A Regulatory Requirement Non-interventional Study to Monitor the Safety and Effectiveness of Pradaxa (Dabigatran Etexilate Mesilate, 110 mg or 150 mg b.i.d.) in Korean Patients With Non-valvular Atrial Fibrillation(SPARK: Safety Study of Pradaxa in AF Patients by Regulatory Requirement of Korea)
Conditions: Atrial Fibrillation
Sponsor: Boehringer Ingelheim

 
 
Non Interventional Study Protocol 
Amendment 
 
 
 
BI Study No.: 
1160.139 
 
 
BI Investigational 
Product(s): 
Dabigatran etexilate mesilate 
Title: 
A regulatory requirement non-interventional study to monitor the safety 
and effectiveness of Pradaxa (Dabigatran etexilate mesilate, 110 mg or 
150 mg b.i.d.) in Korean patients with non-valvular atrial fibrillation 
(SPARK: Safety study of Pradaxa in AF patients by Regulatory 
requirement of Korea) 
Clinical Phase: 
IV 
Trial Clinical 
Monitor: 
 
 
 
 
 
Phone
 Fax:
Principal 
Investigator: 
Not applicable 
 
 
Status: 
Final protocol amendment IV 
Version and Date: 
Version: 
4.0 
          
Date: 10 June 2013 
 
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TITLE PAGE 
 

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NON-INTERVENTIONAL STUDY PROTOCOL SYNOPSIS 
 
Name of company/Marketing Authorisation 
Holder: 
Tabulated 
Study Protocol 
 
Boehringer Ingelheim Korea 
 
Name of finished product: 
Pradaxa 
Name of active ingredient: 
 
Dabigatran etexilate mesilate 
 
Protocol date: 
Trial number: 
 
Revision date: 
10 June 2013 
29 April 2011 
1160.139 
Title of study: 
A regulatory requirement non-interventional study to monitor the safety and 
effectiveness of Pradaxa (Dabigatran etexilate mesilate, 110 mg or 150 mg b.i.d.) in 
Korean patients with non-valvular atrial fibrillation (SPARK: Safety study of Pradaxa 
in AF patients by Regulatory requirement of Korea) 
Principal     
Investigator: 
Not Applicable 
Study site(s) : 
Multi-centre study 
Clinical phase: 
IV 
Objectives: 
To monitor the safety profile and effectiveness of dabigatran etexilate mesilate in 
patients with non-valvular atrial fibrillation in a routine clinical practice setting  
Methodology: 
Prospective, non-interventional, open-label, multi-centre national study 
No. of patients:  
 
 
Total entered: 
3,000 approximately  
No. of patients for short-term surveillance: 1,500 
No. of patients for long-term surveillance: 1,500 
 
each treatment: 
Single arm (N=3,000 approximately) 
Diagnosis: 
Patients diagnosed with non-valvular atrial fibrillation and at risk of stroke or 
systemic embolism  
Main criteria for 
inclusion: 
1) Age ≥ 18 years at enrollment 
2) Patients who have been started on Pradaxa in accordance with the approved 
label in Korea 
3) Patients who have signed on the data release consent form 

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Name of company/Marketing Authorisation 
Holder: 
Tabulated 
Study Protocol 
 
Boehringer Ingelheim Korea 
 
Name of finished product: 
Pradaxa 
Name of active ingredient: 
 
Dabigatran etexilate mesilate 
 
Protocol date: 
Trial number: 
 
Revision date: 
10 June 2013 
29 April 2011 
1160.139 
Main criteria for 
exclusion: 
1) Patients with previous exposure to Pradaxa 
2) Clinically significant bleeding 
3) Increased risk of bleeding due to following diseases; 
Recent gastrointestinal ulceration 
Recent intracranial or intracerebral bleeding history 
Intraspinal or intracerebral vascular abnormalities 
Recent brain, spinal or ophthalmic surgery 
Recent brain or spinal injury 
Known or suspected oesophageal varices 
Arteriovenous malformations 
Vascular aneurysms 
Presence of malignant neoplasms at high risk of bleeding 
4) Concomitant treatment with any other anticoagulants e.g. unfractionated 
heparin (UFH), low molecular weight heparins (enoxaparin, dalteparin etc), 
heparin derivatives (fondaparinux etc), oral anticoagulants (warfarin, 
rivaroxaban, apixaban etc) except under the circumstances of switching 
therapy to or from Pradaxa or when UFH is given at doses necessary to 
maintain an open central venous or arterial catheter 
5) Severe renal impairment (CrCl < 30mL/min) 
6) Concomitant treatment with oral ketoconazole or dronedarone 
7) Patients hypersensitive to dabigatran or dabigatran etexilate or to any 
ingredient in the formulation  
8) Prosthetic heart valve replacement 
9) No creatinine clearance collected within at least one year prior to enrollment 
10) Current participation in other clinical trials 
Test product(s) : 
Dabigatran etexilate mesilate 
 
dose: 
110 mg b.i.d., 150 mg b.i.d. 
 
mode of admin. : Oral administration 
Comparator product(s): Not applicable 
 
dose: 
 
 
mode of admin. :  

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Name of company/Marketing Authorisation 
Holder: 
Tabulated 
Study Protocol 
 
Boehringer Ingelheim Korea 
 
Name of finished product: 
Pradaxa 
Name of active ingredient: 
 
Dabigatran etexilate mesilate 
 
Protocol date: 
Trial number: 
 
Revision date: 
10 June 2013 
29 April 2011 
1160.139 
Duration of treatment: 
1) Treatment duration for short-term surveillance: 12±2 weeks, long-term 
surveillance: 24±2 weeks 
2) Study duration: 6 years (Study period required by the Ministry of Food and 
Drug Safety (MFDS) is from 18 Feb 2011 to 17 Feb 2017. Interim reports 
are expected biannually for the initial two years and annually thereafter by 
May 2017.) 
Criteria for 
effectiveness:  
Incidence of stroke or systemic embolism 
Criteria for safety: 
All reported adverse events in patients who have taken at least one dose of Pradaxa 
will be noted. 
Statistical methods: 
Descriptive statistics 

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FLOW CHART 
Data points 
Baseline 
Follow-up 
1(Short-term) 
Follow-up 
2(Long-term) 
Visit Number 
1 
2 
3 
Week/s 
0 
12±2 
24±2 
Diagnosis 
X 
 
 
Inclusion / exclusion criteria 
X 
 
 
Demographics 
X 
 
 
Renal Function 
X 
 
 
Lifestyle factors 
X 
 
 
AF disease characteristics 
X 
 
 
Medical history 
X 
 
 
Anti-thrombotic therapy 
X 
X 
X 
Concomitant medications 
X 
X 
X 
Pradaxa administration status 
X 
X 
X 
Vital signs 
X 
X 
X 
Effectiveness endpoints 
 
