GLORIA - AF: Global Registry on Long-Term Oral Anti-thrombotic Treatment In Patients With Atrial Fibrillation (Phase II/III)
Conditions: Stroke, Atrial Fibrillation
Sponsor: Boehringer Ingelheim

 
SIGNATURE INFORMATION 
 
Document: 
                               
                           
Document No.:                                                                                                                        
 
Title 
                             
 
 
 
 
 
 
                         
 
SIGNATURES  (ELECTRONICALLY OBTAINED)  
 
Meaning of Signature: 
Signed by: 
Date signed: (GMT) 
                                   
 
 
 
                               
                                                                                 
                                   
 
 
 
                               
                                                                                 
                                   
 
 
 
                               
                                                                                 
                                   
 
 
 
                               
                                                                                 
                                   
 
 
 
                               
                                                                                 
                                  
 
 
 
                               
                                                                                 
                                   
 
 
 
                               
                                                                                 
1160-129-gloria-phase-IV-protocol-revision-04
U11-1638-03
GLORIA - AF: Global Registry on Long-Term Oral Anti-thrombotic
TReatment In PAtients with Atrial Fibrillation
Author-Trial Clinical Monitor
6/7/2013 19:39:00
Approval-Team Member Medicine
6/8/2013 13:31:43
Qualified Person
Pharmacovigilance
6/8/2013 15:13:03
Approval-Therapeutic Area 
6/9/2013 10:32:03
Approval-Other
6/9/2013 12:30:11
Author-Trial Statistician
6/10/2013 06:56:41
Author-Team Member Medicine
6/10/2013 07:18:14

 
SIGNATURE INFORMATION (continued) 
Document 
                              
                          
Document No.:                                                                                                                        
 
Title 
                             
 
 
 
 
 
 
                         
SIGNATURES  (ELECTRONICALLY OBTAINED)  
(There are no entries on this page if there are up to seven signatures.) 
Meaning of Signature: 
Signed by: 
Date signed: (GMT) 
                                   
 
 
 
                               
                                                                                         
                                   
 
 
 
                               
                                                                                         
                                   
 
 
 
                               
                                                                                         
                                     
 
 
 
                                 
                                                                                                                      
                                     
 
 
                                 
                                                                                                                      
                                     
 
 
                               
                                                                                                                       
                                     
 
 
                                
                                                                                                                       
                                     
 
 
                                 
                                                                                                                     
 
1160-129-gloria-phase-IV-protocol-revision-04
U11-1638-03
GLORIA - AF: Global Registry on Long-Term Oral Anti-thrombotic
TReatment In PAtients with Atrial Fibrillation
Author-Other
6/10/2013 09:28:29
Author-Clinical Monitor - On
behalf of 
6/10/2013 14:16:41
Verify Paper Signature Completion
6/13/2013 20:16:44

 
Post Marketing Surveillance        
Non-interventional Study Protocol  
 
Doc. No.: U11-1638-04 
 
BI Study No.: 
1160.129 
 
BI Investigational 
Product(s): 
Pradaxa  
Title: 
GLORIA - AF: Global Registry on Long-Term Oral Anti-thrombotic 
TReatment In PAtients with Atrial Fibrillation 
(Phase II/III) 
Clinical Phase: 
IV 
Trial Clinical 
Monitor: 
Telephone: 
Telefax:
Telephone:
 
Telefax:    
Chairman/ Co-
Chairman of the 
Steering Committee:  
Telephone: 
 
Telefax: 
 
 
Telephone: 
 
Telefax: 
 
Status: 
Final Protocol Global Amendment 1 
Version and Date: 
Version: 
3.04.0 
Date: 19 July 2011  7 JUNE 2013 
 
Page 1 of 70 
Proprietary confidential information.  
© 2013 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 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 2 of 70 
 
LOCAL SIGNATURES 
(PRINCIPAL INVESTIGATOR OF SITE AND LOCAL CLINICAL MONITOR 
(CML)) 
PMSNon-Interventional Study Title: GLORIA - AF: Global Registry on Long-Term Oral 
Antithrombotic TReatment In PAtients with Atrial Fibrillation 
(Phase II/III) 
Trial Number: 1160.129 
Protocol Version: 3.0 4.0 
 
Local Clinical Monitor: 
 
 
 
 
 
Date 
 
Name 
 
 
 
Full name 
 
 
Organization/Department 
 
 
 
<Add other signatories if applicable.> 
 
 
 
I herewith certify that I agree to adhere to the observational plan and to all 
documents referenced in the observational plan. 
 
 
Principal Investigator (site): 
 
 
 
 
 
 
 
 
Date 
 
Name 
 
 
 
Full name 
 
 
 
Organization/Department 
Signed signature page is located in the electronic Clinical Trial Master File 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 3 of 70 
 
POST MARKETING SURVEILLANCE NON-INTERVENTIONAL 
STUDY PROTOCOL SYNOPSIS 
 
Name of company/Marketing Authorization 
Holder: 
Tabulated 
Study Protocol 
 
Boehringer Ingelheim 
 
Name of finished product: 
PRADAXA 
Name of active ingredient: 
 
Dabigatran (dabigatran etexilate = prodrug) 
 
Protocol date: 
Trial number: 
 
Revision date: 7 June 
2013 
8 June 2011 
1160.129 
Title of study: 
GLORIA-AF: Global Registry, on Long-Term Oral Anti-thrombotic TReatment In 
PAtients with Atrial Fibrillation. 
This protocol describes Phases II and III  (of three phases in total) of the Registry 
Program 
Study site(s) : 
Overall up to about 2,200 sites (including e.g. hospitals, anticoagulant clinics, 
specialists and general practice settings) in up to 60 countries in 5 regions of the world 
Clinical phase: 
IV 
Objectives: 
To investigate the patient characteristics influencing the choice of antithrombotic 
treatment for the prevention of stroke in non-valvular atrial fibrillation (AF) patients. 
To collect real world data on important outcome events of antithrombotic treatments 
for the prevention of stroke. 
Methodology: 
International, multicenter, prospective observational study for patients with newly 
diagnosed non-valvular atrial fibrillation. 
The Registry Program will be run in three different phases. Phase I is conducted 
before approval of dabigatran. This protocol describes the two phases after dabigatran 
is approved for preventing strokes in patients with atrial fibrillation (SPAF) in 
participating countries (Phases II and III).  The phases differ regarding the handling of 
the follow-up period. In Phase II (after the approval of dabigatran), there will be a 
cross-sectional analysis at the patient’s baseline visit for all patients and a follow-up 
for two years for patients initially treated with dabigatran. 
In Phase III (given the comparability of the patient population prescribed either 
dabigatran or vitamin K-antagonists), new patient recruitment will be started and after 
the baseline visit all patients will be followed up for three years regardless of 
antithrombotic therapy treatment status.  
The baseline visit is defined as the physical visit when the patient is enrolled in the 
registry. 
Patients will either participate in Phase II or Phase III. 
zNo. of patients:  
In total, enrolment of up to approximately 16,000 patients in Phase II and another 
32,000 patients in Phase III is planned. 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 4 of 70 
 
Name of company/Marketing Authorization 
Holder: 
Tabulated 
Study Protocol 
 
Boehringer Ingelheim 
 
Name of finished product: 
PRADAXA 
Name of active ingredient: 
 
Dabigatran (dabigatran etexilate = prodrug) 
 
Protocol date: 
Trial number: 
 
Revision date: 7 June 
2013 
8 June 2011 
1160.129 
Diagnosis: 
Patients newly diagnosed with non-valvular atrial fibrillation  
Main criteria for 
inclusion: 
Patients newly diagnosed with non-valvular atrial fibrillation (diagnosed < 3 months 
before patient’s baseline visit) and at risk for stroke (CHA2DS2-VASc score of at 
least 1), aged 18 years or older. 
Duration of follow up: 2 years for patients initiating dabigatran (Phase II); 3 years for all patients (Phase III) 
irrespective of anticoagulation treatment status 
Outcomes:  
Collect data on patient demographics, AF disease information, antithrombotic 
treatment, medical history and concomitant medication at the patient’s baseline visit. 
The patients will be followed for 2 (Phase II) and 3 years (Phase III) respectively and 
information such as change in antithrombotic medication since previous visit 
including compliance and occurrence of any outcome or safety events will be 
captured. In Phase II, follow-up information will be collected for those patients 
initiating dabigatran, in Phase III for all patients. 
Criteria for safety: 
SAEs, ADRs and major and life threatening bleeds 
Statistical methods: 
Descriptive statistics for patient characteristics and treatment patterns, multivariable 
regression models for analyzing predictors of outcomes and for comparative 
analyses.o 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 5 of 70 
 
FLOW CHART 
OVERVIEW 
Phase of 
registry 
Baseline 
(time point 
of start of 
observation) 
Time point 1 
3 months 
from baseline 
(only phase 
II) 
Time point 2 
 6 months 
from 
baseline  
Time point 3 
 12 months 
from baseline 
Time point 4 
24 months 
from 
baseline 
Time point 5 
36 months 
from baseline 
II* 
V-B 
V1§ 
V2§ 
V3§ 
V4 § 
 
III* 
V-B 
- 
V1 
V2 
V3 
V4 
* 
 Individual patients will take part either in Phase II or in Phase III. 
§ 
   Should be performed only in patients initially receiving dabigatran in Phase II 
V-B    Baseline Visit 
V 
   Follow-up Visit 
 
PHASE II 
Data points  
Baseline  
(V-B) 
time point of 
start of 
observation 
Time point 1 
(V1) 
3 months  
from baseline  
(± 1 month)  
Time point 2 
(V2) 
6 months  
from baseline  
(± 1 month) 
Time point 3 
(V3) 
12 months 
from baseline 
(± 2 months) 
Time point 4 
(V4)  
24 months 
from baseline  
(± 2 months) 
 
All patients 
Patients treated with dabigatran only 
Informed consent 
X 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Lifestyle factors 
X 
 
 
 
 
AF disease 
characteristics 
X 
 
 
 
 
Medical history 
including current 
concomitant 
diseases 
X 
 
 
 
 
Concomitant 
diseases (current, 
any change) 
 
X 
X 
X 
X 
 
 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 6 of 70 
 
PHASE II continued 
 
Antithrombotic 
treatment  
X1 
X2 
X2 
X2 
X2 
Selected 
concomitant 
treatment (current, 
any change) 
X 
X 
X 
X 
X 
Collect serum 
creatinine 
information (if 
available) 
X 
X 
X 
X 
X 
Outcome events 
(Vascular and 
bleeding events)3 
 
X 
X 
X 
X 
Therapeutic/ 
diagnostic 
intervention 
 
X 
X 
X 
X 
Serious adverse 
events 4 
 
X 
X 
X 
X 
Non-serious 
adverse drug 
reactions5 
 
X 
X 
X 
X 
Vital Status 
 
X 
V-B 
Baseline Visit 
V 
Follow-up Visit 
 
1. 
Antithrombotic treatment prescribed for stroke prevention in patients with atrial fibrillation at baseline. 
2. 
Antithrombotic treatment (current, any change) including compliance. Changes include temporary/ permanent 
discontinuation and switch to another antithrombotic medication for stroke prevention in patients with atrial 
fibrillation 
3. 
Includes outcome events defined in Section 5. Outcome events, irrespective of causal relationship with dabigatran 
or any other BI concomitant medication, are to be recorded on SAE or AE forms available in the registry eCRF. If 
the outcome event is serious and deemed to be causally related to dabigatran or other BI drug the SAE form will be 
submitted in an expedited manner to the Sponsor. 
4. 
Serious adverse events (SAEs) irrespective of causal relationship with dabigatran or any other BI concomitant 
medication are to be recorded on SAE forms available in the registry eCRF. If SAE, is deemed to be causally 
related to dabigatran or other BI drug the SAE form will be submitted in an expedited manner to the Sponsor 
5. 
Non-serious adverse drug reactions are defined as non-serious adverse events (AEs) with a causal relationship to 
dabigatran, or any other BI concomitant medication, or any other antithrombotic and should be recorded on AE 
forms available in the registry eCRF only. Non-serious adverse events (AEs) that are NOT deemed RELATED to 
(i.e. caused by) dabigatran, or to any other BI concomitant medication, or any other antithrombotic, SHOULD 
NOT BE RECORDED in the registry eCRF.   

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 7 of 70 
 
Phase III 
 
 
 
 
 
Data points  
Baseline  
(V-B) 
time point of 
start of 
observation 
Time point 1 
V1 
6 months from 
baseline  
(± 1 month) 
Time point 2 
V2 
12 months 
from baseline  
(± 2 months) 
Time point 3 
V3 
24 months 
from baseline  
(± 2 months) 
Time point 4 
V4 
36 months 
from baseline 
(± 2 months) 
Informed consent 
X 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Lifestyle factors 
X 
 
 
 
AF disease 
characteristics 
X 
 
 
 
 
Medical history 
including current 
concomitant 
diseases 
X 
 
 
 
 
Concomitant 
diseases (current, 
any change) 
 
X 
X 
X 
X 
Antithrombotic 
treatment  
X1 
X2 
X2 
X2 
X2 
Selected 
concomitant 
treatment (current, 
any change) 
X 
X 
X 
X 
X 
Collect serum 
creatinine 
information (if 
available) 
X 
X 
X 
X 
X 
Outcome events 
(Vascular and 
bleeding events)3 
 
X 
X 
X 
X 
Therapeutic/ 
diagnostic 
intervention 
 
X 
X 
X 
X 
Serious adverse 
events4 
 
X 
X 
X 
X 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 8 of 70 
 
Non-serious adverse 
drug reactions5 
 
X 
X 
X 
X 
Vital Status 
 
 
 
 
X 
V-B 
Baseline visit 
V 
Follow-up Visit 
 
1. 
Antithrombotic treatment prescribed for stroke prevention in patients with atrial fibrillation at baseline 
2. 
Antithrombotic treatment (current, any change) including compliance. Changes include temporary/ permanent 
discontinuation and switch to another antithrombotic medication for stroke prevention in patients with atrial 
fibrillation. 
3. 
Includes outcome events defined in Section 5. Outcome events, irrespective of causal relationship with dabigatran, 
any other antithrombotic treatment or any other BI concomitant medication, are to be recorded on SAE or AE 
forms in the registry eCRF. If the outcome event is serious and deemed to be causally related to dabigatran or any 
other BI drug the SAE form will be submitted in an expedited manner to the Sponsor. 
4. 
Serious adverse events (SAEs) irrespective of causal relationship with dabigatran, any other antithrombotic 
treatment or any other BI concomitant medication are to be recorded on SAE forms in the registry eCRF. If SAE, 
is deemed to be causally related to dabigatran or any other BI drug the SAE form will be submitted in an expedited 
manner  to the Sponsor 
5. 
Non-serious adverse drug reactions are defined as non-serious adverse events (AEs) with a causal relationship to 
dabigatran, any other antithrombotic treatment, or any other BI concomitant medication, and should be recorded 
on AE forms available in the registry eCRF only. Non-serious adverse events (AEs) that are NOT deemed 
RELATED to (i.e. caused by) dabigatran, other BI drugs or antithrombotic therapy SHOULD NOT BE 
INCLUDED in registry eCRF. 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 9 of 70 
 
TABLE OF CONTENTS 
TITLE PAGE .................................................................................................... 1 
POST MARKETING SURVEILLANCE NON-INTERVENTIONAL 
STUDY PROTOCOL SYNOPSIS ........................................................... 3 
FLOW CHART ................................................................................................. 5 
TABLE OF CONTENTS ................................................................................. 9 
ABBREVIATIONS ......................................................................................... 11 
1. 
INTRODUCTION ................................................................................... 13 
1.1 MEDICAL BACKGROUND ............................................................................ 13 
1.2 DRUG PROFILE ............................................................................................... 14 
1.3 GLORIA-AF PROGRAM ................................................................................. 14 
1.4 RATIONALE FOR PERFORMING THE REGISTRY PROGRAM .......... 15 
2. 
RATIONALE, OBJECTIVES, AND BENEFIT-RISK 
ASSESSMENT ........................................................................................ 16 
2.1 RATIONALE FOR PERFORMING THE STUDY ....................................... 16 
2.2 STUDY OBJECTIVES ...................................................................................... 16 
2.2.1 Main Objective ....................................................................................... 16 
2.2.2.  Further Objective ................................................................................... 16 
2.3 BENEFIT-RISK ASSESSMENT ..................................................................... 16 
3. 
DESCRIPTION OF DESIGN AND STUDY POPULATION ............ 17 
3.1 OVERALL DESIGN AND PLAN .................................................................... 17 
3.1.1 Administrative structure of the study .................................................. 18 
3.2 DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S) ..................................................................................... 19 
3.2.1 Potential for bias and confounding ...................................................... 19 
3.3 SELECTION OF POPULATION .................................................................... 21 
3.3.1 Main diagnosis for study entry ............................................................. 21 
3.3.2 Inclusion criteria .................................................................................... 21 
3.3.3 Exclusion criteria ................................................................................... 22 
3.3.4 Removal of patients from therapy or assessments .............................. 22 
3.3.4.1 Removal of individual patients ................................................... 22 
3.3.4.2 Discontinuation of the study by the sponsor .............................. 23 
4. 
TREATMENTS ....................................................................................... 24 
4.1 PRESCRIBED TREATMENTS TO BE OBSERVED ................................... 24 
4.2 CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT .................................................................................................... 24 
4.3 TREATMENT COMPLIANCE ....................................................................... 24 
5. 
VARIABLES AND THEIR ASSESSMENT ........................................ 25 
5.1 OUTCOMES ...................................................................................................... 25 
5.1.1 Outcome measures ................................................................................. 25 
5.1.2 Assessment of outcome measures ......................................................... 25 
5.2 SAFETY .............................................................................................................. 28 
5.2.1 Endpoint(s) of safety .............................................................................. 28 
5.2.2 Assessment of adverse events ................................................................ 28 
5.2.2.1 Definitions of adverse events ..................................................... 28 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 10 of 70 
 
