GLORIA - AF: Global Registry on Long-Term Oral Anti-thrombotic TReatment In PAtients With Atrial Fibrillation (Phase II/III - EU/EEA Member States)
Conditions: Stroke, Atrial Fibrillation
Sponsor: Boehringer Ingelheim

  Non-Interventional Study Protocol
Doc. No.: с01951554-12
BI Study No.:
1160.136
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 – EU/EEA Member States)
Clinical Phase:
IV
Trial Clinical 
Monitor:
Telephone:
Telefax:     
/ Co-
of the 
Steering Committee: 
Telephone:
Telefax:
Telephone:
Telefax:
Status:
Global Amendment 1
Version and Date:
Version:
4.0
Date: 22 October 2014
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TITLE PAGE

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LOCAL SIGNATURES
(PRINCIPAL INVESTIGATOR OF SITE AND LOCAL 
CLINICAL MONITOR (CML))
Non-Interventional Study Title: GLORIA - AF: Global Registry on Long-Term Oral 
Antithrombotic TReatment In PAtients with Atrial Fibrillation
(Phase II/III – in EU/EEA Member States)
Trial Number: 1160.136
Protocol Version: 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

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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:
22 October 2014
23 March 2012
1160.136
Title of study:
GLORIA-AF: Global Registry on Long-Term Oral Antithrombotic TReatment In 
PAtients with Atrial Fibrillation.
This protocol describes Phases II and III  (of three phases in total) of the Registry 
Program in the EU/EEA* member states
Study site(s) :
Overall up to about 680 sites (including e.g. hospitals, anticoagulant clinics, 
specialists and general practice settings) in up to 23 countries 
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.

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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:
22 October 2014
23 March 2012
1160.136
No. of patients: 
For the EU/EEA* member states, enrollment of approximately 5,000 patients in Phase 
II and another 10,000 patients in Phase III is planned in total.
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. 
In addition, compliance with the dabigatran SmPC will be examined. 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
* European Union/European Economic Area

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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

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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 
interventions
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, 
any antithrombotic treatment, 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 
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 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, 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 other BI concomitant medication, or any other antithrombotic therapy SHOULD NOT 
BE RECORDED in the registry eCRF.

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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
Collect serum 
creatinine 
information (if 
available)
X
X
X
X
X
Antithrombotic 
treatment 
X1
X2
X2
X2
X2
Selected 
concomitant 
treatment (current, 
any change)
X
X
X
X
X
Outcome events 
(Vascular and 
bleeding events)3
X
X
X
X
Therapeutic/
diagnostic 
interventions
X
X
X
X
Serious adverse 
events4
X
X
X
X
Non-serious adverse 
drug reactions5
X
X
X
X
Vital Status
X

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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 concomitant medication, or any other antithrombotic therapy
SHOULD NOT BE INCLUDED in registry eCRF.

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TABLE OF CONTENTS
TITLE PAGE .................................................................................................... 1
LOCAL SIGNATURES (PRINCIPAL INVESTIGATOR OF SITE 
AND LOCAL CLINICAL MONITOR (CML)) .................................... 2
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 ........................................................................................ 17
2.1
RATIONALE FOR PERFORMING THE STUDY.......................................17
2.2
STUDY OBJECTIVES......................................................................................17
2.2.1
Main Objective.......................................................................................17
2.3
BENEFIT-RISK ASSESSMENT .....................................................................17
3.
DESCRIPTION OF DESIGN AND STUDY POPULATION............ 18
3.1
OVERALL DESIGN AND PLAN....................................................................18
3.1.1
Administrative structure of the study..................................................19
3.2
DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S).....................................................................................20
3.2.1
Potential for bias and confounding ......................................................20
3.3
SELECTION OF POPULATION....................................................................22
3.3.1
Main diagnosis for study entry.............................................................22
3.3.2
Inclusion criteria....................................................................................23
3.3.3
Exclusion criteria ...................................................................................23
3.3.4
Removal of patients from therapy or assessments..............................24
4.
TREATMENTS....................................................................................... 26
4.1
PRESCRIBED TREATMENTS TO BE OBSERVED...................................26
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT....................................................................................................26
4.3
TREATMENT COMPLIANCE AND COMPLIANCE WITH SmPC ........26
5.
VARIABLES AND THEIR ASSESSMENT ........................................ 27
5.1
OUTCOMES ......................................................................................................27
5.1.1
Outcome measures.................................................................................27
5.1.2
Assessment of outcome measures .........................................................28
5.2
SAFETY..............................................................................................................31
5.2.1
Endpoint(s) of safety..............................................................................31
5.2.2
Assessment of adverse events................................................................31