X 
X 
Changes in lab tests together with action on drugs 
 
X 
X 
Adverse events 
 
X 
X 
Treatment compliance 
 
X 
X 
Study completion 
 
X 
X 
 

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TABLE OF CONTENTS 
TITLE PAGE .................................................................................................... 1 
NON-INTERVENTIONAL STUDY PROTOCOL SYNOPSIS .................. 2 
FLOW CHART ................................................................................................. 5 
TABLE OF CONTENTS ................................................................................. 6 
ABBREVIATIONS ........................................................................................... 9 
1. 
INTRODUCTION ................................................................................... 10 
1.1 MEDICAL BACKGROUND ............................................................................ 10 
1.2 DRUG PROFILE ............................................................................................... 11 
2. 
RATIONALE, OBJECTIVES, AND BENEFIT-RISK 
ASSESSMENT ........................................................................................ 12 
2.1 RATIONALE FOR PERFORMING THE STUDY ....................................... 12 
2.2 STUDY OBJECTIVES ...................................................................................... 12 
2.2.1 Primary objective ................................................................................... 12 
2.2.2 Secondary objective ............................................................................... 12 
2.3 BENEFIT-RISK ASSESSMENT ..................................................................... 12 
3. 
DESCRIPTION OF DESIGN AND STUDY POPULATION ............ 13 
3.1 OVERALL DESIGN AND PLAN .................................................................... 13 
3.1.1 Administrative structure of the study .................................................. 13 
3.2 DISCUSSION OF STUDY DESIGN ................................................................ 13 
3.3 SELECTION OF POPULATION .................................................................... 14 
3.3.1 Main diagnosis for study entry ............................................................. 14 
3.3.2 Inclusion criteria .................................................................................... 14 
3.3.3 Exclusion criteria ................................................................................... 14 
3.3.4 Removal of patients from therapy or assessments .............................. 15 
3.3.4.1 Removal of individual patients (therapy or assessments) .......... 15 
3.3.4.2 Discontinuation of the study by the sponsor .............................. 15 
4. 
TREATMENTS ....................................................................................... 16 
4.1 PRESCRIBED TREATMENTS TO BE OBSERVED ................................... 16 
4.1.1 Identity of the product(s)....................................................................... 16 
4.1.2 Method of assigning patients to treatment groups ............................. 16 
4.1.3 Selection of doses in the study ............................................................... 16 
4.1.4 Drug assignment and administration of doses for each patient ........ 16 
4.2 CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT .................................................................................................... 16 
4.2.1 Rescue medication, emergency procedures, and additional 
treatment(s) ............................................................................................ 16 
4.2.2 Restrictions ............................................................................................. 17 
4.2.2.1 Restrictions regarding concomitant treatment ............................ 17 
4.2.2.2  Restrictions on diet and life style ............................................... 17 
4.3 TREATMENT COMPLIANCE ....................................................................... 17 
5. 
VARIABLES AND THEIR ASSESSMENT ........................................ 18 
5.1 EFFECTIVENESS ............................................................................................. 18 

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5.1.1 Endpoint(s) of effectiveness ................................................................... 18 
5.1.2 Assessment of effectiveness ................................................................... 18 
5.2 SAFETY .............................................................................................................. 18 
5.2.1 Endpoint(s) of safety .............................................................................. 18 
5.2.2 Assessment of adverse events ................................................................ 19 
5.2.2.1 Definitions of adverse events ..................................................... 19 
5.2.2.2 Adverse event and serious adverse event reporting ................... 23 
5.2.3 Assessment of safety laboratory parameters ....................................... 24 
5.2.4 Electrocardiogram ................................................................................. 24 
5.2.5 Assessment of other safety parameters ................................................ 24 
5.3 OTHER ............................................................................................................... 24 
5.4 APPROPRIATENESS OF MEASUREMENTS ............................................. 24 
6. 
INVESTIGATIONAL PLAN ................................................................. 25 
6.1 VISIT SCHEDULE ............................................................................................ 25 
6.2 DETAILS OF STUDY PROCEDURES AT SELECTED VISITS ............... 25 
6.2.1 Screening and run-in period(s) ............................................................. 25 
6.2.2 Treatment period(s) ............................................................................... 25 
6.2.3 End of trial and follow-up period ......................................................... 26 
7. 
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE ........................................................................................ 28 
7.1 STATISTICAL DESIGN - MODEL ................................................................ 28 
7.2 NULL AND ALTERNATIVE HYPOTHESES .............................................. 28 
7.3 PLANNED ANALYSES .................................................................................... 28 
7.3.1 Primary analyses .................................................................................... 28 
7.3.2 Secondary analyses ................................................................................ 28 
7.3.3 Safety analyses ........................................................................................ 28 
7.3.4 Interim analyses ..................................................................................... 29 
7.4 HANDLING OF MISSING DATA .................................................................. 29 
7.5. RANDOMISATION .......................................................................................... 29 
7.6 DETERMINATION OF SAMPLE SIZE ........................................................ 29 
8. 
DATA PROTECTION, STUDY RECORDS ....................................... 30 
8.1 STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT .......................................................................................................... 30 
8.2 DATA QUALITY ASSURANCE ..................................................................... 31 
8.3 RECORDS .......................................................................................................... 31 
8.3.1 Source documents .................................................................................. 31 
8.3.2 Direct access to source data and documents........................................ 31 
8.3.3 Storage of records .................................................................................. 31 
8.4 PROCEDURES FOR REPORTING ADVERSE EVENTS .......................... 32 
8.4.1 Time windows ......................................................................................... 32 
8.4.2 Documentation of adverse events and patient narratives .................. 32 
8.5 STATEMENT OF CONFIDENTIALITY ....................................................... 32 
8.6 PUBLICATION POLICY ................................................................................. 32 
9. 
REFERENCES ........................................................................................ 33 
9.1 PUBLISHED REFERENCES .......................................................................... 33 

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9.2 UNPUBLISHED REFERENCES ..................................................................... 35 
10. APPENDICES ......................................................................................... 36 
10.1 RISK SCORES FOR AF PATIENTS .............................................................. 36 
10.2 CREATININE CLEARANCE .......................................................................... 40 
10.3 ELECTRONIC CASE REPORT FORM ........................................................ 41 
10.4 SAE REPORT FORM ....................................................................................... 41 
10.5 PREGNANCY MONITORING FORM .......................................................... 41 
10.6 PRODUCT LOCAL LABEL ............................................................................ 41 
10.7 SPECIAL PRECAUTIONS FOR USE_RISK OF BLEEDING ................... 41 
11. SUMMARY OF NIS STUDY PROTOCOL MODIFICATIONS ...... 42 
 