5.2.2.2 Adverse event and serious adverse event reporting ................... 29 
5.3 OTHER ............................................................................................................... 32 
5.4 APPROPRIATENESS OF MEASUREMENTS ............................................. 32 
6. 
INVESTIGATIONAL PLAN ................................................................. 33 
6.1 VISIT SCHEDULE ............................................................................................ 33 
6.2 DETAILS OF STUDY PROCEDURES AT SELECTED VISITS ............... 33 
6.2.1 Assessments in Phase II of GLORIA-AF ............................................. 33 
6.2.2 Assessments in Phase III of GLORIA-AF ........................................... 35 
6.2.3 End of study and follow-up period ....................................................... 35 
7. 
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE ........................................................................................ 37 
7.1 STATISTICAL DESIGN - MODEL ................................................................ 37 
7.2 NULL AND ALTERNATIVE HYPOTHESES .............................................. 37 
7.3 PLANNED ANALYSES .................................................................................... 37 
7.3.1 Main analyses ......................................................................................... 38 
7.3.3 Safety analyses ........................................................................................ 41 
7.3.4 Interim analyses ..................................................................................... 42 
7.4 HANDLING OF MISSING DATA .................................................................. 43 
7.5. RANDOMISATION .......................................................................................... 43 
7.6 DETERMINATION OF SAMPLE SIZE ........................................................ 44 
8. 
INFORMED CONSENT, DATA PROTECTION, STUDY 
RECORDS ............................................................................................... 48 
8.1 STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT .......................................................................................................... 48 
8.2 DATA QUALITY ASSURANCE ..................................................................... 48 
8.3 RECORDS .......................................................................................................... 49 
8.3.1 Source documents .................................................................................. 49 
8.3.2 Direct access to source data and documents ........................................ 50 
8.4 PROCEDURES FOR REPORTING ADVERSE EVENTS .......................... 50 
8.4.1 Time windows ......................................................................................... 50 
8.4.2 Documentation of adverse events and patient narratives .................. 50 
8.5 STATEMENT OF CONFIDENTIALITY ....................................................... 50 
8.6 COMPLETION OF STUDY ............................................................................. 51 
8.7 PUBLICATION POLICY ................................................................................. 51 
9. 
REFERENCES ........................................................................................ 52 
9.1 PUBLISHED REFERENCES........................................................................... 52 
9.2 UNPUBLISHED REFERENCES ..................................................................... 55 
10. APPENDICES ......................................................................................... 56 
10.1 RISK SCORES FOR AF PATIENTS .............................................................. 56 
10.2 CREATININE CLEARANCE .......................................................................... 59 
10.3 LIST OF PLANNED REGIONS AND COUNTRIES PER REGION ......... 60 
11. DESCRIPTION OF GLOBAL AMENDMENT(S) ............................... 61 
 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 11 of 70 
 
ABBREVIATIONS 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AF 
Atrial Fibrillation 
BI 
Boehringer Ingelheim  
CA 
Competent (Regulatory) Authority 
CI 
Confidence Interval 
CML 
Local Clinical Monitor  
CRA 
Clinical Research Associate 
CRO 
Clinical Research Organization 
CRF 
Case Report Form 
CrS 
Serum Creatinine Concentration 
CTMF 
Clinical Trial Master File 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
EEA 
European Economic Area 
EF 
Ejection Fraction 
EU 
European Union 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
ICH 
International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ISF 
Investigator Site File 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 12 of 70 
 
LV 
Left Ventricular 
LVD 
Left Ventricular Dysfunction 
MedDRA 
Medical Dictionary for Drug Regulatory Activities 
MI 
Myocardial Infarction 
NYHA 
New York Heart Association 
OPU 
Operative Unit 
PAD 
Peripheral Artery Disease 
PCI 
Percutaneous Coronary Intervention 
SAE 
Serious Adverse Event 
SEAP 
Statistical and Epidemiological Analysis Plan 
SPAF 
Stroke Prevention in Atrial Fibrillation 
TCM 
Trial Clinical Monitor 
TIA 
Transient Ischemic Attack 
VKA 
Vitamin K Antagonist 
 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 13 of 70 
 
1. 
INTRODUCTION 
For consistency reasons the name of the active moiety (dabigatran) of the product Pradaxa® 
is used throughout this document. 
1.1 
MEDICAL BACKGROUND 
Atrial fibrillation (AF) is the most common cardiac arrhythmia and affects approximately 1-
2% of the population (R03-1233).  It is estimated that 6 million people in Europe and 2.7 
million people in the USA suffer from AF (P10-10141, P06-08196). The lifetime risk for 
development of AF is one in four for those over the age of 40 years (R09-4884). 
The prevalence of AF rises with advancing age, increasing from less than 1% in those below 
60 years of age to nearly 20% in those 85 years of age and older (R09-4875).  The overall 
prevalence of AF is also increasing; hospital admissions for AF have increased 60% over the 
past 20 years (R10-1345). The prevalence of AF is estimated to double by 2050 due to the 
aging of the world’s population (R03-1233). 
Thromboembolic complications – particularly stroke – are a major cause of morbidity and 
mortality in patients with AF. Most cases of stroke in patients with AF are the result of 
embolization of a left atrial thrombus, and particularly from the left atrial appendage. Patients 
with AF have a four- to five-fold higher risk for stroke than those without AF (R96-0252, 
R03-1241). Up to 15% of all strokes are due to AF and strokes in patients with AF have 
worse outcomes with higher mortality rates than strokes in patients without AF (R09-4892). 
The risk of stroke and systemic embolization in patients with AF is affected by patient risk 
factors, including a history of previous stroke or TIA, hypertension, left ventricular 
dysfunction (LVD), congestive heart failure (CHF), advanced age, diabetes mellitus, and 
coronary artery disease. Patients without any of these risk factors, i.e., lone AF, have a lower 
likelihood for the occurrence of stroke, thromboembolic events and stroke-related mortality 
(R03-1229, P06-08196, R03-1241). The classic CHADS2 (Congestive heart failure, 
Hypertension, Age > 75, Diabetes, prior Stroke/transient ischemic attack; see Appendix 10.1) 
score is a risk score that was developed to be a simple method for clinicians to assess the risk 
of stroke and thromboembolism in patients with AF (P06-10925).  Given that the CHADS2 
score does not include many stroke risk factors, a modification has been developed 
(CHA2DS2-VASc score, see Appendix 10.1) to refine its predictive value for stroke and 
thromboembolic events (R10-5332, P10-10141).  
Most cases of stroke due to AF are preventable by the use of antithrombotic therapy.  A meta-
analysis of all well-controlled trials demonstrated that warfarin decreased the risk of 
stroke/systemic embolism on average by 62% versus placebo, while antiplatelet therapy 
reduced the occurrence of stroke by 22% compared to placebo, although when the analysis is 
confined to the aspirin only trials, aspirin reduces stroke by a non-significant 19% (95% CI: -
1% to 35%) compared to placebo (P07-07953, R03-1227). Oral anticoagulation with vitamin 
K antagonists (VKAs, e.g. warfarin) is currently the most used treatment for stroke 
prevention in AF patients at moderate to high-risk of stroke (P10-10141, P07-04925, P06-
08196, P10-00811). However, VKAs have important limitations including a narrow 
therapeutic window, an unpredictable dose–response effect, numerous drug-drug and drug-
food interactions, and a slow onset and offset of action. As a result, many patients with AF do 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 14 of 70 
 
not receive VKAs but receive ASA, other antiplatelet agents, both or no antithrombotic 
therapy (R03-1241). Even when VKAs are used, regular anticoagulation monitoring and dose 
adjustments are needed to achieve effective anticoagulation with VKAs.  
In a real-world setting, VKA treatment often results in INR values outside of the target 
therapeutic range (R10-0768, R09-1522), leaving patients at increased risk of stroke or 
bleeding. To address the many shortcomings of VKAs, multiple new oral anticoagulants are 
in clinical development including mainly direct thrombin inhibitors and factor Xa inhibitors 
(P07-08370).  Dabigatran, a direct thrombin inhibitor, has recently been approved for the 
prevention of stroke and systemic emboli in patients with AF in the United States, Canada, 
Japan, Australia, as well as in Korea, and is expected to be approved in the EU countries, in 
mid-2011 and in many other countries throughout the worldyears 2011and 2012. In the RE-
LY trial, an 18,113 randomized clinical patient study (P09-11669) dabigatran (150 mg b.i.d.) 
has been shown to significantly reduce the occurrence of stroke (both ischemic and 
hemorrhagic) and systemic emboli compared to warfarin while having a comparable rate of 
major bleeding.  In the same trial dabigatran (110 mg b.i.d.) was demonstrated to be non-
inferior to warfarin for the prevention of stroke and systemic emboli while resulting in 
statistically significant fewer major bleeds in the same study.  Importantly, both doses of 
dabigatran reduced the occurrence of intracranial hemorrhage in a statistically significant 
manner compared to warfarin (P09-11669).  Of note, dabigatran has been taken up as 
adequate treatment alternative to VKAs in major treatment guidelines (e.g. USA, Canada, 
EU) during recent revisions (P11-00444, P10-14910, P10-10141, P10-14358) 
With the approval of novel anticoagulants for stroke prevention in patients with AF, changes 
in antithrombotic treatment patterns will occur. The GLORIA-AF Registry Program is 
designed to collect real-world data to assess these changes. 
1.2 
DRUG PROFILE 
Dabigatran etexilate is the orally bioavailable prodrug of dabigatran, a direct thrombin 
inhibitor. The prodrug (dabigatran etexilate) does not have any antithrombin activity. 
Following oral administration it is rapidly converted via esterases to the active moiety, 
dabigatran, which is a non-peptidic, potent, competitive, and reversible inhibitor of thrombin. 
For further information refer to the local approved label. 
1.3 
GLORIA-AF PROGRAM 
The GLORIA-AF Registry Program consists of three phases and is an observational study. It 
is designed to characterize newly diagnosed patients with non-valvular atrial fibrillation at 
risk for stroke in different regions of the world and to describe current patterns of 
antithrombotic treatments selected at the patient’s baseline visit.  The baseline visit of each 
phase is defined as the visit in which the patient is enrolled into the registry.  In addition, 
safety data and outcomes of such patients will be collected in Phase II and III of the Registry 
program. Phase I is described in a separate protocol (study 1160.114; U11-1009-02) and is 
only related to the pre-approval time. The present protocol describes the combined Phase II 
and III of the GLORIA-AF Registry Program. 
The inclusion criteria for the different phases of the GLORIA-AF Registry Program are the 
same in all three phases. In each phase newly diagnosed non-valvular AF patients at risk of 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 15 of 70 
 
stroke, as characterized by a CHA2DS2-VASc score of at least 1 (for derivation of the score 
see Appendix 10.1) are planned to be included (R10-5332).  
The introduction of new antithrombotic therapies for the prevention of stroke in patients with 
AF is changing treatment decisions.  Dabigatran is the first of these new treatment choices 
and has been approved in an ever increasing number of countries for the prevention of stroke 
and systemic emboli. Therefore, Phase I of this Registry Program is conducted only in 
countries where dabigatran is not yet approved in order to describe the patient population and 
the treatments selected for stroke prevention in different regions of the world before the 
introduction of new oral anticoagulant therapies.  Phases II and III will focus on the time after 
the introduction of new oral anticoagulant therapies, as defined by the approval of dabigatran 
in the respective country, and will also collect data on safety and outcome events of 
antithrombotic therapies for stroke prevention. 
In all phases, data will be collected to characterize patients at the time of the baseline visit 
including the treatment strategy selected. In Phase I (before approval of dabigatran) no 
further follow-up data are collected. In Phase II (after the approval of dabigatran in a 
country), a two year follow-up for newly diagnosed AF patients initiating dabigatran 
treatment will be added.  In Phase III, which only starts after comparability has been 
established between important patient baseline characteristics of those initiating dabigatran 
and those initiating VKAs, a three-year follow-up for all patients will be conducted.  
1.4 
RATIONALE FOR PERFORMING THE REGISTRY PROGRAM 
When evaluating new drugs, the collection of real-world data is important for studying large 
patient numbers that include a broad spectrum of comorbidities and co-medication use with 
the use of the new drug. Observational studies can provide supplementary data to data 
collected in randomized clinical trials, which generally have stricter inclusion criteria and 
structured monitoring schemes. 
VKAs have been shown to be effective in preventing strokes and systemic emboli in 
controlled clinical trials, but despite these data, they are not prescribed to as many as one half 
of the AF patients for whom they are indicated (R09-1482, R09-1483, R10-0756). The 
approval of new antithrombotic agents for the prevention of stroke in AF patients is expected 
to alter the use of existing antithrombotic agents and there is consequently a need to 
understand how the patients with different characteristics are treated in the real-world.  
Also, when evaluating the safety and outcome events associated with the use of new drugs, 
real-world data are important to accrue larger patient numbers and broader and more 
heterogeneous patient populations with respect to co-morbidities and co-medication use.   

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 16 of 70 
 
2. 
RATIONALE, OBJECTIVES, AND BENEFIT-RISK 
ASSESSMENT 
2.1 
RATIONALE FOR PERFORMING THE STUDY 
The rationale of the GLORIA-AF Registry Program is described in Section 1.4. Phase II and 
III of the GLORIA-AF Registry Program collect data on patients with newly diagnosed non-
valvular AF, their treatments and outcomes in a real-world setting.  
2.2 
STUDY OBJECTIVES 
2.2.1 
Main Objective 
The main objectives are: 
• To investigate the patient characteristics influencing the choice of antithrombotic 
treatment for the prevention of stroke in non-valvular AF patients  
• To collect real world data on important outcome events of antithrombotic treatments for 
the prevention of stroke. 
2.2.2.  
Further Objective 
The following further objectives are defined: 
• To explore subgroups with different risk profiles impacting safety and effectiveness of 
dabigatran.  
• To investigate compliance and persistence of antithrombotic treatments for the prevention 
of stroke. 
• To collect data on treatment strategies in patients with vascular and bleeding events. 
• To collect real-world data on potential side effects of antithrombotic treatments. 
 