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5.3
OTHER...............................................................................................................34
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................34
6.
INVESTIGATIONAL PLAN................................................................. 35
6.1
VISIT SCHEDULE............................................................................................35
6.2
DETAILS OF STUDY PROCEDURES AT SELECTED VISITS ...............36
6.2.1
Assessments in Phase II of GLORIA-AF.............................................36
6.2.2
Assessments in Phase III of GLORIA-AF ...........................................37
6.2.3
End of study and follow-up period.......................................................38
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE ........................................................................................ 39
7.1
STATISTICAL DESIGN - MODEL................................................................39
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................39
7.3
PLANNED ANALYSES....................................................................................39
7.3.1
Main analyses .........................................................................................40
7.3.3
Safety analyses........................................................................................44
7.3.4
Interim analyses .....................................................................................45
7.4
HANDLING OF MISSING DATA ..................................................................45
7.5. RANDOMISATION ..........................................................................................45
7.6
DETERMINATION OF SAMPLE SIZE........................................................45
8.
INFORMED CONSENT, DATA PROTECTION, STUDY
RECORDS ............................................................................................... 48
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................48
8.2
DATA QUALITY ASSURANCE.....................................................................49
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 PARTICIPATING COUNTRIES ...............................60

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ABBREVIATIONS
ADR
Adverse Drug Reaction
AE
Adverse Event
AF
Atrial Fibrillation
BI
Boehringer Ingelheim 
CA
Competent (Regulatory) Authority
CI
Confidence Interval
CML
Clinical Monitor Local
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
LV
Left Ventricular

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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
SmPC
Summary of Product Characteristics
SPAF
Stroke Prevention in Atrial Fibrillation
TCM
Trial Clinical Monitor
TIA
Transient Ischemic Attack
VKA
Vitamin K Antagonist

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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 embolisation 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 

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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 
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 short comings 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 been approved for the prevention 
of stroke and systemic emboli in patients with AF in many countries worldwide, including 
the United States, Canada, Japan, Australia, Korea, Mexico, Brazil, as well as EU. 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 Phases II and III for the 

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EU/EEA-member states and is considered a substudy of the global Phases II/III of the 
Registry Program (1160.129; U11-1638-04).  
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 
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 the global GLORIA-AF Registry Program (Phases I-III) up to 56,000 patients are planned 
to be included. 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.  

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The here described study (1160.136) will provide information on the utilization of dabigatran 
after approval and examine the compliance with the dabigatran SmPC. Specifically Phase II 
is designed as a Drug Utilization Study (DUS) and will allow the analysis of data collected 
specifically in EU/EEA member states. 

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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.
2.3
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.

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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 three separate protocols: The present core protocol covering all global regions 
participating in Phase II and III of the Registry Program (1160.129, U11-1638-03) and two 
protocols with focus on the EU/EEA-member states (1160.136), as well as India (substudy 
1160.171). The main design features within the protocols are identical and the analysis of the 
global study (1160.129) will also contain the data collected in patients entered in the present 
substudies (1160.136 and 1160.171).
Phase II, which is planned to be initiated after approval of dabigatran in the respective 
country consists of a baseline visit and a two-year follow-up for patients treated with 
dabigatran for the prevention of stroke. Thus, data on the use of dabigatran in routine clinical 
practice will be collected to describe how dabigatran is prescribed and used in the population 
of newly diagnosed non-valvular AF patients and how these factors influence important 
outcome and safety events. In addition, compliance with the dabigatran SmPC with regards to 
indication, posology, contraindications and warnings will be evaluated. The utilization of 
dabigatran will be assessed with regards to treatment persistence, compliance, proportion of 
patients discontinuing treatment and reason for discontinuation. 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 e.g. age, gender, hypertension, diabetes mellitus, prior stroke, prior transient 
ischemic attack, prior bleeding and concomitant medication use) of these groups has been 
established and the likely amount of residual channeling bias after confounder adjustment is 
comparatively small, 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. 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. 
It could turn out that Phase III cannot be conducted in the EU region; i.e. if after two years of 
assessing baseline characteristics of dabigatran and VKA initiators in Phase II comparability 