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ABBREVIATIONS 
AE 
Adverse Event 
AF 
Atrial Fibrillation 
aPTT 
Activated Partial Thromboplastin Time 
ASA 
Acetyl Salicylic Acid 
CA 
Competency Authority 
CABG 
Coronary Artery Bypass Graft 
CHF 
Congestive Heart Failure 
CK-MB 
Creatinine Kinase-Myocardial Band 
CML 
Clinical Monitor Local 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CSO 
Clinical Safety Officer 
CT 
Computed Tomography 
eCRF 
Electronic Case Report Form 
ECG 
Electrocardiograph 
EDC 
Electronic Data Capture 
FU 
Follow up 
KIMS 
Korea Index of Medical Specialties 
KPAC 
Korean Pharmaceutical Affairs Code 
KPMA 
Korea Pharmaceutical Manufacturers Association 
KRPIA 
Korean Research-based Pharmaceutical Industry Association 
GCP 
Good Clinical Practice 
LVD 
Left Ventricular Dysfunction 
ICH 
International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human 
Use 
ID 
Identification 
IEC 
Independent Ethics Committee 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
MedDRA 
Medical Dictionary for Drug Regulatory Activities 
MFDS 
The Ministry of Food and Drug Safety 
MR 
Magnetic Resonance 
mRS 
Modified Rankin Scale 
NCE 
New Chemical Entity 
NIS 
Non-Interventional Study 
PCI 
Percutaneous Coronary Intervention 
PMS 
Post Marketing Surveillance study 
SAE 
Serious Adverse Event 
TIA 
Transient Ischemic Attack 
TSAP 
Trial Statistical Analysis Plan 
ULN 
Upper Level of Normal 
VKA 
Vitamin K antagonist 

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1. 
INTRODUCTION 
1.1 
MEDICAL BACKGROUND 
Atrial fibrillation (AF) is the most common cardiac arrhythmia seen in the community and 
affects approximately 12% of 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 the development of AF is one in four for those over the age of 40 years (R09-
4884). In Korea, the number of patients visited hospital for AF or atrial flutter was 80,000, 
approximately, according to the 2009 National Health Insurance Statistical Yearbook.1 On 
average, the number of patients diagnosed with AF between 2001~2004 was 52,025 and AF 
prevalence in the age over 60 and over 70 was 1.95% and 2.41%, respectively, according to 
the KORAF (KORean Atrial Fibrillation Registry).2 
The prevalence of AF rises with advancing age, increasing from less than 1% in those under 
60 years of age to nearly 20% in those aged 85 years or more (R09-4875). The overall 
prevalence of AF in hospital setting is also increasing; hospital admissions due to AF have 
increased by 60% over the past 20 years (R10-1345). Furthermore, the prevalence of AF is 
estimated to double by 2050 due to the aging of the world’s population (R03-1233). 
Thromboembolic complications, particularly strokes, are a major cause of morbidity and 
mortality in patients with AF. Most of the strokes associated with AF are due to distal 
embolization of a left atrial thrombus, particularly arising from the left atrial appendage. 
Patients with AF have a four to five fold higher risk of stroke than those without AF (R96-
0252, R03-1241). Furthermore, approximately 15% of all strokes are directly attributed to AF 
and patients with strokes associated with AF have worse outcome with higher mortality than 
those with strokes not associated with AF (R09-4892). 
The risk of stroke or systemic embolism in patients with AF is influenced by other vascular 
risk factors including the history of previous strokes or transient ischemic attacks (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, and 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 as 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-related risk factors, a 
modification has been developed (CHA2DS2-VASc score, see Appendix 10.1) to improve its 
predictive value of stroke and thromboembolic events (R10-5332, P10-10141). 
Strokes due to AF are partly preventable by antithrombotic therapy. A meta-analysis of 
controlled clinical 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. However when the analysis was confined 
to aspirin only trials, aspirin reduced stroke by a non-significant 19% (95% CI: -1% to 35%) 

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compared to placebo (P07-07953, R03-1227). Oral anticoagulation with vitamin K 
antagonists (VKAs, e.g. warfarin) is the current standard therapy for stroke prevention in AF 
patients with moderate to high-risk of stroke (P10-10141, P07-04925, P06-08196, P10-
00811). However, VKAs have clinically important limitations including a narrow therapeutic 
window, an unpredictable dose-response effect, numerous drug-drug and drug-food 
interactions, and slow onset and offset of action. As a result, many patients with AF do not 
receive VKAs and instead receive ASA, 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. 
In a real-life setting, VKA treatment often results in INR (International Normalized Ratio) 
values outside of the target therapeutic range (R10-0768, R09-1522), leaving patients at 
increased risk of either stroke or bleeding. Due to the clinical and practical limitations of 
VKAs, multiple new oral anticoagulants are in clinical development including, mainly, direct 
thrombin inhibitors and factor Xa inhibitors (P07-08370). Pradaxa (dabigatran etexilate 
mesilate), a direct thrombin inhibitor, has been approved for the risk reduction of stroke or 
systemic embolism in patients with AF since February 2011, in Korea. In a clinical trial 
involving l18,113 patients, compared to warfarin, dabigatran etexilate mesilate (150 mg b.i.d.) 
reduced the occurrence of stroke (both ischemic and hemorrhagic) and systemic embolism 
significantly, while the rate of major bleeding was similar with both treatment. RE-LY (P09-
11669). Furthermore, dabigatran etexilate mesilate (110 mg b.i.d.) was found to be non-
inferior to warfarin for the prevention of stroke or systemic embolism while resulting in 
fewer major bleeds. Importantly, both doses of dabigatran etexilate mesilate were associated 
with significantly reduced occurrence of intracranial haemorrhage compared to warfarin 
(P09-11669). 
1.2 
DRUG PROFILE 
Dabigatran etexilate mesilate is the orally bioavailable prodrug of dabigatran, a novel, 
synthetic, direct thrombin inhibitor. Dabigatran etexilate mesilate itself does not have any 
antithrombin activity. Following oral administration it is rapidly converted via serum esterase 
to the active moiety, dabigatran, which is a non-peptidic, potent, competitive, and reversible 
inhibitor of thrombin. (U98-3208) 
 

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2. 
RATIONALE, OBJECTIVES, AND BENEFIT-RISK 
ASSESSMENT 
2.1 
RATIONALE FOR PERFORMING THE STUDY 
According to the local regulations, when a new chemical entity (NCE) is registered, a post 
marketing surveillance study (NIS) of an extended period (4 or 6 years) should be conducted. 
Such NIS can provide supplementary data to monitor the safety of NCEs in a real-life 
situation. Data collected in randomised clinical trials with strict inclusion/exclusion criteria 
and rigorous monitoring schemes have limitations. 
This is a prospective, non-interventional, open-label, multi-centre study. It will provide 
additional safety information of Pradaxa in Korean patients with non-valvular AF in clinical 
settings. 
2.2 
STUDY OBJECTIVES 
2.2.1 
Primary objective 
The primary objective of this study is to monitor the safety profile of Pradaxa in Korean 
patients with non-valvular AF in a routine clinical setting. 
2.2.2 
Secondary objective 
The secondary objective of the study is to monitor the effectiveness of Pradaxa in reducing 
the risk of stroke or systemic embolism in Korean patients with non-valvular AF, by 
observing the incidence of stroke or systemic embolism. 
2.3 
BENEFIT-RISK ASSESSMENT 
Patients will be managed according to the local practice guidelines. The choice of treatment 
will be solely at the discretion of the participating physician. Pradaxa will be administered 
according to the approved label in Korea. Hence there are no additional risks to patients by 
participating in this NIS.  