2.3 
BENEFIT-RISK ASSESSMENT 
As in any observational study, patients will be managed according to local medical practice. 
The choice of treatment is solely at the discretion of the participating physicians. This means 
there are no additional risks to patients by participating in this registry.  No additional 
medical procedures are required, over and above those that the patient would receive if not 
enrolled.  
Data from this Registry Program may contribute to the scientific knowledge regarding the 
management of patients with atrial fibrillation. 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 17 of 70 
 
3. 
DESCRIPTION OF DESIGN AND STUDY POPULATION 
3.1 
OVERALL DESIGN AND PLAN  
GLORIA-AF Phase II/III is part of a global, multi-center, prospective Registry Program 
investigating patients with newly diagnosed non-valvular AF at risk for stroke (defined as a 
CHA2DS2-VASc stroke risk score of at least 1); Phase I (data collection before approval of  
dabigatran) of this Registry Program is described elsewhere (U11-1009-02). Phase II/III is 
outlined in two three separate protocols: The present core protocol covering all global regions 
participating in Phases II and III of the Registry Program and one two protocols with focus on 
the EU/EEA-member states. (substudy 1160.136), as well as India and Switzerland (substudy 
1160.171) . The main design features within the protocols are identical and the analysis of 
this global study will also contain the data collected in patients entered in 1160.136, and 
1160.171. All information collected in the present study will also at least be collected in 
countries participating in both substudies the EU/EEA-member states substudy 1160.136. 
The present protocol describes the core protocol for Phase II/III for all participating regions. 
Phase II, which is planned to be initiated after approval of dabigatran in the respective 
country, consists of a baseline visit and two-year follow-up for patients treated with 
dabigatran for the prevention of stroke. Patients enrolled in Phase II initially receiving other 
oral anticoagulants than dabigatran (e.g. VKAs) or antithrombotic therapy, or no therapy for 
stroke prevention, will only participate in the baseline visit without participation in any 
subsequent follow-up visits. 
Before initiation of Phase III, regular interim analyses will be conducted during Phase II on 
patients initiating dabigatran and those initiating VKA at the baseline visit to evaluate the 
similarity of patients in these two groups. These interim analyses will occur on a regional 
basis, based on the number of patients enrolled (approximately once or twice a year).  Once 
comparability regarding important baseline characteristics (known risk factors for stroke and 
bleeding such as age, gender, hypertension, diabetes mellitus, prior stroke, prior transient 
ischemic attack, and prior bleeding) (such as e.g. stroke and bleeding risk factors and 
concomitant medication use) of these groups has been established and the likely amount of 
residual channeling bias after confounder adjustment is comparatively small,  potential 
channeling bias is considered therefore minimal, Phase III will be initiated. The main 
measure to determine comparability of the two treatment groups regarding their important 
baseline characteristics will be the overlap on the propensity score, as measured by the 
proportion of patients in the region of overlap of the propensity score.  
  
The decision to start with Phase III will be region-specific (see Section 7.3.4). Patients 
already enrolled in Phase II will complete their visit schedule as planned. Each patient 
enrolled into GLORIA-AF can only participate in one phase, i.e. those patients enrolled into 
Phase II are not eligible to participate in Phase III. In Phase III all newly diagnosed non-
valvular AF patients will be followed up for three years regardless of antithrombotic therapy 
treatment status.  
The main comparison of interest is the comparison of dabigatran versus VKA. However, 
potential other pair-wise comparisons may be conducted as further analyses, given the 
comparability of these treatment groups regarding important baseline characteristics. The 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 18 of 70 
 
interim analyses to compare the baseline characteristics of patients initiating dabigatran or 
VKAs will be continued during Phase III, in order to address the potential changing relevance 
of VKAs. Further comparisons of drugs may be added in order to reflect the possible 
approval of other new oral anticoagulants.  
It could turn out that Phase III cannot be conducted on a regional level; i.e. if e.g. after two 
years of assessing baseline characteristics of dabigatran and VKA initiators in Phase II 
comparability has not been achieved, which would preclude any meaningful comparisons, 
then a comparative data collection will not be started in that region under this protocol.  
Phase II/III data will be collected in up to 60 countries in up to about 2,200 sites and is 
planned to involve as many as 6,000 or more investigators from regions all over the world. 
Five regions are defined: 1) Asia/ Australia, 2) Europe, 3) North America, 4) Latin America 
and 5) Africa/ Middle East (for planned participating countries per region see Appendix 
10.3).  Depending on the sample size, regions might be pooled for analysis purposes.  
Inclusion of participating centers in the registry will be based on the goal to represent the 
proportion of patients treated within the different health care settings of the respective 
country. 
In total, an enrolment goal of approximately 16,000 patients is planned for Phase II and 
another 32,000 patients for Phase III.   
The planned registry period is from July 2011 to December 2019 June 2020, which covers the 
total expected duration of Phase II and III.  
Enrollment into Phase III of the study will end after the overall enrollment goal has been met, 
or by June 2017, whichever comes first.  Individual regions may end earlier depending on 
recruitment. 
3.1.1 
Administrative structure of the study 
Steering Committee 
A Steering Committee will provide scientific leadership for the planning and conduct of all 
phases of the Registry Program.  It will be composed of experts in cardiology, vascular 
medicine, neurology and epidemiology with one Chair and Co-Chair as well as 
representatives of the Sponsor.  A charter describing the tasks and responsibility of the 
committee will be developed.  Membership in the Steering Committee may change over time 
for various reasons.  
Operations Committee 
The study conduct will be overseen by an Operations Committee (OC), consisting of the 
Chair, Co-Chair and, the epidemiologist of the Steering Committee and representatives of the 
sponsor. The Operations Committee will oversee the execution of the Registry Program and, 
in conjunction with the SC, facilitate the publications. Membership in the Operations 
Committee may change over time. In Phase II, the OC will evaluate the results of the periodic 
analyses of the patient baseline characteristics, which will determine the initiation of Phase 
III of the Registry Program. In Phase III, the OC will continue to evaluate the results of 
periodic interim analyses to compare the baseline characteristics of patients initiating 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 19 of 70 
 
dabigatran or VKAs. The number of members can be changed if warranted. A charter of the 
Operations Committee will be developed. 
The OC will meet regularly, based upon the volume of work. Meetings will generally be by 
teleconference or web-conference. Face-to-face meetings may occasionally be held if there is 
a necessity. 
3.2 
DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S) 
The registry includes newly diagnosed non-valvular AF patients at risk for stroke. This 
permits comparison of treatment initiators and facilitates correct adjustment for predictors of 
treatment rather than for consequences of treatments (intermediates).  In addition, this allows 
for the assessment of treatment hazards over time and avoids the inclusion of prevalent users 
of anticoagulants who are potentially healthier and less susceptible to adverse outcomes (so 
called “VKA survivors”) compared to new users (R11-2308).  
Furthermore, the assessments of channeling bias in Phase II will allow for collecting 
longitudinal data on patients starting dabigatran and VKA only after they are deemed 
comparable regarding their important baseline characteristics, and thus reduce the potential 
for biased comparisons in Phase III. 
3.2.1 
Potential for bias and confounding 
Selection bias 
Selection bias may occur on two different levels: The site level and the patient level. If sites 
where dabigatran is most used differ systematically with respect to patients or routine 
procedures from sites in which it is less used, the between-site difference would lead to non-
comparability between dabigatran patients and others, even if no clinician accounted for 
patient characteristics in his or her decision to use the product. 
To minimize selection bias at the site level, the goal is to have participating centers reflect a 
(country specific) balance between general practices, specialist offices, community hospitals, 
university hospitals, outpatient care centers and anticoagulation clinics. Basic characteristics 
of sites that did not participate will be summarized. 
Selection bias at the patient level might occur if for example, sites preferentially reported 
"interesting" cases to the Registry, and particularly if they did so differently for initiators of 
dabigatran and VKAs.  To minimize selection bias at the patient level, consecutive patients 
from each site who meet entry criteria of this Registry Program are expected to be invited to 
participate in the registry.  
Consecutive enrolment of patients to avoid selection bias should be emphasized. As 
participation in another international registry is an exclusion criteria for entry into the study 
(please refer to section 3.3.3), parallel enrolment in another international registry on the use 
of oral anticoagulation in AF in the same department should be avoided, as otherwise 
consecutive enrolment would be challenging. In addition, it should be ensured that both 
dabigatran and VKAs are available at participating sites or that availability for both treatment 
options is foreseen in the near future. In the latter case, information on treatment availability 
has to be documented. 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 20 of 70 
 
Loss to follow up 
All efforts will be made to minimize loss to follow up in patients with a pre-planned follow 
up (such as patients initiating dabigatran in Phase II and all patients in Phase III), particularly 
in the assessment. Also, patients lost to follow up will be characterized compared to the 
remaining patients and reason and time point of loss to follow up will be evaluated. 
Channeling bias 
Channeling bias can occur due to preferential prescribing in relation to different risks for the 
events of interest: e.g., if dabigatran would be more often prescribed to higher risk patients 
compared to other treatments, higher incidences of outcome events were then expected in the 
dabigatran group.  The potential for channeling bias will be reduced due to the two-phase 
design of the Registry Program and will be assessed throughout the study. The assumption is 
that some channeling bias may occur in the immediate post-approval period, but will not 
persist; therefore periodic assessment of choice of treatment in relation to the patients' 
important baseline characteristics will allow appropriate timing of initiating Phase III. In 
order to control for potential channeling bias after approval of dabigatran, regular 
assessments will be conducted, i.e. patients initiating VKAs and dabigatran will be assessed 
regarding the comparability of important patient baseline characteristics (known risk factors 
for stroke and bleeding such as age, gender, hypertension, diabetes mellitus, prior stroke, 
prior transient ischemic attack, prior bleedinge.g. age, sex, comorbidities, stroke and bleeding 
risk scores, concomitant medications). Further comparisons of drugs may be added in order 
to reflect the possible approval of other new oral anticoagulants. This will be performed 
within regions. Details of the decision process for triggering the start of Phase III will be 
described in the Statistical and Epidemiological Analysis Plan (SEAP).  
Depletion of susceptibles and healthy user/ adherence bias 
Depletion of susceptibles occurs, when persons most at risk for an event suffer the event early 
on in therapy, so that cohorts ascertained later in therapy have a lower prevalence of than 
such at risk patients. In the absence of a direct measure of susceptibility, depletion of 
susceptibles manifests itself as an apparently declining risk with the passage of time. Other 
common reasons for a risk that decline with time elapsed since initiation of therapy include 
metabolic adaptations that diminish the effect of the product (tachyphylaxis) and the 
prescriber's acquisition of skill in managing the drug for a particular patient. Whatever the 
origin, when the risk of an outcome varies over time especially when the risk is higher just 
after initiating therapy and declines thereafter, the comparison of prevalent users and incident 
(new) users will be biased, because long-time users will be less likely to manifest the 
outcome of interest. In addition, there is potential healthy user/adherence bias, which is that 
patients who use a drug or are adherent with treatment are more likely to be healthier in 
general (e.g. have other healthy behaviors) than patients who are non-user/non-adherent. The 
effects of changes in risk with time and adherence will be mitigated through the use of 
initiator cohorts and will be assessed through an intention to treat sensitivity analysis. Only 
newly diagnosed AF patients initiating antithrombotic treatment at baseline will be included 
throughout the Registry Program. To account for time varying risks, estimates of cumulative 
risks will be calculated. 
Information and recall bias 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 21 of 70 
 
Information bias can e.g. occur for example, due to selective underreporting of already 
established and known adverse effects for a known product (VKA) as compared to a new 
product (dabigatran), or vice versa. A standardized data collection form will be used for 
assessing exposure and AEs (see Section 6). Medical charts will also be reviewed by site staff 
and during CRA monitoring visits.  These standardized procedures for data collection are 
intended to minimize such biases. Recall bias may be caused, e.g. if visits are separated by 
long time intervals and patients forget certain information (e.g. use of over-the-counter 
medications). It can be reduced by associating questions with specified time intervals (e.g. 
how often did you take this co-medication during the last 5 days?). 
Confounding 
As in any observational study, confounding may affect the estimation of association between 
drug exposure and outcome of interest and statistical techniques such as adjustment for 
covariates, stratified analyses, matching, etc. can be used to correct for these. But as only 
major confounders for selected research questions can be captured, residual (unmeasured) 
confounding may remain. 
3.3 
SELECTION OF POPULATION 
Regarding the consecutive enrollment of patients, please refer to Section 3.2.1. 
3.3.1 
Main diagnosis for study entry 
Patients with newly diagnosed non-valvular AF (documented by 12 lead ECG, ECG rhythm 
strip, pacemaker/ICD electrocardiogram, or Holter ECG) less than 3 months before the 
patient’s baseline visit will be included. Each patient must be at risk for stroke with one or 
more risk factors, as defined by a CHA2DS2-VASc stroke risk score of at least 1 (see Table 
10.1: 2) 
3.3.2 
Inclusion criteria 
1. Age ≥18 years at enrollment  
2. Male or female patient (or legally acceptable representative) willing and able to provide 
written informed consent 
3. Patient newly diagnosed (< 3 months prior to baseline visit) with non-valvular AF. 
Documentation of AF by 12 lead ECG, ECG rhythm strip, pacemaker/ICD 
electrocardiogram, or Holter ECG (duration of AF episode at least 30 seconds) needed for 
all enrolled patients. 
4. Patient must have a CHA2DS2-VASc score of at least 1 (see Table 10.1: 2). This requires 
the presence of at least one of the following risk factors: 
a. Congestive heart failure (NYHA Class 2 or greater) or moderate to severe LV systolic 
dysfunction (e.g. LV EF ≤ 40%) 
b. History of hypertension or systolic blood pressure >160mmHg 
c. Diabetes mellitus 
d. History of stroke, transient ischemic attack, or systemic embolism 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 22 of 70 
 
e. Vascular disease defined as prior myocardial infarction, peripheral artery disease, 
complex aortic plaque 
f. Age ≥ 65 
g. Female gender 
Although AF diagnosis is a baseline requirement, patients are not required to have an 
ongoing AF episode at the time of entry into this Registry Program. 
3.3.3 
Exclusion criteria 
1. Presence of any mechanical heart valve, or valve disease that is expected to require valve 
replacement intervention (surgical or non-surgical) during the course of the assigned 
registry phase. 
2. Patients who have received more than 60 days of VKA treatment in their lifetime prior to 
the patient’s baseline visit 
3. AF with a generally reversible cause (e.g., cardiac surgery, pulmonary embolism, 
untreated hyperthyroidism) 
4. Patient’s life expectancy is expected to be less than one year at the time of potential 
enrolment as assessed by the investigator 
5. Patients with a medical condition other than atrial fibrillation for which chronic use of an 
oral anticoagulant (for example, a VKA) is indicated 
6. Current participation in any clinical trial of an experimental a drug or device 
7. Current participation in an international registry on the use of oral anticoagulation in AF 
8. Patient was enrolled in any other phase of the GLORIA-AF Program 
9. Patient with no further follow-up possible with enrolling investigator during planned 
study period (such as anticipated relocation) 
 
3.3.4 
Removal of patients from therapy or assessments 
3.3.4.1 Removal of individual patients 
A patient can be withdrawn from the registry for the following reasons: 
• A patient or legally accepted representative withdraws consent  
• Persistent failure of the patient to comply with the protocol and study procedures 
• The patient was erroneously included in the Registry Program 
• Participation in another international atrial fibrillation drug study or registry 
• Participation in another international atrial fibrillation drug study or registry on the use of 
oral anticoagulaton in AF 
• Participation in a clinical trial with a drug or device 
• Any other reason as agreed to by the Investigator and the BI Clinical Monitor 
The Clinical Monitor at BI or BI’s designees must be immediately notified if a patient is 
discontinued prematurely for any of the instances reasons cited above. The Investigator will 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 23 of 70 
 
indicate on the End of Study form the Patient Disposition CRF page the reason/s for 
discontinuation.  If a patient discontinues the study prematurely, another follow-up 
assessment should be performed if possible (unless the reason for discontinuation is 
erroneous enrollment of the patient into the study at baseline), and data should be entered on 
the eCRFs of the next planned visit. 
Patients should NOT be discontinued from the registry study due to an SAE or a non-serious 
AE unless the patient withdraws their consent to participate in the study.  Ongoing 
information on adverse events is important data that should be collected on all patients who 
are being followed up, for the full duration of the follow-up period.  
3.3.4.2 Discontinuation of the study by the sponsor 
Boehringer Ingelheim reserves the right to discontinue the study overall (cf. Section 3.1) or at 
a particular study site at any time for the following reasons: 
1. Failure to meet expected enrolment goals overall or at a particular study site, 
2. Emergence of any efficacy/safety information that could significantly affect continuation 
of the study or any other administrative reasons, 
3. Violation of GCP, the protocol, or the contract by a study site or investigator, disturbing 
the appropriate conduct of the registry. 
4. It could turn out that Phase III might not be conducted; e.g. if after two years of assessing 
baseline characteristics of dabigatran and VKA initiators in Phase II comparability has 
not been achieved, which would preclude any meaningful comparisons, a comparative 
data collection will then not be started (cf. Section 3.1). If during Phase III, the 
comparability of VKA and dabigatran initiators with regard to important baseline 
comparisons is not maintained and no other unbiased comparisons of interest are feasible 
then Phase III may be stopped. 
The investigator / the study site will be reimbursed for reasonable expenses incurred in case 
of study termination (except in case of the third reason). 
A specific registry site could be terminated for the following reasons: 
• Failure of the Investigator to enroll patients into the registry at an acceptable rate; 
• Failure of the Investigator to comply with pertinent regulations;  
• Knowingly submitting false information from the site to the Sponsor, CRO and/or 
regulatory bodies 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 24 of 70 
 
