
SE 
o
Stent Thrombosis

Composite endpoint of death + MI + 
stroke

Unplanned revascularisation by 
PCI/CABG
Rationale for change
Efficacy parameters (e.g. all death, myocardial 
infarction, stroke/systemic embolism), including the 
original co-primary composite endpoint (DTE), will 
now be evaluated as secondary endpoints.
A composite endpoint of thrombotic events or death 
(DTE: all death + MI + stroke/SE) and unplanned 
revascularisation by PCI/CABG has been included 
comparable to the composite efficacy secondary 
endpoint included in the WOEST study.
Section to be changed
Clinical Trial Protocol Synopsis Criteria for Safety
Description of change
See criteria for efficacy
Has been changed to:
The primary endpoint for this trial is time to first 
ISTH Major or Clinically Relevant Non-Major 
Bleeding Event.
Rationale for change
The study design has been revised to focus on 
safety. 
Section to be changed
Clinical Trial Protocol Synopsis Statistical methods
Description of change
The following text has been added:
To control the Type I error rate at a one-sided 
0.025 level, a hierarchical procedure for multiple 
testing will be used to test the safety 
hypotheses. Additional testing for safety and 
efficacy endpoints will also be included in this 
hierarchical procedure.
Rationale for change
To clarify that a hierarchical approach will replace 
the original Benjamini-Hochberg procedure as the 
Type I error rate control method.
Section to be changed
1.1
Medical Background
Description of change
The present recommendation of the European and 


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 130 of 150
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.
Number of global amendment
2
North American Consensus of using triple therapy 
for patients with recent MI and/or PCI and 
concurrent AF is established because of OAC being 
indicated for AF patients with stroke risk factors and 
DAT being indicated after ACS or PCI [P10-07397, 
P11-09369].
Has been changed to:
Recommendation of the European and North 
American Consensus of using triple therapy for 
patients with recent MI and/or PCI and concurrent 
AF is established because of OAC being indicated
for AF patients with stroke risk factors and DAT 
being indicated after ACS or PCI [P10-07397, P11-
09369].  The WOEST results have been reflected 
in some of the recent guidelines for NVAF 
patients undergoing PCI with stenting [P14-
05384, P14-12794, P16-02545] which recommend 
to consider the use of DAT in certain patients.
Rationale for change
Updated to include reference to recently issued
guidelines and publications
Section to be changed
2.2
Trial Objectives
Description of change
The study aims to show non-inferiority of both 
doses of DE-DAT when compared to Warfarin-TAT 
in efficacy and safety. Efficacy will be determined 
by comparing a composite event rate of death, MI, 
stroke and SE. Safety will be determined by 
comparing the rates of clinically relevant bleeding, 
assessed using the modified International Society of 
Thrombosis and Haemostasis (ISTH) major 
classification.
Has been changed to:
The study aims to show non-inferiority of each dose
of DE-DAT when compared to Warfarin-TAT in 
terms of safety. Safety will be determined by 
comparing the rates of bleeding events, assessed 
using the modified International Society of 
Thrombosis and Haemostasis (ISTH) classification 
of Major Bleeding and CRNMBE.
Rationale for change
See rationale for first change, objective aligned with 
new study design focusing on safety.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 131 of 150
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.
Number of global amendment
2
Section to be changed
2.3
Benefit - Risk Assessment
Description of change
Therefore, a thorough exploration of a less-is-more 
approach is crucial as no firm knowledge exists on 
the effectiveness of adding 2 instead of 1 antiplatelet 
agent on top of OAC.
……
A dual antithrombotic regimen is particularly 
appealing due to the potential benefit in terms of 
reduced risk of intracranial bleeding as well as due 
to the potential benefit of a reduced risk of major 
bleeding events in a post-PCI setting while 
maintaining the required level of efficacy for 
preventing the major ischaemic thrombotic events 
post-procedure (death, stroke, MI).
Has been changed to:
The WOEST results have nevertheless been 
reflected in some of the recent guidelines for 
NVAF patients undergoing PCI with stenting 
[P14-05384, P14-12794, P16-02545] which 
recommend to consider the use of DAT in certain 
patients. However, data from clinical trials 
concerning the possibility of implementing DAT 
regimens with dabigatran etexilate and other 
new NOACs in this setting are needed.
……….
A dual antithrombotic regimen with a NOAC is 
particularly appealing due to the potential benefit in 
terms of reduced risk of intracranial bleeding as well 
as due to the potential benefit of a reduced risk of 
major bleeding events in a post-PCI setting.
Rationale for change
See rationale for first change. Text aligned with the 
change in study design.
Section to be changed
3.1
Overall Trial Design And Plan
Description of change
This trial is designed to test two combined efficacy-
safety hypotheses in NVAF patients that have 
undergone a successful PCI (elective or due to ACS) 


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 132 of 150
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.
Number of global amendment
2
with stenting and were treatment naïve or were 
receiving oral anticoagulant treatment (either with
warfarin, another VKA or other novel oral 
anticoagulant) before the procedure. 
…….
The trial is event driven and is designed to continue 
until 723 deaths or thromboembolic events (in total) 
occur.
Has been changed to:
This trial is designed to test the safety in NVAF 
patients that have undergone a successful PCI 
(elective or due to ACS) with stenting and were 
treatment naïve or were receiving oral anticoagulant 
treatment (either with warfarin, another VKA or 
other novel oral anticoagulant) before the procedure.
…..
The trial is event driven and is designed to continue 
until approximately 500 patients with at least one 
MBE or CRNMBE (in total) occur.
Rationale for change
The study design has been revised to focus on 
safety, for more details refer to rationale for first 
change
Section to be changed
3.2
Discussion Of Trial Design, Including The 
Choice Of Control Group(S)
Description of change
The following text has been added:
The WOEST results have been reflected in some 
of the recent guidelines for NVAF patients 
undergoing PCI with stenting [P14-05384, P14-
12794, P16-02545] which recommend to consider 
the use of DAT in certain patients. However, data 
from clinical trials concerning the possibility of 
implementing DAT regimens with dabigatran 
etexilate and other new NOACs in this setting are 
needed.
Rationale for change
Updated to include reference to recent guidelines 
and publications


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 133 of 150
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.
Number of global amendment
2
Section to be changed
3.3
Selection Of Trial Population
Description of change
In order to test the two combined efficacy-safety 
hypotheses in NVAF patients that have undergone a 
successful PCI, at least 2840 patients per treatment 
group are estimated to be required (see Section 7.6).
Approximately 700 trial centres worldwide will 
participate in the trial.
Has been changed to:
In order to test the two combined efficacy-safety 
hypotheses in NVAF patients that have undergone a 
successful PCI, at least 834 patients per treatment 
group are estimated to be required (see Section 7.6).
Approximately 550 trial centres worldwide will 
participate in the trial.
Rationale for change
See rationale for first change, sample size 
calculations now based on revised study design 
focusing on safety.
Section to be changed
4.1.1
Identity Of BI Investigational Product And 
Comparator Products
Description of change
For easy identification warfarin tablet strengths will 
have a different colour bottle label.
Has changed to:
For easy identification warfarin tablet strengths will 
have a different colour label.
Rationale for change
Reference to packaging removed to take into 
account the plan for the new warfarin packaging.
Section to be changed
4.1.6
Packaging, Labelling, And Re-Supply
Description of change
Patients on warfarin will receive the required 
combination of 1mg, 3mg and 5mg tablets in bottles 
according to their actual needs as defined by the 
measured INR value. Each warfarin bottle will 
contain 66 tablets. Warfarin bottles should be 
checked at each visit to ensure the patient has 
sufficient supplies and that expiry dates will not be 
compromised prior to the next clinic visit.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 134 of 150
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.
Number of global amendment
2
Has been changed to:
Patients on warfarin will receive the required 
combination of 1mg, 3mg and 5mg tablets in bottles 
or blister packs according to their actual needs as 
defined by the measured INR value. Each warfarin 
bottle will contain 66 tablets. Each blister pack will 
contain 70 tablets. Warfarin supplies should be 
checked at each visit to ensure the patient has 
sufficient quantity and that expiry dates will not be 
compromised prior to the next clinic visit.
Rationale for change
Updated to also reflect the new warfarin packaging
that is planned.
Section to be changed
4.1.7
Storage conditions
Description of change
All unused medication including bottles and outer 
boxes (empty or filled) must be either returned to 
the Sponsor, or, following written authorisation 
from the Sponsor, may be destroyed at site.
Has been changed to:
All unused medication including bottles, blisters
and outer boxes (empty or filled) must be either 
returned to the Sponsor, or, following written 
authorisation from the Sponsor, may be destroyed at 
site.
Rationale for change
Updated to also reflect the new warfarin packaging
that is planned.
Section to be changed
Figure 4.2.1.1: 1 Management of bleeding on 
dabigatran therapy
Description of change
The following text has been added:
Administration of reversal agent4
4 see Section 4.2.1.7 Overdose, for more 
information regarding the specific reversal agent 
for dabigatran
Rationale for change
To add the reversal agent for dabigatran into the 
guidance on management of bleeding on dabigatran 
therapy.
Section to be changed
4.2.1.7 Overdose  Specific reversal agent to 
dabigatran


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 135 of 150
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.
Number of global amendment
2
Description of change
A specific reversal agent (idarucizumab) has been 
developed and is currently being reviewed for 
registration in various countries.
Has been changed to:
A specific reversal agent (idarucizumab) has been 
developed and is currently available in many
countries and being reviewed for registration in 
various other countries.
Rationale for change
Updated to reflect current approval status of 
idarucizumab
Section to be changed
5.1.1 Endpoints of efficacy
Description of change
The dual primary endpoints for this trial are a
composite endpoint of efficacy and a safety 
endpoint:
1. Time to death or first thrombotic event 
(DTE) (all death, MI, stroke/SE)
2. Time to first ISTH Major Bleeding Event 
(MBE)  
The secondary endpoints of efficacy are (all time to 
event endpoints):
1. Individual outcome events: 
o
All death 

Cardiovascular death

Non-cardiovascular death

Undetermined
o
MI
o
Stroke
o
SE
o
Stent thrombosis
2. Composite endpoint of death + MI + stroke 
3. Repeated revascularisation by PCI/CABG
Has been changed to:
The primary endpoint for this trial is a safety 
endpoint. See section 5.2.1. There are no primary 
efficacy endpoints.
The secondary efficacy endpoints  (all time to first


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 136 of 150
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.
Number of global amendment
2
event) are:
1. A combined endpoint of thrombotic events or 
death (DTE: all death + MI + stroke/SE) and 
unplanned revascularisation by PCI/CABG
2. A combined endpoint of thrombotic events or 
death (DTE: all death + MI + stroke/SE)
3. Individual outcome events: 
o
All death 
o
Cardiovascular death
o
Non-cardiovascular death
o
Undetermined
o
MI
o
Stroke
o
SE
o
Stent thrombosis
4. Composite endpoint of death + MI + stroke 
5.Unplanned revascularisation by PCI/CABG
Rationale for change
Efficacy parameters including combined endpoints 
(e.g. all death, myocardial infarction, 
stroke/systemic embolism) will now be evaluated as 
secondary endpoints.
Section to be changed
5.1.2.6 Repeated revascularisation by PCI/CABG
Description of change
Repeated revascularisation due to objectively 
documented recurrent ischaemia, stent thrombosis 
or ACS. These cases will not undergo adjudication. 
Has been changed to:
Repeated revascularisation due to objectively 
documented recurrent ischaemia, stent thrombosis 
or ACS. Unplanned revascularisation is any 
repeated revascularisation not planned prior to 
informed consent. These cases will not undergo 
adjudication. 
Rationale for change
To add clarity that unplanned revascularisation is 
any repeated revascularisation not planned prior to 
informed consent
Section to be changed
5.2.1
Endpoints of safety
Description of change
The dual primary endpoints for this trial are a 
composite endpoint of efficacy and a safety 


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 137 of 150
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.
Number of global amendment
2
endpoint (see Section 5.1.1).
Other safety endpoints are:
1.Clinically relevant bleeding measured using the 
following definitions:

Bleeding Academic Research Consortium 
(BARC) ≥3

TIMI group - Major and Minor
2.Minor and total bleeding (ISTH, BARC and TIMI)
3.Intracranial haemorrhage
Has been changed to:
The primary endpoint for this trial is time to first 
ISTH MBE or CRNMBE. For definition of 
CRNMBE see section 5.2.2.1.
Other safety endpoints are:
1.Major bleeding (ISTH)
2.CRNMBE (for definition see section 5.2.2.1)
3.Clinically relevant bleeding measured using the 
following definitions:

Bleeding Academic Research Consortium 
(BARC) ≥3

TIMI group - Major and Minor
4.Minor and total bleeding (ISTH, BARC and TIMI)
5.Intracranial haemorrhage
Rationale for change
The study design has been revised to focus on 
safety, for more details refer to rationale for first 
change
Section to be changed
5.4
Appropriateness Of Measurements
Description of change
The primary endpoints for this study are combined 
efficacy and safety endpoints 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]).  
Has been changed to:
The primary endpoint for this study is a safety 
endpoint using the ISTH definition for major 


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 138 of 150
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.
Number of global amendment
2
bleeding and CRNMBEs which are similar 
endpoints to those used in other contemporary 
clinical trials in the same setting 
(ClinicalTrials.gov: NCT01830543 and 
NCT02415400).
Rationale for change
Updated to reflect new study design
Section to be changed
7.1  Statistical Design - Model
Description of change
This study is designed to test two combined 
efficacy-safety hypotheses in NVAF patients that 
have undergone a successful PCI (elective or due to 
ACS) with stenting and were treatment naïve or 
were receiving oral anticoagulant treatment (either 
with warfarin, another VKA or other novel oral 
anticoagulant) before the procedure.
The two primary outcomes (one composite efficacy 
outcome and one safety outcome) are stated in 
Section 5.1.1.
1. Efficacy: combined thrombotic events or 
death (DTE: all death + MI + stroke/SE).
2. Safety: ISTH Major Bleeding Events (MBE)
Has been changed to:
This study is designed to test a safety hypothesis in 
NVAF patients that have undergone a successful 
PCI (elective or due to ACS) with stenting and were 
treatment naïve or were receiving oral anticoagulant 
treatment (either with warfarin, another VKA or 
other novel oral anticoagulant) before the procedure.
The primary outcome is stated in Section 5.2.1.
1. ISTH MBE and CRNMBE
Rationale for change
The study design has been revised to focus on 
safety, for more details refer to rationale for first 
change
Section to be changed
7.2
Null And Alternative Hypotheses


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 139 of 150
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.
Number of global amendment
2
Description of change
Two combined efficacy-safety hypotheses (110mg 
Dabigatran Etexilate (DE-DAT) vs. warfarin-TAT 
and 150mg DE-DAT vs. warfarin-TAT) will be 
tested:
1.110mg DE-DAT is non-inferior to 
warfarin-TAT over the duration of the trial 
with respect to DTE AND non-inferior1 with 
respect to MBE over the duration of the trial
2.150mg DE-DAT is non-inferior to 
warfarin-TAT over the duration of the trial 
with respect to DTE AND non-inferior1 with 
respect to MBE over the duration of the trial.
The study will be considered a success if either 
combined hypothesis above is accepted.
To control the Type I error rate at a one-sided 0.025 
level, the Benjamini-Hochberg [P05-11198] 
procedure for multiple testing will be used to test the 
above hypotheses.  Specifically, the study will be 
considered a statistical success under the following 
scenarios:  

Scenario A
o
Hypothesis 1 is proven if the non-
inferiority of 110mg DE-DAT to 
warfarin-TAT in DTE AND the non-
inferiority2 of 110mg DE-DAT to 
warfarin-TAT in MBE are both met 
at a one-sided 0.025 level of 
significance. 
                  AND
o
Hypothesis 2 is proven if the non-
inferiority of 150mg DE-DAT to 
warfarin-TAT in DTE AND the non-
inferiority1 of 150mg DE-DAT to 
warfarin-TAT in MBE are both met 
at a one-sided 0.025 level of 
                                                          


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 140 of 150
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.
Number of global amendment
2
significance