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has not been achieved, which would preclude any meaningful comparisons, then one of the 
following three scenarios to assess long-term comparative outcomes will be pursued:
1. If substantial overlap is achieved, and comparability in Phase II is expected to be 
achieved within the following six months, i.e. overlap is expected to be very soon 
sufficient, then Phase II will be prolonged for six more months before entering Phase III.
2. If some overlap is achieved, but comparability is expected not to be achievable in Phase II 
within the following six months due to persistent channeling bias, then Phase III will be 
started and a matched analysis will be conducted, being aware of the draw back that the 
power could not be sufficient for all outcomes.
3. If little or no overlap is achieved, and it appears highly unlikely that comparability would 
be achievable even if the study were extended for a prolonged period of time as 
significant channeling bias persists, then a separate database study based on existing data 
(e.g. claims data, electronic medical records) on long-term outcomes will be initiated to 
ensure sufficient power within matched cohorts.
The variables that will be considered for matching in scenario 2 and 3 will consist of a subset 
of those that were used for the assessment of comparability. Their choice will be based on the 
strength of the association of those variables with the outcome under study and the learnings 
from the interim results. At least age and gender will be matching variables. In addition, 
scores derived from those variables (e.g. the estimated propensity score) could be considered 
as a matching variable.
The study described in this protocol will collect data in up to 23 European countries (for 
planned participating countries see Appendix 10.3) in up to about 680 sites and is planned to 
involve as many as 2,000 investigators. It is planned to enroll approximately 5,000 patients 
in Phase II and another 10,000 patients in Phase III.
The planned registry period is from July 2011 to June 2020, which covers the total expected 
duration of Phase II and III. 
Enrollment into Phase III of the global 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. 

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Operations Committee
The study conduct will be overseen by an Operations Committee (OC), consisting of the 
Chair, Co-Chair, 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 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. However, if comparability of baseline characteristics is 
insufficient, alternative approaches will be followed to assess long-term outcomes (see 
section 3.1).
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 
noncomparability 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 

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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 enrollment 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 enrollment in another international registry on the use 
of oral anticoagulation in AF in the same department should be avoided, as otherwise 
consecutive enrollment 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.
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. 
However, if comparability of baseline characteristics is insufficient, alternative approaches 
will be followed to assess long-term outcomes (see section 3.1).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, e.g.
age, gender, hypertension, diabetes mellitus, prior stroke, prior transient ischemic attack, 
prior bleeding and concomitant medication use). 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

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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 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
Information bias can occur for example, due to selective under-reporting 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 7 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 

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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
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)

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4. Patient’s life-expectancy is expected to be less than one year at the time of potential 
enrollment 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 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 

The patient was erroneously included in the Registry Program

Participation in another international drug study or registry on the use of oral 
anticoagulation 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 reasons cited above. The Investigator will indicate on
the End of Study form 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 enrollment 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,

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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

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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 AND COMPLIANCE WITH SmPC
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; objective 
measure).

Proportion of days with compliant medication intake (based on reference period as 
specified in the CRF from each planned visit, subjective measure)
Compliance with the SmPC of dabigatran will be evaluated by analysing different patient 
characteristics such as age, weight, hepatic disease, renal function, further stroke and 
bleeding risk factors and concomitant medications in relation to the prescription of dabigatran 
(including dose selection)

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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 will be recorded. In Phase II the utilization of 
dabigatran will be assessed with regards to treatment persistence, compliance, and changes in 
antithrombotic therapy (e.g., dose adjustments, proportion of patients discontinuing treatment 
and reason for discontinuation). In addition compliance with the dabigatran SmPC with 
regards to indication, posology, contraindications and warnings will be evaluated. In Phase 
III the utilization of antithrombotic therapy will be collected for all antithrombotic therapies 
prescribed for the prevention of stroke.
The following events are considered important clinical 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, 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

Vascular death
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)

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5.1.2
Assessment of outcome measures
Compliance
Compliance with antithrombotic therapy prescribed for the prevention of stroke 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; objective 
measure).

Proportion of  days with compliant medication intake (based on reference period as 
specified in the CRF from each planned visit, subjective measure)
Treatment persistence
Treatment persistence will be assessed as time until permanent discontinuation of the 
treatment (number of days or years).
Compliance with the dabigatran SmPC
Compliance with the dabigatran SmPC will be captured by collecting the appropriate 
variables, such as renal function, stroke and bleeding risk factors, concomitant medications 
and diseases at baseline and during follow-up. 