4. 
TREATMENTS 
4.1 
PRESCRIBED TREATMENTS TO BE OBSERVED 
In this observational (i.e. non-interventional) study, no specific treatment is mandated and no 
treatment will be withheld from patients. The choice of antithrombotic agent and dosing 
should be according to local clinical practice and is at the discretion of the treating physician.  
4.2 
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT 
All concomitant medications are prescribed based on the underlying medical condition and 
upon the discretion of the treating physician. 
4.3 
TREATMENT COMPLIANCE 
Compliance with antithrombotic therapy for stroke prevention is measured over a period of 
time and will be assessed by derivation of the following variables on a patient-level:  
• Proportion of filled prescriptions reported by the patient relative to written prescriptions 
by the physician for this patient (based on CRF data from each planned visit). 
• Proportion of days with compliant medication intake (based on reference period as 
specified in the CRF from each planned visit) 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 25 of 70 
 
5. 
VARIABLES AND THEIR ASSESSMENT 
5.1 
OUTCOMES  
5.1.1 
Outcome measures 
The patient's baseline characteristics including the antithrombotic treatment selected at the 
baseline visit will be captured.  
During the follow-up of patients initiating dabigatran in Phase II and all patients in Phase III, 
respectively, antithrombotic treatment for the prevention of stroke and systemic embolism 
will be recorded. This includes compliance changes in antithrombotic therapy and (e.g., dose 
adjustments, proportion of patients discontinuing treatment and reason(s) for 
discontinuation). 
The following events are considered important outcomes (definitions are provided in Section 
5.1.2). Additional events of interest might be included based on new information that could 
become available during the course of the registry and based on results obtained by the 
described main analysis: 
• Stroke (hemorrhagic and ischemic, uncertain classification) 
• Transient ischemic attack (TIA) 
• Systemic embolism 
• Pulmonary embolism 
• Myocardial infarction 
• Life-threatening bleeding events  
• Major bleeding events (including life-threatening bleeding events; see definition in 
Section 5.1.2) 
• All cause death 
• Non-vascular death 
• Vascular death 
• Death of unknown cause 
In addition, the following two composite endpoints will be analyzed: 
• Stroke, systemic embolism, myocardial infarction, life-threatening bleeding events 
and vascular death 
• Stroke, systemic embolism, myocardial infarction and vascular death (vascular 
composite endpoint) 
5.1.2 
Assessment of outcome measures 
The following definitions apply and should be used as a guide when reporting a thrombotic 
event: 
Stroke: 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 26 of 70 
 
Stroke is an acute onset of a focal neurological deficit of presumed vascular origin lasting for 
24 hours or more or resulting in death. The stroke is categorized as ischemic or hemorrhagic 
or uncertain classification (based on CT or MR scanning or autopsy). Fatal stroke is defined 
as death from any cause within 30 days of stroke. Severity of stroke will be assessed by 
modified Rankin scale (see Table 10.1:4) at discharge from hospital and/or at 3-6 months 
later (if available). 
Transient ischemic attack (TIA): 
TIA is defined as a transient episode of neurological dysfunction caused by focal brain, spinal 
cord, or retinal ischemia without acute infarction (P11-00444). 
Systemic embolism: 
Systemic embolism is an acute vascular occlusion of the extremities or any organ (kidneys, 
mesenteric arteries, spleen, retina or grafts), typically documented by angiography, surgery, 
scintigraphy, or autopsy. 
 
Pulmonary embolism: 
• A patient has to fulfill the following criteria: 
1. Typical symptoms or signs (e.g., dyspnea, left or right sided chest pain worsening 
on respiration, etc) suggestive of pulmonary embolism 
AND at least one of the following two criteria: 
2. CT pulmonary angiography demonstrating an intraluminal filling defect in 
segmental or more proximally located pulmonary arteries 
3. High probability ventilation - perfusion lung scan, i.e. at least segmental perfusion 
defect at perfusion scan with normal ventilation at ventilation scan 
• The definition of pulmonary embolism is also met if a patient fulfils at least criteria 2) or 
3) above. 
 
Myocardial infarction: 
• In patients not undergoing PCI or CABG: A patient has to fulfill either the criteria: 
 
- 
Development of significant Q-waves in at least 2 adjacent ECG leads. 
 
Or at least 2 of the following three criteria: 
 
- 
Typical prolonged severe chest pain of at least 30 min 
- 
ECG changes suggestive of myocardial infarction including ST-changes of T-
wave inversion in the ECG). 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 27 of 70 
 
- 
Elevation of troponin or CK-MB1 to more than upper level of normal (ULN) or, if 
CK-MB was elevated at baseline, re-elevation to more than 50% increase above 
the previous level. 
 
• After PCI (within 24 h)   
Elevation of troponin or CK-MB1 to more than 3xULN or, if CK-MB is elevated at 
baseline, re-elevation to more than 3xULN and a more than 50% increase above the 
previous level, and/or development of significant Q-waves2 in at least two adjacent ECG 
leads. 
• After coronary artery bypass grafting (within 72 h)   
Elevation of CK-MB1 to more than 5xULN or, if CK-MB was elevated at baseline, re-
elevation to more than 5xULN and a more than 50% increase above the previous level, 
and/or development of significant Q-waves2 in at least two adjacent ECG leads. 
1 Total CK if CK-MB was not available 2 A new Q-wave with a duration of at least 0.04 seconds and a depth of more than a quarter of the 
   amplitude of the corresponding R-wave, in at least 2 adjacent leads 
 
Major bleeding, defined as meeting one or more of the following criteria (R11-1250, P11-
05406): 
• Overt bleeding associated with a reduction in hemoglobin of at least 20 grams per liter or 
leading to a transfusion of at least 2 units of blood or packed cells 
• Symptomatic bleeding in a critical area or organ: Intraocular, intracranial, intraspinal or 
intramuscular with compartment syndrome, retroperitoneal bleeding, intra-articular 
bleeding or pericardial bleeding 
• Life-threatening bleeding 
• Fatal bleeding 
 
 
Life-threatening bleeding, as defined as meeting one or more of the following criteria: 
• Symptomatic intracranial bleed 
• Reduction in hemoglobin of at least 50 grams per liter  
• Transfusion of at least 4 units of blood or packed cells, associated with hypotension 
requiring the use of intravenous inotropic agents  
• Necessitated surgical intervention 
• Fatal bleeding 
 
 
Deaths  
Deaths will be classified as being: vascular (including bleeding); non-vascular, due to other 
specified causes (e.g., malignancy), or unknown cause, when cause is not known.  
 
Treatment compliance 
Please refer to Section 4.3. 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 28 of 70 
 
Treatment persistence 
Treatment persistence will be assessed as time until permanent discontinuation of the 
treatment. 
5.2 
SAFETY 
5.2.1 
Endpoint(s) of safety 
Please refer to safety related outcome events as described in Section 5.1. 
5.2.2 
Assessment of adverse events 
5.2.2.1 Definitions of adverse events 
Adverse Event (AE): 
An adverse event (AE) is defined as any untoward medical occurrence, including an 
exacerbation of a pre-existing condition, in a patient in a clinical investigation who received a 
pharmaceutical product. The event does not necessarily have to have a causal relationship 
with the drug of interest. 
Serious Adverse Event (SAE): 
• results in death,  
• is immediately life-threatening,  
• results in persistent or significant disability/incapacity,  
• requires or prolongs patient hospitalization,  
• is a congenital anomaly/birth defect or  
• is to be deemed serious for any other reason representing a significant hazard, which is 
comparable to the aforementioned criteria. 
The basis for judging the causal relationship between the product of interest and the adverse 
event is described below. 
(Serious) Adverse Drug Reaction (S)ADR: 
If an adverse event has been deemed by the investigator to have a causal relationship with a 
drug, it is regarded as an adverse drug reaction. 
Causality assessment: 
The expression “Reasonable causal relationship” is meant to convey in general that there are 
facts (evidence) or arguments to suggest a causal relationship. Medical judgment should be 
used to determine the causal relationship, considering all relevant factors, including pattern of 
reaction, temporal relationship, positive de-challenge or re-challenge and/or confounding 
factors such as concomitant medication, concomitant diseases and relevant history. 
Assessment of causal relationship to the antithrombotic drug given for stroke prevention 
should be recorded in the eCRF.  

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 29 of 70 
 
• Yes: 
There is a reasonable causal relationship between the drug administered  
 
 
and the AE.  
• No: 
There is no reasonable causal relationship between the drug administered and 
 
 
the AE.  
 
Intensity of event: 
• Mild 
 
Awareness of a sign or symptom which is easily tolerated 
• Moderate  
Discomfort enough to cause interference with usual activity 
• Severe 
 
Incapacitating or causes inability to work or undertake usual  
 
 
 
activities 
Changes in vital signs, ECG, physical examination, and laboratory test results 
Changes in vital signs including blood pressure, pulse rate, ECG, physical examination, and 
laboratory tests will be only then recorded as AEs if they are not associated with an already 
reported AE, symptom or diagnosis, and the investigational drug is either discontinued, 
reduced or increased, or additional treatment is required, i.e. concomitant medication is added 
or changed. 
Worsening of Pre-existing Conditions: 
Worsening of the underlying disease or of other pre-existing conditions will be recorded as an 
(S)AE in the eCRF. If serious, an SAE form should also be completed. 
5.2.2.2 Adverse event and serious adverse event reporting 
During the course of the Registry Program, i.e. from signing the informed consent onwards 
until up to 6 days after the end of the last follow-up visit, all SAEs, Outcome Events 
described in Section 5 of this protocol and certain non-serious AEs are to be collected, 
documented, and reported by the Investigator on the appropriate forms (SAE or AE forms) 
available in the EDC systems..  
For patients who undergo a baseline visit only, with no follow-up visits, only events that 
occur between the signing of the consent form and the conclusion of the baseline visit need to 
be reported. 
Reporting will be done according to the specific definitions detailed in the “Adverse Event 
Reporting” section of this protocol and according to the instructions provided thereafter. 
All SADRs continuing after the end of the Registry Program need to be followed up until the 
patient recovered or the event is sufficiently followed up.  
Any SADR related to dabigatran or any other BI drug the Investigator may become aware of 
in the period up to 6 days after completion of the last follow-up visit must also be collected in 
the SAE form available in the EDC system and reported according to the specific definitions 
detailed in the “Adverse Event Reporting” section of this protocol and followed up until the 
patient recovered or the event is sufficiently followed up.  

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 30 of 70 
 
BI has set up a list of AEs which are defined to be always serious.  This means that these 
events are, by their very nature, always defined as serious even if an occurrence of one of 
these events does not technically meet the usual criteria for seriousness (for example, stroke).  
In order to support the investigator with identification of these “always serious adverse 
events”, a list of these events is provided in the EDC system.  In addition, if a non serious AE 
is identified to be serious per BI definition, a query will be raised.  The investigator must 
verify the description of the event.  If the event description is correct, then it must be reported 
by the investigator as an SAE in an expedited fashion, the same as for other SAEs. 
 
 ADVERSE EVENT REPORTING IN PHASE II: 
 
Patients receiving dabigatran:  
 
• 
All SAEs and Outcome Events irrespective of causal relationship with dabigatran or any 
other BI drug will be collected on SAE or AE forms in the EDC System. 
• 
In rare occasions, if an Outcome Event was non-serious, it will be collected on the AE 
form in the EDC system 
• 
The SAE forms of SADRs and Outcome Events which are deemed by the Investigator to 
have a causal relationship with dabigatran or any other BI drug also have to be submitted 
in an expedited manner to the Sponsor 
• 
Non-seriouos AEs with a causal relationship to dabigatran or any other BI drug are 
collected in the AE form in the EDC system only.  Non-serious AEs that are NOT demed 
RELATED to (i.e. caused by) dabigatran or any other BI concomitant medication 
SHOULD NOT be included in the EDC System. 
 
ADVERSE EVENT REPORTING IN PHASE III: 
Patients receiving dabigatran:  
• All SAEs and Outcome Events irrespective of causal relationship with dabigatran or any 
other BI drug will be collected on SAE or AE forms in the EDC System.  In other words, 
all SAEs are collected, and all Outcome Events are collected irrespective of drug intake 
or causality assessment. 
• In rare occasions, if an Outcome Event was non-serious, it will be collected on the AE 
form in the EDC system (instead of the SAE form). 
• The SAE forms of SADRs and Outcome Events which are deemed by the Investigator to 
have a causal relationship with dabigatran or any other BI drug also have to be submitted 
in an expedited manner to the Sponsor 
• Non-serious AEs with a causal relationship to any antithrombotic drug including 
dabigatran or VKA, or any other BI drug, are collected on AE forms in the EDC System 
only.   Non-serious AEs that are deemed NOT related to (i.e. caused by) dabigatran, 
VKA, any other antithrombotic therapy, or to ato other BI concomitant medication 
SHOULD NOT be entered included in the EDC System.  For example, a non-serious AE 
deemed related to a non-BI diabetes drug would not be entered into the EDC system at 
all.  Similarly, a non-serious AE which is not deemed related to any drug would not be 
entered into the EDC system at all. 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 31 of 70 
 
• Non-serious AEs which are deemed related to a BI drug must be reported to BI within 
seven days of the site learning of the AE. 
Patients receiving another antithrombotic therapy or no therapy:  
• All SAEs and Outcome Events irrespective of causal relationship with any other 
antithrombotic therapy or any other BI drug will be collected on SAE forms in the EDC 
System. 
• The SAE forms of SADRs and Outcome Events which are deemed by the Investigator to 
have a cabusal relationship to any BI drug also have to be submitted in an expedited 
manner to the Sponsor. 
• Non-serious AEs with a causal relationship to any other antithrombotic therapy or any BI 
drug will be collected on AE forms in the EDC System only.  Non-serious AEs that are 
NOT deemed RELATED to (i.e. caused by) dabigatran or to any other BI concomitant 
medication or to antithrombotic therapy SHOULD NOT be included in the EDC System. 
For SADRs and causally related Outcome Events, the Investigator should provide all 
information requested on the SAE form immediately (i.e. within 24 hours or next business 
day, whichever is shorter) of becoming aware of the event. The EDC System is will be 
configured in such a way that the SAE form will be forwarded to the Sponsor automatically 
upon electronic signature by the Investigator, or within 24 hours of the initial data entry, 
whichever is shorter. For back up purposes (e.g. if computer problems or a blackout of the 
internet connection do not allow a timely completion of the SAE form in the EDC System), a 
hardcopy of the SAE form will also be available in the Investigators Site File (ISF) and 
should be forwarded to the fax number provided in the ISF immediately. In case the hardcopy 
had to be used, it has to be ensured that the SAE form in the EDC system is completed 
afterwards in addition. 
With receipt by the site of any further information to the events, a follow-up SAE report has 
to be completed immediately (within 24 hours or next business day). If the SAE form is 
updated with new or corrected information, a follow-up report is created and forwarded to the 
Sponsor upon submission by the Investigator. If the hardcopy has to be used this has to be 
updated manually and faxed immediately.  
For BI products a link to website: boehringer-ingelheim.com is provided in the EDC System. 
Further guidance on how to navigate on BI’s websites is provided in the ISF. In addition, the 
Investigator should refer to the local pharmacopoeia. 
 Reporting of drug exposure during pregnancy:  
In rare cases pregnancy might occur. Once a female subject has been enrolled into the 
Registry Program and was exposed to either dabigatran or any other BI drug, the Investigator 
must report immediately any drug exposure to the Sponsor to the fax number provided in the 
ISF for SAE reporting. The outcome of the pregnancy must be followed up. In the absence of 
an (S)AE, only the Pregnancy Monitoring Form (available for download in the EDC system)  
is to be completed. If pregnancy is associated with an SAE, both the SAE form available in 
the EDC System and the Pregnancy Monitoring Form should be completed and 
forwarded/submitted to the sponsor. The ISF will contain the Pregnancy Monitoring Form 
(Part A and Part B) and it is also available for download in the EDC System. 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 32 of 70 
 
5.3 
OTHER 
Not applicable 
5.4 
APPROPRIATENESS OF MEASUREMENTS 
The measures conducted within this Registry Program reflect the current real-world approach 
regarding clinical practice across the different global regions.  