Scenario B
o
Hypothesis 1 is proven if the non-
inferiority of 110mg DE-DAT to 
warfarin-TAT in DTE AND the non-
inferiority1 of 110mg DE-DAT to 
warfarin-TAT in MBE are both met 
at a one-sided 0.0125 level of 
significance. 
                OR
o
Hypothesis 2 is proven if the non-
inferiority of 150mg DE-DAT to 
warfarin-TAT in DTE AND the non-
inferiority1 of 150mg DE-DAT to 
warfarin-TAT in MBE are both met 
at a one-sided 0.0125 level of 
significance
The Non-Inferiority (NI) margin used for DTE and 
MBE will be 1.38 (on the relative HR scale).  See 
Section 7.6 for a clinical justification of this margin.  
The upper bound of the CI of the HR of DE-DAT 
vs. warfarin-TAT (one-sided 97.5% or one-sided 
98.75%) will be compared to this NI margin for the 
NI testing.
1
Superiority will be tested if non-inferiority has been demonstrated first
Has been changed to:
Two safety hypotheses (110mg Dabigatran Etexilate 
(DE-DAT) vs. warfarin-TAT and 150mg DE-DAT 
vs. warfarin-TAT) will be tested:
1. 110mg DE-DAT is non-inferior to warfarin-
TAT with respect to MBE/CRNMBE over 
the duration of the trial
2. 150mg DE-DAT is non-inferior to warfarin-
TAT with respect to MBE/CRNMBE over 
the duration of the trial.
To control the Type I error rate at a one-sided 0.025 


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 141 of 150
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.
Number of global amendment
2
level, a hierarchical procedure for multiple testing 
will be used to test the above hypotheses.
Additional testing for safety and efficacy 
endpoints will also be included in this 
hierarchical procedure. The following 
hierarchical procedure will be applied:
Step 1 – Non-inferiority of 110mg DE-DAT to 
warfarin-TAT in MBE/CRNMBE is met at the 
one-sided 0.025 level of significance
Step 2 – Non-inferiority of 150mg DE-DAT to 
warfarin-TAT in MBE/CRNMBE is met at the 
one-sided 0.025 level of significance
Step 3 – Non inferiority of 150mg DE-DAT and 
110mg DE-DAT combined to warfarin-TAT in 
DTE and unplanned revascularisation by 
PCI/CABG is met at the one-sided 0.025 level of 
significance
Step 4 –Superiority of 110mg DE-DAT to 
warfarin-TAT in MBE/CRNMBE is met at the 
one-sided 0.025 level of significance
Step 5 – Non inferiority of 150mg DE-DAT and 
110mg DE-DAT combined to warfarin-TAT in 
DTE is met at the one-sided 0.025 level of 
significance
Step 6 – Superiority of 150mg DE-DAT to 
warfarin-TAT in MBE/CRNMBE is met at the 
one-sided 0.025 level of significance
If any of the steps above fail to meet statistical 
significance, the testing procedure will stop at 
that step and subsequent tests will not be 
performed.
The Non-Inferiority (NI) margin used for 
MBE/CRNMBE will be 1.38 (on the relative HR 
scale).  See Section 7.6 for a clinical justification of 
this margin.  The upper bound of the Wald 
confidence interval (CI) of the HR of DE-DAT vs. 
warfarin-TAT (one-sided 97.5%) will be compared 
to this NI margin for the NI testing.


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 142 of 150
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.
Number of global amendment
2
Rationale for change
To clarify that a hierarchical approach will replace 
the original Benjamini-Hochberg procedure as the 
Type I error rate control method.
Section to be changed
7.3.1
Primary Analyses
Description of change
The dual primary endpoints (both measured from 
date of randomisation to end of observation period) 
are: 

Time to first DTE (composite efficacy 
outcome)

Time to first MBE (safety outcome)
as determined by the IAC.  They will be analysed 
using the stratified Cox proportional hazards 
regression model including factors for age (<80 or 
≥80 years old) and treatment arm (110mg DE-DAT 
vs warfarin-TAT and 150mg DE-DAT vs warfarin-
TAT)
…. 
Patients who discontinue study medication will be 
followed until the end of the trial for vital status 
(DTE and MBE).  Patients who are lost to follow-up 
for vital status will be censored for the primary 
endpoints at the time of their last known vital status.  
………..
The robustness of the primary analyses will be 
assessed by an on-treatment analysis.  This on-
treatment analysis will only count events that occur 
while a patient is taking study medication (including 
the REP of 6 days – see Section 5.2.2.2).  
Has been changed to 
The primary endpoint (measured from date of 
randomisation to end of observation period) is:

Time to first MBE/CRNMBE
as determined by the IAC. It will be analysed using 
the stratified Cox proportional hazards regression 


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 143 of 150
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.
Number of global amendment
2
model including factors for age (<80 or ≥80 years 
old) and treatment arm (110mg DE-DAT vs 
warfarin-TAT and 150mg DE-DAT vs warfarin-
TAT).
……..
Patients who discontinue study medication will be 
followed until the end of the trial.    Patients who are 
lost to follow-up for vital status will be censored for 
the primary endpoint at the time of their last known 
vital status.  
………..
The robustness of the primary analysis will be 
assessed by an on-treatment analysis.  This on-
treatment analysis will only count events that occur 
while a patient is taking study medication (including 
the REP of 6 days – see Section 5.2.2.2).  It will also 
analyse patients by the actual treatment that was 
being taken while the event occurred.
Rationale for change
The study design has been revised to focus on 
safety, for more details refer to rationale for first 
change. Patients will be followed up per section 
6.2.2.2 of the protocol
Section to be changed
7.3.2
Secondary analyses
Description of change
Secondary efficacy endpoints (all time to first event, 
measured from date of randomisation to end of 
observation period) are:

All death 
o
Cardiovascular death
o
Non-cardiovascular death
o
Undetermined

MI

Stroke

SE

Stent thrombosis

Composite of death + MI + stroke

Repeated revascularisation by PCI /CABG
Time to first event endpoints will be analysed using 
the same methods as for the primary endpoints.  No 


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 144 of 150
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.
Number of global amendment
2
multiplicity adjustments are planned for secondary 
endpoints.  Nominal one-sided p-values will be 
reported for descriptive purposes.
All secondary analyses will be performed on the 
FAS. The robustness of these analyses will be 
assessed by on-treatment analyses (see Section 
7.3.1). 
The other endpoint of TIA (see Section 5.3.1) will 
be analysed using the same approaches as above.
Has been changed to:
Secondary efficacy endpoints (all time to first event, 
measured from date of randomisation to end of 
observation period) are:

A combined endpoint of thrombotic events 
or death (DTE: all death + MI + 
stroke/SE) and unplanned 
revascularisation by PCI /CABG

A combined endpoint of thrombotic events 
or death (DTE: all death + MI + 
stroke/SE) 

All death 
o
Cardiovascular death
o
Non-cardiovascular death
o
Undetermined

MI

Stroke

SE

Stent thrombosis

Composite of death + MI + stroke

Unplanned revascularisation by PCI /CABG
Time to first event endpoints will be analysed using 
the same methods as for the primary endpoint.  No 
multiplicity adjustments are planned for secondary 
endpoints (apart from those mentioned in the 
hierarchy, see Section 7.2).  Nominal one-sided p-
values will be reported for descriptive purposes.
All secondary analyses will be performed on the 
FAS. The robustness of these analyses will be 
assessed by on-treatment analyses (see Section 


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 145 of 150
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.
Number of global amendment
2
7.3.1). 
TIA (further endpoint, see Section 5.3.1) will be 
analysed using the same approaches as above.
Rationale for change
All efficacy parameters (e.g. all death, myocardial 
infarction, stroke/systemic embolism), including the 
original co-primary endpoint (DTE), will now be 
evaluated as secondary endpoints.
Section to be changed
7.3.3. Safety Analyses
Description of change
These endpoints will be analysed using the same 
methods as the primary endpoints.  No multiplicity 
adjustments are planned for safety endpoints (apart 
from those mentioned in the hierarchy, see Section 
7.2).
Has been changed to:
These endpoints will be analysed using the same 
methods as the primary endpoints.  No multiplicity 
adjustments are planned for safety endpoints (apart 
from those mentioned in the hierarchy, see 
Section 7.2).
Rationale for change
To clarify that a hierarchical approach will replace 
the original Benjamini-Hochberg procedure as the 
Type I error rate control method.
Section to be changed
7.3.4
Interim analyses
Description of change
Has been updated to say:
No interim analysis is planned, but blinded sample 
size re-calculations may be performed.  The conduct 
of the trial will be monitored by a DMC. The DMC 
will hold regular meetings to monitor imbalance in 
endpoints, with the focus on MBE/CRNMBE. The 
DMC’s objectives and working practices are 
documented in the DMC charter. 
The DMC may recommend terminating the study at 
any time for DE-DAT safety concerns.  Further 
details will be included in the DMC charter.
The DMC will have unblinded safety reviews every 


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 146 of 150
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.
Number of global amendment
2
2 months.
Rationale for change
Removal of unblinded interim analyses due to study 
design changes. The DMC will continue with the 
tasks specified in the DMC charter.
Section to be changed
7.6
Determination Of Sample Size
Description of change
Has been updated to say:
This is an event-driven trial where it is assumed that 
the first patient recruited into the study will be 
followed up for a maximum of approximately 30 
months and the last patient recruited into the trial 
will be followed up for a minimum of 6 months. It is 
assumed that patient accrual will be approximately 
uniform over the 24 month recruiting period.
The proportion of patients with at least one
MBE/CRNMBE at one year is estimated to be 
14% based on current blinded trial data.
A relative NI margin for the original co-primary 
endpoint (DTE) was chosen in analogy to recent 
SPAF trials with primary endpoints of stroke/SE, 
where 1.38 was used by the FDA for ximelagatran, 
apixaban, rivaroxaban and dabigatran to preserve at 
least 50% of the relative reduction (on the log scale) 
in the risk associated with warfarin in six previous 
(historical), randomised, controlled trials. See 
publication by Jackson K, Gersh BJ, Stockbridge N, 
et al. [R08-2662]. The same NI margin has been 
applied to MBE/CRNMBE as it was considered 
the most clinically relevant available reference in 
the absence of any other type of data.
The overall sample size is driven by the non-
inferiority comparison of  MBE/CRNMBE between 
110mg DE-DAT or 150mg DE-DAT and warfarin-
TAT.  With alpha=0.025 (one-sided) and 14% of
patients with at least one event at one year, 334 
patients with at least one MBE/CRNMBE in each 
pair of treatment groups (i.e. 167 patients with 
MBE/CRNMBE per treatment group) are required 
to achieve 83.6% power for this endpoint, yielding 
a final sample size estimated at 834 patients in each 
treatment group (i.e. 2502 randomised patients in 


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 147 of 150
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.
Number of global amendment
2
total). Therefore approximately 500 patients with at 
least one MBE/CRNMBE are required in total 
across the three treatment groups.
As described in Section 7.3.1, for the comparison of 
150mg DE-DAT vs warfarin-TAT, patients from the 
EU/ROW who are ≥80 years old will be excluded 
from the warfarin-TAT arm (as patients who are ≥80 
years old from the EU/ROW are not randomised to 
150mg DE-DAT).  The actual number of patients 
entered may increase or decrease based upon actual 
event rates. As this is an event-driven trial, the trial 
can conclude earlier, if an adequate number of 
events are reported sooner or later, if more events 
are needed. Because the last patient entered must be 
followed up for a minimum of 6 months and to 
avoid accruing too many events, recruitment will 
need to be stopped before the required number of 
events are observed.  Blinded event rates will be 
monitored closely by BI (and the Executive Steering 
Committee) to predict the time at which recruitment 
should be stopped.  Sites will be notified when 
recruitment ends.
Rationale for change
See rationale for first change, sample size 
calculations now based on revised study design 
focussing on safety. 
Section to be changed
9.1
Published References
Description of change
The following references have been added:
P14-05384
January CT, Wann LS, Alpert JS, 
Calkins H, Cleveland JC, Cigarroa JE, Conti JB, 
Ellinor PT, Ezekowitz MD, Field ME, Murray 
KT, Sacco RL, Stevenson WG, Tchou PJ, Tracy 
CM, Yancy CW. 2014 AHA/ACC/HRS guideline 
for the management of patients with atrial 
fibrillation: a report of the American College of 
Cardiology/American Heart Association Task 
Force on Practice Guidelines and the Heart 
Rhythm Society: developed in collaboration with 
the Society of Thoracic Surgeons. J Am Coll 
Cardiol, 64(21):2246-2280 (2014)
P14-12794
Lip GYH, Windecker S, Huber K, 
Kirchhof P, Marin F, Berg JM ten, Haeusler KG, 


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 148 of 150
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.
Number of global amendment
2
Boriani G, Capodanno D, Gilard M, Zeymer U, 
Lane D. Management of antithrombotic therapy 
in atrial fibrillation patients presenting with 
acute coronary syndrome and/or undergoing 
percutaneous coronary or valve interventions: a 
joint consensus document of the European 
Society of Cardiology Working Group on 
Thrombosis, European Heart Rhythm 
Association (EHRA), European Association of 
Percutaneous Cardiovascular Interventions 
(EAPCI) and European Association of Acute 
Cardiac Care (ACCA) endorsed by the Heart 
Rhythm Society (HRS) and Asia-Pacific Heart 
Rhythm Society (APHRS). Eur Heart J, 
35(45):3155-79 (2014)
P16-02545
Windecker S, et al, 
2014ESC/EACTS guidelines on myocardial 
revascularization: the Task Force on Myocardial 
Revascularization of the European Society of 
Cardiology (ESC) and the European Association 
for Cardio-Thoracic Surgery (EACTS): 
developed with the special contribution of the 
European Association of Percutaneous 
Cardiovascular Interventions (EAPCI). Eur 
Heart J 35, 2541 - 2619 (2014)
Rationale for change
Recently released publications added
Section to be changed
9.2
Unpublished References
Description of change
The following reference has been added:
U11-1642-01
 
. Amendment to 
Pradaxa ® CCDS after approval of dabigatran 
etexilate for SPAF in US and EU Amendment to 
Pradaxa ® CCDS concerning the use of 
fibrinolytic agents for acute ischemic stroke and 
the simultaneous use of ticagrelor (plus ASA), 
selective serotonin re-uptake inhibitors or 
dronedarone (Multaq®). 23 September 2011
Rationale for change
Previous omission.
Section to be changed
10.1.3 Bridging Therapy (e.g. for temporary 
interruptions of study drug due to interventions)


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 149 of 150
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.
Number of global amendment
2
Description of change
For recommendations how to switch back to study 
drug (dabigatran etexilate or warfarin) see Sections 
10.2.1 and 10.2.2.
Has been changed to:
For recommendations how to switch back to study 
drug (dabigatran etexilate or warfarin) see Sections 
10.1.1 and 10.1.2.
Rationale for change
Correction in sections referenced


Boehringer Ingelheim                                                                                                         21 Jul 2016    
BI Trial No.: 1160.186
Doc. No.: c02214385-09                            Trial Protocol Version 4.0                            Page 150 of 150
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.
Number of global amendment
3
Date of CTP revision
21 July 2016
EudraCT number
2013-003201-26
BI Trial number
1160.186
BI Investigational Product(s)
Pradaxa®, dabigatran etexilate
Title of protocol
A prospective Randomised, open label, blinded 
endpoint (PROBE) study to Evaluate DUAL 
antithrombotic therapy with dabigatran etexilate 
(110mg and 150mg b.i.d.) plus clopidogrel or 
ticagrelor vs. triple therapy strategy with warfarin 
(INR 2.0 – 3.0) plus clopidogrel or ticagrelor and 
aspirin in patients with non valvular atrial 
fibrillation (NVAF) that have undergone a 
percutaneous coronary intervention (PCI) with 
stenting (RE-DUAL PCI)
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
5.1.2.6 Repeated revascularisation by PCI/CABG
Description of change
These cases will not undergo adjudication.
Has been changed to:
These cases will undergo adjudication for 
confirmation of whether the event was unplanned, 
the type of procedure, the indication and if it is a 
target lesion revascularisation.
Rationale for change
The DMC have requested that repeated 
revascularisations are adjudicated by the IAC. 


