Non-interventional Study Describing Patients' Perception on Anticoagulant Treatment and Treatment Convenience When Treated With Pradaxa or Vitamin K Antagonist for Stroke Prophylaxis in Atrial Fibrillation.
Conditions: Atrial Fibrillation
Sponsor: Boehringer Ingelheim

ABCD
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
TITLE PAGE
Non-interventional Study Protocol
.
Document Number:
c09063488-07
BI Study Number:
1160.261
BI Investigational
Product(s):
Dabigatran etexilate (Pradaxa®)
Title:
Non-interventional study describing  patients´ perception 
on anticoagulant treatment and treatment convenience 
when treated with Pradaxa® or Vitamin K Antagonist for 
Stroke Prophylaxis in Atrial Fibrillation
Brief lay title
Patient Convenience Study
Protocol version 
identifier:
1.0
Date of last version of 
protocol:
25 Jan 2016
PASS:
No
EU PAS register 
number:
Study not registered
Active substance:
B01AE07 - Dabigatran etexilate.
Medicinal product:
Dabigatran etexilate
Product reference:
EU/1/08/442/001-019
Procedure number:
NA
Marketing 
authorisation 
holder(s):
Boehringer Ingelheim International GmbH 
Binger Str. 173
D-55216 Ingelheim am Rhein, Germany 
Joint PASS:
No
Research question and 
objectives:
Primary objective:
Describe the atrial fibrillation patient´s treatment 
perception by using the PACT-Q© (Perception 
on Anticoagulant Treatment Questionnaire).
Secondary objective:
Characterization of patient population (including dosing of
Pradaxa®) 

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Country(-ies) of 
study:
6 SEASK countries ( Indonesia, Malaysia, Singapore, 
South Korea, Thailand and Vietnam)
Author:
phone: 
 
mobile: 
 
fax: 
Email: 
Phone: 
Mobile: 
Fax: 
  Email:
Marketing 
authorisation 
holder(s):
Boehringer Ingelheim International GmbH 
Binger Str. 173
D-55216 Ingelheim am Rhein, Germany
Date:
25 Jan 2016
Page 1 of 56
Proprietary confidential information
© 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission

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1.
TABLE OF CONTENTS
1.
TABLE OF CONTENTS....................................................................................... 3
2.
LIST OF ABBREVIATIONS................................................................................ 5
3.
RESPONSIBLE PARTIES.................................................................................... 7
4.
ABSTRACT........................................................................................................... 8
5.
AMENDMENTS AND UPDATES..................................................................... 11
6.
MILESTONES..................................................................................................... 12
7.
RATIONALE AND BACKGROUND................................................................ 13
8.
RESEARCH QUESTION AND OBJECTIVES ................................................. 15
9.
RESEARCH METHODS .................................................................................... 16
9.1
STUDY DESIGN............................................................................................ 16
9.2
SETTING........................................................................................................ 16
9.2.1
Study sites ............................................................................................... 16
9.2.2
Study population ..................................................................................... 17
9.2.2.1
Inclusion Criteria.............................................................................. 17
9.2.2.2
Removal of patients from the study ................................................. 18
9.2.2.3
Visit schedule................................................................................... 18
9.2.3
Study visits .............................................................................................. 20
9.2.3.1
Treatments........................................................................................ 21
9.2.3.2
Concomitant medications and restrictions ....................................... 22
9.2.3.3
Representativeness of the study population ..................................... 22
9.2.4
Study discontinuation.............................................................................. 22
9.3
VARIABLES .................................................................................................. 22
9.4
DATA SOURCES........................................................................................... 23
9.5
STUDY SIZE.................................................................................................. 24
9.6
DATA MANAGEMENT................................................................................ 26
9.7
DATA ANALYSIS......................................................................................... 26
9.7.1
Study Design ........................................................................................... 26
9.7.2
Planned Analysis..................................................................................... 27
9.7.3
Main analysis........................................................................................... 27
9.7.5
Safety Analyses....................................................................................... 28
9.7.6
Handling Of Missing Data ...................................................................... 29
9.8
QUALITY CONTROL................................................................................... 30

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9.9
LIMITATIONS OF THE RESEARCH METHODS...................................... 30
9.10
OTHER ASPECTS ......................................................................................... 32
9.10.1
Informed Consent, Data Protection, Study Records ............................... 32
9.10.2
Study Approval, Patient Information, And Informed Consent ............... 32
9.10.3
Data quality assurance............................................................................. 33
9.10.4
Study records........................................................................................... 33
9.10.4.1
Source documents ............................................................................ 33
9.10.4.2
Direct access to source data and documents .................................... 34
10.
PROTECTION OF HUMAN SUBJECTS .......................................................... 35
10.1
Study approval, patient information, and informed consent........................... 35
10.2
Statement of confidentiality............................................................................ 36
10.3
COMPLETION OF STUDY........................................................................... 36
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS....................................................................................................... 37
11.1
Definitions of adverse events.......................................................................... 37
11.2
Adverse event and serious adverse event collection and reporting................. 38
11.3
Reporting to health Authorities....................................................................... 40
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
............................................................................................................................. 41
13.
REFERENCES .................................................................................................... 42
13.1
PUBLISHED REFERENCES......................................................................... 42
13.2
UNPUBLISHED REFERENCES................................................................... 43
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.............................................. 44
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .............................. 45
ANNEX 3. ADDITIONAL INFORMATION.............................................................. 46
ANNEX 3.1  Perception of anticoagulant treatment Questionnaire, part 1 (PACT-Q1)47
ANNEX 3.2  Perception of anticoagulant treatment Questionnaire, part 2 (PACT-Q2)50