Compliance with SmPC Indication: All patients included in the study are non-valvular 
atrial fibrillation (NVAF) patients at risk for stroke. The AF diagnosis and all risk factors 
for stroke will be collected at baseline, so that compliance with the SmPC indication for 
dabigatran can be analysed. 

Compliance with SmPC Contraindications: To investigate, if a contraindication to 
dabigatran is present, such as severe renal or hepatic impairment, impairment of 
hemostasis and contraindicated concomitant medications the respective variables will be 
recorded at baseline and during the follow up of the patients.

Compliance with SmPC Posology: All factors relevant for dose selection, such as age, 
concomitant drugs and renal function (by computing the creatinine clearance based on 
collected serum creatinine, if a blood test was performed) will be analysed.

Compliance with SmPC Warnings: The treatment with dabigatran will be recorded at 
each visit including interruptions for outcome events (including major bleeds), procedures 
and other events which necessitate treatment interruptions (e.g. major trauma). If known 
by the investigator also information on bridging strategies will be collected. Whether the 
physician is compliant to the warnings section of the dabigatran SmPC, can be 
investigated using data captured on dose selection, comedications, comorbidities 
including factors that increase the bleeding risk and important outcome events.

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The following definitions apply and should be used as a guide when reporting a thrombotic 
event:
Stroke:
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 fulfil the following criteria:
1. Typical symptoms or signs (e.g., dyspnoea, 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 fulfil either the criteria:
-
Development of significant Q-waves in at least 2 adjacent ECG leads.
Or at least 2 of the following three criteria:

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-
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).
-
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 haemoglobin 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
Life-threatening bleeding, defined as meeting one or more of the following criteria:

Symptomatic intracranial bleed

Reduction in haemoglobin 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.

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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. 

Yes:
There is a reasonable causal relationship between the drug administered 
and the AE. 

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
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. 
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 

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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:

All SAEs and Outcome Events irrespective of causal relationship with dabigatran or any 
other 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).

Non-serious AEs with a causal relationship to any antithrombotic drug including
dabigatran or VKA, or any BI drug are collected on AE forms in the EDC System. Non-
serious AEs that are deemed NOT related to (i.e. caused by) dabigatran, VKA, any other 
antithrombotic therapy, or to BI concomitant medication SHOULD NOT be entered 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.

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.
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) of becoming aware of the event. The EDC System is 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.

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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.
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 countries. 

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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 from each visit 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 made to ensure 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
* Due to the observational design, the dates for follow-up visits are only recommendations. Visit windows allow for 
flexibility. Collection of data in the study should be managed during routine practice visits
**Patients will take part either in Phase II or in Phase III
§ Follow-up in patients prescribed dabigatran (at baseline) only

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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 enrollment, for the purposes 
of cross-sectional analyses. Follow-up assessments will be done only in patients who receive 
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

Medical history (including current concomitant diseases)

Selected concomitant treatments (antihypertensive, heart failure and anti-arrhythmic
therapies, metabolic and anti-inflammatory) and other selected drugs. 

Antithrombotic treatment selected including start date (all antithrombotic therapies, for 
stroke prevention as well as other indications).
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 any BI drug (see section 
5.2.2.2)

Non-serious adverse events judged as related to any antithrombotic therapy including
dabigatran or to any BI drug (see section 5.2.2.2) 

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
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.
If a patient prematurely discontinues from the registry, a follow-up assessment 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 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 any drug (see section 5.2.2.2)

Non-serious adverse events judged as related to any antithrombotic therapy including
dabigatran, or to any BI drug (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 should be 
performed at time of study discontinuation if possible, and the end of study eCRF completed.

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6.2.3
End of study and follow-up period
For early Discontinuation:

Date of Registry discontinuation

Reason for Registry discontinuation

Vital status

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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. 
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. However, if comparability of baseline characteristics is insufficient, alternative 
approaches will be followed to assess long-term outcomes (see section 3.1).
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
!"# $% $&# '($ ")# %* $&+, %-,#).($+%'(/ ,$"01
there is no (confirmatory) hypotheses testing 
foreseen in a strict statistical sense. 2'(/1,#, 
()# 0#,3)+4$+.# +' '($")# +'3/"0+'5 46.(/"#, ('0 
3%'*+0#'3# +'$#).(/, *)%7 ,$($+,$+3(/ 7%0#/, ",#0 *%) #84/%)($+.# 4")4%,#,9 
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 