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02214385
9.0
1160-0186-clinical-trial-protocol-version-04
A prospective Randomised, open label, blinded endpoint (PROBE) study to Evaluate
DUAL antithrombotic therapy with dabigatran etexilate (110mg and 150mg b.i.d.)
plus clopidogrel or ticagrelor vs. triple therapy strategy with warfarin (INR 2.0 – 3.0)
plus clopidogrel or ticagrelor and aspirin in patients with non valvular atrial
fibrillation (NVAF) that have undergone a percutaneous coronary…
Approval-Therapeutic Area 
01 Aug 2016 09:24 CEST
Author-Trial Statistician
01 Aug 2016 10:32 CEST
Author-Trial Clinical Monitor
01 Aug 2016 11:39 CEST
Approval-Pharmacovigilance
01 Aug 2016 14:26 CEST
Approval-Team Member Medicine
01 Aug 2016 16:07 CEST
Verification-Paper Signature
Completion
02 Aug 2016 12:11 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02214385
9.0

SAP_001.pdf: 
TI T L E P A G E
Tri al St atisti c al A n al ysis Pl a n
c 1 7 3 8 4 7 8 7- 0 1
BI Tri al N o.:
1 1 6 0. 1 8 6
Title:
A pr os pecti ve R a n d o mise d, o pe n la bel, bli n de d e n d p oi nt ( P R O B E) 
st u d y t o E val uate D U A L a ntit hr o m b otic t hera p y wit h da bi gatra n 
ete xilate ( 1 1 0 m g a n d 1 5 0 m g b.i. d.) pl us cl o pi d o grel or tica grel or 
vs. tri ple t hera p y strate g y wit h warfari n (I N R 2. 0 – 3. 0) pl us 
cl o pi d o grel or tica grel or a n d as piri n i n patie nts wit h n o n val v ular 
atrial fi brillati o n ( N V A F) t hat ha ve u n der g o ne a perc uta ne o us 
c or o nar y i nter ve nti o n (P CI ) wit h ste nti n g
( R E-D U A L P CI)
I ncl u di n g Pr ot oc ol A me n d me nt 3 [ c 0 2 2 1 4 3 8 5- 0 9]
I n vesti g ati o n al
Pr o d uct :
Pra da xa ® , da bi gatra n ete xilate
Res p o nsi ble tri al 
st atistici a n:
P h o ne
Fa x:  
D ate of st atistic al 
a n al ysis pl a n:
9 J u ne 2 0 1 7 SI G N E D
Versi o n:
Fi nal
P a ge 1 of 3 6
Pr o priet ar y c o nfi de nti al i nf or m ati o n
2 0 1 7 B oe hri n ger I n gel hei m I nter n ati o n al G m b H or o ne or m ore of its affili ate d c o m p a nies. All ri g hts reser ve d.
T his d oc u me nt ma y n ot - i n f ull or i n part - be passe d o n, re pr o d uce d, p u blis he d or ot her wise use d wit h o ut pri or writte n per missi o n.


B oe hri n ger I n gel hei m
T S A P f or BI Tri al N o: 1 1 6 0. 1 8 6
P a ge 2 of 3 6
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 7 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
1.
T A B L E O F C O N T E N T S
TI T L E P A G E ......................................................................................................1
1.
T A B L E O F C O N T E N T S ......................................................................2
LI S T O F T A B L E S ..............................................................................................3
2.
LI S T O F A B B R E VI A TI O N S ...............................................................4
3.
I N T R O D U C TI O N..................................................................................7
4.
C H A N G E S I N T H E P L A N N E D A N A L Y SI S O F T H E S T U D Y ......8
5.
E N D P OI N T S ..........................................................................................9
5. 1 
P RI M A R Y E N D P OI N T S.................................................................................... 9
5. 2
S E C O N D A R Y E N D P OI N T S ..............................................................................9
5. 2. 1
Ke y sec o n d ar y e n d p oi nts ................................................................................9
5. 2. 2
( Ot her) Sec o n d ar y e n d p oi nts .........................................................................9
6.
G E N E R A L A N A L Y SI S D E F I NI TI O N S ...........................................1 1
6. 1
T R E A T M E N T S ..................................................................................................1 1
6. 2
I M P O R T A N T P R O T O C O L VI O L A TI O N S ..................................................1 1
6. 3
P A TI E N T S E T S A N A L Y S E D ..........................................................................1 7
6. 5
P O O LI N G O F C E N T R E S ................................................................................ 2 1
6. 6
H A N D LI N G O F MI S SI N G D A T A A N D O U T LI E R S ...................................2 2
6. 7
B A S E LI N E, TI M E WI N D O W S A N D C A L C U L A T E D VI SI T S ..................2 2
7.
P L A N N E D A N A L Y SI S .......................................................................2 3
7. 1
D E M O G R A P HI C A N D O T H E R B A S E LI N E C H A R A C T E R I S TI C S ........2 3
7. 2
C O N C O MI T A N T DI S E A S E S A N D M E DI C A TI O N ....................................2 3
7. 3
T R E A T M E N T C O M P LI A N C E .......................................................................2 4
7. 4
P RI M A R Y E N D P OI N T ....................................................................................2 5
7. 5
S E C O N D A R Y E N D P OI N T S ............................................................................2 9
7. 5. 1
Ke y sec o n d ar y e n d p oi nts ..............................................................................2 9
7. 5. 2
( Ot her) Sec o n d ar y e n d p oi nts .......................................................................2 9
7. 7
E X T E N T O F E X P O S U R E................................................................................ 3 1
7. 8
S A F E T Y A N A L Y SI S .........................................................................................3 1
7. 8. 1
A d verse e ve nts ...............................................................................................3 1
7. 8. 2
L a b or at or y d at a .............................................................................................3 2
7. 8. 3
Vit al si g ns .......................................................................................................3 3
7. 8. 4
E C G ................................................................................................................3 3
7. 8. 5
Ot hers .............................................................................................................3 3
8.
R E F E R E N C E S .....................................................................................3 4
1 0.
HI S T O R Y T A B L E ...............................................................................3 6


B oe hri n ger I n gel hei m
T S A P f or BI Tri al N o: 1 1 6 0. 1 8 6
P a ge 3 of 3 6
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 7 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
LI S T O F T A B L E S
Ta ble 6. 2: 1
I m p orta nt pr ot oc ol vi olati o ns........................................................................... 1 2
Ta ble 6. 3: 1
Patie nt sets a nal y se d ......................................................................................... 1 9
Ta ble 1 0: 1
Hist or y  ta ble..................................................................................................... 3 6


B oe hri n ger I n gel hei m
T S A P f or BI Tri al N o: 1 1 6 0. 1 8 6
P a ge 4 of 3 6
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 7 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
2.
LI S T O F A B B R E VI A TI O N S
Ter m
Defi niti o n / descri pti o n
A C S
Ac ute C or o nar y  S yn dr o mes
A C E F
A ge, creati ni ne a n d left ve ntric ular ejecti o n fracti o n
A D S
A nal y sis Dataset
A E
A d verse E ve nt
A F
Atrial Fi brillati o n
A L T
Ala ni ne ami n otra nsferase
A P
Al kali ne P h os p hatase
A S A
Acet yl salic ylic aci d (As piri n )
A S T
As partate tra nsa mi nase
B A R C
Blee di n g Aca de mic Researc h C o ns orti u m
BI
B oe hri n ger I n gel hei m
b.i. d.
T wice a da y
B MI
B o d y Mass I n de x
B M S
Bare Metal Ste nt
C A B G
C or o nar y  Arter y B ypass Graft
C A D
C or o nar y  Arter y Disease
C H A 2D S 2
V A S C
C o n gesti ve heart fail ure, H y perte nsi o n, A ge, Dia betes mellit us, pri or 
Str o ke or TI A or T hr o m b oe m b olis m, Vasc ular disease, Se x
CI
C o nfi de nce I nter val
Cr Cl
Creati ni ne Cleara nce
C T P
Cli nical Trial Pr ot oc ol
C T R
Cli nical Trial Re p ort
D A P T
D ual A nti platelet T hera p y
D A T
D ual A ntit hr o m b otic T hera p y
D B L
Data base L oc k
D B L M
Data base L oc k Meeti n g
D E S
Dr u g El uti n g Ste nt
D M C
Data M o nit ori n g C o m mittee
D T E
Deat h or T hr o m b otic E ve nt


B oe hri n ger I n gel hei m
T S A P f or BI Tri al N o: 1 1 6 0. 1 8 6
P a ge 5 of 3 6
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 7 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
Ter m
Defi niti o n / descri pti o n
E C G
Electr ocar di o gra m
e C R F
Electr o nic Case Re p ort F or m
E M A
E ur o pea n A ge nc y  f or t he E val uati o n of Me dici nal Pr o d ucts
E O T
E n d of Treat me nt
E U
E ur o pea n U ni o n
F A S
F ull A nal ys is Set
GI
Gastr oi ntesti nal              
H A S -B L E D
H y perte nsi o n, A b n or mal re nal a n d li ver f u ncti o n, Str o ke, Blee di n g, 
La bile I N Rs, El derly, Dr u gs or alc o h ol
H F
Heart Fail ure
H R
Hazar d Rati o
I A C
I n de pe n de nt A dj u dicati o n C o m mittee
I C H
I nter nati o nal C o nfere nce o n Har m o nisati o n
I N R
I nter nati o nal N or malise d Rati o
I P V
I m p orta nt Pr ot oc ol Vi olati o n
I R T
I nteracti ve Res p o nse Tec h n ol o g y
I S T H
I nter nati o nal S ociety of T hr o m b osis a n d Hae m ostasis
L A D
Left A nteri or Desce n di n g C or o nar y  Arter y
L M
Left Mai n C or o nar y  Arter y
L V E F
Left Ve ntric ular Ejecti o n Fracti o n
M B E
Maj or Blee di n g E ve nt
Me d D R A
Me dical Dicti o nar y  f or Re g ulat or y Acti vities
m g
milli gra ms
MI
M y ocar dial I nfarcti o n
m R S
m o difie d Ra n ki n Scale
NI
N o n -I nferi ority
N O A C
Ne w Oral A ntic oa g ula nt
N S AI D
N o n - Ster oi dal A nti-I nfla m mat or y Dr u g
N S T E MI
N o n -S T Ele vati o n M y ocar dial I nfarcti o n
N V A F
N o n Val v ular Atrial Fi brillati o n
N Y H A
Ne w Y or k Heart Ass ociati o n


B oe hri n ger I n gel hei m
T S A P f or BI Tri al N o: 1 1 6 0. 1 8 6
P a ge 6 of 3 6
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 7 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
Ter m
Defi niti o n / descri pti o n
O A C
Oral A ntic oa g ula nt
O E
O utc o me E ve nt
P CI
Perc uta ne o us C or o nar y  I nter ve nti o n
P- g p
P- gl yc o pr otei n
P PI
Pr ot o n P u m p I n hi bit or
P P S
Per Pr ot oc ol S et
P R O B E
Pr os pecti ve, Ra n d o mise d, O pe n- la bel, Bli n de d E n d p oi nt
P T
Preferre d T er m
P V
Pr ot oc ol V i olati o n
Q 1
L o wer q uartile ( 2 5t h perce ntile)
Q 3
U p per q uartile ( 7 5t h perce ntile ) 
R E P
Resi d ual Effect Peri o d
R O W 
Rest of W orl d
R P M
Re p ort Pla n ni n g Meeti n g
S C R
Scree ne d Set
S D
Sta n dar d D e viati o n
S E
S y ste mic E m b olis m
S O C
S y ste m Or ga n Class
S T E MI
S T Ele vati o n M y ocar dial I nfarcti o n
T A T
Tri ple A ntit hr o m b otic T hera p y
TI A
Tra nsie nt Isc hae mic Attac k
TI MI
T hr o m b ol y sis I n My ocar dial I nfarcti o n
T S
Treate d Set
T S A P
Trial Statistical A nal y sis Pla n
T T R
Ti me i n T hera pe utic Ra n ge
U A
U nsta ble A n gi na
U L N
U p per Li mit of N or mal
V K A
Vita mi n K A nta g o nist
W H O
W orl d Healt h Or ga nisati o n


B oe hri n ger I n gel hei m
T S A P f or BI Tri al N o: 1 1 6 0. 1 8 6
P a ge 7 of 3 6
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 7 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
3.
I N T R O D U C TI O N
As per I C H E 9 [4 ], t he p ur p ose of t his d oc u me nt is t o pr o vi de a m ore tec h nical a n d detaile d 
ela b orati o n of t he pri nci pal feat ures of t he a nal ys is descri be d i n t he pr ot oc ol, a n d t o i ncl u de 
detaile d pr oce d ures f or e xec uti n g t he statistical a nal y sis of t he pri mar y a n d sec o n dar y 
varia bles a n d ot her data.
T his Trial Statistical A nal y sis Pla n (T S A P ) ass u mes fa miliarit y wit h t he Cli nical Trial 
Pr ot oc ol ( C T P) [5 ], i ncl u di n g Pr ot oc ol A me n d me nts. In partic ular, t he T S A P is base d o n t he 
pla n ne d a nal ys is s pecificati o n as writte n i n C T P Secti o n 7 “ Statistical Met h o ds a n d 
Deter mi nati o n of Sa m ple Size”. T heref ore, T S A P rea ders ma y c o ns ult t he C T P f or m ore 
bac k gr o u n d i nf or mati o n o n t he st u d y , e. g., o n st u d y o bjecti ves, st u d y desi g n a n d p o p ulati o n, 
treat me nts, defi niti o n of meas ure me nts a n d varia bles, pla n ni n g of sa mple size, 
ra n d o mizati o n.
S A S ® Versi o n 9. 2 ( or a later versi o n) will be use d f or all a nalys es.


B oe hri n ger I n gel hei m
T S A P f or BI Tri al N o: 1 1 6 0. 1 8 6
P a ge 8 of 3 6
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 7 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
4.
C H A N G E S I N T H E P L A N N E D A N A L Y SI S O F T H E S T U D Y
D uri n g t he c o urse of t he st u d y , t he D M C ma y a d vise t o st o p e nr ol me nt i nt o certai n treat me nt 
ar ms or t o st o p t he st u d y c o m pletel y.  F or f urt her i nf or mati o n, see C T P [5 ], Secti o n 7. 3. 4.  
C ha n ges t o t he pla n ne d a nal ysis were i ntr o d uce d i n pr ot oc ol a me n d me nts 1 a n d 2.  I n 
a d diti o n, s o me f urt her c ha n ges were i m ple me nte d as f oll o ws.
D ue t o t he Ja pa nese l ocal a me n d me nt ( w here t he ra n d o misati o n a ge gr o u p stratificati o n 
fact or was c ha n ge d fr o m < 8 0 or ≥8 0 y ears ol d t o < 7 0 or ≥7 0 y ears ol d f or Ja pa nese patie nts), 
it will be necessar y t o c ha n ge t he wa y t he a ge gr o u p stratificati o n fact or is defi ne d i n t he 
a nal ys is.  I nstea d a ge gr o u p will be c ha n ge d t o be n o n -el derl y vs . el derl y a n d t his will be 
u se d as t he stratificati o n fact or i n s o me a nalys es.
D ue t o t he relati vel y fe w n u m bers of el derl y patie nts fi nall y recr uite d i n t he U S re gi o n, it will
n ot be p ossi ble t o fit a n a ge -gr o u p stratifie d C o x pr o p orti o nal hazar ds re gressi o n m o del f or 
t he 1 5 0 m g D E-D A T vers us warfari n -T A T c o m paris o n f or a n y  of t he e n d p oi nts.  Instea d a n 
u nstratifie d m o del will be a p plie d c o m pari n g 1 5 0 m g D E -D A T vers us warfari n -T A T. 
(e xcl u di n g el derl y E U/ R O W patie nts i n t he warfari n-T A T gr o u p). I n a d diti o n, u nstratifie d 
se nsiti vit y a nal yses of t he n o n-el derl y strat u m o nl y will be c o n d ucte d.  
GI  blee ds, M B Es (I S T H), C R N M B Es , life-t hreate ni n g blee ds a n d fatal blee ds were a d de d as 
ot her safet y e n d p oi nts.
T he f urt her e n d p oi nt of h os pitalisati o n a n d t he f urt her c o m p osite e n d p oi nt of all-ca use deat h 
or h os pitalisati o n were a d de d at t he re q uest of t he E xec uti ve Steeri n g C o m mittee o n 2 2 n d
N o ve m ber 2 0 1 6.
T he se nsiti vit y  a nalys is t hat ce ns ors patie nts w h o s witc h fr o m st u d y da bi gatra n t o n o n -st u d y 
N O A C/ V K A or fr o m st u d y  warfari n t o n o n-st ud y  N O A C/ V K A, at t he ti me of t he s witc h pl us 
t he Resi d ual Effect Peri o d ( R E P ) of 6 da y s will n ot be perf or me d beca use it will be virt uall y 
i de ntical t o t he o n-treat me nt se nsiti vit y a nalys is alrea d y pla n ne d.