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2.
LIST OF ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Event of Special interest
ADR
Advese Drug Reaction
AF
Atrial Fibrillation
ANCOVA
Analysis of Covaiance
BI
Boehringer Ingelheim
CA
Competent Authority
CHA2DS2-
VASc score
Congestive heart failure, Hypertension, Age (≥ 75), Diabetes 
mellitus, Stroke/TIA, Vascular disease, Age 65-74, Sex category
CI
Confidence Interval
CML
Local Clinical Monitor 
CRA
Clinical Research Associate
CRF
Case Report Form
CTP
Clinical Trial Protocol
DEDP
Drug Exposure During Pregnancy
DMP
Data Management Plan
DVT
Deep Venous Thrombosis
eCRF
Electronic Case Report Form
EC
Ethics Committee
ECG
Electrocardiogram
EDC
Electronic Data Capture
EMA
European Medicine Agency
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GEP
Good Epidemiological Practice
GPP
Good Pharmacoepidemiology Practice
GVP
Good Pharmacovigilance Practices
GPV CTC
Global Pharmacovigilance Clinical Trial Coordinator
HAS-BLED
Hypertension, Abnormal renal and liver function, Stroke (1 point), 
Bleeding history or predisposition, Labile INR, Elderly (>65 years), 
Drugs and Alcohol.
ICH
International Conference of Harmonisation
ICSR
Individual Case Safety Report
IEC
Independent Ethics Committee
INR
International Normalized Ratio
IRB
Institutional Review Board
ISF
Investigator Site File
MAH
Marketing Authorisation Holder
Activities
n.a.
Not applicable / not available
NIS
Non-Interventional Study
NVAF
Non valvular atrial fibrillation
OPU
Operative Unit
OAC
Oral Anticoagulation
PACT-Q©
Perception of Anticoagulant Treatment Questionnaire

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PE
Pulmonary Embolism
SAE
Serious Adverse Event
SDV
Source Data Verification
SEAP
Statistical and Epidemiological Analysis Plan
SEASK
South East Asia South Korea
SOP
Standard Operating Procedure
SPAF
Stroke Prophylaxis (or Prevention) in Atrial Fibrillation
TMF
Trial Master File
VKA
Vitamin K Antagonist

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3.
RESPONSIBLE PARTIES
Therapeutic Area 
 Cardiovascular Medicine (TA )
Team Member Medical Affairs (TM MA)
Team Member Epidemiology (TM Epi)
 Global Epidemiology (  GEpi)
Therapeutic Area
 Risk Management  (TA
RM), and
Pharmacovigilance Working Group  (PVWG) 
Trial Clinical Monitor (TCM)
Trial Statistician (TSTAT)

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4.
ABSTRACT
Name of company:
Boehringer Ingelheim
Name of finished medicinal product:
Pradaxa® (Dabigatran etexilate), or
Vitamin K Antagonist (VKA)
Name of active ingredient:
Dabigatran, or VKA
Protocol date:
Study number:
Version/Revision:
Version/Revision 
date:
25 January 2016
1160.261
1.0
n.a.
Title of study:
Non-interventional study describing patients´ perception on anticoagulant 
treatment and treatment convenience when treated with Pradaxa® or
Vitamin K Antagonist for Stroke Prophylaxis in Atrial Fibrillation.
Rationale and 
background:
Pradaxa® (Dabigatran etexilate) is a direct Thrombin inhibitor approved in 
Europe, USA and many other Asian countries worldwide for the prevention 
of stroke and systemic embolism in adult patients with non- valvular atrial 
fibrillation with one or more risk factors. There is a lack of data on how 
atrial fibriallation patients in Asia perceive Pradaxa® treatment in the 
context of anticoagulation management. 
The decision in clinical practice to use Pradaxa® as the first novel 
anticoagulant or established vitamin K antagonists depends on many factors 
related to the patient and prescribing physician.
The aim of this non-interventional study is to describe patients’ perception 
of anticoagulant treatment when using Pradaxa® to prevent stroke and 
systemic embolism while suffering from non-valvular atrial fibrillation 
(according to its approved indication at the approved dosages in respective 
countries) in comparison to using Vitamin K Antagonist (VKA).
Research question 
and objectives:
Objective 1: How do patients perceive anticoagulation treatment with 
Pradaxa® for stroke prevention in non-valvular atrial fibrillation (NVAF) in 
comparison with VKA?

 
 
What is treatment expectation of newly diagnosed NVAF patients 
before they start treatment with VKA or Pradaxa®

Objective 2: What are the characteristics of patients receiving 
anticoagulation treatment for stroke prevention regarding
demographics, physician rated scores, kidney function, treatment
(choice of treatment, dosing)?
Study design:
Non-interventional study of AF patients in Asia with a current VKA 
therapy and subsequent initiation of Pradaxa® OR patients being newly 

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diagnosed with AF and initiated on Pradaxa® or VKA.
Population:
Patients diagnosed with non-valvular atrial fibrillation (NVAF) and eligible 
for Pradaxa® or VKA treatment according to Pradaxa® or respective VKA 
label.
Variables:
For objective 1: 
Primary Outcome
For Cohort A (NVAF patients on VKA who are switched to
Pradaxa®)):
-
Mean PACT-Q2 scores at second and last assessment 
compared to baseline assessment.
For Cohort B (newly diagnosed NVAF patients initiated to either
VKA or Pradaxa®)):
-
Mean PACT-Q2 scores at second and last assessment 
compared between treatment groups.
Secondary outcome:
For Cohort A (switched to Pradaxa®):
-
Mean PACT-Q2 scores at last assessment compared to second 
assessment.
For Cohort B (newly initiated to VKA or Pradaxa®):
-
Description of PACT-Q1 items at baseline.
 