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3. 
DESCRIPTION OF DESIGN AND STUDY POPULATION 
3.1 
OVERALL DESIGN AND PLAN  
This NIS is a prospective, non-interventional, open-label, multi-centre study. As per 
regulation, the re-examination period extends from 18 Feb 2011 until 17 Feb 2017 (6 years). 
However, active enrolment is to be initiated in 2012 after finalizing the re-imbursement 
agreement with the authority. Before initiation of the study, any newly reported adverse 
events will be closely monitored. The last patient follow up is expected in 2015. 
3.1.1 
Administrative structure of the study 
This study will be managed by a project manager of Boehringer Ingelheim Korea. Data 
management and statistics will be outsourced to a qualified contract research organization 
(CRO). 
3.2 
DISCUSSION OF STUDY DESIGN 
This is a single arm study with dabigatran etexilate mesilate cohort.  
Loss to follow up 
All efforts will be made to minimize loss to follow up, particularly in the tracking of lost 
patients. To the extent possible, vital status, at minimum, for patients lost to follow up will be 
obtained. This allows assessing the impact of informative censoring due to treatment 
discontinuation. 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. 
 
Information and recall bias 
Information bias can e.g. occur due to selective reporting of already established and known 
adverse effects for a known product as compared to a new product (dabigatran), or vice versa. 
A standardized data collection form will be used for assessing exposure and AEs. 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 patient forget certain 
information. It can be reduced by associating questions with specified time intervals (e.g. 
how often did you take this co-medication during the last 5 days). 
 

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Confounding 
As in any observational study, confounding may affect the estimation of associated between 
drug exposure and outcome of interest and statistical techniques. However, as only major 
confounders for selected research questions can be captured, residual (unmeasured) 
confounding may remain. 
3.3 
SELECTION OF POPULATION 
Minimum 3,000 patients will be enrolled at approximately 40 sites by as many as 80 or more 
investigators. The treating physicians will mainly be cardiologists or neurologists. To 
minimize the selection bias, consecutive patients from each site who meet inclusion criteria 
will be enrolled in this study. 
3.3.1 
Main diagnosis for study entry 
Patients diagnosed with non-valvular AF and at risk of stroke or systemic embolism will be 
included. Physician should carefully review the product label in Korea before prescribing 
Pradaxa to patients (Attachment 4). Updated label information is found in eCRF and ISF 
(Investigator Site File). The exclusion criteria reflect the contraindication of the product label. 
Thus if the contraindication section of the label is updated, the physician should follow the 
up-to-date prescribing information ahead of the inclusion / exclusion criteria of this protocol.  
3.3.2 
Inclusion criteria 
• Age ≥ 18 years at enrollment 
• Patients who have been started on Pradaxa in accordance with the approved label in 
Korea 
• Patient who has signed on the data release consent form 
3.3.3 
Exclusion criteria 
• Patients with previous exposure to Pradaxa 
• Clinically significant bleeding 
• Increased risk of bleeding due to following diseases; 
Recent gastrointestinal ulceration 
Recent intracranial or intracerebral bleeding history 
Intraspinal or intracerebral vascular abnormalities 
Recent brain, spinal or ophthalmic surgery 

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Recent brain or spinal injury 
Known or suspected oesophageal varices 
Arteriovenous malformations 
Vascular aneurysms 
Presence of malignant neoplasms at high risk of bleeding 
• Concomitant treatment with any other anticoagulants e.g. unfractionated heparin 
(UFH), low molecular weight heparins (enoxaparin, dalteparin etc), heparin 
derivatives (fondaparinux etc), oral anticoagulants (warfarin, rivaroxaban, apixaban 
etc) except under the circumstances of switching therapy to or from Pradaxa or when 
UFH is given at doses necessary to maintain an open central venous or arterial 
catheter 
• Severe renal impairment (CrCl < 30mL/min) 
• Concomitant treatment with oral ketoconazole or dronedarone 
• Patients hypersensitive to dabigatran or dabigatran etexilate or to any ingredient in the 
formulation  
• Prosthetic heart valve replacement 
• No creatine clearance collected within at least one year prior to enrollment 
• Current participation in other clinical trials 
3.3.4 
Removal of patients from therapy or assessments 
3.3.4.1 Removal of individual patients (therapy or assessments) 
This section is not applicable. 
3.3.4.2 Discontinuation of the study by the sponsor  
Boehringer Ingelheim Korea reserves the right to discontinue the study overall or at a 
particular study site at any time for the following reasons: 
1. Emergence of any efficacy/safety information that could significantly affect continuation 
of the study 
2. Violation of applicable local regulations, the NIS protocol, or the contract by a study site 
or participating physician, disturbing the appropriate conduct of the study. 

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4. 
TREATMENTS 
4.1 
PRESCRIBED TREATMENTS TO BE OBSERVED 
4.1.1 
Identity of the product(s)  
Pradaxa will be prescribed according to the local label and at the discretion of the treating 
physician. Since this is a non-interventional study, the drug will not be supplied by the 
sponsor. Furthermore, the sponsor will not cover the expenses related to other medications 
taken by the patient, interventions, procedures, or diagnostic tests.  
4.1.2 
Method of assigning patients to treatment groups 
The choice of treatment is fully at the discretion of the physician and the patient. There is no 
treatment assignment by a third party. 
4.1.3 
Selection of doses in the study 
The choice of dabigatran dose, from those two options described below, should be 
determined according to the local label (attachment 4) and at the discretion of the treating 
physician. Physician should carefully review the special precautions for use in patients with 
risk of bleeding (Attachment 5) before determining the dose of Pradaxa. 
• Dabigatran etexilate mesilate 110 mg b.i.d. (one capsule twice daily) 
• Dabigatran etexilate mesilate 150 mg b.i.d. (one capsule twice daily) 
4.1.4 
Drug assignment and administration of doses for each patient 
This section is not applicable. 
4.2 
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT 
The protocol will allow additional drugs considered necessary for the patient’s welfare to be 
prescribed at the discretion of the treating physician. It is required, however, to record the 
details of all concomitant medication administered to the patient during the course of 
treatment in eCRF. This includes concomitant therapies started one month prior to Pradaxa 
initiation until the patient completes the final follow-up visit. 
4.2.1 
Rescue medication, emergency procedures, and additional treatment(s) 
Please refer to the current local label (Attachment 4). 