B oe hri n ger I n gel hei m
T S A P f or BI Tri al N o: 1 1 6 0. 1 8 6
P a ge 9 of 3 6
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 7 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
5.
E N D P OI N T S
5. 1
P RI M A R Y E N D P OI N T S
T he pri mar y  e n dp oi nt f or t his st u d y  is a safet y e n d p oi nt: 

T i me t o first I nter nati o nal S ociet y of T hr o m b osis a n d Hae m ostasis (I ST H ) Maj or 
Blee di n g E ve nt ( M B E) or Cli nicall y  Rele va nt N o n-Maj or Blee di n g E ve nt 
( C R N M B E).  Please refer t o t he C T P f or t he IS T H criteria.  
T he pri mar y  e n d p oi nt will be a dj u dicate d b y a n I nde pe n de nt A dj u dicati o n C o m mittee ( I AC).   
Details of a dj u dicati o n criteria ca n be f o u n d i n t he A dj u dicati o n C harter.
5. 2
S E C O N D A R Y E N D P OI N T S
5. 2. 1
Ke y sec o n d ar y e n d p oi nts 
N ot a p plica ble.
5. 2. 2
( Ot her) Sec o n d ar y e n d p oi nts
T he ot her sec o n dar y e n d p oi nts of efficac y are (all ti me t o first e ve nt e n d p oi nts):
1.
C o m p osite e n d p oi nt s of: 

D T E a n d u n pla n ne d re vasc ularisati o n b y  P CI/ C A B G.
( D T E = all deat h, M y ocar dial I nfarcti o n ( M I), str o ke/S y ste mic Em b olis m ( S E ))

D T E                              
2.
I n di vi d ual o utc o me e ve nts: 

All deat h (a n d t he f oll o wi n g s u b-cate g ories se paratel y)
o
Car di o vasc ular deat h
o
N o n -car di o vasc ular deat h
o
U n deter mi ne d

MI

Str o ke

S E

Ste nt t hr o m b osis ( defi nite)


B oe hri n ger I n gel hei m
T S A P f or BI Tri al N o: 1 1 6 0. 1 8 6
P a ge 1 0 of 3 6
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 7 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
3.
C o m p osite e n d p oi nt of deat h + MI + str o k e 
4.
U n pla n ne d re vasc ularisati o n b y Perc uta ne o us C or o nar y  Inter ve nti o n ( P CI) /C or o nar y  
Arter y  B ypass Graft ( C A B G )
All sec o n dar y e n d p oi nts will be a dj u dicate d b y a n I A C.   Details of a dj u dicati o n criteria ca n 
be f o u n d i n t he A dj u dicati o n C harter.


B oe hri n ger I n gel hei m
T S A P f or BI Tri al N o: 1 1 6 0. 1 8 6
P a ge 1 1 of 3 6
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 7 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
6.
G E N E R A L A N A L Y SI S D E F I NI TI O N S
6. 1
T R E A T M E N T S
T he f oll o wi n g treat me nt peri o d s base d o n act ual start a n d st o p dates/ti mes of ra n d o mise d 
st u d y dr u g a d mi nistrati o n are defi ne d:

Scree ni n g: date of i nf or me d c o nse nt t o date of ra n d o misati o n.

P ost -ra n d o misati o n: Date of ra n d o misati o n t o ti me -p oi nt of first i nta ke ( date a n d ti me) of 
ra n d o mise d st u d y dr u g.

O n -treat me nt (i g n ori n g te m p orar y i nterr u pti o ns): first i nta ke ( date a n d ti me) of 
ra n d o mise d st u d y dr u g t o last i nta ke ( date a n d ti me) of ra n d o mise d st u d y dr u g.  T he R E P 
of 6 da ys  will be a d de d t o t he e n d of t his peri o d.  I nter mitte nt off-treat me nt peri o ds will 
be i g n ore d i n cases of a n y te m p orar y i nterr u pti o ns i n st u d y me dicati o n.

P ost -treat me nt:  E n d of o n -treat me nt peri o d (i ncl u di n g t he R E P) u ntil date of trial 
c o m pleti o n .  T his is t he date gi ve n o n t he ter mi nati o n (T E R M ) pa ge of t he electr o nic 
Case Re p ort F or m (e C R F).

P o st-st u d y: d a y after date of trial c o m pleti o n o n war ds.
T he R E P is t he ti me peri o d after t he la st a d mi nistrati o n of trial me dicati o n w he n meas ura ble 
dr u g le vels or P D effects are still li kel y  t o be prese nt. E ve nts occ urri n g i n t he R E P are 
ha n dle d as occ urri n g o n -treat me nt (f or t he Treate d Set). T he R E P is defi ne d as 6 da ys after 
last i nta ke of trial me dicati o n.  Dat a fr o m t he p ost -st u d y peri o d will o nl y be liste d .
F or r ules o n ce ns ori n g, refer t o Secti o n 7. 4 .
Des pite t he trial bei n g o pe n la bel, all acti vities c o n d ucte d by t he trial tea m will be perfor me d 
i n a bli n de d ma n ner ( w here p ossi ble) u ntil data base l oc k ( D B L).  F or e xa m ple , data 
ta b ulati o ns a n d listi n gs will be prese nte d usi n g d u m m y  treat me nt gr o u p i nf or mati o n i nstea d 
of act ual treat me nt gr o u p all ocati o ns.  
6. 2
I M P O R T A NT P R O T O C O L VI O L A TI O N S
T he f oll o wi n g ta ble defi n es t he differe nt cate g ories of Im p orta nt Pr ot oc ol Vi olati o ns ( IP Vs ).
T he fi nal c ol u m n descri bes w hic h I P Vs will be use d t o e xcl u de patie nts fr o m t he differe nt 
patie nt a nal ys is sets. I n t his st u d y, patie nts are eit her e xcl u de d fr o m “ All” a nal ys is sets, t he 
Per Pr ot oc ol a nal ys is Set ( P P S), t he F ull A nal ysis Set ( F A S) or “ N o ne” of t he a nal ys is sets. 
Refer t o Secti o n 6. 3 f or m ore details.  M ost I PVs will be i de ntifie d b y  t he trial tea m pri or t o 
D B L , w here p ossi ble i n a bli n de d ma n ner.   S o me pr o gra m maticall y- i de ntifie d IP Vs (e. g. 
treat me nt s witc hi n g) will nee d t o be i de ntifie d after D B L.


B oe hri n ger I n gel hei m
T S A P f or BI Tri al N o: 1 1 6 0. 1 8 6
P a ge 1 2 of 3 6
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 7 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
Ta ble 6. 2: 1 
I m p orta nt p r ot oc ol v i olati o ns
Cate g or y/
C o de
Descri pti o n
E xa m ple/ C o m me nt
E xcl u de d 
fr o m
A
E ntr a nce criteri a n ot m et
A 1. 1
Male or fe male patie nts a ge d 1 8 years or 
year s i n Ja pa n.
I ncl usi o n criteri o n 1 n ot met
P P S
A 1. 2
Patie nts wit h N V A F t hat ha ve bee n recei vi n g 
oral a ntic oa g ula nt ( O AC ) treat me nt (eit her 
wit h warfari n, a n ot her Vita mi n K A nta g o nist 
(V K A ) or ot her n o vel oral a ntic oa g ula nt) , or 
were treat me nt naï ve pri or t o P CI. Atrial 
Fi brillati o n ( A F ) ma y be par o x ys mal, 
persiste nt or per ma ne nt, b ut m ust n ot be 
sec o n dar y t o a re versi ble dis or der s uc h as MI, 
p ul m o nar y e m b olis m, rece nt s ur ger y, 
pericar ditis or t h yr ot o xic osis
I ncl usi o n criteri o n 2 n ot met
P P S
A 1. 3
Patie nt s prese nti n g wit h:
A n A c ute C or o nar y S y n dr o me ( AC S) [ S T 
ele vati o n MI ( S T E MI), N S T E MI or u nsta ble 
a n gi na ( U A)] t hat was s uccessf ull y treate d b y 
P CI a n d ste nti n g [eit her Bare Metal Ste nt 
( B M S) or Dr u g El uti n g Ste nt ( D E S)]
Or
Sta ble C or o nar y Arter y Disease ( C A D) wit h 
at least o ne lesi o n eli gi ble f or P CI t hat was 
s uccessf ull y treate d b y electi ve P CI a n d 
ste nti n g (eit her B M S or D E S)
I ncl usi o n criteri o n 3 n ot met
P P S
A 2 . 1
Patie nts wit h a mec ha nical or bi ol o gical heart 
val ve pr ost hesis
E xcl usi o n criteri o n 1 met
P P S
A 2. 2
Car di o ge nic s h oc k d uri n g c urre nt 
h os pitalisati o n
E xcl usi o n criteri o n 2 met
P P S
A 2. 3
Patie nts w h o ha ve use d fi bri n ol ytic a ge nts 
wit hi n 2 4 h o urs of ra n d o misati o n t hat, i n t he 
o pi ni o n of t he I n vesti gat or, w ill p ut t he patie nt 
at hi g h ris k of blee di n g
E xcl usi o n criteri o n 3 met
P P S
A 2. 4
Str o ke wit hi n 1 m o nt h pri or t o scree ni n g visit
( A d diti o nall y i n Ja pa n: a hae m orr ha gic str o ke, 
6 m o nt hs pri or t o a d mi nistrati o n of st u d y 
treat me nt)
E xcl usi o n criteri o n 4 met
P P S
A 2. 5
Patie nts, w h o i n t he o pi ni o n of t he 
I n vesti gat or, ha ve ha d maj or s ur ger y wit hi n 
t he m o nt h pri or t o scree ni n g
E xcl usi o n criteri o n 5 met .  
Nat ure a n d ti mi n g of s ur ger y t o 
be re vie w e d at Re p ort Pla n ni n g 
Meeti n g ( R P M).
N o ne
A 2. 6
Patie nt has recei ve d a n or ga n tra ns pla nt or is 
o n a w aiti n g list f or a n or ga n tra ns pla nt
E xcl usi o n criteri o n 6 met
P P S
A 2. 7
Hist or y of i ntra oc ular, s pi nal, retr o perit o neal 
or a tra u matic i ntra -artic ular blee di n g u nless 
t he ca usati ve fact or has bee n per ma ne ntl y 
eli mi nate d or re paire d (e. g. b y s ur ger y)
E xcl usi o n criteri o n 7 met
P P S


B oe hri n ger I n gel hei m
T S A P f or BI Tri al N o: 1 1 6 0. 1 8 6
P a ge 1 3 of 3 6
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 7 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
Ta ble 6. 2: 1 (c o nti n ue d)
I m p orta nt pr ot oc ol vi olati o ns
Cate g or y/
C o de
Descri pti o n
E xa m ple/ C o m me nt
E xcl u de d 
fr o m
A 2. 8
Gastr oi ntesti nal ( GI) hae m orr ha ge wit hi n o ne 
m o nt h pri or t o scree ni n g, u nless, i n t he o pi ni o n of 
t he I n vesti gat or, t he ca use has bee n per ma ne ntl y 
eli mi nate d (e. g. b y s ur ger y)
E xcl usi o n criteri o n 8 met
P P S
A 2. 9
Maj or blee di n g e pis o de (re d ucti o n i n t he 
hae m o gl o bi n le vel of at least 2 g/ d L, tra nsf usi o n of 
at least t w o u nits 1 of bl o o d, or s y m pt o matic 
blee di n g i n a critical area or or ga n) i ncl u di n g life -
t hreate ni n g blee di n g e pis o de (s y m pt o matic 
i ntracra nial blee di n g, blee di n g wit h a decrease i n 
t he hae m o gl o bi n le vel of at least 5 g/ d L or blee di n g 
re q uiri n g tra nsf usi o n of at least 4 u nits2 of bl o o d or 
i n otr o pic a ge nts or necessitati n g s ur ger y) i n o ne 
m o nt h pri or t o scree ni n g visit
E xcl usi o n criteri o n 9 met
P P S
A 2. 1 0
Hae m orr ha gic dis or der or blee di n g diat hesis (e. g. 
v o n Wille bra n d disease, hae m o p hilia A or B or 
ot her here ditar y b lee di n g dis or der, hist or y of 
s p o nta ne o us i ntra-artic ular blee di n g, hist or y of 
pr ol o n ge d blee di n g after s ur ger y/i nter ve nti o n)
E xcl usi o n criteri o n 1 0 met
P P S
A 2. 1 1
A nae mia ( hae m o gl o bi n < 1 0 g/ d L ) or 
t hr o m b oc yt o pe nia i ncl u di n g he pari n-i n d uce d 
t hr o m b oc yt o pe nia ( platelet c o u nt < 1 0 0 1 0 9/ L) at 
scree ni n g ( Visit 1)
E xcl usi o n criteri o n 1 1 met
P P S
A 2. 1 2
Se vere re nal i m pair me nt (esti mate d Cr Cl calc ulate d 
b y C oc kcr oft -Ga ult e q uati o n) < 3 0 m L/ mi n at 
scree ni n g ( Visit 1)
E xcl usi o n criteri o n 1 2 met
P P S
A 2. 1 3
Acti ve li ver disease as i n dicate d b y at least o ne of 
t he f oll o wi n g:
Pri or a n d persiste nt ala ni ne a mi n otra nsferase 
( A L T) or As partate tra nsa mi nase ( A S T) or al kali ne 
p h os p hatase ( A P) > 3 u p per li mit of n or m al 
( U L N)
K n o w n acti ve he patitis C
K n o w n acti ve he patitis B
K n o w n acti ve he patitis A
E xcl usi o n criteri o n 1 3 met
P P S
A 2. 1 4
Rece nt mali g na nc y or ra diati o n t hera p y ( ≤6 
m o nt hs) u nless, i n t he o pi ni o n of t he I n vesti gat or, 
t he esti mate d life e x pecta ncy is greater t ha n 3 6 
m o nt hs
E xcl usi o n criteri o n 1 4 met
P P S
A 2. 1 5
Nee d f or c o nti n ue d treat me nt wit h s yste mic 
ket oc o naz ole, itrac o naz ole, p osac o naz ole, 
c ycl os p ori ne, tacr oli m us, dr o ne dar o ne, rifa m pici n, 
p he n yt oi n, car ba maze pi ne or St. J o h n’s W ort.
E xcl usi o n criteri o n 1 5 met
P P S
                                                
1 E q ui vale nt t o 4. 5 u nits i n Ja pa n
2 E q ui vale nt t o 9 u nits i n Ja pa n


B oe hri n ger I n gel hei m
T S A P f or BI Tri al N o: 1 1 6 0. 1 8 6
P a ge 1 4 of 3 6
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 7 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
Ta ble 6. 2: 1 (c o nti n ue d)
I m p orta nt pr ot oc ol vi olati o ns
Cate g or y/
C o de
Descri pti o n
E xa m ple/ C o m me nt
E xcl u de d 
fr o m
A 2. 1 6
Patie nts w h o, i n t he I n vesti gat or’s o pi ni o n, nee d 
c o nti n u o us treat me nt wit h N o n-Ster oi dal A nti -
I nfla m mat or y Dr u gs ( N S AI Ds)
E xcl usi o n criteri o n 1 6 met
P P S
A 2. 1 7
Patie nts wit h a k n o w n aller g y t o da bi gatra n 
ete xilate or t o t he e xci pie nts use d f or t he ca ps ule of 
t he dr u g
E xcl usi o n criteri o n 1 7 met
P P S
A 2. 1 8
Patie nts wit h a k n o w n aller g y t o wa rfari n ta blets or 
t o t he e xci pie nts
E xcl usi o n criteri o n 1 8 met
P P S
A 2. 1 9
Patie nts w h o, i n t he I n vesti gat or’s o pi ni o n, s h o ul d 
n ot be treate d w it h O A C
E xcl usi o n criteri o n 1 9 met
P P S
A 2. 2 0
Patie nts wit h a c o ntrai n dicati o n t o cl o pi d o grel, 
tica grel or or as piri n ( A S A)
E xcl usi o n criteri o n 2 0 met
P P S
A 2. 2 1
Pr e -me n o pa usal w o me n (last me nstr uati o n ≤1 y ear 
pri or t o scree ni n g) w h o:
Are pre g na nt or breast fee di n g or
Are n ot s ur gicall y sterile or
Are of c hil d beari n g p ote ntial a n d n ot practisi n g 
t wo acce pta ble met h o ds of birt h c o ntr ol, or d o n ot 
pla n t o c o nti n ue practisi n g a n acce pta ble met h o d of 
birt h c o ntr ol t hr o u g h o ut t he trial. Acce pta ble 
met h o ds of birt h c o ntr ol are oral or pare nteral 
( patc h, i njecti o n, i m pla nt) h or m o nal c o ntrace pti o n 
w hic h has b ee n use d c o nti n u o usl y f or at least o ne 
m o nt h pri or t o t he first d ose of st u d y me dicati o n, 
i ntra uteri ne de vice or i ntra uteri ne s yste m, d o u ble-
barrier met h o d of c o ntrace pti o n (c o n d o m a n d 
occl usi ve ca p or c o n d o m a n d s per mici dal a ge nt), 
male sterilisati o n a n d c o mplete se x ual a bsti ne nce 
(if acce pta ble b y l ocal a ut h orities). Peri o dic 
a bsti ne nce is n ot a n acce pta ble met h o d of 
c o ntrace pti o n.
E xcl usi o n criteri o n 2 1 met .  
Pre g na nt patie nts will be 
e xcl u de d fr o m t he P P S.
N o ne
A 2. 2 2
Patie nts w h o ha ve partici pate d i n a n ot her trial wit h 
a n i n vesti gati o nal dr u g or de vice wit hi n t he past 3 0 
da ys prece di n g t he scree ni n g visit or are 
partici pati n g i n a n ot her trial ( patie nts partici pati n g 
i n a n o bser vati o nal st u d y o nl y will n ot be e xcl u de d)
E xcl usi o n criteri o n 2 2 met
P P S
A 2. 2 3
Patie nts n ot willi n g or a ble t o c o m pl y wit h t he 
pr ot oc ol re q uire me nts or c o nsi dere d u nrelia ble b y 
t he I n vesti gat or c o ncer ni n g t he re q uire me nts f or 
f oll o w-u p d uri n g t he st u d y a n d/ or c o m plia nce wit h 
st u d y dr u g a d mi nistrati o n, w h o ha ve a life 
e x pecta nc y less t ha n t he e x pecte d d urati o n of t he 
trial d ue t o c o nc o mita nt disease, or w h o ha ve a n y 
c o n diti o n w hic h i n t he o pi ni o n of t he I n vesti gat or, 
w o ul d n ot all o w safe partici pati o n i n t he st u d y (e. g. 
dr u g a d dicti o n, alc o h ol a b use).
E xcl usi o n criteri o n 2 3 met
P P S