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(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 a country level might be performed in addition, once the report or interim report 
of phase II (or phase III) 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 baseline.
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.
Additionally, similar primary and other analyses as described for the total Registry Program 
also will be conducted using data from only patients enrolled in the EU/EEA member states 
covered by this protocol (1160.136). 
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.
The antithrombotic treatment choice for stroke prevention at the baseline visit (e.g. none, 
VKAs, ASA, clopidogrel, dabigatran, etc.) will be described. 
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, e.g. age, gender, hypertension, diabetes mellitus, 
prior stroke, prior transient ischemic attack, prior bleeding and concomitant medication use)
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 at 
baseline. The analysis will be based on all eligible patients initiating dabigatran for stroke 

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prevention 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 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)
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.
This analysis will be repeated within subgroups. Examples of subgroup variables are age, 
gender and stroke and bleeding risk factors. In addition the calculation of incidence rates and 
cumulative risks will be done stratified by chronic antiplatelet treatment.  If the patients 
initiating dabigatran treatment for stroke prevention at baseline are comparable (in terms of 
important baseline characteristics) to those initiating VKA treatment, incidence rates within 
these two groups will also be reported.
The analysis will be based on antithrombotic treatment choice prescribed for stroke 
prevention 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).

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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 for stroke prevention). 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 for stroke prevention they have received at the time 
of the event. If no current antithrombotic treatment for stroke prevention 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 for stroke prevention 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 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 for stroke prevention)

ADRs (related to antithrombotic therapy for stroke prevention) leading to discontinuation 
of antithrombotic treatment 

Serious ADRs (related to antithrombotic therapy for stroke prevention)

Deaths

SAEs
Additionally, an analysis of ADRs restricted to those events which are related to the 
antithrombotic treatment for stroke prevention initiated at baseline will be performed. 
Systematic collection of vital signs and laboratory parameters is not planned.

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7.3.4
Interim analyses
Analysis of baseline characteristics will be performed 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. The comparability of the patient baseline 
characteristics prescribed either VKAs or dabigatran will be evaluated at regular intervals 
(e.g. approximately twice per year, dependent on the recruitment). For these analyses 
appropriate statistical methods, which will include propensity scores will be used to assess 
channeling bias. The decision to start with Phase III will be made by the steering committee 
(SC) and will be based on the interim analyses performed in context of the global study Phase 
II and III (1160.129, U11-1638-03),
Additional types of interim analyses will be performed in context of the global study 
(1160.129), including regional analyses of Phase II / Phase III baseline data.
At the time of those analyses or afterwards, additional interim analyses on the baseline and/or 
follow-up data for the EU/EEA patients (i.e. all patients included in 1160.136 study) might be 
done (including e.g. respective analysis on compliance with SmPC). 
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.
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. 
7.6
DETERMINATION OF SAMPLE SIZE
It is planned to recruit approximately 5,000 patients in Phase II and approximately 10,000 
patients in Phase III. 
The number of patients included in Phase II and duration of enrollment is not driven by a 
formal sample size calculation but is primarily dependent on the availability of eligible 
patients treated with dabigatran 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 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.

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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:
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
5000
10000
5
Expected n
25
50
100
200
250
500
95%-CI width
4.03
2.81
1.96
1.38
1.23
0.86
10
Expected n
50
100
200
400
500
1000
95%-CI width
5.46
3.82
2.68
1.88
1.68
1.19
20
Expected n
100
200
400
800
1000
2000
95%-CI width
7.2
5.05
3.55
2.5
2.24
1.58
30
Expected n
150
300
600
1200
1500
3000
95%-CI width
8.21
5.77
4.06
2.86
2.56
1.81
40
Expected n
200
400
800
1600
2000
4000
95%-CI width
8.77
6.17
4.34
3.06
2.74
1.93
50
Expected n
250
500
1000
2000
2500
5000
95%-CI width
8.94
6.29
4.43
3.12
2.79
1.97
For Phase II a total sample size of 5,000 patients allows an estimation of a population 
attribute with a precision of less than 2.8% (i.e. width of 95% CI). 
For subgroups which consist of at least 500 patients; this allows an estimation of a population 
attribute within the subgroup with a precision of approximately 8.9% (i.e. width of 95% CI).
For Phase III a total sample size of 10,000 patients allows an estimation of a population 
attribute with a precision of less than 2.0% (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 2,500 patients from 
EU/EEA member states 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 