 
 
 
For objective 2: 
Primary outcome:
Characterization of patients from both cohorts according to
-
Age
-
Gender
-
CHA2DS2-VASc score (R10-5332)
-
HAS-BLED score (modified HAS-BLED for newly initiated 
patients) (R10-6394)
-
Kidney function (creatinine clearance) 
-
Co-morbidities
-
Co-medication
-
Dosing of Pradaxa
-   Duration of previous VKA treatment (for Cohort A)
Data sources:
-
New data collection

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-
Questionnaires completed by patients
-
Patient characteristics completed by physician’s judgement and 
records.
Study size:
1790  patients in 6 SEASK countries
Data analysis:
In this  non-interventional study, baseline and longitudinal follow-up data 
over 6 months will be collected for non-valvular AF patients with a current 
VKA therapy and subsequent initiation of Pradaxa®   in Cohort A, and for 
newly diagnosed AF patients initiated on Pradaxa® or VKA in Cohort B.
Data from baseline and the longitudinal follow-up will be summarized 
descriptively. For Cohort A, mean PACT-Q2 scores between assessments 
will be compared using paired t-tests. For Cohort B, mean PACT-Q2 
scores between Pradaxa® and VKA patients will be compared using 
propensity score matched analysis.
Milestones:
Planned start of data collection: 30 Apr 2016
Planned end of data collection: 11 Jan 2018
Planned final study  report:  5 Jul 2018

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5.
AMENDMENTS AND UPDATES
None

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6.
MILESTONES
Milestone
Planned Date
IRB/IEC approval
20 April 2016
Start of data collection
30 April 2016
End of data collection
11 January 2018
Final report of study results:
05 July 2018

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7.
RATIONALE AND BACKGROUND
Pradaxa® (Dabigatran etexilate) is a direct Thrombin inhibitor approved in Europe, USA 
and many other Asian countries worldwide for the prevention of stroke and systemic 
embolism in adult patients with non-valvular atrial fibrillation with one or more risk factors.
Pradaxa® has been studied in the RELY study, one of the largest atrial fibrillation outcome 
studies (P13-05668). Over the course of one year, all anticoagulated patients without 
outcome events (e.g. strokes or major bleedings) had stable HRQoL.  There is a lack of data 
on how atrial fibrillation patients in Asia perceive Pradaxa®   treatment in the context of 
anticoagulation management. 
The decision in clinical practice to use Pradaxa® as the first novel anticoagulant 
or established vitamin K antagonists depends on many factors related to:
a) The patient: Level of information, health status, comorbid conditions and 
demographic factors, perception of anticoagulant treatment, understanding of the 
burden of the disease, access to the medication, educational measures informing 
about medications and reimbursement status in a particular country.
b) The treating physician: Stroke risk assessment, bleeding risk assessment, 
understanding and adherence to guidelines, access and use of medical 
education, interaction with patients and overall local health care system.
It is assumed that these factors in real world clinical practice vary e.g. between countries 
with different health care systems, between patients who start anticoagulation treatment 
versus those who have anticoagulation experience already or between the treatment 
initiation versus the mid-term follow up on Pradaxa® or vitamin K antagonists.
It is the aim of this non-interventional study to describe the patient perception of 
anticoagulation when treated with Pradaxa® to prevent stroke and systemic embolism while 
suffering from non-valvular atrial fibrillation (according to its approved indication in the 
approved dosages of 110 mg or 150 mg twice daily). To evaluate patient understanding of 
treatment and patient values it is important to assess patient’s perception of the treatment in 
the context of overall disease management as close as possible to the clinical practice. 
Furthermore it is important to anchor the Pradaxa® treatment perception data in different 
ways, in order to determine on how previously and newly diagnosed NVAF patients 
perceive treatment with Pradaxa®, in comparison to vitamin K antagonist treatment (being 
considered the standard anticoagulation treatment for stroke prevention in non-valvular 
atrial fibrillation over decades):

Compare the treatment perception data of patients, who are switched to Pradaxa®
treatment, to their perception about their previous anticoagulation (VKA) therapy , and

Compare the treatment perception data of patients who are newly initiated Pradaxa®
treatment to the treatment perception data of patients who are newly initiated to VKA
treatment
These real world data are needed to guide the scientific community in designing 
educational efforts for doctors and their patients and to assess the potential values of 
patient adherence programs when using Pradaxa® as the first novel anticoagulant. Also 
such data, describing patient’s perception on Pradaxa® anticoagulation in the context of 

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patient-physician interaction managing stroke prevention in atrial fibrillation cannot be 
obtained by market research.

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8.
RESEARCH QUESTION AND OBJECTIVES
8.1
RESEARCH QUESTIONS
This non-interventional study will address the following questions:

How do patients with non-valvular atrial fibrillation perceive anticoagulation 
treatment for stroke prevention (stratified in cohorts of patients switched from 
previous treatment to Pradaxa®, newly initiated treatment with Pradaxa®, newly 
initiated treatment with VKA)? 

 
 

What are the characteristics of patients receiving anticoagulation treatment for 
stroke prevention regarding demographics, physician rated risk scores, kidney
function, concomitant diseases and concomitant medications, treatment for 
SPAF (choice of treatment, dosing)?
Two cohorts of patients will be recruited: 
CohortA:
Patients having been treated with VKA and now being switched to Pradaxa®
CohortB:
Patients newly diagnosed with non-valvular atrial fibrillation and initiated on either 
Pradaxa®or VKA.
8.2
OBJECTIVE 
Primary objective

Describe the atrial fibrillation patient´s treatment perception by using the PACT-Q 
at three time-points at baseline, during initiation period and during the continuation 
period.
Secondary objective

Characterization of patient population (incl. dosing) in the participating SEASK 
countries.