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 33 of 70 
 
6. 
INVESTIGATIONAL PLAN 
6.1 
VISIT SCHEDULE 
Recommended timing of assessments is presented in the Flow Charts for Phases II and III of 
the Registry Program, and summarized in Table 6.1: 1. The time intervals given for each of 
the scheduled visits  serve as indicators as to when the contact to the patient as well as the 
respective data entry into the registry data base (eCRF) should take place. All assessments are 
intended to be performed during one visit (cf. Flow Chart), e.g. at the time of a routine, 
scheduled appointment. The information should be entered as quickly as possible into the 
eCRF after patient contact and may only be delayed in case medical record abstraction is 
required e.g. to capture INR data, which may not be immediately available if not performed 
at the site. 
Due to the observational design, the dates for follow-up visits are only recommendations.  
The visit windows allow for flexibility.  Collection of data in the study should be managed 
during routine practice visits (i.e., the visits should not be conducted via telephone.)  In the 
exceptional case that a physical visit is not possible e.g. due to the transient inability of a 
patient to attend the practice, this particular visit can be conducted via telephone with the 
patient. However, all efforts should be done that the following visit is again a physical visit. 
The sites selected for participation in the study are invited to all phases of the Registry 
Program described in the present protocol. However, additional sites may be opened to 
accelerate recruitment for Phase II or Phase III. The site staff will be asked to provide data 
regarding site and physician characteristics, including:  
• type of facility (e.g. general practice, specialist office, community hospital, university 
hospital, out-patient care center, anti-coagulation clinic)  
• specialty of the treating physician/investigator 
• size of clinic/practice  
• numbers of newly diagnosed AF patients during last 12 months 
 
Table 6.1: 1 Schedule of data collection (cf. Flow Chart) 
 
Baseline 
3 months 
(± 1 month) 
6 months 
(± 1 month) 
12 months 
(± 2 month) 
24 months 
(± 2 month) 
36 months 
(± 2 month) 
Phase II* 
X 
X§ 
X§ 
X§ 
X§ 
- 
Phase III* 
X 
- 
X 
X 
X 
X 
* Patients will take part either in Phase II or in Phase III 
§ Follow-up in patients prescribed dabigatran (at baseline) only 
 
6.2 
DETAILS OF STUDY PROCEDURES AT SELECTED VISITS 
6.2.1 
Assessments in Phase II of GLORIA-AF 
The following data will be collected for all patients in Phase II at enrolment, for the purposes 
of cross-sectional analyses. Follow-up assessments will be done only in patients who receive 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 34 of 70 
 
dabigatran. The baseline visit is defined as the physical visit when the patient is enrolled in 
the registry. 
Assessments at Baseline: 
• Date of baseline visit 
• Date of informed consent 
• Date of diagnosis of non-valvular AF 
• Inclusion/exclusion criteria 
• Demographic data, including: date of birth (month and year), gender, weight, height 
(calculated BMI) and race 
• Blood pressure, heart rate and serum creatinine (if available) 
• Information regarding AF 
• Symptomatic, minimally symptomatic, asymptomatic 
• Type (paroxysmal, persistent, permanent) 
• Previous cardioversion, ablation, pacemaker implantation, use of LAA 
occlusion device and/or left atrial procedures 
• Antithrombotic treatment selected for long term use including start date 
• Medical history (including current concomitant diseases) 
• Selected concomitant treatments (antihypertensive, heart failure and anti-arrhythmic 
therapies, metabolic and anti-inflammatory,), antithrombotic therapy for other indications 
than AF) and other selected drugs.  
Assessments at the Follow- up Visits (cf. Flow Chart): 
• Date of follow up visit 
• Type of follow up visit 
• Concomitant diseases (current, any change) 
• Serum creatinine to be recorded (if available) 
• Antithrombotic treatment (current, any change (start and stop dates) including 
compliance, reason for change; including interruptions of antithrombotic treatment due to 
therapeutic/diagnostic interventions) 
• Selected concomitant treatment (current, any change) 
• Outcome events as listed in Section 5.1 
• Information is recorded on any therapeutic/diagnostic interventions that occur as part of 
regular follow-up 
• All serious adverse events judged as related or unrelated to dabigatran or any other BI 
drug (see Section 5.2.2.2) 
• Non-serious adverse events judged as related to any antithrombotic therapy including 
dabigatran, or to any other BI drug (see Section 5.2.2.2)  
• Vital status (only at last follow-up visit) 
 
Only for those patients who are prescribed dabigatran the 3-, 6-month, 12-month (1 year) and 
24 months (2 year) follow-up visits should be conducted. All follow-up visits and 
assessments should be conducted even if the patient discontinues treatment with dabigatran or 
switches to another antithrombotic treatment for AF. 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 35 of 70 
 
If a patient prematurely discontinues from the registry, a follow-up assessment (visit 4) 
should be performed at time of study discontinuation if possible, and the end of study eCRF 
completed. 
6.2.2 
Assessments in Phase III of GLORIA-AF 
In Phase III a baseline assessment is performed for all patients, identical to the baseline 
assessments for Phase II as described in Section 6.2.1.  
Follow-up assessments will be done for ALL patients (i.e. irrespective if of antithrombotic 
treatment status). 
Assessments at Follow-up Visits: 
Follow-up visits: 6-month, 12-months (1 year), 24-months (2 years) and 36-months (3 years) 
after Baseline visit. 
• Date of follow-up visit  
• Type of follow-up visit 
• Concomitant diseases (current, any changes) 
• Serum creatinine to be recorded (if available) 
• Antithrombotic treatment (current, any change (start and stop dates) including 
compliance, reason for change; including interruptions of antithrombotic treatment due to 
therapeutic/diagnostic interventions) 
• Selected concomitant treatment (current, any change) 
• Patients receiving VKAs: the last three INR values and dates performed, from files and if 
necessary by contacting INR clinics, hospitals, etc. 
• Information about VKA therapy such as location of INR testing (physician’s office, 
freestanding lab, home testing), including discontinuations and re-starts, dates, reasons for 
changes, etc. 
• Outcome events as listed in Section 5.1 
• Information is recorded on any therapeutic/diagnostic interventions that occur as part of 
regular follow-up 
• All serious adverse events judged as related or unrelated to dabigatran, any other BI drug 
or antithrombotic treatment (see Section 5.2.2.2)  
• Non-serious adverse events judged as related to any antithrombotic therapy including  
dabigatran, or to any other BI drug or antithrombotic treatment (see Section 5.2.2.2)  
• Vital status (only at last follow-up visit) 
If a patient prematurely discontinues from the registry, a follow-up assessment (visit 4) 
should be performed at time of study discontinuation if possible, and the end of study eCRF 
completed. 
6.2.3 
End of study and follow-up period 
For early Discontinuation: 
• Date of Registry discontinuation 
• Reason for Registry discontinuation 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 36 of 70 
 
• Vital status 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 37 of 70 
 
7. 
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE 
Details of all analyses will be provided in the statistical and epidemiological analysis plan 
(SEAP).  
7.1 
STATISTICAL DESIGN - MODEL 
Phase II and III of this prospective, multi-center observational study consist of a cross-
sectional collection of baseline data for newly diagnosed non-valvular AF patients and a two 
and three years follow-up period, respectively. Within Phase II only patients who receive 
dabigatran for AF treatment at baseline will be followed longitudinally. Within Phase III all 
patients will be followed longitudinally and the groups of newly diagnosed AF patients 
started on VKA and dabigatran, respectively, are assumed to be comparable in terms of 
important baseline characteristics due to the design of the Registry Program.  
All analyses will include data from both all three studies (1160.129 and, EU-member states 
substudy 1160.136 and substudy 1160.171). 
The newly diagnosed non-valvular AF population will be described using a cross-sectional 
approach.  
For Phase II, longitudinal data on dabigatran treated patients will be summarized 
descriptively. 
In Phase III, given that initiators of dabigatran and VKAs are comparable regarding important 
baseline covariates, the comparison between dabigatran and VKAs in terms of the composite 
endpoint in Phase III will be based on multivariable regression models using time-to-event 
methodology. 
Due to the variable time at risk in this registry setting, analysis of outcome events will focus 
on incidence rates and cumulative risk using Kaplan-Meier curves or other life-table 
techniques. 
7.2 
NULL AND ALTERNATIVE HYPOTHESES 
Due to the nature of this observational study there is no (confirmatory) hypotheses testing 
foreseen in a strict statistical sense. Analyses are descriptive in nature including p-values and 
confidence intervals from statistical models used for explorative purposes.  
However, the main and further objectives are defined in Section 2. Additional research 
objectives can be described in the SEAP.  
7.3 
PLANNED ANALYSES 
Analyses will be performed by Boehringer Ingelheim or Boehringer Ingelheim’s designees.  
A final analysis and a report of Phase II will be prepared once the data collection of Phase II 
is completed, the data are cleaned and the database is locked. The final analysis of Phase III 
(if conducted) will be done after Phase III is completed, the data are cleaned and the database 
is locked. It will be described in a combined report of Phases II and III together. Analyses on 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 38 of 70 
 
a country level might be performed in addition, once the report or interim report of phase II 
(or phase III) for a region is available or if required due to regulatory requirements. 
The main analysis population will consist of all eligible patients (i.e. all patients fulfilling all 
inclusion criteria and no exclusion criteria) and the analysis will focus on the antithrombotic 
treatment choice for stroke prevention at the baseline visit with dabigatran vs VKA as the 
main comparison.. The main comparison of dabigatran vs VKA in terms of outcome events 
will be based on Cox regression models which are restricted to those two treatment groups. 
Summary statistics for continuous variables will include the N, mean, standard deviation, 
minimum, Q1 (lower quartile), median, Q2 (upper quartile), and maximum value; tabulations 
of categorical variables will present all possible categories and will display the number of 
observations per category as well as percentages. All estimates will be presented with 95% 
confidence intervals. 
7.3.1 
Main analyses 
A) Patient characteristics influencing choice of antithrombotic treatment for stroke 
prevention at baseline 
Demographics and baseline characteristics (including specifically stroke/bleeding risk scores 
(CHADS2, CHA2DS2 -VASc and HAS-BLED, see Appendix 10.1)) will be summarized 
descriptively for all eligible patients by antithrombotic treatment choice for stroke prevention 
at the baseline visit. This analysis will be repeated by region. 
The antithrombotic treatment choice for stroke prevention at the baseline visit (e.g. none, 
VKAs, ASA, aspirin clopidogrel, dabigatran, etc.) will be described overall and by region.  
Potential channeling bias between patients initiating dabigatran and VKA at the patient's 
baseline visit will be explored using comparisons of important baseline characteristics 
(known risk factors for stroke and bleeding such as age, gender, hypertension, diabetes 
mellitus, prior stroke, prior transient ischemic attack, prior bleeding) such as stroke or 
bleeding risk factors between the two groups at regular intervals during Phase II and Phase 
III. This includes the generation of two-way comparisons for each of the baseline 
characteristics (dabigatran versus VKA) and calculation of a propensity score using multiple 
regression models to predict the probability of treatment choices (see also interim analyses 
7.3.4). 
B) Important outcome events (Phase II only) 
Incidence rates and cumulative risks over time since initiation with 95%-confidence intervals 
for important outcome events (see Section 5.1.) will be calculated within the dabigatran 
cohort. In addition these analyses will be done stratified by chronic antiplatelet treatment for 
indication other than AF at baseline. The analysis will be based on all eligible patients 
initiating dabigatran at baseline. Patients who discontinue initial dabigatran treatment for 
stroke prevention permanently will be censored at date of last drug intake + 3 days or at first 
intake of other relevant chronic antithrombotic treatment for stroke prevention, whatever 
comes first (unless the event occurred prior to the time of censoring). A patient is considered 
to have permanently stopped initial dabigatran treatment if other relevant chronic 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 39 of 70 
 
antithrombotic treatment is initiated for stroke prevention or otherwise dependent on the 
duration of a treatment interruption (thresholds of treatment interruption duration and other 
details will be described in the SEAP). 
C) Important outcome events / analysis of composite endpoint of stroke, SEE, vascular 
death, MI, life-threatening bleeds (Phase III only) 
Patients initiating dabigatran treatment for stroke prevention at baseline will be compared to 
those initiating VKA treatment in terms of the composite endpoint by means of a 
multivariable Cox regression model (if those patient groups are determined to be comparable 
and if both groups consist of a minimum of 6000 patients). The multivariable regression 
model will include the following variables as core variables: treatment, age, gender and 
stroke and bleeding risk factors and concomitant antiplatelets use (time dependent). Further 
baseline covariates including e.g. comorbidities and concomitant medications will be selected 
within a model selection procedure, which will be specified in detail in the SEAP. The 
analysis will be based on antithrombotic treatment choice prescribed at baseline and all 
eligible patients. Patients who discontinue initial antithrombotic treatment for stroke 
prevention permanently will be censored at date of last drug intake + 3 days (for dabigatran 
and non VKA treatments) and +6 days (for VKA treatment or combinations of VKA with 
other antithrombotic treatments) or at first intake of other relevant chronic antithrombotic 
treatment for stroke prevention, whatever comes first (unless the event occurred prior to the 
time of censoring). A patient is considered to have permanently stopped initial antithrombotic 
treatment for stroke prevention, if other relevant chronic antithrombotic treatment is initiated 
for stroke prevention or otherwise dependent on the duration of treatment interruption (details 
will be described in the SEAP). This analysis will be restricted to the group of eligible 
patients prescribed to dabigatran or VKA at baseline that are comparable. 
Incidence rates and cumulative risks with 95%-confidence intervals for the composite 
endpoint and for the individual components of the composite endpoint will be calculated.  In 
addition these analyses will be done stratified by antiplatelet treatment at baseline for 
indication other than AF.  

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 40 of 70 
 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 41 of 70 
 
7.3.3 
Safety analyses 
The safety analysis will include all patients enrolled in Phase II and Phase III with planned 
follow up (i.e. only patients starting on dabigatran in phase II). Statistical analysis and 
reporting of AEs will be descriptive in nature, will be based on BI standards and will focus on 
adverse drug reactions (related to antithrombotic therapy). No hypothesis testing is planned. 
Occurrences of AEs will be analyzed relative to the number of patients treated and 
additionally relative to observed patient-years (i.e. time at risk). The safety analysis will be 
based on the concept of treatment emergent adverse events. Patients will be analyzed 
according to the antithrombotic treatment they have received at the time of the event. If no 
current antithrombotic treatment is administered then events occurring within a washout 
period of three days (in case of dabigatran and non VKA treatments) or six days (in case of 
VKA treatment or combination of VKA with other antithrombotic treatment) after 
discontinuation of antithrombotic treatment will be assigned to the last treatment given. This 
washout period will also be included as time at risk for derivation of total patient-years. 
Adverse events that deteriorate under treatment will also be considered as 'treatment 
emergent'.  Adverse events occurring prior to first intake of antithrombotic treatment 
prescribed at baseline, during periods without any antithrombotic treatment (excluding 
washout period) or after the individual 2 year (Phase II) or 3 year (Phase III) follow-up visit 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 42 of 70 
 
dates (excluding washout periods) will not be considered treatment emergent events and will 
not be included in summary tables.  
The safety analyses will include the following parameters: 
• ADRs (related to antithrombotic therapy) 
• ADRs (related to antithrombotic therapy) leading to discontinuation of antithrombotic 
treatment  
• Serious ADRs (related to antithrombotic therapy) 
• Deaths 
• SAEs 
 