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total of approximately 3,802 patient-years in patients from EU/EEA member states starting 
dabigatran will be observed. 
When observing 3,802 dabigatran patient years, we will observe at least one patient with an 
event (ADR, MBE, stroke/SEE, etc), if the underlying incidence rate for this event is 0.079 
occurrences per 100 patient years or above with a power of 95%. If we do not observe any 
event within the 3,802 patient years, it can be excluded with 95% confidence that the 
underlying true event rate is above 0.079 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 3,802 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 3,802 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
0.70773
1.372465
2
1.575877
2.503151
3
2.474761
3.603743
The calculation of confidence intervals is based on the method described in Hahn, Meeker (section 7.2.2; using χ2-quantiles).
(R12-3048)
As an example, assume that the event rate for stroke per 100 patient years is 1, i.e. we 
observe ~38 strokes within the 3,802 patient years. The two-sided 95% confidence interval for 
the population incidence rate per 100 patient years is 0.71 to 1.37. Thus it can be excluded 
with 95% confidence that the true rate of strokes per 100 patient years is above 1.37 in the 
population.
For Phase III, for treatment group cohorts which initially consist of at least 2,000 patients, 
approximately 4,019 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 
2,000 patients will have approximately the same precision as described above (for 2,500 
patients in Phase II). 
95% confidence intervals will be calculated for several outcome events. 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.

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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. 
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.

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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 
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.

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Data entered in the eCRFs that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The Investigator may need 
to request previous medical records or transfer records, depending on the trial; also current 
medical records must be available. For eCRFs all data must be derived from source 
documents.
8.3.2
Direct access to source data and documents
The Investigator / institution will permit 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 fulfil 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 needs 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. 

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The data collected in the eCRFs will be transferred to the database via the Internet through 
secure web-sites. 
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.

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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)

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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)
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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
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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 

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D, American Heart Association Stroke Council, Council on Cardiovascular 
Nursing, Council on Clinical Cardiology, and Interdisciplinary Council on 
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)
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Stroke Prevention in Atrial Fibrillation Investigators
Stroke Prevention in Atrial Fibrillation study: final results.
Circulation 84 (2), 527 - 539 (1991)
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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)
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Ray WA, Evaluating medication effects outside of clinical trials: new-user 
designs. Am J Epidemiol 158 (9), 915 - 920 (2003)
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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.
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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 
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European Heart Rhythm Association, endorsed by the European Society of 
Cardiology Working Group on Thrombosis.
Europace 13, 723 - 746 (2011)
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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)
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International Epidemiological Association (IEA) Good epidemiological 
practice (GEP): IEA guidelines for proper conduct of epidemiological 
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Guidelines for good pharmacoepidemiology practices 
(GPP).Pharmacoepidemiol Drug Saf 17, 200 - 208 (2008)
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Gliklich RE, Dreyer NA, eds. Registries for Evaluating Patient Outcomes: A 
User's Guide. (Prepared by Outcome DEcIDE Center [Outcome Sciences, Inc. 
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Publication No. 07-EHC001-1. Rockville, MD: Agency for Healthcare 
Research and Quality.April 2007
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Hahn G, Meeker W. Statistical intervals: a guide for practitioners. 1991
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
U11-1638-01 GLORIA - AF: Global Registry on Long-Term Oral Antithrombotic
TReatment In PAtients with Atrial Fibrillation (Phase II/III). 1160.129.
 8 Jun 2011
U11-1638-03 GLORIA - AF: Global Registry on Long-Term Oral Antithrombotic 
TReatment In PAtients with Atrial Fibrillation (Phase II/III). 1160.129. 
 19 Jul 2011
U11-1638-04 GLORIA - AF: Global Registry on Long-Term Oral Antithrombotic 
TReatment In PAtients with Atrial Fibrillation (Phase II/III). 1160.129. 
 7 June 2013

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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).

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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).

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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 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).

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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 and attention.
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)

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10.3
LIST OF PLANNED PARTICIPATING COUNTRIES 
Table 10.3: 1 List of planned participating countries 
Planned Participating Countries (EU and/or EEA)
Austria
Finland
Latvia
Slovenia
Ukraine
Belgium
France
Lithuania
Spain
Bulgaria
Germany
Norway
Sweden
Croatia
Greece
Poland
Switzerland
Czech Republic
Hungary
Portugal
Turkey
Denmark
Ireland
Romania
The Netherlands
Estonia
Italy
Slovakia
UK
Note: Not all planned countries will participate, and it is possible that some countries not 
listed here will later be added.