B oe hri n ger I n gel hei m
T S A P f or BI Tri al N o: 1 1 6 0. 1 8 6
P a ge 1 5 of 3 6
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 7 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
Ta ble 6. 2: 1 (c o nti n ue d)
I m p orta nt pr ot oc ol vi olati o ns
Cate g or y/
C o de
Descri pti o n
E xa m ple/ C o m me nt
E xcl u de d 
fr o m
B
I nf or me d c o nse nt
B 1
I nf or me d c o nse nt n ot gi ve n
I ncl usi o n Criteri o n 4
All
B 2
I nf or me d c o nse nt gi ve n t o o late or 
t he dates of t he i n vesti gat or’s a n d 
patie nt’s si g nat ures d o n ot matc h 
N o ne
B 3
I nf or me d c o nse nt wit h dra w n
O nl y a p plies fr o m t he date at w hic h 
c o nse nt is wit h dra w n.
All
C
Tri al me dic ati o n a n d 
r a n d o miz ati o n
C 1
I nc orrect trial me dicati o n ta ke n
Me dicati o n kit assi g ne d n ot matc hi n g 
treat me nt patie nt was ra n d o mise d t o 
(e. g. patie nt ra n d o mize d t o warfari n -
T A T b ut recei ve d 1 1 0 m g D E -D A T )
P P S
C 2
Ra n d o misati o n or der n ot f oll o we d 
e. g. f orce d ra n d o mizati o n, mis -
stratificati o n
P P S
C 3
N o n -c o mplia nce
C o m plia nce < 8 0 % or > 1 2 0 % o ver t he 
c o urse of t he st u d y f or da bi gatra n 
patie nts ( deter mi ne d o n a visit-wise 
basis), or ti me i n t hera pe utic tar get 
ra n ge f or warfari n patie nts < 4 5 % (als o 
o n a visit -wise basis) .  See Secti o n 7. 3
f or details o n c o m plia nce calc ulati o ns.  
Patie nts will be fla g ge d if t he y e x hi bit 
n o n- c o mplia nce f or t w o c o nsec uti ve 
visits or m ore (f or b ot h da bi gatra n a n d 
warfari n patie nts).
N o n -c o mplia nce ca use d b y te mp orar y  
i nterr u ptio n of  treat me nt d ue t o a 
pr oce d ure or a dr o p i n Cr Cl t o less t ha n 
3 0 m L/ mi n s h o ul d n ot be classifie d as a 
pr ot oc ol vi olati o n.
P P S , b ut 
o nl y fr o m 
start of n o n -
c o m plia nce 
o n war ds
C 4
Trial m e dicati o n ta ke n at t he wr o n g 
ti me
First d ose of st u d y dr u g n ot
a d mi nistere d at t he c orrect ti me (s h o ul d 
be bet w ee n 6 h o urs after s heat h re m o val 
a n d u p t o 1 2 0 h o urs p ost P CI)
P P S
D
C o nc o m it a nt me dic ati o n


B oe hri n ger I n gel hei m
T S A P f or BI Tri al N o: 1 1 6 0. 1 8 6
P a ge 1 6 of 3 6
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 7 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
Ta ble 6. 2: 1 (c o nti n ue d)
I m p orta nt pr ot oc ol vi olati o ns
Cate g or y/
C o de
Descri pti o n
E xa m ple/ C o m me nt
E xcl u de d 
fr o m
D 2 . 1
Pr o hi bite d me dicati o n use
T he f oll o w i n g treat me nts s h o ul d n ot be ta ke n 
d uri n g t he acti ve treat me nt peri o d of t he trial (at 
least o ne o n-treat me nt use, u nless ot her wise state d:
1. Treat me nt wit h ticl o pi di ne or pras u grel
2. Fi bri n ol ytic a ge nts (s ee Secti o n 4. 2. 1. 4 of t he 
pr ot oc ol f or e xce pti o ns)
3. G PII b/IIIa a nta g o nists (e. g. a bci xi ma b, tir ofi ba n)
4. Treat me nt wit h s yste mic ket oc o naz ole, 
itrac o naz ole, p osac o naz ole, c ycl os p ori ne, 
tacr oli m us, dr o ne dar o ne a n d rifa m pici n, p he n yt oi n, 
car ba maze pi ne or St. J o h n’s W ort ( o nl y a p plica ble 
t o patie nts ra n d o mise d t o da bi gatra n ete xilate)
5a . Dip yri da m ole (alt h o u g h it is all o we d f or 
e xce pti o nal cases base d o n C T P S ecti o n, 4. 2. 1. 4; 
f or t he P P S a nal yses all patie nts wit h o n-treat me nt 
use will be e xcl u de d) ,
5 b. O t her oral a ntic oa g ula nts (e. g. V K As)
C o m mercial N O A Cs ( da bi gatra n, ri var o xa ba n, 
a pi xa ba n a n d e d o xa ba n ):
Warfari n Patie nts: At t he e n d of t he treat me nt, fla g 
patie nts wit h m ore t ha n 2 da ys of o verla p of 
w arfari n a n d c o m mercial N O A C + fla g a n y da ys of 
o verla p d uri n g t he treat me nt peri o d (e xce pt f or 
wa s h o ut of pre vi o us treat me nt/titrati o n at st u d y 
start (see I P V C 4))
Da bi gatra n p atie nts: At t he e n d of treat me nt, fla g 
patie nts wit h m ore t ha n 1 da y of o verla p of 
d a big atra n a n d c o m mercial N O A C + fla g a n y da ys 
of o verla p d uri n g t he treat me nt peri o d (e xce pt f or 
wa s h o ut of pre vi o us treat me nt/titrati o n at st u d y 
start (see I P V C 4))
C o m mercial V K As:
Da bi gatra n p atie nts: At t he e n d of treat me nt, fla g 
patie nts wit h m ore t ha n 5 da ys of o verla p of 
d a bigatra n a n d c o m mercial V K A +fla g a n y da ys of 
o verla p d uri n g t he treat me nt peri o d (e xce pt f or 
wa s h o ut of pre vi o us treat me nt/titrati o n at st u d y 
start (see I P V C 4))
Warfari n p atie nts: At t he e n d of treat me nt, fla g 
patie nts wit h m ore t ha n 1 da y of o verla p of 
w arfari n a n d c o m mercial V K A. +fla g a n y da ys of 
o verla p d uri n g t he treat me nt peri o d (e xce pt f or 
wa s h o ut of pre vi o us treat me nt/titrati o n at st u d y 
start (see I P V C 4))
6. A S A i n t he first 1 2 m o nt hs f or all patie nts –
e xce pt f or i n t he first m o nt h f or warfari n patie nts 
wit h a B M S or t he first t hree m o nt hs f or w arfari n 
patie nts wit h a D E S (c o nsec uti ve use of m ore t ha n 
1 4 da ys)
P P S


B oe hri n ger I n gel hei m
T S A P f or BI Tri al N o: 1 1 6 0. 1 8 6
P a ge 1 7 of 3 6
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 7 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
Ta ble 6. 2: 1 (c o nti n ue d)
I m p orta nt pr ot oc ol vi olati o ns
Cate g or y/
C o de
Descri pti o n
E xa m ple/ C o m me nt
E xcl u de d 
fr o m
D 2. 2
Pr o hi bite d use of he pari n
A n y o n -treat me nt use of he pari n w here 
n o me dical i n dicati o n is gi ve n.
P P S
D 3. 1
Ma n dat or y me dicati o n n ot ta ke n
per 
pr ot oc ol ( A S A)
A S A n ot ta ke n f or t he first m o nt h f or 
warfari n patie nts wit h a B M S or f or t he 
first t hree m o nt hs f or patie nts wit h a 
D E S as i n dicate d o n t he Tri al 
Me dic ati o n C o m pli a nce
e C R F pa ge 
(e xcl u de if at least o ne visit is tic ke d 
“ N o”).
P P S , b ut 
o nl y fr o m 
start of n o n -
c o m plia nce 
o n war ds
D 3. 2
Ma n dat or y me dicati o n n ot ta ke n per 
pr ot oc ol (cl o pi d o grel/tica grel or)
Cl o pi d o grel/tica grel or n o n -c o mplia nce   
d uri n g t he first 1 2 m o nt hs of treat me nt 
as i n dicate d o n t he T ri al M e dic ati o n 
C o m pli a nce e C R F pa ge (e xcl u de if at 
least o ne visit is tic ke d “ N o”).
P P S , b ut 
o nl y fr o m 
start of n o n -
c o m plia nce 
o n war ds
G
Trial S pecific Pr ot oc ol Vi olati o ns
G 1
Patie nt n ot wit h dra w n fr o m 
treat me nt if Cr Cl dr o ps t o 
< 3 0 m L/ mi n at t w o differe nt 
occasi o ns d uri n g t he trial
As per st u d y pr ot oc ol, t his o nl y a p plies 
t o patie nts ra n d o mise d t o da bi gatra n 
ete xilate.
P P S
K E Y: P P S – Per Pr ot oc ol Set
6. 3 
P A TI E N T S E T S A N A L Y S E D
T he f oll o wi n g a nal ys is sets will be defi ne d f or t his trial:

S C R – Scree ne d Set
All patie nts w h o si g ne d i nf or me d c o nse nt a n d c o m plete d at le ast s o me scree ni n g 
pr oce d ures.

F A S – F ull A nal ys is Set
All c o nse nti n g patie nts ra n d o mise d will be a nal ys e d i n t he treat me nt gr o u p t o w hic h t he y 
are ra n d o mise d re gar dless of w het her t he y t o o k st u d y me dicati o n. T he start date of t he 
o bser vati o n peri o d f or t his a nal y sis set is t he date of ra n d o misati o n.  T his f oll o ws t he 
i nte nt-t o-treat pri nci ple.  All patie nt listi n gs will be base d o n t he F A S e xce pt w here 
s pecifie d ot her wise.   Refer t o t he tec h nical T S A P f or m ore detail.

T S – Treate d Set
T he set of patie nts w h o recei ve at least o ne d ose of st u d y  me dicati o n will be a nalys e d 
acc or di n g t o t he treat me nt t he y  ha ve recei ve d.  T he start date of t he o bser vati o n peri o d f or 
t his a nal ysis set is t he date of first i nta ke of trial me dicati o n.


B oe hri n ger I n gel hei m
T S A P f or BI Tri al N o: 1 1 6 0. 1 8 6
P a ge 1 8 of 3 6
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 7 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies

P P S – Per- Pr ot oc ol Set
Patie nts will be i ncl u de d i n t he P P S, if t he y are alrea d y i ncl u de d i n t he T S a n d if t he y 
a d here t o t he trial pr ot oc ol wit h o ut a n y IP Vs. I P Vs are defi ne d i n Secti o n 6. 2 .
F or r ules o n ce ns ori n g, refer t o Secti o n 7. 4 .
T he fi nal decisi o n as t o w het her a patie nt is i ncl u de d i n or e xcl u de d fr o m eac h a nal ys is set 
will be ta ke n bef ore data base l oc k i n a bli n de d ma n ner, w here p ossi ble a n d will be 
d o c u me nte d i n t he mi n utes of t he R P M or Data base L oc k Meeti n g ( D B L M).   S o me decisi o ns 
ma y  nee d t o be ta ke n after D B L (e. g. treat me nt s witc hi n g). If t he n u m ber of patie nts 
e xcl u de d fr o m t he P P S is s mall ( < 1 0 % of t he T S), t he n a nalys es o n t his set ma y n ot be 
c o n d ucte d. T his decisi o n will als o be d oc u me nte d i n t he mi n utes of t he R P M or D B L M.
T he f oll o wi n g ta ble i de ntifies w hic h patie nt set is use d f or w hic h cate g or y of e n d p oi nts.


B oe hri n ger I n gel hei m
T S A P f or BI Tri al N o: 1 1 6 0. 1 8 6
P a ge 1 9 of 3 6
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 7 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
Ta ble 6. 3: 1
Patie nt sets a nal y se d
Patie nt set
Class of e n d p oi nt
F A S *
T S
P P S #
Pri mar y  e n d p oi nt (see Secti o n 5. 1 ) 
X  
X  
X
S ec o n dar y e n d p oi nts (see Secti o n 
5. 2. 2 )
X  
X
F urt her e n d p oi nts (s ee Secti o n 5. 3 )
X  
X
Safet y  e n d p oi nts ot her t ha n t he 
pri mar y  e n d p oi nt (see Secti o n 7. 8 )
X  
X
Ot her safet y  e n d p oi nts (see Secti o n 
7. 8. 5 )
X  
X
D e m o gra p hic/ baseli ne e n d p oi nts 
(see Secti o n 7. 1 )
X
X
N ote t hat t he n u m ber of patie nts wit h a vaila ble data f or a n e n d p oi nt ma y differ. F or details, see Secti o n 6. 6 .
* T he F A S will be t he mai n a nal ysis set f or t he s u m mar y of cli nical o utc o me e ve nt data.  Ot her a nal ysis sets 
will be use d f or se nsiti vit y p ur p oses.
# If t he n u m ber of patie nts e xcl u de d fr o m t he P P S is s mall ( < 1 0 % of t he T S), t he n a nal yses o n t his set ma y n ot 
be c o n d ucte d


B oe hri n ger I n gel hei m
T S A P f or BI Tri al N o: 1 1 6 0. 1 8 6
P a ge 2 0 of 3 6
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 7 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies


B oe hri n ger I n gel hei m
T S A P f or BI Tri al N o: 1 1 6 0. 1 8 6
P a ge 2 1 of 3 6
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 7 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
6. 5 
P O O LI N G O F C E N T R E S
T his secti o n is n ot a p plica ble beca use ce ntre/re gi o n is n ot i ncl u de d i n t he statistical m o del.  
H o we ver, c o nsiste nc y  of treat me nt effects acr oss re gi o nal s u b gr o u ps will be i n vesti gate d (see 
Secti o n 6. 4 ). 