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4.2.2 
Restrictions 
4.2.2.1 Restrictions regarding concomitant treatment 
Please refer to the current local label (Attachment 4). 
4.2.2.2  Restrictions on diet and life style 
Please refer to the current local label (Attachment 4). 
4.3 
TREATMENT COMPLIANCE 
During the follow-up visits, treatment compliance will be evaluated by treating physician. To 
minimize the recall bias, the physician could ask associating questions with specified time 
intervals (e.g. how often did you take Pradaxa during the last 5 days) to patients. An 
explanation for any discrepancy will be inquired and provided in the eCRF. 

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5. 
VARIABLES AND THEIR ASSESSMENT 
5.1 
EFFECTIVENESS  
5.1.1 
Endpoint(s) of effectiveness 
The effectiveness endpoint is the incidence rate of stroke or systemic embolism (definitions 
are provided in Section 5.1.2.) 
5.1.2 
Assessment of effectiveness 
Since the patient follow-up period is only 12 weeks (in case of long-term FU, 24 weeks), it is 
not possible to perform any meaningful effectiveness assessment of Pradaxa in this NIS. 
However, since it is a requirement to evaluate also effectiveness in all regulatory requisite 
NIS in Korea and as requested by MFDS, a descriptive analysis of effectiveness endpoint will 
be performed.  
Effectiveness analysis will be performed to the patients who have been on Pradaxa more than 
12 weeks (in case of long-term FU, 24 weeks).  
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). 
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, 
scinitigraphy, or autopsy. 
5.2 
SAFETY 
5.2.1 
Endpoint(s) of safety 
All reported adverse events in patients who take at least one dose of Pradaxa will be noted. 
Endpoints pertaining to safety will be presented descriptively and will include: 
 
adverse events 

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 
unexpected adverse events 
 
serious adverse events 
 
drug-related adverse events 
 
adverse events leading to discontinuation  
 
adverse events by intensity, outcome of the event, causality  
5.2.2 
Assessment of adverse events 
5.2.2.1 Definitions of adverse events 
Adverse event 
An adverse event (AE) is defined as any untoward medical occurrence, including an 
exacerbation of a pre-existing condition, in a patient in a clinical investigation who received a 
pharmaceutical product. The event does not necessarily have to have a causal relationship 
with this treatment. 
 
The following definitions apply and should be used as a guide when reporting a thrombotic 
event: 
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). 
Pulmonary embolism 
• A patient has to fulfil the following criteria: 
1. Typical symptoms or signs (e.g., dyspnea, left or right sided chest pain worsening on 
respiration, etc) suggestive of pulmonary embolism 
AND at least one of the following two criteria: 
2. CT pulmonary angiography demonstrating an intraluminal filling defect in segmental 
or more proximally located pulmonary arteries 
3. High probability ventilation-perfusion lung scan, i.e. at least segmental perfusion 
defect at perfusion scan with normal ventilation at ventilation scan 
• The definition of pulmonary embolism is also met if a patient fulfils at least criteria 2) 
or 3) above. 

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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: 
- 
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-MB 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 24h) 
Elevation of troponin or CK-MB* 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 developing of significant Q-waves** in at least two 
adjacent ECG leads. 
• After coronary artery bypass grafting (within 72h) 
Elevation of CK-MB* 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-waves** in at least two 
adjacent ECG leads. 
*Total CK if CK-MB was not available **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 
• Fatal bleeding 

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Life-threatening bleeding, as 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 
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. 
Serious adverse event 
A serious adverse event (SAE) is defined as any AE which results in death, is immediately 
life-threatening, results in persistent or significant disability / incapacity, requires or prolongs 
patient hospitalisation, is a congenital anomaly / birth defect, or is to be deemed serious for 
any other reason if it is an important medical event when based upon appropriate medical 
judgement which may jeopardise the patient and may require medical or surgical intervention 
to prevent one of the other outcomes listed in the above definitions. 
 
Always serious adverse events 
 
BI has set up a list of AEs which are defined to be always serious. In order to support the 
investigator with the identification of these “always serious adverse events”, if a non serious 
AE is identified to be serious per BI definition, a query will be raised. The investigator must 
verify the description and seriousness of the event. If the event description is correct, the item 
“serious” needs to be ticked and an SAE has to be reported in expedited fashion. The list of 
these adverse events can be found via the eCRF system. 
 
Adverse drug reaction 
Adverse drug reaction (ADR) refers to any harmful, unintended reaction to the 
pharmaceutical product of any dose at which a causal relationship with the pharmaceutical 
product cannot be ruled out. 
 
Non serious adverse drug reaction 
Non serious adverse drug reaction is defined as any ADR which does not meet the SAE 
criteria.  
 

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Intensity of adverse event 
The intensity of the AE should be defined based on the following three categories and 
according to medical and scientific judgment: 
Mild: 
Transient symptoms which are subjective or objective but no interference with 
the patient’s daily activities. No change in dosage is needed to continue the 
treatment. 
Moderate: 
Marked symptoms with moderate interference with the patient’s daily 
activities. Reduced dosage or unplanned treatment is necessary for the relief of 
adverse events. 
Severe: 
Considerable and unacceptable interference with the patient’s daily activities. 
Discontinuation of the study drug is required because of significant adverse 
events. 
 
To ensure that no confusion or misunderstanding of the difference between the terms ‘serious’ 
and ‘severe’ which are not synonymous, it should be noted that SAE does not necessarily 
correspond to serious or not serious AE to severe ones. All SAEs will be reported regardless 
of the intensity as mentioned above. 
Causal relationship of adverse event 
Medical judgment will be used to determine the causal relationship, after considering all 
relevant factors, including pattern of reaction, temporal relationship, de-challenge or re-
challenge, confounding factors such as concomitant medication, concomitant diseases and 
relevant history. Assessment of causal relationship will be recorded in the eCRF.  
Related 
a. Certain: An event occurring in a plausible time relationship to drug administration and that 
cannot be explained by concurrent disease or other drugs or chemicals. The response to 
withdrawal of the drug (dechallenge) should be clinically plausible. The event must be 
definitive pharmacologically or phenomenologically, using a satisfactory rechallenge 
procedure if necessary. 
b. Probable/Likely: An event with a reasonable time sequence to administration of the drug, 
unlikely to be attributed to concurrent disease or other drugs or chemicals, and which follows 
a clinically reasonable response on withdrawal (dechallenge). Rechallenge information is not 
required to fulfill this definition. 
c. Possible: An event with a reasonable time sequence to administration of the drug, but 
which could also be explained by concurrent disease or other drugs or chemicals. Information 
on drug withdrawal may be lacking or unclear. 
Unrelated 
d. Unlikely: An event with a temporal relationship to drug administration which makes a 
causal relationship improbable, and in which other drugs, chemicals or underlying disease 
provide plausible explanations. 
Worsening of the underlying disease or other pre-existing conditions 

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Worsening of the underlying disease or of other pre-existing conditions will be recorded as an 
(S)AE in the (e)CRF. 
 
Changes in vital signs, ECG, physical examination, and laboratory test results  
Changes in vital signs, ECG, physical examination and laboratory test results will be 
recorded as an (S)AE in the (e)CRF, if they are judged clinically relevant by the NIS 
physician. 
 