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9.
RESEARCH METHODS
9.1
STUDY DESIGN
This is a non-interventional multi-national, multi-centre study based on newly collected data.
The study will enrol consented patients with non-valvular atrial fibrillation (AF) in SEASK
with a current VKA therapy and subsequent initiation of Pradaxa® (Cohort A) OR patients
being newly diagnosed with AF and initiated on Pradaxa® or VKA (Cohort B).
Patients will be followed over an observation period of 6 months. Data will be collected at 
three time points:
1.   At Baseline ( initiation on Pradaxa® or VKA)
2.   30-45 days after initiation on Pradaxa® or VKA (initiation period)
3.   150-210 days after initiation on Pradaxa® or VKA (continuation period)
9.2
SETTING
It is planned that data of approximately 1790 patients will be collected from approximately 
80 sites in 6 SEASK countries. Planned participating countries are Indonesia, Malaysia, 
Singapore, South Korea, Thailand and Vietnam.
9.2.1
Study sites
Cardiologists and non-cardiologist sites regularly prescribing Pradaxa® and VKA for 
stroke prevention in atrial fibrillation according to the respective country approved label 
will participate.
Selected sites within each country should include those physicians (e.g. cardiologists, non-
cardiologists) and facilities (e.g. specialist offices, hospitals, outpatient care centres etc.) 
that reflect the clinical practice in that country. Investigators that are currently participating 
in the BI registry program 1160.129 (GLORIA) are not allowed to participate in this study.
These site selection criteria will help to ensure that the patients recruited into this study
will represent the patients treated within that country. After initiation, every site should 
include the first consecutive suitable patients where decision for switch to Pradaxa®
(Cohort A) or decision for initiation on Pradaxa® or VKA (Cohort B) has been made. In 
consecutive sampling, every eligible patient is selected until the required sample size is 
enrolled. This approach helps to reduce the likelihood of selection bias.
Balance between Cohorts within each  country
Within each participating country, the recruitment of patients in Cohort A and Cohort B
needs to be balanced (A:B = 1:2). Within Cohort B, the patient enrolment will be controlled
as well, in order to ensure that an equal amount of data will be collected of AF patients 
newly treated with Pradaxa®
(sub-Cohort B1) or
with VKA (sub-Cohort B2) 

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(Pradaxa®:VKA = 1:1). Therefore, the sponsor may have to decide to close the enrolment of 
patients for one of the Cohorts (or sub-Cohorts) during the recruitment period, if the other
(sub) Cohort is exceeding the maximum number of enrolled patients planned for that 
country/site.
The decision for therapy has to be taken prior to and independently of enrolment into the 
study. Only after the treatment decision for the patient is taken, the investigator can check 
and decide if a patient can be enrolled in Cohort A or Cohort B.
Patients will then have to sign informed consent before they can take part in the 
non- interventional study.
A log of all patients included into the study (i.e. having given informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been 
treated or not.
9.2.2
Study population
9.2.2.1
Inclusion Criteria
Cohort A:
1A.
Written informed consent prior to participation
2A.
Female and male patient’s ≥ 18 years of age with a diagnosis of non-valvular 
          atrial fibrillation.
3A.
At least 3 months of continuous VKA treatment for stroke prevention prior to 
           baseline assessment.
4A.
Patients switched to Pradaxa® according  approved country label and 
           physician`s discretion.
OR
Cohort B:
1B.
Written informed consent prior to participation.
2B.
Female and male patients ≥ 18 years of age newly diagnosed with non-
          valvular atrial fibrillation and no previous treatment for stroke prevention (no 
          use of any OAC within one year prior to enrolment).
3B.
Stroke prevention treatment initiated with Pradaxa® or VKA according to approved 
country label and physician`s discretion.
Exclusion Criteria
1.   Contraindication to the use of Pradaxa® or VKA as described in the approved 
country label

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2.   Patients receiving Pradaxa® or VKA for any other condition than stroke prevention 
in atrial fibrillation.
3.   Current participation in any clinical trial of a drug or device
4.   Current participation in a Registry, e.g. the Gloria registry program, on the use of 
oral anticoagulation in AF
9.2.2.2
Removal of patients from the study
Every patient has the right to withdraw consent at any time during the study, without the 
need for justification and without any impact on the routine therapy.
A patient is considered permanently discontinued or withdrawn from treatment if the patient 
did not complete the treatment with Pradaxa or VKA for the entire continuation period until 
Visit 3 and did not perform all visit 3 assessments.
Boehringer Ingelheim reserves the right to discontinue the study overall or at a particular 
study site at any time for the following reasons:
1.   Failure to meet expected enrolment goals overall or at a particular study site.
2.   Emergence of any efficacy/safety information that could significantly affect 
continuation of the study, or any other administrative reasons.
3.   Violation of the protocol, or the contract by a study site or investigator, disturbing the 
appropriate conduct of the study.
In the framework of NIS study, the Investigators are responsible for treatment and may 
remove patients at any time according to his/her medical judgement.
The investigator / the study site will be reimbursed for reasonable expenses incurred in case 
of study termination (except in case of the third reason).
9.2.2.3
Visit schedule
Collection of patient data should be managed during routine practice visits. The time-
schedule below can only be a recommendation; if a patient does not visit the site at these 
time points, data will not be collected (no visits will be conducted solely for study 
purposes).
Visits must be performed face-to-face and cannot be performed by phone, email or fax, as 
the patient has to complete the self-administered questionnaires.
1.   At Baseline (at initiation on Pradaxa® or VKA)
2.   30-45 days after initiation on Pradaxa® or VKA (initiation period)