B oe hri n ger I n gel hei m
T S A P f or BI Tri al N o: 1 1 6 0. 1 8 6
P a ge 2 2 of 3 6
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 7 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
6. 6
H A N D LI N G O F MI S SI N G D A T A A N D O U T LI E R S
A maj or g oal of t he trial is t o o btai n virt uall y  c o m plete f oll o w-u p of vital stat us a n d f ull 
c ollecti o n of o utc o me e ve nt data .  As me nti one d i n Secti o n 7. 4 , all patie nts l ost t o f oll o w-u p 
will be treate d as ce ns ore d at t he ti me of last k n o w n vital sta t us.  T his secti o n c o nta i ns details 
of h o w ce ns ori n g will be perf or me d f or patie nts w h o d o n ot e x perie nce o utc o me e ve n ts.
T he C T R will c o ntai n a s u m m ar y of t he n u m ber a n d perce nta ge of patie nts wit h (a n d 
wit h o ut) c o m plete f oll o w -u p of vital stat us i n eac h treat me nt gr o u p.
D ue t o t he nat ure of t he a dj u dicati o n pr ocess, it ma y n ot be p ossi ble t o classif y  blee ds u n der 
e ver y blee d defi niti o n (i.e. TI MI a n d B A R C). I n t hese i nsta nces, t he blee d classificati o n will 
be left missi n g a n d n o i m p utati o n will be atte m pte d. Classificati o n of blee ds u n der t he I S T H 
defi niti o ns s h o ul d n ot be left missi n g b y  t he I A C.
I n ge neral, missi n g i nvesti gat or I N R ra n ges will be i m p ute d wit h t he sta n dar d g ui deli ne ra n ge 
f or t his patie nt p o p ulati o n w hic h is 2- 3. T he e xce pti o n t o t his is f or patie nts i n Ja pa n w h o are 
7 0 y ears ol d. T he g ui deli ne ra n ge f or t hese patie nts is 2 – 2. 6.
Missi n g or i nc o m plete
A E dates /ti mes are i m p ute d acc or di n g t o BI sta n dar ds (see “ Ha n dli n g 
of mi ssi n g a n d i nc o m plete A E dates”) [1 ].  T he sa me p hil os o p h y will be a p plie d t o missi n g 
or i nc o m plete o utc o me e ve nt a n d c o nc o mita nt me dicati o n dates /ti mes.  Inc o m p lete dates of 
te m p orar y st u d y me dicati o n disc o nti n uati o n a n d restart will be i m p ute d. See t he T S A P 
A nal y sis Dataset ( A D S) Pla n f or f urt her details. Ot her s pecial ha n dli n g f or 
missi n g/i nc o m plete dates /ti mes will be d oc u me nte d i n t he R P M.
Ot her missi n g data will n ot be i m p ute d.  If date of birt h/a ge is missi n g f or a patie nt, t he y  will 
n ot be i ncl u de d i n m o dels t hat use a ge gr o u p as a stratif y i n g fact or.
6. 7
B A S E LI N E, TI M E WI N D O W S A N D C A L C U L A T E D VI SI T S
T he baseli ne assess me nt is t he last meas ure me nt ma de ( or s a m ple ta ke n) pri or t o first st u d y  
dr u g a d mi nistrati o n. T he first st u d y dr u g a d mi nistrati o n s h o ul d occ ur at Visit 2. A n y
assess me nts ma de o n t his da y, w here ti me is n ot c ollecte d, are ass u me d t o be pri or t o st u d y  
dr u g a d mi nistrati o n.  T his d oes n ot a p pl y  t o a d verse e ve nts a n d o utc o me e ve nts w here it will 
be ass u me d t hat e ve nts occ urre d o n -treat me nt.
C o nc o mita nt m e dicati o n is c o nsi dere d a baseli ne me dicati o n, if ta ke n o n t he da y  of 
ra n d o misati o n.
Act ual dates will be use d f or assi g ni n g a d verse e ve nts a n d o utc o me e ve nts t o t he a p pr o priate 
treat me nt peri o d as defi ne d i n Secti o n 6. 1 .  Wi n d o wi n g will n ot be a p plie d as t he mai n 
o bjecti ve of t his trial is t he c ollecti o n of o utc o me e ve nts, w h ic h are n ot necessaril y  ass ociate d 
wit h cli nic visits.


B oe hri n ger I n gel hei m
T S A P f or BI Tri al N o: 1 1 6 0. 1 8 6
P a ge 2 3 of 3 6
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 7 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
7.
P L A N N E D A N A L Y SI S
Patie nt dis p ositi o n ( n u m ber of patie nts scree ne d, ra n d o mise d, treate d, disc o nti n ue d, etc...) 
will be prese nte d f or all patie nts.
T he fre q ue nc y  of patie nts wit h IP V s will be prese nted . T h ose w hic h lea d t o a patie nt bei n g 
e xcl u de d fr o m t he P P S will be prese nte d se paratel y t o t h ose w hic h d o n ot .
Descri pti ve statistics f or c o nti n u o us varia bles will ge nerall y be n ( n u m ber of patie nts wit h 
n o n- missi n g val ues), mea n, sta n dar d de viati o n (S D ), mi ni m u m, Q 1 (l o wer q uartile), me dia n, 
Q 3 ( u p per q uartile), ma xi m u m. I n ge neral, mea ns, me dia ns, Q 1 a n d Q 3 will be prese nte d t o 
o ne m ore deci mal place t ha n t he ra w data a n d S Ds will be prese nte d t o t w o m ore deci mal 
places. Mi ni ma a n d ma xi ma will be prese n te d t o t he sa me n u m ber of deci mal places as t he 
ra w data.
Ta b ulati o ns of fre q ue ncies f or cate g orical data will i ncl u de all p ossi ble cate g ories a n d will 
dis pla y  t he n u m ber of o bser vati o ns i n a cate g or y as well as t he perce nta ge relati ve t o t he 
res pecti ve p o p ulati o n . Perce nta ges will be r o u n de d t o o ne deci mal place. A missi n g cate g or y  
will be dis pla y e d if a n d o nl y if t here are act uall y missi n g val ues. Perce nta ges will be base d 
o n all patie nts i n t he res pecti ve patie nt set w het her t he y  ha ve n o n-missi n g val ues or n ot.
7. 1
D E M O G R A P HI C A N D O T H E R B A S E LI N E C H A R A C T E R I S TI C S
Data fr o m t he de m o gra p hic , me dical hist or y, P CI details a n d me dicati o n hist or y e C R F pa ges 
will be prese nte d descri pti vel y b y  treat me nt gr o u p.
7. 2
C O N C O MI T A N T DI S E A S E S A N D M E DI C A TI O N
O nl y  descri pti ve statistics are pla n ne d f or t his secti o n of t he re p ort.
T he fre q ue nc y  of patie nts wit h differe nt c o nc o mita nt diseases ( baseli ne c o n diti o ns) will be 
prese nte d. 
Me dicati o ns will be classifie d usi n g t he W orl d Healt h Or ga nisati o n ( W H O) dicti o nar y  (i nt o
e. g. antit hr o m b otic t hera p ies, bri d gi n g me dicati o n s, P-g p i n hi bit ors, P -g p i n d ucers , etc...) a n d 
will be prese nte d acc or di n g t o w het her t he y  were c o nc o mita ntl y ta ke n d uri n g t he o n-
treat me nt peri o d (i g n ori n g t he R E P) defi ne d i n Sect i o n 6. 1 or w het her t he y are pri or (i.e. 
t h ose ta ke n at baseli ne ( =ra n d o mizati o n visit)) or p os t t hera py .  A d diti o nal p o oli n g of 
me dicati o n cate g ories ma y  als o be necessar y.
T he usa ge of eac h c o nc o mita nt me dicati o n of s pecial i nterest d uri n g t he treat me nt p eri o d 
(i g n ori n g te m p orar y i nterr u pti o ns) will be cate g orise d acc or di n g t o t he % of ti me t hat patie nts 
use d t hat me dicati o n:

Ne ver use d ( 0 %)
Use d at least o ne ti me

0 % < a n d ≤5 0 % of t he ti me


B oe hri n ger I n gel hei m
T S A P f or BI Tri al N o: 1 1 6 0. 1 8 6
P a ge 2 4 of 3 6
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 7 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies

5 0 % <a n d < 1 0 0 % of t he ti me

Al wa y s use d ( 1 0 0%)
O nl y  me dicati o ns i n t he f oll o wi n g cate g ories will be prese nte d:

A nti platelet me dicati o n

T hr o m b ol y tic a ge nts

N o vel direct oral a ntic oa g ula nts

Pare nteral a ntic oa g ula nts

Vita mi n K a nta g o nists

G PII b/ IIIa a nta g o nists

T hera pies f or blee di n g ma na ge me nt
Me dicati o ns ma y be c o m bi ne d or re m o ve d fr o m t he ta ble, if t o o fe w patie nts ha ve ta ke n t he m 
d uri n g t he treat me nt peri o d.
7. 3
T R E A T M E N T C O M P LI A N C E
C o m plia nce will be s u m maris e d descri pti vel y usi n g t he T S .  T he ti me peri o d after per ma ne nt 
disc o nti n uati o n fr o m st u d y me dicati o n a n d t he ti me peri o d d uri n g a n y te m p orar y 
disc o nti n uati o n of st u d y  me dicati o n will n ot be i ncl u de d i n t he calc ulati o n of t he 
de n o mi nat or .
C o m plia nce t o da bi gatra n ete xilate
Base d o n ca ps ule c o u nts, treat me nt c o m plia nce ( %) will be calc ulate d as :
N u m ber of ta blets act uall y  ta ke n 1 0 0
N u m ber of ta blets w hic h s h o ul d ha ve bee n ta ke n
T his val ue will be e ntere d directl y  i nt o t he e C R F.
F or patie nts w h o ha d a te m p orar y disc o nti n uati o n of da bi gatra n ete xilate, t he ti me i nter val 
bet wee n t he da y after te m porar y  disc o nti n uati o n a n d restart of me dicati o n s h o ul d n ot be use d 
i n t he calc ulati o n of t he de n o mi nat or .
A patie nt will be c o nsi dere d as n o n -c o m plia nt f or a partic ular d osi n g i nter val if t he n u m ber of 
d oses ta ke n is n ot bet wee n 8 0 - 1 2 0 % of t he e x pecte d n u m ber of d oses.
Descri pti ve statistics will be prese nte d f or patie nts’ o verall c o m plia nce wit h da bi gatra n 
ete xilate d uri n g t he treat me nt peri o d. T his will be assesse d usi n g i nf or mati o n fr o m t he trial 
me dicati o n c o m plia nce e C R F pa ge. Mea n c o m plia nce will b e calc ulate d per patie nt b y 
wei g hti n g t heir re p orte d % c o m plia nce acc or di n g t o h o w l o n g it has bee n si nce t heir last 
cli nic visit.
T he mea n c o m plia nce a n d t he perce nta ge of patie nts wit h c o m plia nce < 5 0 %, 5 0 - < 8 0 %, 8 0 -
< 1 2 0 %, 1 2 0 % will be s u m marise d b y  visit a n d o verall.


B oe hri n ger I n gel hei m
T S A P f or BI Tri al N o: 1 1 6 0. 1 8 6
P a ge 2 5 of 3 6
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 7 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
Ti me i n t hera pe utic ra n ge ( T T R, w arfari n )
T he q ualit y  of warfari n t hera p y f or eac h patie nt will be assesse d b y re p orti n g t he n u m ber of 
I nter nati o nal N or malise d Rati o (I N R) val ues wit hi n t he i n vesti gat or i n dicate d t hera pe utic 
tar get ra n ge at t he ti me of t he meas ure me nt, as well as t h ose a b o ve a n d bel o w t hese ra n ges. 
T he f oll o wi n g a d diti o nal ra n ges will be i n vesti gate d: 2. 0 t o 3. 0, 2. 0 t o 2. 5 a n d 2. 5 t o 3. 0.  T he
R ose n daal met h o d will be use d t o e val uate t he perce nta ge of ti me t hat a patie nt’s I N R is i n 
ra n ge (i.e. ti me i n t hera pe utic ra n ge, T T R). T his will be calc ulate d f or eac h patie nt, f or eac h 
ce ntre, f or eac h c o u ntr y a n d f or t he w h ole st u dy. T he mea n a n d me dia n perce nta ge of ti me i n 
tar get I N R ra n ge will be calc ulate d f or eac h ce ntre a n d eac h c o u ntr y d uri n g t he trial c o n d uct 
t o m o nit or t he IN R c o ntr ol . T he perce nta ge of ti me i n tar get I N R ra n ge f or eac h c o u ntr y a n d 
f or t he trial will be re p orte d.
F or patie nts w h o ha d a te m p orar y disc o nti n uati o n of st u d y warfari n, t he ti me i nter val 
bet wee n t he da y after t he te m p orar y disc o nti n uati o n a n d restart of me dicati o n will n ot be 
c o u nte d. If I N R is e val uate d duri n g t he first wee k after ra n d o misati o n, t hose I N R val ues will 
n ot be u se d i n calc ulati n g T T R.
T he R ose n daal met h o d: ass u me t he I N R val ue bet wee n t w o meas ure me nts will var y  li nearly 
fr o m t he val ue of t he first t o t he val ue of t he sec o n d meas ure me nt, di vi de t he ti me bet wee n 
t w o meas ure me nts i n da ys, fit a li near e q uati o n usi n g t he t w o meas ure d I NR val ues, a n d t he n 
calc ulate t he I N R f or eac h da y i n t he i nter val.  T he perce nta ge of ti me w he n I N R is i n tar get 
ra n ge is calc ulate d f or eac h patie nt. T he i nte n de d tar get ra n ge f or eac h patie nt is i n dicate d b y 
t he i n vesti gat or o n t he IN R l o g pa ge of t he e C R F.
T he fre q ue nc y  of t he I N R m o nit ori n g will be assesse d usi n g descri pti ve statistics.
E val uati o n of I N R meas ure me nt s will i ncl u de t he f oll o wi n g:
Mea n a n d me dia n perce nta ge of ti me i n tar get I N R ra n ge o ver ti me
Fre q ue nc y  of patie nts wi t h perce nta ge of ti me i n tar get I N R ra n ge: < 4 5 %, ≥4 5- < 5 5 %, ≥5 5-
< 6 5 % a n d ≥6 5 % 
Fre q ue nc y  of patients wit h perce nta ge of ti me i n tar get I N R ra n ge: < 6 0 %, ≥6 0- < 7 5 % a n d ≥
7 5 %
Me dicati o n i nterr u pti o ns :
T he n u m ber of p atie nts wit h te m p orar y i nterr u pti o ns of st u d y me dicati o ns a n d t he reas o ns f or 
t he i nterr u pti o ns will be s u m maris e d.  I n a d diti o n, t he nu m ber of da y s wit h i nterr u pti o ns of 
st u d y me dicati o ns will be s u m mar ise d descri pti vel y. T his will n ot i ncl u de t he a d diti o n of t he 
R E P ( 6 da y s).  T he n u m ber of pa tie nts wit h per ma ne nt i nterr u pti o ns of st u d y me dicati o n are 
s u m marise d i n t he patie nt dis p ositi o n ta bles.
7. 4
P RI M A R Y E N D P OI N T
T his is a pr os pecti ve, ra n d o mise d, o pe n la bel, bli n de d e n d p oi nt ( P R O B E), acti ve c o m parat or 
trial a n d t he cli nical e n d p oi nts are bei n g a dj u dicate d b y a n I A C i n a bli n de d fas hi o n. T he I A C 


B oe hri n ger I n gel hei m
T S A P f or BI Tri al N o: 1 1 6 0. 1 8 6
P a ge 2 6 of 3 6
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 7 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
C harter c o ntai ns details of t he o utc o me e ve nt a dj u dicati o n criteria.  T he st u d y  will e m pl o y a 
ti me t o first e ve nt a nalys is ( usi n g a stratifie d C o x pr o p orti o nal hazar ds re gressi o n m o del) a n d 
it is assu me d t hat all patie nt s will be o bser ve d u ntil first pri mar y e n d p oi nt e ve nt or u ntil t he 
last patie nt e ntere d has c o m plete d at least si x m o nt hs of treat me nt ( u p t o a n a ntici pate d 
ma xi m u m d urati o n of a p pr o xi matel y  3 0 m o nt hs f or t he first patie nt e ntere d).  The trial will be 
m o nit ore d b y  a n i n de pe n de nt D M C.
T his st u d y  is desi g ne d t o test t w o safety h y p ot heses i n N V A F patie nts t hat ha ve u n der g o ne a 
s uccessf ul P CI (electi ve or d ue t o A C S) wit h ste nti n g a n d were treat me nt naï ve or were 
recei vi n g oral a ntic oa g ula nt treat me nt (eit her wit h warfari n, a n ot her V K A or ot her n o vel oral 
a ntic oa g ula nt) bef ore t he pr oce d ure.
T he pri mar y  e n d p oi nt, meas ure d fr o m date of ra n d o misati o n t o e n d of o bser vati o n peri o d, is: 