Additionally, an analysis of ADRs restricted to those events which are related to the 
antithrombotic treatment prescribed at baseline will be performed. 
Systematic collection of vital signs and laboratory parameters is not planned. 
7.3.4 
Interim analyses 
There are three four different types of interim analyses planned within Phase II and III.  
1. Analysis of baseline characteristics during the conduct of Phase II and Phase III on a 
regular basis in order to assess comparability of VKA and dabigatran treatment 
cohorts and potential other treatment groups 
2. Optional interim analysis on Phase II and/or Phase III data prior to database lock for 
Phase II/III to obtain preliminary results on safety, compliance/persistence, and 
outcome events of dabigatran and on baseline characteristics of AF population  
3. Optional interim analyses for Phase II/III on a regional level once enrollment and 
follow up for all patients within a region in Phase II/III is completed  
4. Interim analysis on baseline characteristics in Phase II (e.g. at least 8,000 eligible 
patients) + III (e.g. at least 15,000 eligible patients) 
Notes on 1) Within Phase II, the comparability of the patient characteristics prescribed either 
VKAs or dabigatran will be evaluated at regular intervals (e.g. approximately once per year, 
dependent on the recruitment within Phase II). For this analysis appropriate statistical 
methods, which will include propensity scores will be used to assess channeling bias. 
Comparability in terms of important baseline characteristics will be checked based on 
regions. The overlap on the propensity score, as measured by the proportion of patients in the 
region of overlap of the propensity score, will be the main measure to determine 
comparability of the two treatment groups regarding their important baseline characteristics. 
The goal is to start Phase III always for the full subset of countries within one region. Details 
will be described in the SEAP. Based on these comparisons, a decision will be made by the 
steering committee (SC) if and when Phase III will be initiated in the above mentioned 
subsets of countries. The interim analyses to compare the baseline characteristics of patients 
initiating dabigatran or VKAs will be continued during Phase III, in order to address the 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 43 of 70 
 
potential changing relevance of VKAs. Further comparisons of drugs may be added in order 
to reflect the possible approval of other new oral anticoagulants.  
Notes on 2) As the end of Phase II is driven by the region where channeling bias is most 
persistent and as the number of dabigatran patients in Phase II is highly dependent on market 
access in the different regions, an interim analysis might be performed 2 years after inclusion 
of the 3,000th dabigatran patient in Phase II. The interim analysis will be based on all patients 
recruited up to the point in time of inclusion of the 3,000th dabigatran patient. For this 
interim analysis it is planned to run all analyses as specified in sections 7.3.1, 7.3.2 and 7.3.3 
(i.e. including analysis of longitudinal data of dabigatran patients). Afterwards, analyses on 
country level might be performed in addition based on the data snapshot used for this interim 
analysis and/or country-specific amendments. 
Following the same rules, an interim analysis of cross-sectional and longitudinal data of 
patients enrolled in phase III might be conducted using the methodology as specified for the 
final analysis of phase III data. Once a reasonable number of dabigatran and VKA patients 
completed follow up, this analysis might be conducted to obtain preliminary phase III results. 
Notes on 3) As the switch to phase III will be done on a regional level, the time point of stop 
of phase II and thereby start of phase III will differ for the regions. Analyses on the complete 
data for a region within phase II/III might be conducted following the same methodology as 
described for the final analysis, if required (e.g. due to a long time distance between 
completion of a phase within a region and database lock for the phase).  
Notes on 3 4) Within Phase II an interim analysis of baseline characteristics might be 
conducted after recruitment of e.g. 8,000 patients in the registry is completed. Within Phase 
III an interim analysis of baseline characteristics will be conducted after recruitment of e.g. 
15,000 patients in the registry is completed. Analyses on country level might be performed in 
addition based on the data snapshot used for these interim analyses and/or country-specific 
amendments. 
As the planned analyses confidence intervals for occurrence of outcome events are to be 
interpreted on a descriptive level and as the interim analysis otherwise focus on anlysis of 
baseline characteristics, no adjustment for multiplicity will be done.   
7.4 
HANDLING OF MISSING DATA 
In order to assess the effects of lost to follow-up patients, percentages of dropouts and reason 
for loss to follow-up will be summarized in patients with a pre-planned follow up (such as 
patients initiating dabigatran in Phase II and all patients in Phase III). In addition, baseline 
characteristics of patients who were lost to follow-up in comparison to patients with a 
complete follow-up will be described, depending on proportion of patients lost to follow-up. 
Any reasonable attempt will be undertaken to ensure completeness of data collection in this 
registry. Imputation might be performed dependent on amount and distribution of missing 
values. 
7.5. 
RANDOMISATION 
Not applicable.  

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 44 of 70 
 
7.6 
DETERMINATION OF SAMPLE SIZE 
It is planned to recruit a minimum of 500 patients per region in Phase II and a minimum of 
1,000 patients per region in Phase III. Overall, the planned sample sizes for Phase II and 
Phase III are 16,000 and 32,000 patients, respectively representing data from all both studies 
(1160.129, 1160.171, andand EU-member states substudy 1160.136). 
The number of patients included in Phase II and duration of enrolment is not driven by a 
formal sample size calculation but is primarily dependent on the availability of eligible 
patients treated with dabigatran in the regions and on the presence of channeling bias.  
Throughout the Registry Program the aim is to describe characteristics of the newly 
diagnosed non-valvular AF population in the five regions, in treatment regimen cohorts and 
overall by calculation of estimates and confidence intervals for relevant attributes. The 
following paragraphs describe the statistical precision (width of 95% confidence interval) 
when estimating prevalence and incidence. 
Estimates for proportions/prevalences (Phase II-III) 
Categorical attributes will be estimated with the following precision (i.e. width of descriptive 
95% confidence interval), depending on sample size and prevalence of the attribute: 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 45 of 70 
 
Table 7.6: 1 
Width of 95% confidence interval dependent on attribute prevalence 
and sample size 
Sample size (for subgroup or overall) 
Attributes prevalence 
[%] 
500 
1000 
2000 
4000 
8000 
16000 
32000 
5 
Expected n 
25 
50 
100 
200 
400 
800 
1600 
  
95%-CI width 
4.03 
2.81 
1.96 
1.38 
0.97 
0.68 
0.48 
10 
Expected n 
50 
100 
200 
400 
800 
1600 
3200 
  
95%-CI width 
5.46 
3.82 
2.68 
1.88 
1.33 
0.94 
0.66 
20 
Expected n 
100 
200 
400 
800 
1600 
3200 
6400 
  
95%-CI width 
7.2 
5.05 
3.55 
2.5 
1.77 
1.25 
0.88 
30 
Expected n 
150 
300 
600 
1200 
2400 
4800 
9600 
  
95%-CI width 
8.21 
5.77 
4.06 
2.86 
2.02 
1.43 
1.01 
40 
Expected n 
200 
400 
800 
1600 
3200 
6400 
12800 
  
95%-CI width 
8.77 
6.17 
4.34 
3.06 
2.16 
1.52 
1.08 
50 
Expected n 
250 
500 
1000 
2000 
4000 
8000 
16000 
95%-CIwidth 
8.94 
6.29 
4.43 
3.12 
2.2 
1.56 
1.1 
 
For Phase II a total sample size of 16,000 patients allows an estimation of a population 
attribute with a precision of less than 1.6% (i.e. width of 95% CI). The smallest sample size 
per region in Phase II is 500 patients; this allows an estimation of a population attribute for 
the region with a precision of approximately 8.9% (i.e. width of 95% CI). 
For Phase III a total sample size of 32,000 patients allows an estimation of a population 
attribute with a precision of less than 1.1% (i.e. width of 95% CI). The smallest sample size 
per region in Phase III is 1,000 patients; this allows an estimation of a population attribute for 
the region with a precision of less than 6.3% (i.e. width of 95% CI). 
Estimates for incidence rates (Phase II-III):  
Estimates and confidence intervals for incidence rates (interpreted on a descriptive level) will 
be computed. For Phase II it is estimated to recruit approximately 8,000 patients in the 
dabigatran treatment cohort whom are followed up for up to 2 years. Assuming a total 
treatment discontinuation and lost to follow-up rate of 25% per year a total of approximately 
12,166 patient-years in patients starting dabigatran will be observed.  

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 46 of 70 
 
When observing 12,166 dabigatran patient years, at least one patient with an event (ADR, 
MBE, stroke/SEE, etc) will be observed, if the underlying incidence rate for this event is 
0.025 occurrences per 100 patient years or above with a power of 95%. If we do not observe 
any event within the 12,166 patient years, it can be excluded with 95% confidence that the 
underlying true event rate is above 0.025 per 100 patient years in the population. 
Based on the recent RE-LY trial (warfarin, dabigatran), it is expected that the incidence rates 
for stroke/SEE and MBE will be in a range of 1 to 3 per 100 patient years in the total 
population. The width of the two-sided 95% confidence interval of the population depends on 
the obtained estimate from the sample of 12,166 patient years; the following table illustrates 
this relationship: 
Table 7.6: 2 
95% Confidence intervals based on different scenarios for observed 
event rates (based on 12,166 patient years) 
Observed event rate per 100 
patient years 
Lower 95% CI for event rate per 
100 patient years 
Upper 95% CI for event rate per 
100 patient years 
1 
0.830214 
1.194296 
2 
1.756575 
2.267726 
3 
2.700082 
3.324127 
The calculation of confidence intervals is based on the method described in Hahn, Meeker (chapter 7.2.2; using χ2- 
quantiles). 
 
As an example, assume that the event rate for stroke per 100 patient years is 1, i.e. we 
observe ~120 strokes within the 12,166 patient years. The two-sided 95% confidence interval 
for the population incidence rate per 100 patient years is 0.83 to 1.19. Thus it can be excluded 
with 95% confidence that the true rate of strokes per 100 patient years is above 1.19 in the 
population. 
For Phase III, for treatment group cohorts which initially consist of at least 6,000 patients, 
approximately 12,057 patient-years will be observed within the treatment regimen cohort. 
This approximation is based on the assumptions of a total treatment discontinuation and lost 
to follow-up rate of 25% per year and an individual follow-up of three years. Therefore, due 
to the longer individual follow-up in Phase III and thereby the longer observation time per 
patient, estimates of incidences based on treatment regimen cohorts which initially consist of 
6,000 patients will have approximately the same precision as described above (for 8,000 
patients in Phase II).  
Comparison of dabigatran vs. VKA treatment groups (Phase III) 
Based on the recent RE-LY trial (warfarin, dabigatran) results the proportion of patients 
experiencing the composite endpoint of stroke/SEE, vascular death, MI, life- threatening 
bleeds within one year of treatment can be estimated to be  5% for dabigatran, and 6% for 
well controlled warfarin. Given the less controlled environment of this registry it is expected 
that the occurrence of the composite endpoint within one year of treatment may vary between 
5% to 15% depending on treatment options and patient compliance. Consequently, the annual 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 47 of 70 
 
event-free survival rate (in terms of the composite endpoint) will vary between 85% and 
95%. 
Treatment regimen cohorts which are to be compared in terms of the composite endpoint will 
consist of at least 6,000 patients. Assuming an individual follow-up period of three years per 
patient and a 25% yearly treatment discontinuation and lost to follow-up rate, it will be 
possible to detect true absolute differences between yearly event rates of at least 1.6% (HR 
1.13; calculated at the lower end of the expected range of annual event-free survival rates of 
85% to 95%) with more than 90% power. This applies for a single pair-wise comparison 
between treatment groups of 6,000 patients at the 5% significance level. The actual power 
will be dependent on the covariates included in the analysis model, their degree of imbalance 
between the treatment groups, and their strength of association with the outcome, and might 
therefore differ. 
95% confidence intervals will be calculated for several outcome events and the statistical 
model used for comparison of treatment regimen cohorts observed in Phase III in terms of the 
composite endpoint will not be fully pre-specified. Therefore, it can be expected that false 
positive significant differences may arise, i.e. a treatment regimen cohort may appear by 
chance with a lower or a higher incidence rate for specific outcome events or for the 
composite endpoint variable; consequently, results have to be interpreted with care. 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 48 of 70 
 
8. 
INFORMED CONSENT, DATA PROTECTION, STUDY 
RECORDS 
Phase II and III as part of the Registry Program will be conducted in accordance with the 
protocol, the principles of  Good Clinical Practice (GCP), the Declaration of Helsinki as of 
October 2008 (R10-1167), guidelines for Good Epidemiological Practice (R10-4560), Good 
Pharmacoepidemiologic Practice (R09-0182), “Registries for Evaluating Patient Outcomes: 
A User’s Guide” (R10-4561) , relevant BI Standard Operating Procedures (SOPs) and local 
regulations. 
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. 
8.1 
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT 
This study will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments. All protocol 
amendments must be documented, dated and signed by all appropriate signatories. Local, 
country specific amendments may be generated. Prior to patient participation in Phase II or 
III of the Registry Program, written informed consent must be obtained from each patient (or 
the patient’s legally accepted representative) according to International Committee on 
Harmonization GCP and to the regulatory and legal requirements of the participating country. 
The patient should be given appropriate time to consider if he/she accepts to participate in the 
Registry Program.  
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 Registry 
Program 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. 
The patient must be informed that his/her personal study-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of 
disclosure must also be explained to the patient. 
The patient must be informed that his / her medical records may be examined by authorized 
monitors (CML/CRA) or Clinical Quality Assurance auditors appointed by Boehringer 
Ingelheim, by Boehringer Ingelheim’s designees, by appropriate IRB / IEC members, and by 
inspectors from regulatory authorities. 
8.2 
DATA QUALITY ASSURANCE 
A quality assurance audit (monitoring) of Phase II or III of the Registry Program may be 
conducted by the Sponsor or Sponsor’s designees. The quality assurance auditor must be 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 49 of 70 
 
provided access to all medical records, the investigator’s registry-related files and 
correspondence, and the informed consent documentation that is relevant to this Registry 
Program. 
A data management plan (DMP) will be created to describe all functions, processes, and 
specifications for data collection, cleaning and validation. The electronic CRFs (eCRFs) will 
include programmable edits to obtain immediate feedback if data are missing, out of range, 
illogical or potentially erroneous. These rules may encompass simple checks such as range 
validation or presence/absence of data, or complex cross-form verifications such as lab result 
deviations across visits. Concurrent manual data review may be performed based on 
parameters dictated by the DMP. Ad hoc queries to the sites may be generated and followed 
up for resolution. A source data quality audit may be initiated to ensure that the data in the 
database is accurate. Source data verification (SDV) will be performed at sites identified by a 
risk-based approach outlined in the monitoring plan, as needed.  
The database will be housed in a physically and logically secure computer system maintained 
in accordance with a written security policy. The system will meet the standards of the 
International Committee on Harmonization guideline E6R1 regarding electronic study data 
handling. Patient confidentiality will be strictly maintained. 
8.3 
RECORDS 
All of the clinical data and site/investigator characteristics will be captured via a web-based 
EDC System. The Investigator site staff will enter and edit the data via a secure network, with 
secure access features (username, password and secure identification – an electronic 
password system). A complete electronic audit trail will be maintained. The Investigator will 
approve the data using an electronic signature: (21 CFR Part 11 compliant). 
Patients must not be identified on the eCRF by name. Appropriate coded identification (i.e., 
patient number) must be used. The Investigator must make a separate confidential record of 
these details (patient identification code list) to permit identification of all patients enrolled in 
Phase II or III of the Registry Program in case follow-up is required. Likewise, any 
supporting documentation must be redacted of any patient identifying information, and the 
patient ID number clearly written on the documents. 
The clinical data the Investigator entered into the EDC System together with all data changes 
made will be available to the Investigator for download at the end of Phase II or III of the 
Registry Program. The Investigator will be responsible for retaining all records pertaining to 
the Registry Program as specified in the appropriate contract. 
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 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 50 of 70 
 
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 study-related monitoring, audits, IRB / IEC review 
and regulatory inspection, providing direct access to all related source data / documents. 
CRFs/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 
representative(s) and or designee(s), auditor and inspection by health authorities (e.g. FDA). 
The Clinical Research Associate (CRA) / on site monitor and auditor may review all 
CRFs/eCRFs, and written informed consents. The accuracy of the data will be verified by 
reviewing the documents described in Section 8.3.1 and in the Monitoring Plan. 
8.4 
PROCEDURES FOR REPORTING ADVERSE EVENTS 
8.4.1 
Time windows 
To fulfill the regulatory requirements for expedited safety reporting, the Sponsor evaluates 
whether a particular adverse event is "listed", i.e. is a known side effect of the drug or not. 
For the BI product(s) this is the Company Core Data Sheet (CCDS) i.e. the applicable 
Summary of Product Characteristics (SPC). The documents can be referred to via a link to 
website: boehringer-ingelheim.com provided in the EDC System and guidance document on 
how to navigate on BI’s websites provided in the ISF. 
8.4.2 
Documentation of adverse events and patient narratives 
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 
Investigator Site File. 
8.5 
STATEMENT OF CONFIDENTIALITY 
Individual patient medical information obtained as a result of Phase II or III of this Registry 
Program 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 
study need to be available for inspection on request by the participating physicians, by the 
IRB / IEC competent health authorities and the sponsor and/or its representatives and/or 
designees.  
The data collected in the eCRFs will be transferred to the database via the Internet through 
secure web-sites.  