5.2.2.2 Adverse event and serious adverse event reporting 
All adverse events occurring from the start of Pradaxa treatment up to 7 days after last 
follow‐up visit need to be collected, documented and reported to the sponsor using the AE 
reporting form of eCRF (Attachment 1). All SAEs must be reported with details of non-
serious AEs occurring at the same time, within 24 hours of occurrence via telephone/fax to 
the Clinical Safety Officer (CSO) of BI Korea using the SAE report form (Attachment2). If 
any new or further information to these events is available, a follow-up SAE report has to be 
sent to BI. All SAEs and non-serious AEs must include a causal relationship assessment from 
the physician. 
 
All other Adverse Events must be reported on the eCRFs within 2 weeks to the Sponsor.  
 
Contact details:   
Clinical Safety Officer 
Tel:  +82.2.709.0171 
Fax:  +82.2.749.0062 
Address: Boehringer Ingelheim Korea, Medical Dept.  
15F, Yonsei Severance Bldg. 84-11, Namedaemunro-5Ka, Chung-Ku, Seoul, Korea 
  
Pregnancy 
Rarely, patients taking part in non interventional studies can get pregnant. Once a patient 
enrolled into the study and exposed to Pradaxa becomes pregnant, the NIS physician will stop 
the drug and report immediately to the sponsor. Drug exposure during pregnancy has to be 
reported immediately (within 24 hours or next business day, whichever is shorter) to CSO. 
Furthermore, the details of all the drugs to which the patient exposed at the time of pregnancy 
will be recorded. The outcome of the pregnancy associated with the drug exposure will be 
assessed. In the absence of an (S)AE, only the Pregnancy Monitoring Form (Attachment 3) 
for NIS, not the SAE form is to be completed. The ISF will contain the Pregnancy 
Monitoring Form (Part A and Part B) and those forms could be downloaded from eCRF 
website. 
 
 

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5.2.3 
Assessment of safety laboratory parameters 
This section is not applicable. 
5.2.4 
Electrocardiogram 
This section is not applicable. 
5.2.5 
Assessment of other safety parameters 
This section is not applicable. 
5.3 
OTHER 
This section is not applicable. 
5.4 
APPROPRIATENESS OF MEASUREMENTS 
This section is not applicable. 
 

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6. 
INVESTIGATIONAL PLAN 
6.1 
VISIT SCHEDULE 
The flow chart at the front of the protocol summarizes the data to be collected at each visit. 
The procedures are further described below. 
6.2 
DETAILS OF STUDY PROCEDURES AT SELECTED VISITS 
6.2.1 
Screening and run-in period(s) 
This section is not applicable as this is a non-interventional study. 
6.2.2 
Treatment period(s) 
As per regulations, enrolled patients will be followed up for a 12 week or 24 week treatment 
period. There will be a visit window of ±2 weeks. To minimize the selection bias at the site 
level, the goal is to have participating centers reflect a balance between general hospitals and 
clinics for short-term or long-term surveillances. 
 
6.2.2.1 Visit 1 – Baseline Visit  
Upon patient enrollment, the following will be recorded on the patient’s eCRF.  
• 
Visit date 
• 
Diagnosis: date of the diagnosis and the diagnostic procedures performed  
• 
Inclusion / exclusion criteria 
• 
Demographic data: date of birth, gender, pregnancy, previous allergy, height, weight 
• 
Renal function: record creatinine clearance collected within at least one year prior to 
enrolment 
• 
Lifestyle factors: smoking habits and alcohol use 
• 
Atrial fibrillation disease characteristics: categorization, type, procedures since 
confirmation of AF diagnosis 
• 
Medical history: history of thromboembolic episodes, cardiovascular diseases, history of 
bleeding events, other relevant medical history 
• 
Anti-thrombotic therapy: record all the anti-thrombotic therapy received since one 
month prior to the baseline visit (excluding Pradaxa) 
• 
Concomitant medications: record all medications as well as continuous medications since 
one month prior to the baseline visit except for anti-thrombotic therapy (but including 
vitamins and food supplements) 
• 
Dose of Pradaxa given 
• 
Vital signs: average blood pressure (sitting arm) and pulse rate  
 
At Visit 1, the patient will be requested to contact the treating physician in the event of any 
adverse events noted after initiating Pradaxa treatment. 
 
6.2.2.2 Visit 2 (12±2 weeks from Visit 1)  
After 12±2 weeks from Visit 1, the patients will return for follow-up. The followings will be 
noted and recorded in the eCRF:  

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• 
Visit date 
• 
Any change of Pradaxa dose given 
• 
Any changes in laboratory tests which required actions on drug dosage since last visit or 
any laboratory values performed to monitor the increased risk of bleeding ie. aPTT 
• 
Vital signs: average blood pressure (sitting arm) and pulse rate  
• 
Effectiveness endpoints: incidence of stroke or systemic embolism 
• 
Anti-thrombotic therapy: any change in the anti-thrombotic therapies since last visit 
(excluding Pradaxa) 
• 
Concomitant medications including new medications taken since last visit: any change in 
the concomitant medications (dose and dosing intervals)  
• 
Any adverse events noted  
• 
Treatment compliance  
• 
Study completion status: for the prematurely withdrawn patients, this section should be 
recorded to assess the safety information and the reason for withdrawal 
• 
NIS physician’s electronic signature for data integrity (do not record this section for long-
term FU cases) 
 
At Visit 2, the patients on long-term follow-up will be reminded to contact the NIS physician in 
the event of any adverse events noted hereafter.  
 
6.2.2.3 Visit 3 (24±2 weeks from Visit 1, Long-term follow-up cases only)  
After 24±2 weeks from Visit 1 or 12±2 from Visit 2, the patients will return for follow-up. The 
followings will be noted and recorded in the eCRF:  
• 
Visit date 
• 
Any change of Pradaxa dose given 
• 
Any changes in laboratory tests which required actions on drug dosage since last visit or 
any laboratory values performed to monitor the increased risk of bleeding ie. aPTT 
• 
Vital signs: average blood pressure (sitting arm) and pulse rate  
• 
Effectiveness endpoints: incidence of stroke or systemic embolism 
• 
Anti-thrombotic therapy: any change in the anti-thrombotic therapies since last visit 
(excluding Pradaxa) 
• 
Concomitant medications including new medications taken since last visit: any change in 
the concomitant medications (dose and dosing intervals)  
• 
Any adverse events noted  
• 
Treatment compliance  
• 
Study completion status: for the prematurely withdrawn patients, this section should be 
recorded to assess the safety information and the reason for withdrawal 
• 
NIS physician’s electronic signature for data integrity 
 
6.2.3 
End of trial and follow-up period 
For patients prematurely withdrawn from the study, it is important to collect the safety 
information whether or not any adverse event occurred after administration of Pradaxa and 
reflect the information in the eCRF section of “study completion status”. Patients with 
adverse events noted at the final follow-up visit or upon premature discontinuation of Pradaxa 
will be monitored further until the resolution of those adverse events. Alternatively, those 

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patients will be followed up until the NIS physician and sponsor agree that no further follow-
up is necessary. To the extent possible, vital status, at minimum, for patients lost to follow up 
will be obtained.  
 