Ti me t o first I ST H M B E
or C R N M B E
as deter mi ne d b y t he I AC.  O nl y  p ositi vel y a dj u dicate d e ve nts will be i ncl u de d i n t he 
a nal ys es.  T he y  will be a nal yse d usi n g t he stratifie d C o x pr o p orti o nal hazar ds re gressi o n 
m o del i ncl u di n g a ge gr o u p ( n o n-el derl y or el derl y [ <7 0 or ≥7 0 ye ars ol d i n Ja pa n a n d < 8 0 or 
≥8 0 y ears ol d e ver yw here else] ) as a stratif yi n g fact or a n d treat me nt ar m ( 1 1 0 m g D E -D A T vs 
warfari n -T A T a n d 1 5 0 m g D E -D A T a n d 1 1 0 m g D E -D A T c o m bi ne d vs warfari n -T A T ). F or 
t he 1 5 0 m g D E -D A T vers us warfari n -T A T c o m paris o n, a n u nstratifie d m o del will be a p plie d
c o m pari n g 1 5 0 m g D E -D A T vers us warfari n -T A T (e xcl u di n g el derl y E U/ R O W patie nts i n t he 
warfari n - T A T gr o u p).  I n a d diti o n, a n u nstratifie d se nsiti vit y a nalys is of t he n o n-el derl y 
patie nts o nl y  will be c o n d ucte d.
M o dels will be fitte d f or
eac h c o m paris o n se paratel y ( 1 1 0 m g D E-D A T vs warfari n -T A T a n d 
1 5 0 m g D E -D A T vs warfari n -T A T) .  T he Bresl o w met h o d [9 ] will be use d t o ha n dle tie d 
fail ure ti mes.
T he pri mar y  a nalys is will be perf or me d u n der t he i nte nti o n-t o-treat fra me w or k o n t he F A S .  
Patie nts w h o disc o nti n ue st u d y  me dicati o n will be f oll o we d u ntil t he e n d of t he trial f or vital 
stat us, E C Gs, AE s, OEs (i ncl u di n g c o m pleti o n of t he blee di n g q uesti o n naire) a n d 
c o nc o mita nt me dicati o ns.   All patie nts will be a nal y se d acc or di n g t o t he treat me nt ar m t o 
w hic h t he y  were ra n d o mise d.
S ur vi val ti me
F or t h ose patie nts wit h a n O E wit hi n t he a nal ys is peri o d, t he s ur vi val ti me will be calc ulate d 
as:
< date of e ve nt > - <date of ra n d o misati o n > + 1
F or t h ose patie nts wit h o ut a n O E wi t hi n t he a nalys is peri o d, t he ce ns ore d s ur vi val ti me will 
be calc ulate d as 
< ce ns ori n g date as per bel o w > - <date of ra n d o misati o n > + 1
W he n
ce ntres are i nf or me d a b o ut t he st u d y e n d, t he y will sc he d ule E O T visits f or t h ose 
patie nts t hat di d n ot alrea d y  ha ve t heir E O T visit.  As t his is t he desi g n of t he st u d y , t h ose 


B oe hri n ger I n gel hei m
T S A P f or BI Tri al N o: 1 1 6 0. 1 8 6
P a ge 2 7 of 3 6
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 7 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
patie nt’s E O T visits d o n ot relate t o a n y patie nt c o n diti o ns.  T heref ore , f or t he pri mar y 
a nal ys is, patie nts wh o di d n ot pre mat urel y st o p trial me dicati o n (as d oc u me nte d o n t he 
“ter mi nati o n of trial me dicati o n” ( TT M ) C R F pa ge) will be ce ns ore d at t heir E O T visit.  I f 
s uc h a patie nt w h o di d n ot pre mat urel y st o p trial me dicati o n as per t he TT M C R F pa ge , base d 
o n t he call of t he ce ntre f or t he E O T visit, has st o p pe d st u d y  me dicati o n bef ore t he E O T, t he 
date of last trial me dicati o n i nta ke will be use d f or ce ns ori n g p ur p oses (if a vaila ble), as it was 
tri g gere d by t he i nf or mati o n o n e n d of t he st u d y.   F or patie nts w h o alrea d y ha d t heir E O T 
visit (i.e. t h ose w h o st o p pe d treat me nt pre mat urel y  acc or di n g t o t he TT M C R F pa ge ), t he y 
will be ce ns ore d at t he date of t heir fi nal visit. Ce ntres were as ke d t o sc he d ule fi nal visits f or 
a n y pre mat urely disc o nti n ue d patie nts bet wee n 1 st Fe b 2 0 1 7 a n d 3 0 t h A pril 2 0 1 7 . In or der t o 
acc o u nt f or patie nts f or w h o m pre mat u re treat me nt disc o nti n uati o n occ urs rat her late d uri n g 
t he trial c o n d uct, t he first visit w hic h occ urs after t he date of 1 st Fe b 2 0 1 7 will be use d t o 
ce ns or t hese patie nts.
F or patie nts w here t his data is n ot a vaila ble, t he ce ns ori n g will be base d o n t he d ate last see n .  
Dates use d i n deter mi ni n g t he date last see n are:
•
Date of E O T visit
•
Date of last i nta ke of st u d y  me dicati o n
•
Date of f oll o w -u p visit
•
Date of last k n o w n vital stat us , if a vaila ble (i ncl u di n g i nf or mati o n o btai ne d b y a t hir d 
part y , w here p ossi ble ) if patie nts wit h dra w fr o m t he st u d y [ data c ollecte d o n t he vital 
stat us f or m a n d t he T E R M pa ge]
•
Date of wit h dra wal of c o nse nt b y  t he patie nt (if a p plica ble)
•
Date of deat h (if a patie nt dies).
•
Date of a n y e ve nt re p orte d o n t he O E pa ges of t he e C R F or dates c o nfir me d b y  
a dj u dicati o n
F or patie nts wit h D T Es a n d ot her O Es t hat i ncl u de deat h (see Secti o n 7. 5. 2 ), t he date of deat h 
will n ot be use d f or ce ns ori n g p ur p ose s, b ut i nstea d will c o u nt as a n e ve nt. I n ge neral, if t he 
date last see n c oi nci des wit h t he date of a ny o utc o me e ve nt re p orte d, t his o utc o me e ve nt will 
be c o u nte d f or t he pri mar y a nal ys is.
T hese ce ns ori n g r ules deter mi ne t he “ti me at ris k” f or c o u nti n g of e ve nts f or t he pri mar y  
a nal ys is.
T he r o b ust ness of t he pri mar y a nal ys is will be assesse d b y a n o n-treat me nt a nalys is of t he T S
a n d t he P P S .  T he sa me ce ns ori n g r ules as defi ne d a b o ve will be use d.  H o we ver, f or patie nts 
w h o alrea d y ha d t heir E O T visit (i.e. t h ose w h o st o p pe d treat me nt pre mat urel y ), t he y will be 
ce ns ored at t he date of t heir last trial me dicati o n i nta ke pl us 6 da y s. It will als o a nalys e 
patie nts b y  t he act ual treat me nt ta ke n.
T he ce ns ori n g r ules defi ne d f or t he o n -treat me nt a nal ysis deter mi ne t he “ti me at ris k” f or 
c o u nti n g of e ve nts f or t he o n -treat me nt a nalys is, i.e. t he o n-treat me nt a nalysis will o nl y  c o u nt 
e ve nts t hat occ ur w hile a patie nt is ta ki n g st u d y me dicati o n ( + R E P of 6 da ys, if st u d y 


B oe hri n ger I n gel hei m
T S A P f or BI Tri al N o: 1 1 6 0. 1 8 6
P a ge 2 8 of 3 6
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 7 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
me dicati o n is st o p pe d pre mat urel y bef ore st u d y e n d ).  T he date of first i nta ke of st u d y 
me dicati o n wil l be use d as t he start of t he a nal ysis peri o d i n t his a nal ysis i nstea d of t he date 
of ra n d o misati o n.  I nter mitte nt off-treat me nt peri o ds will be i g n ore d i n cases of a n y 
te m p orar y i nterr u pti o ns i n st u d y me dicati o n.
T hese a nal y ses will be base d o n t he T S a n d t he o n-treat me nt peri o d.
T he pr o p orti o nal hazar ds ass u m pti o n will be i n vesti gate d f or t he pri mar y a nal ysis o nly. T he 
f oll o wi n g tec h ni q ues will be use d:
Pl otti n g l o g ( -l o g (s ur vi val f u ncti o n)) a gai nst t he l o g of ti me b y treat me nt gr o u p.  
Parallel c ur ves are c o nsiste nt wit h t he pr o p orti o nal hazar ds ass u m pti o n.
A d di n g ti me -de pe n de nt varia bles t o t he C o x m o del
F or eac h varia ble i n t he m o del a n i nteracti o n ter m is deri ve d b y m ulti pl yi n g b y t he l o g 
of ti me a n d a d di n g t o t he m o del. N o n- si g nifica nce at t he 5 % le vel is c o nsiste nt wit h 
t he pr o p orti o nal hazar ds ass u m pti o n.
A s u m mar y  of a dj u dicati o n will be prese nte d s h o wi n g t he n u m ber of i n vesti gat or-re p orte d 
O E s al o n g wit h w het her t he y were p ositi vel y or ne gati vely a dj u dicate d or w het her t he y  were 
n o n- assessa ble . F urt her a nal ys es will be perf or me d o n i n vesti gat or re p orte d e ve nts (i.e. t h ose 
t hat are p ositi vely a n d ne gati vel y a dj u dicate d).   A se nsiti vit y a nalys is will be perf or me d t hat 
i ncl u des a ny n o n -assessa ble e ve nts i nt o t he p ositi vel y a dj u dicate d MB E/ C R N M B E cate g or y .
T w o safet y h y p ot heses ( 1 1 0 m g D E - D A T vs. warfari n-T A T a n d 1 5 0 m g D E -D A T vs. 
warfari n -T A T) will be teste d:
1.
1 1 0 m g D E -D A T is n o n -i nferi or t o warfari n- T A T wit h res pect t o M B E /C R N M B E
o ver t he d urati o n of t he trial
2.
1 5 0 m g D E -D A T is n o n -i nferi or t o warfari n- T A T wit h res pect t o M B E /C R N M B E
o ver t he d urati o n of t he trial.
T o c o ntr ol t he T y pe I err or rate at a o ne -si de d 0. 0 2 5 le vel, a hierarc hical pr oce d ure f or 
m ulti ple testi n g will be use d t o test t he a b o ve h y p ot heses. A d diti o nal testi n g f or safet y  an d 
efficac y e n d p oi nts will als o be i ncl u de d i n t his hierarc hical pr oce d ure. T he f oll o wi n g 
hierarc hical pr oce d ure will be a p plie d : 
Ste p 1 – N o n -i nferi ority of 1 1 0 m g D E - D A T t o warfari n- T A T i n M B E/ C R N M B E is met at 
t he o ne-si de d 0. 0 2 5 le vel of si g nifica nce
St e p 2 – N o n -i nferi ority of 1 5 0 m g D E -D A T t o warfari n- T A T i n M B E/ C R N M B E is met at 
t he o ne-si de d 0. 0 2 5 le vel of si g nifica nce
Ste p 3 – N o n i nferi orit y  of 1 5 0 m g D E- D A T a n d 1 1 0 m g D E-D A T c o m bi ne d t o warfari n -T A T 
i n D T E a n d u n pla n ne d re vasc ularisati o n by P CI / C A B G is met at t he o ne-si de d 0. 0 2 5 le vel of 
si g nifica nce


B oe hri n ger I n gel hei m
T S A P f or BI Tri al N o: 1 1 6 0. 1 8 6
P a ge 2 9 of 3 6
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 7 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
Ste p 4 – S u peri orit y  of 1 1 0 m g D E- D A T t o warfari n- T A T i n M B E/ C R N M B E is met at t he 
o ne -si de d 0. 0 2 5 le vel of si g nifica nce 
Ste p 5 – N o n i nferi orit y  of 1 5 0 m g D E- D A T a n d 1 1 0 m g D E-D A T c o m bi ne d t o warfari n -T A T 
i n D T E is met at t he o ne -si de d 0. 0 2 5 le vel of si g nifica nce
Ste p 6 – S u peri orit y  of 1 5 0 m g D E-D A T t o warfari n -T A T i n M B E/ C R N M B E is met at t he 
o ne- si de d 0. 0 2 5 le vel of si g nifica nce
If a ny of t he ste ps a b o ve fail t o meet statistical si g nifica nce, t he testi n g pr oc e d ure will st o p at 
t hat ste p a n d s u bse q ue nt tests will n ot be perf or me d.
T he N o n -I nferi ority ( NI ) mar gi n use d will be 1. 3 8 ( o n t he relati ve hazar d rati o ( H R ) scale).  
See Secti o n 7. 6 of t he C T P f or a cli nical j ustificati o n of t his mar gi n.  T he u p per b o u n d of t he 
Wal d c o nfi de nce i nter val ( CI ) of t he H R of D E- D A T vs. warfari n-T A T ( o ne -si de d 9 7. 5 %) 
will be c o m pare d t o t his NI mar gi n f or t he NI testi n g.
Ka pla n -Meier s ur vi val fi g ures will be prese nt e d b y treat me nt gr o u p/strata a n d b y treat me nt 
gr o u p .
Fre q ue nc y  c o u nts will be pr o vi de d s h o wi n g t he n u m ber of patie nts e x perie nci n g rec urre nt 
e ve nts. I n a d diti o n, t he n u m ber of e ve nts will be prese nte d as f oll o ws: t he n u m ber of i nitial 
e ve nts, t he n u m ber of a d diti o nal e ve nts a n d t he t otal n u m ber of e ve nts. I ST H M B Es a n d 
C R N M B Es will be prese nte d se paratel y a n d c o m bi ne d i n t hese s u m maries.
7. 5
S E C O N D A R Y E N D P OI N T S
7. 5. 1
Ke y sec o n d ar y e n d p oi nts
T his secti o n is n o t a p plica ble as n o ke y sec o n dar y e n d p oi nts ha ve bee n s pecifie d i n t he 
pr ot oc ol.
7. 5. 2
( Ot her) Sec o n d ar y e n d p oi nts
Ot her s ec o n dar y efficac y e n d p oi nts (all ti me t o first e ve nt, meas ure d fr o m date of 
ra n d o misati o n t o e n d of o bser vati o n peri o d) are:

A c o m bi ne d e n d p oi nt of D T E a n d u n pla n ne d re vasc ularisati o n b y  P CI/ C A B G

A c o m bi ne d e n d p oi nt of D T E

I n di vi d ual OE s:
o
All deat hs
- Car di o vasc ular deat h
- N o n -car di ovasc ular deat h
- U n deter mi ne d
o
MI
o
Str o ke
o
S E
o
Ste nt t hr o m b osis ( defi nite)


B oe hri n ger I n gel hei m
T S A P f or BI Tri al N o: 1 1 6 0. 1 8 6
P a ge 3 0 of 3 6
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 7 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies

C o m p osite of deat h + MI + str o ke

U n pla n ne d re vasc ularisati o n b y P CI / C A B G
Ti me t o first e ve nt e n d p oi nts will be a nal y se d usi n g t he sa me met h o ds as f or t he pri mar y  
e n d p oi nt.  H o we ver, c o m paris o ns will be f or s u peri orit y  of 1 1 0 m g D E -D A T o ver warfari n -
T A T , 1 5 0 m g D E-D A T o ver warfari n -T A T a n d 1 5 0 m g D E -D A T a n d 1 1 0 m g D E -D A T 
c o m bi ne d o ver warfari n -T A T (f or D T E/ u n pla n ne d re vasc ularisati o n a n d D T E, NI will be 
teste d first).  N o m ulti plicit y  a dj ust me nts are pla n ne d f or sec o n dar y e n d p oi nts, u nless t he y 
are part of t he hierarc hical pr oce d ure (see Secti o n 7. 4 ).  N o mi nal o ne -si de d p-val ues will be 
re p orte d f or descri pti ve p ur p oses.  F or a nal ys is of ste nt t hr o m b osis, Ka pla n Meier pl ots will 
be pr o vi de d a d diti o nall y b y  ste nt ty pe ( D E S, B M S,..) a n d b y “ I n de x P CI f or A C S vs. electi ve 
i n de x P CI ( n o n-A C S)”.
O nl y  p ositi vel y a dj udicate d e ve nts will be i ncl u de d i n t he a nal ys es.  Sec o n dar y  a nalys es will 
als o i ncl u de prese ntati o ns of n u m ber ( %) of patie nts wit h e ve nts.
All sec o n dar y  a nal ys es will be perf or me d o n t he F A S. T he r o b ust ness of t hese a nal ys es will 
be assesse d b y o n -treat ment a nal ys es of t he T S . 
F urt her se nsiti vit y  a nalys es will be perf or me d o n i n vesti gat or re p orte d e ve nts (i.e. t h ose t hat 
are p ositi vel y a n d ne gati vel y a dj u dicate d).   P ost -treat me nt e ve nts will als o be s u m marise d
an d a s u m mar y  of a dj u dicati o n will be prese nte d s h o wi n g t he n u m ber of i n vesti gat or -re p orte d 
O E s al o n g wit h w het her t he y were p ositi vel y or ne gati vely a dj u dicate d or w h et her t he y were 
n o n -assessable .
Fre q ue nc y  c o u nts will be pr o vi de d s h o wi n g t he n u m ber of patie nts e x perie nci n g rec urre nt 
e ve nts b y  e n d p oi nt. T he n u m ber of e ve nts will be prese nte d as f oll o ws: t he n u m ber of i nitial 
e ve nts, t he n u m ber of a d diti o nal e ve nts a n d t he t otal n u m ber of e ve nts. I n di vi d ual o utc o me 
e ve nts ( wit h t he e xce pti o n of deat h), as descri be d a b o ve, will be prese nte d i n t hese 
s u m maries.