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 51 of 70 
 
8.6 
COMPLETION OF STUDY 
The EC/competent authority in each participating EU member state needs to be notified about 
the end of the study (last patient out) or early termination of the registry.  
8.7 
PUBLICATION POLICY 
It is the joint task of the Operations and the Steering Committee to facilitate publications 
and/or presentations of data from Phase II or III of this Registry Program. Authorship will be 
determined jointly by the OC, SC and the Sponsor. The rights of the Operations Committee, 
of the Investigators and of the Sponsor with regards to publication of the result of Phase II or 
III of this Registry Program are described in the individual contracts and in the SC and OC 
charters. Any publication on the Phase II or III of this Registry Program though must be 
consistent with the BI publication policy and guided by the current version of the Uniform 
Requirements for Manuscripts Submitted to Biomedical Journals: Writing and Editing for 
Biomedical Publication of the International Committee of Medical Journals (ICMJE) As a 
general rule, no national study results should be published prior to finalization and 
publication of the overall results of the interim and final analyses of the respective phase. 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 52 of 70 
 
9. 
REFERENCES  
9.1 
PUBLISHED REFERENCES 
R03-1233 
Go AD, Hylek EM, Phillips KA, Chang YC, Henault LE, Selby JV, Singer 
DE. Prevalence of Diagnosed Atrial Fibrillation in Adults. National 
Implications for Rhythm Management and Stroke prevention: the 
AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. 
JAMA 2001, 285; 2370-2375. 
P10-10141 
Camm AJ, et al. Guidelines for the management of atrial fibrillation: the Task 
Force for the Management of Atrial Fibrillation of the European Society of 
Cardiology (ESC): developed with the special contribution of the European 
Heart Rhythm Association (EHRA), endorsed by the European Association for 
Cardio-Thoracic Surgery (EACTS). Eur Heart J 31 (19), 2369 - 2429 (2010) 
P06-08196 
Fuster V, Ryden LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, et al. 
ACC/AHA/ESC 2006 guidelines for the management of patients with atrial 
fibrillation - executive summary: a report of the American College of 
Cardiology/American Heart Association Task Force on Practice Guidelines 
and the European Society of Cardiology Committee for Practice Guidelines 
(Writing Committee to Revise the 2001 Guidelines for the Management of 
Patients With Atrial Fibrillation): developed in collaboration with the 
European Heart Rhythm Association and the Heart Rhythm Society. 
Circulation 2006;114:700-752.  
R09-4884 
Lloyd-Jones DM, Wang TJ, Leip EP, Larson MG, Levy D, Vasan RS, et al. 
Lifetime risk for development of atrial fibrillation: the Framingham Heart 
Study. Circulation. 2004;110:1042–6.  
R09-4875 
Heeringa J, van der Kuip DA, Hofman A et al. Prevalence, incidence and 
lifetime risk of atrial fibrillation: the Rotterdam study. Eur Heart J 2006; 
27(8):949-953. 
R10-1345 
Friberg J, Buch P, Scharling H, Gadsbphioll N, Jensen GB. Rising rates of 
hospital admissions for atrial fibrillation. Epidemiology 2003; 14(6):666-672. 
R96-0252 
Wolf PA, Abbott RD, Kannel WB Atrial fibrillation as an independent risk 
factor for stroke: the Framingham Study. Stroke 22 (8), 983 - 988 (1991) 
R03-1241 
Peters NS, Schilling RJ, Kanagaratnam P, Markides V. Atrial Fibrillation: 
strategies to control, combat, and cure. The Lancet 2002; 359: 593-603 
R09-4892 
Lin HJ, Wolf PA, Kelly-Hayes M, Beiser AS, Kase CS, Benjamin EJ, 
D’Agostino RB. Stroke severity in atrial fibrillation. The Framingham. Study. 
Stroke. 1996;27:1760 –1764 
R03-1229 
Falk  RH Atrial fibrillation. N Engl J Med 344 (14), 1067 - 1078 (2001) 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 53 of 70 
 
P06-10925 
Gage BF, Waterman AD, Shannon W et al. Validation of Clinical 
Classification Schemes for Predicting Stroke: Results From the National 
Registry of Atrial Fibrillation. JAMA. 2001;285(22):2864-2870   
R10-5332 
Lip GYH, Nieuwlaat R, Pisters R, Lane DA, Crijns HJGM. Refining clinical 
risk stratification for predicting stroke and thromboembolism in atrial 
fibrillation using a novel risk factor-based approach: the Euro Heart Survey on 
Atrial Fibrillation. Chest 137 (2), 263 - 272 (2010) 
P07-07953 
Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to 
prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern 
Med 146 (12), 857 - 867 (2007) 
R03-1227 
Laupacis A, Boysen G, Connolly S, Ezekowitz M, Hart R, James K, et al. The 
efficacy of aspirin in patients with atrial fibrillation: analysis of pooled data 
from 3 randomized trials. Arch Intern Med 1997;157:1237-40. 
P07-04925 
Watson T, Shanstila E, Lip GYH. Management of atrial fibrillation: an 
overview of the NICE guidance on AF management. Br J Cardiol 
2007;14(1):23-28.   
P10-00811 
Ogawa S, Working Group of JCS Guideline; Guidelines for pharmacotherapy 
of atrial fibrillation (JCS 2008). Original in Japanese. Circ J 72 (Suppl 4), 
1581 - 1638 (2008) 
R10-0768 
Gladstone DJ, Bui E, Fang J, Laupacis A, Lindsay MP, Tu JV, Silver FL, 
Kapral MK Potentially preventable strokes in high-risk patients with atrial 
fibrillation who are not adequately anticoagulated. Stroke 40 (1), 235 - 240 
(2009) 
R09-1522 
Jones M, McEwan P, Morgan CL, Peters JR, Goodfellow J, Currie CJ.  
Evaluation of the pattern of treatment, level of anticoagulation control, and 
outcome of treatment with warfarin in patients with non-valvular atrial 
fibrillation: a record linkage study in a large British population. Heart 91 (4), 
472 - 477 (2005) 
P07-08370 
Eikelboom J, Weitz J. A replacement for warfarin: The search continues. 
Circulation 2007;116(2):131-133 
P09-11669 
Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, 
Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu 
J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L, RE-LY 
Steering Committee and Investigators. Dabigatran versus warfarin in patients 
with atrial fibrillation. N Engl J Med 2009; 361 (12): 1139-1151 
P11-00444 
Furie KL, Kasner SE, Adams RJ, Albers GW, Bush RL, Fagan SC, Halperin 
JL, Johnston SC, Katzan I, Kernan WN, Mitchell PH, Ovbiagele B, Palesch 
YY, Sacco RL, Schwamm LH, Wassertheil-Smoller S, Turan TN, Wentworth 
D, American Heart Association Stroke Council, Council on Cardiovascular 
Nursing, Council on Clinical Cardiology, and Interdisciplinary Council on 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 54 of 70 
 
Quality of Care and Outcomes Research. Guidelines for the Prevention of 
Stroke in Patients with Stroke or Transient Ischemic Attack: A Guideline for 
Healthcare Professionals From the American Heart Association/American 
Stroke Association. Stroke 42 (1), 227 - 276 (2011) 
P10-14910 
Wann LS, Curtis AB, January CT, Ellenbogen KA, Lowe JE, Estes NAM, 
Page RL, Ezekowitz MD, Slotwiner DJ, Jackman WM, Stevenson WG, Tracy 
CM. 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 123, 104 - 123 (2011) 
P10-14358 
Lindsay MP, Gubitz G, Bayley M, Hill MD, Davies-Schinkel C, Singh S, 
Phillips S, Canadian Stroke Strategy Best Practices and Standards Writing 
Group. Canadian best practice recommendations for stroke care (update 2010). 
Website: strokebestpractices.ca/wp-
content/uploads/2010/12/2010_BP_ENG.pdf (access date: 10 December 2010) 
; Ottawa: Canadian Stroke Network (2010) 
R09-1482 
Petersen P, Boysen G, Godtfredsen J, Andersen ED, Andersen B 
Placebo-controlled, randomised trial of warfarin and aspirin for prevention of 
thromboembolic complications in chronic atrial fibrillation. 
Lancet 333 (8631), 175 - 179 (1989) 
R09-1483 
Stroke Prevention in Atrial Fibrillation Investigators 
Stroke Prevention in Atrial Fibrillation study: final results. 
Circulation 84 (2), 527 - 539 (1991) 
R10-0756 
Gage BF, Boechler M, Doggette AL, Fortune G, Flaker GC, Rich MW, 
Radford MJ. Adverse outcomes and predictors of underuse of antithrombotic 
therapy in Medicare beneficiaries with chronic atrial fibrillation. 
Stroke 31, 822 - 827 (2000) 
R11-2308 
Ray WA, Evaluating medication effects outside of clinical trials: new-user 
designs. Am J Epidemiol 158 (9), 915 - 920 (2003) 
R11-1250 
Schulman S, Angerås U, Bergqvist D, Eriksson B, Lassen MR, Fisher W; 
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 surgical patients. J Thromb Haemost 
2010;8:202-4. 
P11-05406 
Lip GYH, Andreotti F, Fauchier L, Huber K, Hylek E, Knight E, Lane DA, 
Levi M, Marin F, Palareti G, Kirchhof P, Bleeding risk assessment and 
management in atrial fibrillation patients: a position document from the 
European Heart Rhythm Association, endorsed by the European Society of 
Cardiology Working Group on Thrombosis. 
Europace 13, 723 - 746 (2011) 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 55 of 70 
 
R11-1252 
Wei LJ, Lin DY, Weissfeld L. Regression analysis of multivariate incomplete 
failure time data by modeling marginal distributions. JASA 1989; 84(408): 
1065-1073. 
R10-1167 
World Medical Association: World Medical Association Declaration of 
Helsinki - ethical principles for medical research involving human subjects: 
59th WMA General Assembly, Seoul, October 2008. website: 
wma.net/en/30publications/10policies/b3/index.html (dated 22.10.2008) 
(2008) 
R10-4560 
International Epidemiological Association (IEA) Good epidemiological 
practice (GEP): IEA guidelines for proper conduct of epidemiological 
research. Website: ieaweb.org/iea/ (2007) 
R09-0182 
Guidelines for good pharmacoepidemiology practices 
(GPP).Pharmacoepidemiol Drug Saf 17, 200 - 208 (2008) 
R10-4561 
Gliklich RE, Dreyer NA, eds. Registries for Evaluating Patient Outcomes: A 
User's Guide. (Prepared by Outcome DEcIDE Center [Outcome Sciences, Inc. 
dba Outcome] under Contract No. HHSA29020050035I TO1.) AHRQ 
Publication No. 07-EHC001-1. Rockville, MD: Agency for Healthcare 
Research and Quality.April 2007 
R10-6394 
Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel 
user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in 
patients with atrial fibrillation: the Euro Heart Survey. Chest. 2010 
Nov;138(5):1093-100 
9.2 
UNPUBLISHED REFERENCES 
U11-1009-02 
 GLORIA - AF: Global Registry on Long-Term Oral 
Antithrombotic TReatment In PAtients with Atrial Fibrillation (Phase I). 
1160.114. 3 Mar 2011 
001-MCS-50-408 (4.0)  Medical and Quality Review in Clinical Trials and Projects – 
Corporate SOP. 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 56 of 70 
 
10. 
APPENDICES 
10.1 
RISK SCORES FOR AF PATIENTS 
Data collected at the baseline visit will be used to generate the following scores for use in the 
respective analysis: 
Table 10.1: 1  
CHADS2 Stroke Risk Score 
CHADS2 components 
Points 
Congestive heart failure 
1 
Hypertension 
1 
Age 75 years or older 
1 
Diabetes mellitus 
1 
Prior cerebral ischemia (i.e., stroke, TIA) 
2 
Maximum score 
6 
 
CHADS2 score is based on a point system in which 2 points are assigned for a history of 
stroke or transient ischemic attack and 1 point each is assigned for age 75 years or older, 
hypertension, diabetes, or clinical heart failure or impaired left ventricular systolic function 
(generally interpreted as an ejection fraction ≤ 40%). A CHADS2 score of 0 identifies 
patients at low stroke risk, a score of 1 to 2 identifies patients at moderate stroke risk, and a 
score greater than 2 identifies patients at high stroke risk (P06-10925). 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 57 of 70 
 
Table 10.1: 2 
CHA2DS2-VASc Stroke Risk Score 
CHA2DS2VASc score 
Risk factors for stroke and thrombo-embolism in non-valvular AF 
Major risk factors 
Clinically relevant non-major risk factors 
Previous stroke, TIA, or systemic embolism 
Age ≥ 75 years 
Heart failure or moderate to severe LV 
systolic dysfunction (e.g. LV EF ≤40 %) 
Hypertension - Diabetes mellitus  Female 
sex - Age 65-74 years Vascular disease 
Risk factor-based approach expressed as a point based scoring system, with the 
acronym CHA2DS2-VASc 
(Note: maximum score is 9 since age may contribute 0, 1, or 2 points) 
Risk factor 
Score 
Congestive heart failure/LV dysfunction 
1 
Hypertension 
1 
Age ≥75 
2 
Diabetes mellitus 
1 
Stroke/TIA/systemic embolism 
2 
Vascular disease* 
1 
Age 65-74 
1 
Sex category (i.e. female sex) 
1 
Maximum score 
9 
* myocardial infarction, complex aortic plaque and PAD 
 
The CHA2DS2-VASc risk score is based on a point system in which 2 points are assigned for 
a history of stroke or TIA, or age ≥75; and 1 point each is assigned for age 65–74 years, a 
hypertension, diabetes, cardiac failure, vascular disease and female sex. On the basis of the 
risk strata defined in previous guidelines, a CHA2DS2-VASc score of 0 corresponds to “low 
risk”, a score of 1 corresponds to “intermediate risk”, and a score of 2 or more corresponds to 
“high risk” (R10-5332). 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 58 of 70 
 
Table 10.1: 3  
HAS-BLED Bleeding Risk SCORE  
Clinical characteristics comprising the HAS-BLED bleeding risk score 
Letter Clinical characteristic 
Points awarded 
H 
Hypertension 
1 
A 
Abnormal renal and liver 
 function (1 point each) 
1 or 2 
S 
Stroke 
1 
B 
Bleeding 
1 
L 
Labile INRs 
1 
E 
Elderly (e.g. age >65 years) 
1 
D 
Drugs or alcohol (1 point each) 
1 or 2 
Maximum score 
9 
 
Hypertension is defined as history of hypertension and current uncontrolled systolic blood 
pressure >160 mmHg. ‘Abnormal kidney function’ is defined as the presence of chronic 
dialysis or renal transplantation or serum creatinine ≥200 µmol/L. ‘Abnormal liver function’ 
is defined as chronic hepatic disease (e.g. cirrhosis) or biochemical evidence of significant 
hepatic derangement (e.g. bilirubin >2 x upper limit of normal, in association with aspartate 
aminotransferase/alanine aminotransferase/alkaline phosphatase >3 x upper limit normal). 
‘Bleeding’ refers to previous bleeding history and/or predisposition to bleeding, e.g. bleeding 
diathesis, anemia, etc. ‘Labile INRs’ refers to unstable/high INRs or poor time in therapeutic 
range (e.g. <60%). Within this study information on “Labile INRs” is not captured for any of 
the patients (neither for VKA-treated nor for non-VKA-treated patients), therefore this 
component will be set to 0 for all patients.  Drugs/alcohol use refers to concomitant use of 
drugs, such as antiplatelet agents, non-steroidal anti-inflammatory drugs, or alcohol abuse, 
etc. If a patient is not on VKA the value for ‘labile INRs’ will not be assessed. Further details 
will be given in the SEAP. 
A HAS-BLED score of ≥3 indicates ‘high risk’ for AF patients to develop a bleed and some 
caution and regular review of the patient is needed following the initiation of antithrombotic 
therapy, whether with VKA or aspirin (R10-6394). 
 
 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 59 of 70 
 
Table 10.1:4  
Modified Rankin Scale (mRS)  
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 andattention. 
Grade 6: 
dead 
 
 
10.2 
CREATININE CLEARANCE 
The serum creatinine clearance will be calculated according to Cockroft-Gault: 
Clcr (ml/min) = (140-age)*weight (kg) * GF 
72 * Scr (mg/dL) 
Clcr 
= 
Creatinine clearance 
ScrCrs = 
Serum creatinine  
(when serum creatinine is given in µmol/L, divide the value by 88.4) 
GF 
= 
Gender correction factor (0.85 for women and 1.00 for men) 
 
 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 60 of 70 
 
10.3 
LIST OF PLANNED REGIONS AND COUNTRIES PER REGION 
Table 10.3: 1 List of planned regions and countries per region 
 
Region 1 
Asia/Australia 
Region 2 
Europe 
Region 3 
North America 
Region 4 
Latin America 
Region 5 
Africa/ 
Middle East 
Australia 
Austria 
Latvia 
Canada 
Argentina 
Egypt 
Bangladesh 
Belgium 
Lithuania 
USA  
Brazil 
Kingdom of 
Saudia Arabia 
China 
Bulgaria 
Norway 
 
Chile 
Kuwait 
Hong Kong 
Croatia 
Poland 
 
Columbia 
Lebanon 
Indonesia 
Czech 
Republic 
Portugal 
 
Ecuador 
Nigeria 
India 
Denmark 
Romania 
 
Mexico 
Pakistan 
Malaysia 
Estonia 
Slovakia 
 
Peru 
South Africa 
Philippines 
Finland 
Slovenia 
 
Venezuela 
Turkey 
Russia 
France 
Spain 
 
 
United Arab 
Emirates 
Singapore 
Germany 
Sweden 
 
 
 
South Korea 
Greece 
Switzerland 
 
 
 
Taiwan 
Hungary 
The 
Netherlands 
 
 
 
Thailand 
Ireland 
UK 
 
 
 
 
Italy 
Ukraine 
 
 
 
Note: Not all planned countries will participate, and it is possible that some countries not 
listed here will later be added. 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 61 of 70 
 
11. DESCRIPTION OF GLOBAL AMENDMENT(S) 
Number of global amendment 
 
1 
Date of CTP revision 
 
21 May 2013 
EudraCT number 
 
NA 
BI Trial number 
 
1160.129 
BI Investigational Product(s) 
 
None 
Title of protocol 
 
GLORIA-AF:  Global Registry on Long-Term  
Oral Anti-thrombotic TReatment In PAtients with 
Atrial Fibrillation (Phase II/III) 
 
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     
Change #1 
 
Title Page and subsequent sections in the 
protocol (eg. Table of Contents, Synopsis, 
Signature Page) 
Description of change 
 
Change heading from “Post Marketing 
Surveillance Study Protocol” to Non-
interventional Study Protocol” 
Rationale for change 
 
Updated corporate SOP and new template for 
observational studies. 
Section to be changed     
Change #2 
 
Title Page 
Description of change 
 
Enter name and contact information of current 
TCM (
.) 
Rationale for change 
 
New TCM 
Section to be changed     
Change #3 
 
Flow Chart Phase II and Phase III 
Description of change 
 
Added to Flow Chart Phase II and Phase III, 
collection of serum creatinine information if 
available and any therapeutic/diagnostic 
interventions.  Clarify Non-Serious Adverse Event 
Reporting in Phase II to match that of phase III.  