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7. 
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE 
Details are provided in the statistical Trial Statistical Analysis Plan (TSAP). 
7.1 
STATISTICAL DESIGN - MODEL 
In this non-interventional study, all statistical analyses will be descriptive in nature. The 
degree of statistical significance (p-values) and precision (confidence intervals) for the 
statistical methods used for explorative purposes will be shown. No confirmatory hypotheses 
are pre-specified. 
 
7.2 
NULL AND ALTERNATIVE HYPOTHESES 
No hypotheses are tested. (See Section 7.1) 
7.3 
PLANNED ANALYSES 
7.3.1 
Primary analyses 
A descriptive analysis of effectiveness endpoints is planned. For patients treated with Pradaxa 
incidence of stroke or systemic embolism will be calculated. Effectiveness analyses will be 
performed based on demographics and baseline characteristics. However, if data for patients 
who have been treated with Pradaxa beyond the scope of approved label are collected, 
separate effectiveness analyses will be conducted. 
7.3.2 
Secondary analyses 
There is no secondary effectiveness analysis planned in this study. However, additional 
exploratory analyses will be conducted as deemed appropriate. 
7.3.3 
Safety analyses 
Demographic and baseline characteristics (including specifically stroke/bleeding risk scores 
(CHADS2, CHA2DS2-VASc and HAS-BLED)) will be summarized descriptively for the 
entire cohort of eligible patients. 
 
Adverse events (AEs) will be coded according to the latest version of Medical Dictionary for 
Drug Regulatory Affairs (MedDRA) coding system. Concomitant therapies will be coded 
according to the latest version of KIMS (Korea Index of Medical Specialties) coding system. 
The trial database will not be locked until coding is complete.  
 
Safety analyses will be based on all patients treated, i.e. all patients who received at least one 
dose of Pradaxa. However, if data for patients who have been treated with Pradaxa beyond 
the scope of approved label are collected, separate safety analyses will be performed. Safety 
analyses will be performed based on demographics and baseline characteristics. 
 

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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. 
 
7.3.4 
Interim analyses 
In accordance with local regulation for NIS studies, interim analyses are planned biannually 
for the initial two years and annually thereafter.  
7.4 
HANDLING OF MISSING DATA 
As this is non-interventional study, there are no required investigations and diagnostic 
procedures (e.g. lab, ultrasound).  
Maximum attempt will be made to ensure the completeness of data collection. All available 
data will be used in the data analysis. There will be no imputation of data to fill the missing 
values. 
 
7.5. 
RANDOMISATION 
This section is not applicable as this is a non-interventional study. 
7.6 
DETERMINATION OF SAMPLE SIZE 
Sample size of 3,000 patients is based on the requirement of the local regulatory authority 
(Korean FDA). The number of patients enrolled for short-term surveillance will be 1,500 and for 
long-term follow up 1,500. As per regulation, long-term surveillance is necessary for the 
indication. It will be conducted to 50% of total number of enrolled patients. 

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8. 
DATA PROTECTION, STUDY RECORDS 
The International Conference on Harmonization/Harmonized Tripartite Guideline for Good 
Clinical Practice (ICH/GCP) does not often apply to NIS studies as most elements are 
relevant for controlled clinical trials. However, in this NIS study, all attempts will be made to 
adhere, as close as possible, to the standards of ICH/GCP.  
The protocol of this regulatory requisite NIS study will be submitted to the Ministry of Food 
and Drug Safety (MFDS) for notification. It is not a local requirement in Korea to obtain 
Institutional Review Board (IRB) approval for the conduct of regulatory requisite NIS studies. 
However, the protocol of this NIS study will be submitted to IRBs whenever required or 
requested by these institutions. This study will be conducted in accordance with the Standards 
for Re-examination of New Medicines notified by MFDS, Korean Pharmaceutical Affairs 
Code (KPAC), Enforcement Regulation of KPAC and other applicable local laws and 
industry code (including but not limited to the Regulations on Fair Competition in the Trade 
of Medicines of KPMA and KRPIA).  
Boehringer Ingelheim Korea will submit periodic reports during re-examination period, and 
the final report to MFDS upon study completion. The periodic report for the final year will be 
substituted with the final report. When required, the interim reports and the final report will 
be submitted to the IRBs as well.  
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 IRB/IEC and the competent authority (CA) according to the local 
regulations. The same applies for the implementation of changes introduced by amendments. 
Prior to patient participation in the study, written data release consent shall be obtained from 
each patient (or the patient’s legally accepted representative). Each signature must be 
personally dated by each signatory and the data release consent and any additional patient-
information form retained by the NIS physician as part of the trial records. A signed copy of 
the data release 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 Korea in accordance with the local data protection law. The level of 
disclosure shall also be explained to the patient. 
The patient shall be informed that his/her medical records may be examined by authorised 
monitors (NIS Managers) or Clinical Quality Assurance auditors appointed by sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 

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8.2 
DATA QUALITY ASSURANCE 
A quality assurance audit/inspection of this study may be conducted by the sponsor or 
sponsor’s designees or by IRBs/IECs or by regulatory authorities. The quality assurance 
auditor will have access to all medical records, the participating physician’s study-related 
files and correspondence, and the data release agreement documentation of this study. 
8.3 
RECORDS 
All of the clinical data will be captured via a web-based EDC (Electronic Data Capture) 
System. The 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 treating physician will approve the 
data using an electronic signature. 
Patients will not be identified on the eCRF by name. Appropriate coded identification (i.e., 
patient number) will be used. The treating physician will make a separate confidential record 
of these details (patient identification code list) to permit identification of all patients enrolled 
in this study in case follow-up is required. Likewise, any supporting documentation will be 
redacted of any patient identifying information, and the patient ID number clearly written on 
the documents. 
 
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 will be filed at the treating physician’s site. 
It is necessary that the data entered in the eCRFs that are transcribed from the source 
documents are consistent with the source documents or the discrepancies need to be 
explained. The treating physician may need to request previous medical records, transfer 
records, and current medical records.  
8.3.2 
Direct access to source data and documents 
The NIS physician / site will permit study-related monitoring, audits and regulatory 
inspection, providing direct access to all related source data/documents. All source 
documents including eCRFs will be made available for review by sponsor’s Medical Project 
Manager (MPM) or designees and inspection by health authorities (e.g., MFDS). The MPM 
and auditor may review all eCRFs, and written data release agreements.  The accuracy of the 
data will be verified by reviewing the documents described in Section 8.3.1. 
8.3.3 
Storage of records 
The NIS physician and the site are jointly responsible for maintaining essential study 
documents for 3 years after completion of the study (defined as termination date of re-
examination period) by the Pharmaceutical Affairs Law and shall take measures to prevent 
accidental or premature destruction of these documents.  