B oe hri n ger I n gel hei m
T S A P f or BI Tri al N o: 1 1 6 0. 1 8 6
P a ge 3 1 of 3 6
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 7 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
7. 7 
E X T E N T O F E X P O S U R E
D urati o n of e x p os u re is calc ulate d i n da ys as:
Date of last a d mi nistrati o n of trial me dicati o n – date of first a d mi nistrati o n of trial me dicati o n 
+ 1.
If t he date of t he first i nta ke of st u d y me dicati o n is missi n g, t he ra n d o misati o n date will be 
use d t o calc ulate e x p os ure.
T otal treat me nt ti me t heref ore i ncl u des ti me w he n treat me nt was te m p oraril y  disc o nti n ue d
a n d s u bse q ue ntl y rei ntr o d uce d. Descri pti ve statistics a n d fre q ue nc y  c o u nts as descri be d i n 
Secti o n 7 will be prese nte d f or e xte nt of e x p os ure. C ate g orisati o ns f or t otal treat me nt ti me are 
defi ne d as f oll o ws:

< 3 m o nt hs

3 m o nt hs - < 6 m o nt hs

6 m o nt hs - < 1 2 m o nt hs

1 2 m o nt hs - < 1 8 m o nt hs

1 8 m o nt hs -  < 2 4 m o nt hs

2 4 m o nt hs -  < 3 0 m o nt hs

≥3 0 m o nt hs
I n a d diti o n, e xte nt of e x p os ure ta ki n g i nt o acc o u nt a n y te m p orar y disc o nti n uati o ns i n st u d y 
me dicati o n will be c o m p ute d ( R E P n ot i ncl u de d).
7. 8
S A F E T Y A N A L Y SI S
T his secti o n descri bes t he a nal ys is of sta n dar d safet y data s uc h as a d verse e ve nts, la b orat or y 
data, vital si g ns, E C Gs, etc.  T he a nal ys is of blee di n g o utc o me e ve nt data is c o vere d i n 
Secti o n 7. 6 .  All safet y a nal yses will be perf or me d o n t he T S (i ncl u di n g t he R E P, w here 
a p plica ble). 
7. 8. 1
A d verse e ve nts
T he a nal ys es of a d verse e ve nts will be descri pti ve i n nat ure. All a nal ys es of A E s will be 
base d o n t he n u m ber (a n d %) of patie nts wit h A E s a n d n ot o n t he n u m ber of A Es. I n a d diti o n 
t o t he us ual s u m maries of a d verse e ve nts, s o me a nal yses will be base d o n t he n u m ber of A Es 
per patie nt ye ar.
F urt her m ore, f or a nal ys is of A E attri b utes s uc h as d urati o n, se verity, etc. m ulti ple A E 
occ urre nce data o n t he e C R F, will be c olla pse d i nt o A E e pis o des pr o vi de d t hat all of t he 
f oll o wi n g a p plies:
•
T he sa me Me d D R A l o west le vel ter m was re p orte d f or t he occ urre nces


B oe hri n ger I n gel hei m
T S A P f or BI Tri al N o: 1 1 6 0. 1 8 6
P a ge 3 2 of 3 6
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 7 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
•
T he occ urre nces were ti me -o verla p pi n g or ti me -a djace nt (ti me-a djace nc y of 
2 occ urre nces is gi ve n if t he sec o n d occ urre nce starte d o n t he sa me da y or o n t he da y 
after t he e n d of t he first occ urre nce )
•
Treat me nt di d n ot c ha n ge bet wee n t he o nset of t he occ urre nces or treat me nt c ha n ge d 
bet wee n t he o nset of t he occ urre nces, b ut n o deteri orati o n was o bser ve d f or t he later 
occ urre n ce
F or f urt her details o n s u m marizati o n of A E data, please refer t o t he g ui deli ne ‘Ha n dli n g a n d 
s u m marizati o n of a d verse e ve nt data f or cli nical trial re p orts a n d i nte grate d s u m maries’ [ 2 ].
T he a nal ys is of a d verse e ve nts will be base d o n t he c o nce pt of treat me nt e mer ge nt a d verse 
e ve nts. Refer t o Secti o n 6. 1 f or a f ull list of t he differe nt treat me nt peri o ds t o w hic h a d verse 
e vents will be assi g ne d base d o n t he o nset da te/ti me of t he e ve nt.  I n ge neral, a d verse e ve nts 
attri b ute d t o ‘ Scree ni n g’, ‘ P ost-treat me nt’ or ‘P ost -st u d y’ will be liste d o nl y .
A n o verall s u m mar y  of a d verse e vents will be prese nte d. 
Se parate s u m maries will be create d f or patie nts wit h seri o us a d vers e e ve nts. 
A E s will als o be a nalys e d wit h res pect t o dr u g relati o ns hi p, w orst i nte nsit y a n d 
disc o nti n uati o ns of st u d y dr u g.
A d verse e ve nts per patie nt y ear will be s u m marise d b y  treat me nt, pri mar y s yste m or ga n class 
( S O C) a n d preferre d ter m ( P T). T he S O C s will be s orte d acc or di n g t o t he sta n dar d s ort or der 
s pecifie d by t he E ur o pea n A ge nc y  f or t he E val uati o n of Me dici nal Pr o d ucts ( E MA).  T he 
P T s will be s orte d b y desce n di n g i nci de nce wit hi n S O C. T he n u m ber of e ve nts per patie nt 
ye ar is calc ulate d per treat me nt ar m as f oll o ws:
e x p os ure
da ys
of
n u m ber 
3 6 5. 2 5
A E
 wit h
patie nts
of
n u m ber 
t otal

F urt her details will be pr o vi de d i n t he tec h nical T S A P (c o m pre he nsi ve list of ta bles, fi g ures, 
a n d listi n gs, e xa m ple ta ble a n d listi n g te m plates a n d A D S s pecificati o ns).
7. 8. 2
L a b or at or y d at a
C ha n ges i n la b orat or y data will be re p orte d descri pti vel y  a n d will be base d o n BI sta n dar ds 
[3 ].
O nl y  ce ntral la b orat or y data will be s u m marise d. L ocal la b orat or y data will be liste d 
se paratel y. T he f oll o wi n g dis pla ys will be prese nte d:

C ha n ge fr o m baseli ne i n la b orat or y  para meters o ver ti me ( ori gi nal val ues)

Fre q ue nc y  of patie nts cate g orise d b y refere nce ra n ge at baseli ne a n d last val ue o n-
treat me nt, mi ni m u m val ue p ost- baseli ne or ma xi m u m val ue p ost-baseli ne

Fre q ue nc y  of patie nts wit h tra nsiti o ns relati ve t o t he refere nce ra n ge


B oe hri n ger I n gel hei m
T S A P f or BI Tri al N o: 1 1 6 0. 1 8 6
P a ge 3 3 of 3 6
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 7 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies

Fre q ue nc y  of patie nts wit h p ossi bl y cli nically si g nifica nt a b n or malities (as defi ne d by t he 
I n vesti gat or)

Descri pti ve statistics f or baseli ne, last val ue o n -treat me nt, a n d differe nce fr o m baseli ne

La b orat or y  val ues o ver ti me b y  para meter
Cr Cl will be esti mate d base d o n ser u m creati ni ne a n d use of t he C oc kr oft -Ga ult e q uati o n (see 
Secti o n 5. 2. 3 of t he C T P).  Cr Cl will als o be esti mate d usi n g t he M D R D a n d C K D- E PI  
e q uati o ns.
7. 8. 3
Vit al si g ns
O nl y  descri pti ve statistics are pla n ne d f or t his secti o n of t he re p ort .
7. 8. 4
E C G
E C Gs will be e val uate d ce ntrall y  b y a n e xter nal ve n d or.  S u m mar y  statistics will be dis pla ye d 
at baseli ne a n d f urt her s u m maries will be pr o d uce d f or t he n u m ber of patie nts w h o de vel o p 
si g nifica nt Q wa ves, atrial fl utter, atrial fi brillati o n, S T se g me nt c ha n ges a n d ot her c ha n ges.
I n a d diti o n, E C G a b n or malities will be s u m marise d i n t he A E or baseli ne c o n diti o ns ta bles.
7. 8. 5
Ot hers
Ot her safet y  e n d p oi nts are:
1. I ST H M B E
2. C R N M B E
3. Cli nicall y  rele va nt blee di n g meas ure d usi n g t he f oll o wi n g defi niti o ns:
 
Blee di n g Aca de mic Researc h C o ns orti u m ( B A R C) ≥3

TI MI  gr o u p – Maj or , Mi n or
a n d Mi ni mal
4 . Mi n or a n d t otal blee di n g (IS T H, B A R C a n d TI MI)
5 . Intracra nial hae m orr ha ge
6 . Gastr oi ntesti nal blee ds
7. L ife-t hreate nin g blee ds
8. Fatal blee ds
T hese e n d p oi nts will be a nal y se d usi n g t he sa me met h o ds as t he pri mar y e n d p oi nt. N o
m ulti plicit y  a dj ust me nts are pla n ne d f or safety e n d p oi nts.   Se nsiti vit y  a nal yses will o nly be 
d o ne t o a li mite d e xte nt (see Ta ble 6. 3: 1 ) a n d m o del ass u m pti o n c hec ki n g will n ot be 
perf or me d.
M o difie d Ra n ki n Scale
( m R S)
F or patie nts wit h a n o utc o me e ve nt of str o ke, fre q ue nc y  c o u nts will be prese nte d f or eac h 
gra de of t he m R S at eac h ti me p oi nt (at ti me of str o ke a n d 9 0 da y s t hereafter).


B oe hri n ger I n gel hei m
T S A P f or BI Tri al N o: 1 1 6 0. 1 8 6
P a ge 3 4 of 3 6
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 7 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
8.
R E F E R E N C E S
1
0 0 1- M C G- 1 5 6 _ R D -0 1 : “Ha n dli n g of missi n g a n d i nc o m plete A E dates ”, 
c urre nt versi o n; I D E A f or C O N .
2
0 0 1- M C G- 1 5 6 : “Ha n dli n g a n d s u m marizati o n of a d verse e ve nt data f or 
cli nical trial re p orts a n d i nte grate d s u m maries”, c urre nt versi o n; I D E A f or 
C O N.
3
0 0 1- M C G- 1 5 7 : “Dis pla y  a n d A nalys is of La b orat or y Data”, c urre nt versio n, 
I DE A f or C O N.
4
C P M P/I C H/ 3 6 3/ 9 6 : “Statistical P ri nci ples f or Cli nical Trials ”, I C H G ui deli ne 
T o pic E 9, N ote f or G ui da nce o n Statistical Pri nci ples f or Cli nical Trials, 
c urre nt versi o n.
5
Cli nical Trial Pr ot oc ol Versi o n 4 [c 0 2 2 1 4 3 8 5- 0 9]
6
Li p G Y H, Nie u wlaat R, Pisters R, L a ne D A, Crij ns HJ G M. Refi ni n g Cli nical 
Ris k Stratificati o n f or Pre dicti n g Str o ke a n d T hr o m b oe m b olis m i n Atrial
Fi brillati o n Usi n g a N o vel Ris k Fact or- Base d A p pr oac h : t he E ur o Heart 
S ur ve y  o n Atrial Fi brillati o n. C hest 1 3 7 ( 2), 2 6 3 - 2 7 2 ( 2 0 1 0) [ R 1 0- 5 3 3 2]
7
Pisters R, L a ne D A, Nie u wlaat R, V os C B de, Crij ns HJ G M, L i p G Y H. A 
n o vel user -frie n dly sc ore ( H A S -B L E D) t o assess 1 -ye ar ris k of maj or 
blee di n g i n patie nts wit h atrial fi brillati o n: t he E ur o Heart S ur ve y . C hest 1 3 8 
(5 ), 1 0 9 3 - 1 1 0 0 ( 2 0 1 0) [ R 1 0- 6 3 9 4]
8
Ma uri L , Kereia kes DJ, N or ma n d S L T, Wi vi ott S D, C o he n DJ, H ol mes D R,
Ba n gal ore S, C utli p D E, Pe nci na M, Massar o J M. Rati o nale a n d desi g n of t he 
d ual a nti platelet t hera p y st u d y, a pr os pecti ve, m ultice nter, ra n d o mize d,
d o u ble - bli n d trial t o assess t he effecti ve ness a n d safet y of 1 2 vers us 3 0 
m o nt hs of d ual a nti platelet t hera p y  i n s u bjects u n der g oi n g perc uta ne o us 
c or o nar y i nter ve nti o n wit h eit her dr u g-el uti n g ste nt or bare metal ste nt 
place me nt f or t he treat me nt of c or o nar y arter y lesi o ns. A m Heart J 1 6 0 ( 6 ), 
1 0 3 5 – 1 0 4 1.e 1 ( 2 0 1 0) [ R 1 3- 4 1 3 7]
9
Bresl o w, N . C o varia nce a nalys is of ce ns ore d s ur vi val data, Bi o metrics 3 0, 8 9
- 9 9 ( 1 9 7 4) [ R 1 4- 2 0 2 3]
1 0
Ra n ucci M, Castle vecc hi o S, Me nica nti L , Fri gi ola A, Pelisser o G. Ris k of 
assessi n g m ortalit y ris k i n electi ve car diac o perati o ns: a ge, creati ni ne, ejecti o n 
fracti o n, a n d t he la w of parsi m o n y. Circ ulati o n 1 1 9 ( 2 4), 3 0 5 3 - 3 0 6 1 ( 2 0 0 9)
[ R 1 7-0 5 0 3]
1 1
Gi bs o n C M, Pi nt o D S, C hi G, Ar better D, Yee M, Me hra n R, et al.  Rec urre n t 
h os pitalizati o n a m o n g patie nts wit h atrial fi brillati o n u n der g oi n g 
i ntrac or o nar y ste nti n g treate d wit h 2 treat me nt strate gies of ri var o xa ba n or a 
d ose -a dj uste d oral vita mi n K a nta g o nist treat me nt strate g y . Circ ulati o n 1 3 5 
( 4), 3 2 3 - 3 3 3 ( 2 0 1 7) [ R 1 7- 0 6 1 0]


B oe hri n ger I n gel hei m
T S A P f or BI Tri al N o: 1 1 6 0. 1 8 6
P a ge 3 5 of 3 6
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 7 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies


B oe hri n ger I n gel hei m
T S A P f or BI Tri al N o: 1 1 6 0. 1 8 6
P a ge 3 6 of 3 6
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 7 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
1 0.
HI S T O R Y T A B L E
Ta ble 1 0: 1
Hist or y  ta ble
Versi o n
D ate
( D D-M m m- Y Y)
A ut h or
Secti o ns 
c h a n ge d
Brief descri pti o n of c h a n ge
1
1 4 - Ma y -1 4
N o ne 
T his is t he first T S A P w it h o ut a n y 
m o dificati o n
Fi nal
9- J u n -1 7
All
U p date d d ue t o gl o bal pr ot oc ol 
a me n d me nts 1, 2 a n d 3 .