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Summary of High Level Changes from Version 3 dated 23 March 2012
Number of global amendment
1
Date of CTP revision
22 October 2014 
EudraCT number
NA
BI Trial number
1160.136
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 changed #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 changed #2
Title Page
Description of change
Enter name and contact information of current 
TCM (
.)
Rationale for change
New TCM
Section changed #3    
Flow Chart Phase II and Phase III
Description of change
Added to Flow Chart Phase II and Phase III, 
information if available on serum creatinine and 
any therapeutic/ diagnostic interventions.  Clarify 
Non-Serious Adverse Event Reporting in Phase II 
to match that of phase III.  Any Non-Serious 
Adverse events related to any antithrombotic use 
will now be recorded on eCRFs in Phase II as 

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Number of global amendment
1
well as Phase III.
Rationale for change
Include serum creatinine and 
therapeutic/diagnostic interventions. Clarify and 
streamline Non-Serious Adverse Event reporting.
Section changed #4
1.1 Medical Background
Description of change
Clarify countries where dabigatran has been 
approved.
Rationale for change
Section required updating.
Section changed #5
3.1 Overall Design and Plan
Description of change
Add substudy 1160.171 to be conducted in India.  
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 was 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.  
Section changed #6
3.1 Overall Design and Plan
Description of change
Clarify planned number of countries, sites and 
patients in the EU.  Clarify planned registry 
period will be from July 2011 to June 2020.  
Enrollment will end after the overall enrollment 
goal has been met, or by June 2017, whichever 
comes first. 
Rationale for change
Clarification of registry period and to indicate 
possibility for some regions to end early.
Section changed #7
3.2 Discussion Of Study Design, Including The 
Choice Of Control Group(s)
Description of change 
Clarification that if comparability of baseline 
characteristics is insufficient, alternative 
approaches will be followed to assess long-term 
outcomes
Rationale for change 
Clarification of assessments of long-term 
outcomes.
Section changed #8
3.2.1 Potential for bias and confounding 
3.3  Selection of Population
Description of change
Consecutive enrollment of patients to avoid 
selection bias is emphasised and parallel 
enrollment in another international registry 
should be avoided. Sites should also be selected 
wherever possible if both dabigatran and VKA is 
available.

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Number of global amendment
1
Rationale for change
Clarification to minimize potential for bias by 
confirming consecutive enrollment and ensure 
selected sites have capability to enrol both 
dabigatran and other VKAs are available.
Section changed #9
3.3.3 Exclusion Criteria
Description of change
Exclusion criterion #6 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 changed #10
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 
violation of exclusion criterion #6 (participation 
in a clinical trial with a drug or device) is revised 
to be consistent with the new wording of exclusion 
criterion #6. Removal of a patient due to violation 
of exclusion criterion #7 (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 enrollment of the patient into the study 
at baseline), and data should be entered on the 
eCRFs 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 changed #11
5.1.1 Outcome Measures
Description of change
There are some changes to the list of Outcome 

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Number of global amendment
1
measures.  ”Non vascular death” and “Death of 
unknown cause” have been removed from follow-
up. Two composite endpoints will now be 
analysed.  
Clarification that information on all 
antithrombotic medications will be collected 
irrespective of indication.
Rationale for change
Clarification
Section changed #12
5.1.2 Assessment of outcome measures
Description of change 
“Fatal bleeding” removed from “Major bleeding, 
defined as meeting one or more of the following 
criteria” and placed under “Life-threatening 
bleeding, as defined as meeting one or more of 
the following criteria”.
Rationale for change 
Clarification
Section changed #13
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 changed #14
5.2.2.2 Assessment of Adverse Events
AE reporting instructions were clarified and 
addition of an always serious list was added.
Description of change
Inclusion of BI 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).   
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 

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reporting of SAEs and non-serious AE and 
required reporting timeline for NSAE reporting of 
related events was clarified.
Section changed #15
6.1 Visit Schedule and Table 6.1: 1 Schedule of 
data collection
Description of change
It is clarified: 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 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 changed #16
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”, and add “Antithrombotic treatment 
selected including start date (all antithrombotic 
therapies, for stroke prevention as well as other 
indications).” For Assessments at the Follow-up 
Visits, add “Type of follow up visit,”, “Serum 
creatinine to be recorded (if available),” and 
“Information is recorded on any 
therapeutic/diagnostic interventions that occur as 
part of regular follow-up”.   The bullet point 
regarding the reporting of SAEs is simplified to 
say “All serious adverse events judged as related 
or unrelated to any BI drug.” (Reference to 
dabigatran or other BI drugs is removed since it 
is unnecessary and potentially 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.)