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8.4 
PROCEDURES FOR REPORTING ADVERSE EVENTS 
8.4.1 
Time windows 
All AEs, serious and non-serious, occurring during the course of the rNIS will be collected, 
documented and reported to the sponsor by the investigator on the appropriate eCRF. 
Reporting will be done according to the specific definitions and instructions detailed in the 
‘Adverse Event Reporting’ section of the site materials (that include all necessary documents, 
the protocol, instructions for conducting rNIS, the package insert etc.). 
The investigator has the responsibility to report AEs during the specified observational phase. 
Any SAE, whether or not considered related to Pradaxa capsules, must be reported 
immediately via eCRF and SAE Report Form. 
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 the local 
regulatory requirements. 
For each AE, the investigator will provide the onset date, end date, intensity, outcome, 
seriousness and action taken with Pradaxa capsules. The investigator will determine the 
relationship of Pradaxa capsules to all AEs as defined in the 'Adverse Event Reporting' 
section of the protocol. 
8.5 
STATEMENT OF CONFIDENTIALITY 
Individual patient medical information obtained as a result of this study will be considered 
confidential and disclosure to third parties will be prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers. 
Treatment data will be made available to the patient’s personal physician or to other 
appropriate medical personnel responsible for the patient’s welfare. Data generated from the 
study will be made available for inspection on request by the participating physicians, the 
sponsor and/or its representatives and/or designees, by the IRBs/IECs and the regulatory 
authorities. 
8.6 
PUBLICATION POLICY 
Boehringer Ingelheim, to the best of their ability will support the process of free exchange of 
relevant scientific information. Any publication of the result of this NIS study must be 
consistent with the Boehringer Ingelheim publication policy.  
 

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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. Guideline for management of atrial fibrillation: the Task Force 
 
 
for the Management of Atrial Fibrillation of the European Society of 
 
 
Cardiology (ESC). Eur Heart J 2010: 31 (19); 2369-2429 
 
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 atrialfibrillation: 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 
 

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R03-1229  
Falk RH Atrial fibrillation. N Engl J Med 344 (14), 1067 - 1078 (2001) 
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) 
P11-00444  
Furie KL, Kasner SE, Adams RJ, Albers GW, Bush RL, Fagan SC, Halperin J
 
 
L, Johnston SC, Katzan I, Kernan WN, Mitchell PH, Ovbiagele B, Palesch YY, 
 
 
Sacco RL, Schwamm LH, Wassertheil-Smoller S, Turan TN, Wentworth D, 
 
 
American Heart Association Stroke Council, Council on Cardiovascular  
 
 
Nursing, Council on Clinical Cardiology, and Interdisciplinary Council on 
 
 
Quality of Care and Outcomes Research. Guideline for the Prevention of  
 
 
Stroke in Patients with Stroke or Transient Ischemic Attach: A Guideline for 
 
 
Healthcare Professionals From the American Heart Association/American 
 
 
Stroke Association. Stroke 42 (1), 227-276 (2011) 
 
R10-0768  
Gladstone DJ, Bui E, Fang J, Laupacis A, Lindsay MP, Tu JV, Silver FL, 
 
 
Kapral MK Potentially preventable strokes in high-risk patients with atrial 
 
 
fibrillation who are not adequately anticoagulated. Stroke 40 (1), 235 - 240 
 
 
(2009) 
 
R09-1522  
Jones M, McEwan P, Morgan CL, Peters JR, Goodfellow J, Currie CJ. 
 
 
Evaluation of the pattern of treatment, level of anticoagulation control, and 
 
 
outcome of treatment with warfarin in patients with non-valvar atrial 
 
 
fibrillation: a record linkage study in a large British population. Heart 91 (4), 

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472 - 477 (2005) 
 
P07-08370  
Eikelboom J, Weitz J. A replacement for warfarin: The search continues. 
 
 
Circulation 2007;116(2):131-133 
 
P09-11669  
Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, 
 
 
Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu 
 
 
J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L, RE-LY 
 
 
Steering Committee and Investigators. Dabigatran versus warfarin in patients 
 
 
with atrial fibrillation. N Engl J Med 2009; 361 (12): 1139-1151 
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) 
 
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 
1 
 
2009 National Health Insurance Statistical Yearbook 
 
2 
 
et al, KORean Atrial Fibrillation Registry (KORAF) abstract 
 
 
Korean CircJ (Supplement III) 2007;37(10):23-23 
 
U98-3208 
Investigator’s Brochure. 9th ed. Boehringer Ingelheim 
GmbH. 2007. 
 
 

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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 component 
Points 
Congestive heart failure 
1 
Hypertension 
1 
Age greater than 75 years 
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 the history of 
stroke or transient ischemic attack and 1 point each for age more than 75 years, 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 
 
CHA2DS2-VASc Stroke 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 
the history of stroke or TIA, or age ≥75; and 1 point each for age 65–74 years, 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 characteristics 
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 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%). 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.  
 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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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 
ELECTRONIC CASE REPORT FORM 
See the Attachment 1. 
10.4 
SAE REPORT FORM 
See the Attachment 2. 
10.5 
PREGNANCY MONITORING FORM 
See the Attachment 3. 
10.6 
PRODUCT LOCAL LABEL 
See the Attachment 4. 
10.7 
SPECIAL PRECAUTIONS FOR USE_RISK OF BLEEDING 
See the Attachment 5. 
 
 

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11. 
SUMMARY OF NIS STUDY PROTOCOL MODIFICATIONS 
Summary of Modifications Sheet (SOMS) 
 
Number of Protocol modification 
 
Amendment IV 
Date of Protocol modification 
 
11 Aug 2011 (Amendment I) 
29 Nov 2012 (Amendment II) 
18 Feb 2013 (Amendment III) 
10 Jun 2013 (Amendment IV) 
BI Trial number 
 
1160.139 
BI Product(s) 
 
Dabigatran etexilate mesilate 
Title of protocol 
 
A regulatory requirement non-interventional 
study to monitor the safety and effectiveness 
of Pradaxa (Dabigatran etexilate mesilate, 110 
mg or 150 mg b.i.d.) in Korean patients with 
non-valvular atrial fibrillation (SPARK: Safety 
study of Pradaxa in AF patients by Regulatory 
requirement of Korea) 
 
To be implemented only after 
approval of the 
IRB/IEC/Competent Authorities 
 
 Mainly according to the revised local label of 
Pradaxa, the patient enrollment was changed. 
To be implemented immediately 
in order to eliminate hazard –  
IRB / IEC / Competent Authority 
to be notified of change with 
request for approval 
 
 
Can be implemented without 
IRB/IEC/ Competent Authority 
approval as changes involve 
logistical or administrative 
aspects only 
 
 
 
Section to be changed 
 
Please refer to the protocol amendment 
table_V4.0 
 
 
 
Description of change 
 
Rationale for change