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3.   150-210 days after initiation on Pradaxa® or VKA (continuation period)
Table 9.2.2.3: 1 Flow Chart / Schedule of Data Collection
Visit
1
2
3
Assessment
Baseline
Initiation period
Continuation period
Day
1
30-45 days
150 – 210 days
Informed Consent1
X
Patient demographics: age, gender
X
Concomitant diseases / co-
morbidities
X
X
X
Concomitant therapies
X
X
X
Healthcare system characteristics2
X
HAS- BLED score (to be calculated 
in the eCRF)
X
CHA2DS2-VASc score (to be 
calculated in the eCRF)
X
Inclusion/exclusion criteria
X
Duration of previous VKA
treatment (for Cohort A)
X
Reasons for switch to Pradaxa® (for
Cohort A)
X
Start Pradaxa® or VKA
X
Pradaxa® dosing (110 or 150 mg)
and reasons for dose changes
X
X
X
Creatinine clearance calculation3
X
X
X
Weight4
X
X4
X4
ADR (serious and non-serious), 
fatal AE, pregnancy collection
X
X
Reason for Pradaxa®/VKA
discontinuation
X
X
PACT-Q1 questionnaire
X (for Cohort B only)
PACT-Q2 questionnaire
X (for Cohort A only)
X (both Cohorts)
X (both Cohorts)
Footnotes:
1.
Written Informed Consent must be obtained prior to the baseline visit assessments.
2.
The type of hospital/practice and speciality of treating physician must be entered
3.
Creatinine clearance can only be calculated in the eCRF (via Cockroft-Gault Formula) if
serum creatinine value is available from already existing laboratory reports. No lab
assessment must be performed for the study at the baseline Visit 1, Visit 2 and/or Visit 3. See
also footnote 4.
4.  Weight must be determined at Visit 1. At Visit 2 and/or 3, only if existing serum creatinine value
is available at Visit 2 and/or 3.

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9.2.3
Study visits
Baseline visit:
No data collection for study purposes must be performed unless the patient has consented to 
participate in the study. Once the patient has signed the informed consent form, the patient 
is considered to be enrolled in the study and patient details should be recorded on the 
enrolment log.
The following procedures will be performed at the baseline visit:

Sign informed consent form

Review of inclusion and exclusion criteria

Collection of demographic data: age, gender,

Collection of concomitant diseases/co-morbidities in the medical history and
at baseline

Collection of current concomitant therapies

Weight

Creatinine Clearance: serum creatinine value (if available) to be entered on 
eCRF, Creatinine Clearance according to Cockcroft-Gault formula to be 
automatically calculated CHA2DS2-VASc and HAS-BLED score calculation in 
eCRF

For Cohort A only: duration of previous treatment with VKA to be documented

For Cohort A only: reasons for switch to Pradaxa® to be documented

Documentation of Pradaxa® dosing

Patient will be asked to complete the following patient related questionnaires:
-
PACT-Q2 (Cohort A only)
-
PACT-Q1 (Cohort B only)

Treatment with Pradaxa® or VKA will be initiated
Initiation period:
During a routine practice visit occurring at 30 – 45 days after initiation of treatment, 
the following assessments will be documented:

Current dosing of Pradaxa® and reasons for dose change (if applicable)

New or changed concomitant diseases/co-morbidities

Changes in concomitant therapies

Creatinine Clearance: serum creatinine value (if available) to be entered on eCRF, 
Creatinine Clearance according to Cockcroft-Gault formula to be automatically 
calculated

Weight (if needed for creatinine clearance calculation at V2)

Collection and reporting of ADR (serious and non-serious), fatal AEs, or pregnancies
(if applicable)

Reasons for Pradaxa® or VKA discontinuation (if applicable)

Patients will be asked to complete the PACT-Q2 questionnaire
Continuation period:

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During a routine practice visit occurring at 150-210 days after initiation of treatment, 
the following assessments will be documented:

Current dosing of Pradaxa® and reasons for dose change (if applicable)

New or changed concomitant diseases/co-morbidities

Changes in concomitant therapies

Creatinine Clearance: serum creatinine value (if available) to be entered on 
eCRF, Creatinine Clearance according to Cockcroft-Gault formula to be 
automatically calculated

Weight (if needed for creatinine clearance calculation at V3)

Collection and reporting of ADR (serious and non-serious), fatal AEs, or   
      pregnancies  (if applicable)

Reasons for Pradaxa® or VKA discontinuation (if applicable)

Patients will be asked to complete the PACT-Q2 questionnaire
With this visit, the patient´s participation in the study will be completed.
Description and justification of patient questionnaires:
-
PACT-Q©:
The PACT-Q was developed as a means to investigate patients´ satisfaction with
anticoagulant treatment and treatment convenience in patients with deep venous 
thrombosis (DVT), pulmonary embolism (PE) or atrial fibrillation (AF) (R15-1314; 
R15-1316). The PACT-Q is a self-administered questionnaire. It can be completed in 
about ten minutes. No specific training is required to complete this document.
The original PACT-Q consists of two parts and contains 27 items:
The PACT-Q1 is composed of a single dimension (7 items), covering the 
expectations of patients regarding their anticoagulant treatment, and is to be
administered before treatment initiation.