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 62 of 70 
 
Number of global amendment 
 
1 
Any Non-Serious Adverse events related to any 
antithrombotic use will now be recorded on 
eCRFs in Phase II as well as Phase III. 
Rationale for change 
 
Include available information on serum 
creatinine and any therapeutic/diagnostic 
interventions.  Clarify and streamline Non-
Serious Adverse Event reporting. 
Section to be changed     
Change #4 
 
1.1 Medical Background 
Description of change 
 
Clarify countries where dabigatran has been 
approved. 
Rationale for change 
 
Section required updating. 
Section to be changed     
Change #5 
 
3.1 Overall Design and Plan 
Description of change 
 
Add substudy 1160.171 to be conducted in India 
and Switzerland.  Add that interim analyses will 
occur on a regional basis based on the number of 
patients enrolled (approximately once or twice a 
year).   
Rationale for change 
 
India and Switzerland were added as part of a 
separate substudy (1160.171) for administrative 
and logistical reasons only. 
Timing of interim analysis was formerly 
approximately every 6 months, but the timing of 
analysis is more driven by adequate number of 
patients enrolled.   
Sections to be changed     
Change #6 
 
3.1 Overall Design and Plan  
Section 3.2.1 Potential for bias and confounding, 
Section 7.3.1 Main Analysis 
Description of change 
 
Clarify criteria for comparability of important 
baseline characteristics (known risk factors for 
stroke and bleeding such as age, gender, 
hypertension, diabetes mellitus, prior stroke, 
prior transient ischemic attack, prior bleeding).  
The main measure to determine comparability of 
the two treatment groups regarding their 
important baseline characteristics will be the 
overlap on the propensity score, as measured by 
the proportion of patients in the region of overlap 
of the propensity score. 
Rationale for change 
 
Clarification and alignment with 1160.136 
protocol. 
Section to be changed     
Change #7 
 
3.1 Overall Design and Plan 
Description of change 
 
Add that it may be possible that Phase III cannot 
be conducted on a regional level if comparability 
between baseline characteristics cannot be 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 63 of 70 
 
Number of global amendment 
 
1 
established.  In this case comparative data 
collection will not be started in that region under 
this protocol.   Furthermore, depending on the 
sample size, regions might be pooled for analysis. 
Rationale for change 
 
Clarification regarding decisions to move into 
Phase III based on regional analyses and 
addition of possibility to pool regions for purpose 
of analyses. 
Section to be changed     
Change #8 
 
3.1 Overall Design and Plan 
Description of change 
 
Clarify planned registry period will be from July 
2011 to June2020.  Enrolment will end after the 
overall enrolment goal has been met, or by June 
2017, whichever comes first. Individual regions 
might end earlier depending on recruitment. 
Rationale for change 
 
Clarification of registry period and to indicate 
possibility for some regions to end early. 
Section to be changed     
Change #9 
 
3.2.1 Potential for bias and confounding  
3.3  Selection of Population 
Description of change 
 
Consecutive enrolment of patients to avoid 
selection bias is emphasised and parallel 
enrolment in another international registry 
should be avoided. Sites should also be selected 
wherever possible if both dabigatran and 
warfarin is available. 
Rationale for change 
 
Clarification to minimize potential for bias by 
confirming consecutive enrolment and ensure 
selected sites have capability to enrol both 
dabigatran and other VKAs are available. 
Section to be changed     
Change #10 
 
3.3.3 Exclusion Criteria 
Description of change 
 
Exclusion criterion #8 is changed from “Current 
participation in any clinical trial of an 
experimental drug or device” to “Current 
participation in any clinical trial of a drug or 
device” 
Rationale for change 
 
Participation in any clinical trial of a drug or 
device, including those of marketed drugs or 
devices, should exclude the patient from this 
registry because patient’s treatment would likely 
be influenced by participation in the trial. 
Section to be changed     
Change #11 
 
3.3.4.1 Removal of individual patients 
Description of change 
 
It will no longer be true that a patient may be 
removed from the study due to persistent failure 
of the patient to comply with the protocol and 
study procedures. Removal of a patient due to 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 64 of 70 
 
Number of global amendment 
 
1 
violation of exclusion criterion #8 (participation 
in a clinical trial with a drug or device) is revised 
to be consistent with the new wording of exclusion 
criterion #8. Removal of a patient due to violation 
of exclusion criterion #9 (Participation in another 
international registry on the use of oral 
anticoagulation in AF) is clarified by adhering to 
the language used in Section 3.3.3. The “Patient 
Disposition CRF page” is now referred to by its 
proper designation, “the End of Study form.”  A 
reminder is inserted that “If a patient 
discontinues the study prematurely, another 
follow-up assessment should be performed (if 
possible unless the reason for discontinuation is 
erroneous enrolment of the patient into the study 
at baseline) and data should be entered on the 
eCRF of the next planned visit.”  A reminder is 
inserted that patients should not be discontinued 
from the study due to adverse events.  
Rationale for change 
 
The conditions under which a patient may be 
removed from the study are clarified to be 
consistent with the principles of a registry study 
and with changes made elsewhere in the protocol. 
Section to be changed     
Change #12 
 
5.1.1 Outcome Measures 
Description of change 
 
There are some changes to the list of Outcome 
measures.  “Major bleeding events”now include 
the phrase “(including life-threatening bleeding 
events; see definition in Section 5.1.2  for further 
clarification)”.  “Non-vascular death” and 
“death of unknown cause” are deleted as 
specified outcome measures but are still 
evaluated as part of the outcome measure “all 
cause death.” Vascular death is retained as a 
separate outcome measure because of its 
importance and relevance to this study.   
Rationale for change 
 
Align with requests from EMA to be incorporated 
into study 1160.136. 
Section to be changed     
Change #13 
 
5.1.1 Outcome Measures 
Description of change 
 
Clarifications of definitions of bleeding events.   
“Fatal bleeding” is moved from “Major 
Bleeding” to “Life-threatening bleeding,” which 
is already a part of the definition of “Major 
bleeding.” Thus, “fatal bleeding” is still included 
in the definition of “Major bleeding,” but now as 
a sub-category of “Life-threatening bleeding.” 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 65 of 70 
 
Number of global amendment 
 
1 
Rationale for change 
 
See change #12; align with requests from EMA to 
be incorporated into study 1160.136.   
Section to be changed     
Change #14 
 
5.1.1 Outcome Measures 
Description of change 
 
Add additional composite endpoint: 
-Stroke, systemic embolism, myocardial infarction 
and vascular death (vascular composite endpoint) 
Rationale for change 
 
See change #12; align with requests from EMA to 
be incorporated into study 1160.136. 
Section to be changed     
Change #15 
 
5.2.2.1 Assessment of Adverse Events 
Description of change 
 
Added section on ‘Worsening of Pre-existing 
Conditions’  
Rationale for change 
 
Added to be in conformance to the drug safety 
SOP 001-MCC-40-002  
Section to be changed     
Change #16 
 
5.2.2.2Assessment of Adverse Events 
Description of change 
 
Explanation of “always serious adverse events” 
whereby some events, by their very nature, are 
always categorized as serious (e.g. stroke). 
Rationale for change 
 
Reporting requirement to be incorporated into 
new protocols or amended protocols.   
Section to be changed     
Change #17 
 
5.2.2.2 Assessment of Adverse Events 
Footnote #5 – Phase II Flowchart 
Description of change 
 
Unified instructions for AE reporting for Phases 
II and III.  It was determined that it was not 
necessary to have separate instructions for Phase 
II and III. The only change is clarification that the 
requirement to report non-serious AEs which are 
deemed related to an antithrombotic other than 
dabigatran applies to both Phase II and III.  
Further clarification is provided to the 
investigator about what reporting functions are 
performed automatically by the system and what 
are the responsibilities of the site personnel.  It is 
also clarified that Non-serious AEs which are 
deemed related to a BI drug must be reported to 
BI within seven days of the site learning of the 
AE. 
Rationale for change 
 
Streamlined and simplified instructions for 
reporting of SAEs and non-serious AE and 
required reporting timeline for NSAE reporting of 
related events was clarified. 
Section to be changed     
Change #18 
 
6.1 Visit Schedule 
Description of change 
 
It is clarified: Due to the observational design, 
the dates for follow-up visits are only 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 66 of 70 
 
Number of global amendment 
 
1 
recommendations.  The visit windows allow for 
flexibility.  Collection of data in the study should 
be managed during routine practice visits (i.e., 
the visits should not be conducted via telephone).   
In case a physical visit is not possible e.g. due to 
the transient inability of a patient to attend the 
practice, the visit can be conducted via telephone. 
Rationale for change 
 
Clarification that patients are not mandated to 
come into the clinic for visits during specified 
time windows, and clarification that visits by 
phone can exceptionally occur when needed. 
Section to be changed     
Change #19 
 
6.2.1 Assessments in Phase II of GLORIA-AF  
Description of change 
 
For Assessments at Baseline, add “(if available)” 
after “Blood pressure, heart rate and serum 
creatinine”.  For Assessments at the Follow-up 
Visits, add “Type of follow up visit,”  “Serum 
creatinine to be recorded (if available),” and 
“Therapeutic /diagnostic interventions.” Note 
that the latter refers to simply recording if there 
were any therapeutic or diagnostic interventions, 
not recommending or requiring them.  The bullet 
point regarding the reporting of SAEs is 
simplified to say “All serious adverse events 
judged as related or unrelated to any drug.” 
(Reference to dabigatran or other BI drugs is 
removed since it is unnecessary and could be 
confusing.)  The bullet point regarding the 
reporting of non-serious AE is changed to say, 
“Non-serious adverse events judged as related to 
any antithrombotic therapy including dabigatran, 
or to any BI drug (see Section 5.2.2.2).” (The 
inclusion of any antithrombotic therapy is 
clarified to be consistent with the simplifications 
made in Section 5.2.2.2.) 
 
Also, add clarification that a follow-up 
assessment should be performed at time of study 
discontinuation if possible, and the end of study 
eCRF completed. 
Rationale for change 
 
Clarifications that information pertaining to vital 
signs, creatinine clearance and any therapeutic 
procedures is only recorded if the information is 
available.  The protocol does not mandate any 
additional procedures or lab tests to be 
performed by the physician above those which are 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 67 of 70 
 
Number of global amendment 
 
1 
part of the patient’s normal medical care.  The 
type of follow-up visit (in person or via telephone) 
is recorded.  The descriptions of SAE and non-
serious AE information collected is modified to 
conform with the modifications made to section 
5.2.2.2.   
 
Clarification around follow-up and eCRF 
completion upon early discontinuation was 
added. 
Section to be changed     
Change #20 
 
6.2.2 Assessments in Phase III of GLORIA-AF 
Description of change 
 
This is for Phase III.  Same as for changes for 
follow-up visits for Phase II as described above 
for section 6.2.1. 
Rationale for change 
 
Same as for section 6.2.1. 
Section to be changed     
Change #21 
 
Section 7.1 Statistical Design Model and 7.6 – 
Determination of Sample Size 
Description of change 
 
Information on sub-study 1160.171 was added 
Rationale for change 
 
Sub-study 1160.171 was newly added 
Section to be changed     
Change #22 
 
7.3 Planned Analyses 
Description of change 
 
Analyses on a country level might be performed in 
addition, once the report or interim report of 
phase II (or phase III) for a region is available or 
if required due to regulatory requirements. 
Rationale for change 
 
This statement helps to clarify that the final 
analysis of country data should only be done after 
analysis of the region (for interim analysis, a 
corresponding statement is already included in 
the version 3.0 of the signed protocol)  
Section to be changed     
Change #23 
 
7.3.1 Main Analysis  
B) Important outcome events (Phase II only) 
Description of change 
 
Clarification that outcome event analyses will be 
stratified generally by relevant chronic 
antithrombotic therapy.  
Rationale for change 
 
Clarification of analyses of important outcome 
events in Phase II.  Previously, it was to be 
stratified by chronic antithrombotic use for the 
AF indication but information on antithrombotic 
treatment will be collected independent of 
indication as the effect of antithrombotic 
treatment is also independent of indication. 
Section to be changed     
Change #24 
 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 68 of 70 
 
Number of global amendment 
 
Description of change 
 
Rationale for change 
 
Section to be changed    
Change #25 
 
Description of change 
 
Rationale for change 
 
Section to be changed    
Change #26 
 
Description of change 
 
Rationale for change 
 
Section to be changed    
Change #27 
 
7.3.3 Safety Analysis 
Description of change 
 
An analysis of ADRs restricted to those events 
which are related to the antithrombotic treatment 
prescribed at baseline was added.   
Rationale for change 
 
To support the main outcome event analysis by 
AE data; to adjust the AE analysis for effects 
introduced by differential types and rates of 
switchers 
Section to be changed    
Change #28 
 
7.3.4 Interim Analyses 
Description of change 
 
 Interim analyses on phase II/III baseline and 
outcome event data were added 
Rationale for change 
 
To obtain preliminary phaseII/ III results  
Section to be changed    
Change #29 
 
7.3.4 Interim Analyses 
Description of change 
 
Added that "the overlap on the propensity score 
as measured by the proportion of patients in the 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 69 of 70 
 
Number of global amendment 
 
1 
region of overlap on the propensity score will be 
the main measure to determine comparability of 
the two treatment groups 
Rationale for change 
 
Clarification 
Section to be changed    
Change #30 
 
7.3.4 Interim Analysis 
Description of change 
 
Revised the following section on planned interim 
analysis and multiple comparisons: “As the 
planned analyses are to be interpreted on a 
descriptive level, no adjustment for multiplicity 
will be done.   
Rationale 
 
Clarification due to additional interim analyses; 
see change #28. 
Section to be changed    
Change #31 
 
7.4 Handling of Missing Data 
Description of change 
 
Add that baseline characteristics of patients who 
were lost to follow-up in comparison to patients 
with a complete follow-up will be described, 
“depending on proportion of patients lost to 
follow-up.” 
Rationale for change 
 
Clarification  
Section to be changed    
Change #32 
 
7.6 Determination of Sample Size 
Description of change 
 
Add that “the actual power will be dependent on 
the covariates included in the analysis model, 
their degree of imbalance between the treatment 
groups, and their strength of association with the 
outcome, and might therefore differ.”  
Rationale for change 
 
Clarification 
Section to be changed    
Change #33 
 
Table 10.1:3, Text following HAS-BLED Bleeding 
Risk SCORE Table 
Description of change 
 
Specify definitions of “Hypertension” and 
“Labile INRs” 
Rationale for change 
 
Clarification 
Section to be changed    
Change #34 
 
Appendix 10.3 List of Planned Regions and 
Countries per Region 
Description of change 
 
Added Czech Republic, Estonia and South Africa 
to the table.   Also added note that “Not all 
planned countries will participate, and it is 
possible that some countries not listed will later 
be added.” 
Rationale for change 
 
Update and clarification on country participation 
Section to be changed    
Change #35 
 
All sections 
Description of change 
 
Typographical and grammatical errors corrected 
throughout the document. 

Boehringer Ingelheim 
7 June 2013 19 July 2011 
BI Trial No.: 1160.129 
Observational Plan 
Page 70 of 70 
 
Number of global amendment 
 
1 
Rationale for change 
 
Correction as required to fix minor wording 
errors, spacing, and punctuation.