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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 
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 changed #17
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 changed #18
7.1 Statistical Design - Model
Description of change 
Same as for changes noted in section 3.2 as 
described above.
Rationale for change 
Same as for section 3.2. 
Section changed #19
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) 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 
interim analysis. 
Section changed #20
7.3.1 Main Analysis
A) Patient characteristics influencing choice of 
antithrombotic treatment for stroke prevention at 
baseline
Description of change 
Examples of known risk factors for stroke and 
bleeding added, e.g. age, gender, hypertension, 
diabetes mellitus, prior stroke, prior transient 

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ischemic attack, prior bleeding and concomitant 
medication use.
Rationale for change
Clarification of important baseline 
characteristics.
Section changed #21
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 
antiplatelet therapy. 
Rationale for change
Clarification of analyses of important outcome 
events in Phase II.  Previously, it was to be 
stratified by chronic antiplatelet 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 changed #22
7.3.1 Main Analyses
C) Important outcome events/ analysis of 
composite endpoint of stroke, SEE, vascular 
death, MI, life-threatening bleeds (Phase III only)
Description of change
By adding the term "relevant" it was indicated 
that not each change in e.g. antiplatelets use 
would necessarily result in censoring of a patient 
for the main analysis. 
The stratified analysis of incidence rates and 
cumulative risk by antiplatelets use at baseline 
was removed from the protocol.
Rationale for change
Clarification in terms of the planned analysis 
Section changed #23
7.3.2 Further Analyses
D) Important outcome events/ analysis of 
composite endpoint of stroke, SEE, vascular 
death, MI, life-threatening bleeds/ analysis of 
composite vascular endpoint/ exploration of 
factors impacting safety and effectiveness of 
dabigatran (Phase III only)
F) Potential side effects of antithrombotic 
treatments for stroke prevention
Description of change
D) Add that a multivariable Cox regression model 
and further covariates will be implemented in 
groups where comparability is obtained to 
explore the association between baseline 
characteristics and specific outcome events. 
Hazard ratios will be reported. The analysis will 
be based on antithrombotic treatment choice 
prescribed at baseline, where comparable. Add 

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that patients followed in Phase III will be 
assessed for important outcome events and 
composite vascular endpoint and that interaction 
terms impacting safety and effectiveness will be 
included in multivariable regression models.
Clarification that the regression model will 
include antiplatelet use. Remove that the 
incidence rates for the dabigatran and VKA 
groups by subgroup variables will be assessed.
F) Add that further country-specific analyses 
might be done.
Rationale for change
Clarification of analysis plan multivariable 
regression models and to include further country 
specific analyses.
Section changed #24
7.3.3 Safety analyses
Description of change 
Add “prescribed at baseline”
Rationale for change 
Clarification that adverse events occurring prior 
to first intake of antithrombotic treatment for 
stroke prevention; is referring to antithrombotic 
treatment prescribed at baseline.
Section changed #25
7.3.4 Interim Analyses
Description of change
Details of specific additional interim analyses 
were removed.
Rationale for change
The additional types of interim analyses will be 
performed in the context of the global study 
1160.129 and are further described there.
Section changed #26
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 changed #27
Appendix 10.3 List of Planned Participating
Countries
Description of change
Added additional planned countries to the table 
consistent with 1160.129 protocol. Also added 
note that “Not all planned countries will 
participate, and it is possible that some countries 
not listed here will later be added.”
Rationale for change
Update and clarification on country participation.
Section changed #28
All sections
Description of change
Typographical and grammatical errors corrected 
throughout the document.
Rationale for change
Correction as required to fix minor wording 
errors, spacing, and punctuation.

 
 
 
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1160-0136--protocol-revision-04
GLORIA-AF: Global Registry on Long-Term Oral Anti-thrombotic Treatment in
Patients with Atrial Fibrillation (Phase II/III – EU/EEA Member States)
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14 Nov 2014 07:41 CET
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14 Nov 2014 14:59 CET
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