The PACT-Q2 is composed of three dimensions covering: convenience (11 
items), burden of disease and treatment (2 items), and anticoagulant treatment
satisfaction (7 items). The PACT-Q2 is to be administered to patients once
treatment is ongoing.
Patients will either be switched from VKA treatment to Pradaxa® (cohort A) or 
newly initiated on Pradaxa® or VKA (cohort B).
-
Pradaxa® 110 mg hard capsules
-
Pradaxa® 150 mg hard capsules
-
Vitamin K antagonist
9.2.3.1
Treatments

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Pradaxa® 110 mg and Pradaxa® 150 mg hard capsules contain Dabigatran etexilate 
(active moiety: Dabigatran).
Patients will receive daily dose of Pradaxa® according to the approved country 
label and physician´s discretion.
The choice of vitamin K antagonist and the appropriate dosing is in the discretion of 
the physician. The applicable approved country label of the chosen treatment should
be referred to.
9.2.3.2
Concomitant medications and restrictions
All concomitant medications are prescribed based on the underlying medical condition and 
upon the discretion of the treating physician. No treatment will be withheld from the 
patients. Any prescription is in the responsibility of the treating physician.
9.2.3.3
Representativeness of the study population
Inclusion and exclusion criteria have been limited to the respective approved country label 
of Pradaxa® and VKA. Therefore the patient population recruited in this non-interventional 
study can be seen as representative for patients receiving an oral anticoagulation for stroke 
prevention in non- valvular atrial fibrillation.
9.2.4
Study discontinuation
Boehringer Ingelheim reserves the right to discontinue the study overall or at a particular 
study site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular study site
2. Violation of Good Clinical Practice (GCP) (as applicable), the study protocol, or the 
contract by a study site or investigator, disturbing the appropriate conduct of the study
3. Any other administrative reasons
The investigator / the study site will be reimbursed for reasonable expenses incurred in case 
of study termination (except in case of the second reason).
9.3
VARIABLES
9.3.1
Variables for objective 1
Primary outcome
For Cohort A (switcher):

Mean PACT-Q2 scores at second and last assessment compared to 
baseline assessment

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For Cohort B (newly initiated):

Mean PACT-Q2 scores at second and last assessment between treatment groups
Secondary outcome:
For Cohort A (switcher):

Mean PACT-Q2 score at last assessment compared to second assessment
For Cohort B (newly initiated):

Description of PACT-Q1 items at baseline
 
9.3.2 
Variables for objective 2
Primary outcome:
Characterization of patients from both cohorts according to
-
Age
-
Gender
-
CHA2DS2-VASc score (R10-5332)
-
HAS-BLED score (modified HAS-BLED for newly initiated patients) (R10-6394)
-
Kidney function (creatinine clearance)
-
Stroke- and/or bleeding related risk factors in medical history and at baseline
-
Co-morbidities
-
Concomitant therapies
-
Dosing of Pradaxa®
-
Duration of previous VKA treatment (for Cohort A)
9.4
DATA SOURCES
Data will be newly collected from the patient by the investigator and recorded as source 
data at the site, i.e. the physicians records, and entered in the eCRF by the investigator or 
site staff. Patients will be asked to complete the respective questionnaires during their 
routine visits. Patient demographic data, concomitant diseases and concomitant therapies 
will be completed based on the physician´s records. Information on Pradaxa® and/or VKA 
dosing will be collected from physician´s records. Creatinine clearance for assessment of 
kidney function will be calculated within the eCRF, by entering Creatinine values (from 
existing lab reports, if available), and weight (if applicable) to be measured by the physician 
or delegated site staff.

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9.5
STUDY SIZE
It is planned that a total of approximately 1790 patients from 6 SEASK countries will be 
recruited for Cohort A and Cohort B.
Baseline demographics and disease characteristics of the patient population will be 
described by estimates and confidence intervals (CIs) overall (for Cohort A), by
anticoagulation treatment (for Cohort B), and by additional relevant categories as specified 
in Section 9.7.2 and the SEAP. Categorical attributes will be estimated with the precision 
(i.e. width of descriptive 95% confidence interval) described in Table 9.5: 1, according to 
sample size and prevalence of the attribute.
Table 9.5: 1
Width of 95% confidence interval by sample size and prevalence of 
attribute
Prevalence of attribute
Sample size (overall or per subgroup)
200
500
1000
2000
10%
Expected n
95% CI width
20%
Expected n
95% CI width
30%
Expected n
95% CI width
40%
Expected n
95% CI width
50%
Expected n
95% CI width
20
50
100
200
  8.80
  5.46
   3.82
   2.68
40
100
200
400
  11.53
   7.20
    5.05
    3.55
60
150
300
600
  13.13
    8.21
    5.77
    4.06
80
200
400
800
13.99
8.77
6.17
4.34
  100
   250
   500
   1000
14.26
8.94
6.29
4.43

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* Calculations are based on the Clopper-Pearson method.
For example, for a population attribute with a prevalence of 20%, a total sample size of 
1000 patients for Cohort A allows this proportion to be estimated with a precision of 
5.05% (i.e. width of 95% CI).
 
 
The planned total sample size of 1790 patients is jointly determined by the following 
sample size assessments and additional non-statistical considerations, including feasibility 
assessments for the participating countries.
Due to the limited number of publications on PACT-Q2 (R15-1314, R15-1316, R15-1359) 
and the lack of information regarding the clinical meaning of changes in PACT-Q2 scores, 
sample size assessments are performed using standardized mean differences. In the context 
of this study, they represent the mean differences in PACT-Q2 scores between two 
assessments (for Cohort A) or between the Pradaxa® and VKA groups (for Cohort B) 
divided by the corresponding standard deviations. In general, a standardized effect size of 
0.2 is considered a small change, 0.5 a moderate change, and 0.8 a large change.
For Cohort A, assuming a 2-sided alpha of 0.05 and a 20% loss to follow-up, a total sample 
size of 598 patients will provide over 80% power to detect a standardized mean difference of 
0.13 in PACT-Q2 scores between two assessments.
For Cohort B, assuming a 2-sided alpha of 0.05, a 1:1 ratio of Pradaxa® and VKA patients, 
and a 30% loss to follow-up and matching, a total sample size of 1192 patients will provide 
over 80% power to detect a standardized mean difference of 0.14 in PACT-Q2 scores 
between the Pradaxa® and VKA groups at each assessment.
 
 
Based on results from the PREFER in AF (R15-1312) registry study, a reasonable 
expected standard deviation for the PACT-Q2 convenience and treatment satisfaction 
scores is 16. Based on this estimate, a standardized mean difference of 0.1 corresponds to 
an actual mean difference of 1.6 in the PACT-Q2 convenience and treatment satisfaction 
scores.
The PREFER in AF study (R15-1312) also reported a mean difference between patients 
receiving novel oral anticoagulants and those receiving VKA of -0.6 for the 
convenience score, and of 1.1 for the treatment satisfaction score. Since the clinical 
meaningfulness of such small mean differences in PACT-Q2 scores is unclear, the

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current study is by design not powered to detect statistically significant differences of
such small magnitudes.
9.6
DATA MANAGEMENT
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.
9.7
DATA ANALYSIS
9.7.1
Study Design
In this non-interventional study, cross-sectional data at study baseline and longitudinal 
follow-up data over 6 months will be collected for non-valvular AF patients with a 
current VKA therapy and subsequent initiation of Pradaxa® in Cohort A, and for newly
diagnosed AF patients initiated on Pradaxa® or VKA in Cohort B.
Baseline data will be analyzed using a descriptive approach. Data from the longitudinal 
follow-up will be summarized descriptively. For Cohort A, mean differences in PACT-Q2 
scores between assessments will be assessed using paired t-tests. For Cohort B, mean 
differences in PACT-Q2 scores between Pradaxa® and VKA patients will be assessed 
using propensity score matched analysis.
Due to the nature of this non-interventional study, there is no (confirmatory) hypothesis 
testing foreseen in a strict statistical sense. Analyses are descriptive in nature and 
confidence intervals and p-values from statistical models are used for exploratory purposes.

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9.7.2
Planned Analysis
Analyses will be performed by Boehringer Ingelheim or Boehringer Ingelheim’s designees. 
The main analysis population will consist of all eligible patients (i.e. all patients fulfilling 
all inclusion criteria and no exclusion criteria) from all participating countries.
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. Estimates will 
be presented with 95% confidence intervals.
Additional details of the planned analysis will be provided in the statistical and 
epidemiological analysis plan (SEAP).
9.7.3
Main analysis
Patient demographics and disease characteristics at baseline as described in section 9.3.2 
will be summarized descriptively for all eligible patients in Cohort A and by treatment in 
Cohort B. This analysis may be repeated by additional relevant factors (e.g. country) that 
will be specified in the SEAP.
For Cohort A, the mean PACT-Q2 scores at the second and last assessments will 
be compared with the baseline assessment using paired t-tests.
For Cohort B, mean PACT-Q2 scores will be compared between Pradaxa® and VKA 
patients at the second and last assessments. Given the nature of this non-interventional 
study, patient in the two treatment groups may differ with regard to important baseline
demographics and disease characteristics. When approximately half of the target sample 
size is reached, propensity scores that estimate the probabilities that patients would be 
initiated on Pradaxa® will be calculated using a logistic regression model including relevant 
baseline factors. The percentage of Pradaxa® and VKA patients that are matched with a 1:1 
ratio and without replacement based on propensity scores will be calculated to assess the 
comparability of the two patient populations, and to estimate the loss of patients from the 
comparative analysis. Details of the propensity score model and the matching procedure, 
such as the choice of algorithm and caliper width will be described in the SEAP. If a
sufficient percentage of matching (e.g. 90%) is achieved, the loss is considered minimal. If 
the percentage is considered not to be sufficient, the target sample size might be raised to 
increase the power of the comparative analysis.
For the final comparative analysis for Cohort B, Pradaxa® and VKA patients will be 
matched based on propensity scores following the same approach as described above. To 
assess the performance of the propensity score matching procedure, patient demographics 
and disease characteristics at baseline will be descriptively summarized again for the 
matched patients by treatment. Finally, the mean PACT-Q2 scores at each of the second 
and last assessments will be compared between the matched Pradaxa® and VKA patients 
using a paired t-test.

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For both cohorts, the primary analyses will be based on the actual anticoagulation
treatment the patients receive (i.e. “as treated” analysis). A patient is considered to have 
permanently discontinued initial anticoagulation treatment if other relevant 
anticoagulation treatment is initiated or otherwise dependent on the duration of treatment 
interruption (details will be provided in the SEAP). Patients who have permanently
discontinued initial anticoagulation treatment at the time of an assessment will be
excluded from all analyses where data from that assessment is included.
9.7.5
Safety Analyses
Safety analyses will be performed separately for Cohort A and B, and will include all 
enrolled patients with an actual follow-up. Statistical analysis and reporting of AEs will be 
descriptive in nature, will be based on BI standards, and will focus on adverse drug 
reactions (ADRs) to Pradaxa® and VKA. No hypothesis testing is planned.

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Occurrences of ADRs will be analyzed relative to the number of patients treated as well as 
observed person-years (i.e. time at risk). Safety analysis will be based on the concept of 
treatment emergent ADRs. Patients will be analyzed according to the anticoagulation 
treatment received at the time of the event. If no concurrent anticoagulation treatment is 
administered, then events occurring within a washout period of 3 days (for Pradaxa®) or 6 
days (for VKA) after discontinuation of anticoagulation treatment will be assigned to the 
last treatment given. This washout period will also be included as time at risk for derivation 
of total person-years. ADRs that deteriorate under treatment will also be considered as 
“treatment emergent”. Events occurring prior to first intake of anticoagulation treatment 
prescribed at baseline, during periods without any anticoagulation treatment (excluding 
washout periods), or after the end of the 6 month follow-up (excluding washout periods) 
will not be considered treatment emergent events and will not be included in the summary
tables.
The following parameters will be included in the safety analyses:

Adverse drug reactions

Adverse drug reactions leading to discontinuation of anticoagulation treatment

Serious adverse drug reactions

Adverse events leading to deaths
Schedule of Planned Analyses
No interim analysis is planned for Cohort A.
For Cohort B, it is planned that an interim analysis that assesses the comparability of 
patients in the Pradaxa® and VKA groups based on propensity scores will be performed 
when approximately half of the target sample size is reached (see details in Section 9.7.2.1).
For each cohort, the final analyses as specified in Section 9.7.2 will be performed once the 
data collection is completed, the data sets are cleaned, and the database is locked for that 
cohort. The final analysis for both cohorts may be performed together, if their complete 
data becomes available at the same time. One final report will be prepared at the 
completion of both cohorts.
Additional reports (e.g. for country-specific analyses) may be prepared if deemed 
appropriate and will be specified in the SEAP.
9.7.6
Handling Of Missing Data
Every reasonable attempt will be undertaken to ensure completeness of data collection. 
Imputation will be permitted, if deemed appropriate and on a case-by-case basis, 
depending on the extent and distribution of missing values, and will be described in the 
SEAP.
The percentage of and reason for loss to follow-up will be summarized overall in Cohort 
A, by treatment in Cohort B, and by other relevant factors. In addition, if the proportion of 

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patients with loss to follow-up is substantial enough (e.g. ≥ 10%) to warrant further 
investigation, baseline characteristics will be described for patients who were lost to 
follow- up in comparison to patients who have completed follow-up.
9.8
QUALITY CONTROL
The following processes will be implemented to ensure data completeness and data quality:
Data Edit Checks:
The electronic CRF (eCRF) will include programmable edit checks to obtain feedback if 
data is missing, out of range, illogical or potentially erroneous.
These checks will be performed once data is entered into the eCRF.
Thus the data entered in to the eCRF will be validated within the system and the
physician will receive alerts for missing or inconsistent data. In case any changes of 
already entered data will be required, an audit trail will be available.
Medical monitoring:
A review of applicable entered eCRF data will be performed to verify patient eligibility to
ensure that the analysed patient population corresponds to the protocol–described 
population. In addition eCRFs/completed patient related questionnaires will also be 
reviewed for verification that no non reported safety event is present.
Source data verification:
No regular source data verification is planned in this non-interventional study. However, in
case of issues (i.e. high amount of missing data, data discrepancies, protocol violations, 
etcetera) detected at a site with the measures described above, a for-cause onsite visit can 
be planned to perform a sample check of source data.
9.9
LIMITATIONS OF THE RESEARCH METHODS
Consecutive enrolment will be employed to ensure that specific types of patients are 
not selected by site staff to participate.
VKA has been the mainstay of SPAF for many years. It is widely available, affordable 
but does require regular INR monitoring. Pradaxa® is more expensive, may or may not 
be reimbursed but doesn’t require the continual INR monitoring. There are a number of 
different types of bias that could influence the data collection and analysis from these 
cohorts such as selection bias, information bias and channelling bias.
The study is designed to collect new data. The entry criteria are non-restrictive which will 
permit the enrolment of a broad patient population. The choice of treatment is at the 
discretion of the investigator. Therefore the data collected in this study should reflect the
real world treatment patterns and patient characteristics.
Selection bias:

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Selection bias could occur at both the site (physician) level and the patient level. If sites 
where Pradaxa® is used frequently differ systematically with respect to patient or the 
routine procedures from sites that use Pradaxa® less frequently, the between site difference 
could lead to non-comparability between the patients. To minimize the site level selection 
bias, the goal is to have participating centres that have access to all available treatment 
options for SPAF that are approved for use in that country.
Selection bias at the patient level could occur if sites preferentially enrol specific patients 
into the study. To minimize selection bias at the patient level, consecutive enrolment is
performed.

Information / observer bias:
Information or observer bias may occur when information is collected differently
between
two groups. E.g. if the observer/physician has more knowledge about the use of VKA 
treatment, the patients exposure to VKA treatment or the disease status and 
development as compared to Pradaxa®. Also, a VKA patient will be more often seen. 
Such information may result in differences in the way information is collected, 
measured or interpreted by the investigator in each of the treatment groups (cohort A or 
B (B1, B2)). The use of a standardized protocol and eCRF for data collection, but also 
the use of standardized questionnaires (PACT-Q) which have to be completed by the 
patients themselves, will minimize the information/observer bias.

Loss to follow-up:
All efforts will be made to minimize loss to follow-up in patients who are enrolled. 
Patients who are lost to follow-up will be characterized and compared to the remaining 
patients and the reason and time point of lost to follow-up will be evaluated.
Channelling bias:
Channelling bias can occur due to preferential prescribing in relation to different risks for 
events of interest e.g. if Pradaxa® is prescribed more frequently to high risk patients than 
to other treatments, a high rate of outcome events could be expected in the Pradaxa®
group. In order to control for potential channelling, an assessment will be conducted to 
monitor the comparability of important patient baseline characteristics. Propensity score 
matching is planned to account for potential differences.
Recall bias:
Recall bias refers to the phenomenon when the outcomes of treatment (either good or bad)
may colour the patient’s recollection of events prior to or during the treatment. To minimize 
recall bias, patient reported outcomes will be assessed using validated questionnaires within 
a limited period of time to minimize recall bias.
Confounding:
Statistical techniques, such as adjustment for covariates and propensity score matching will
be used to correct for identified confounders. However unidentified confounders cannot 
be controlled for using statistical analysis. The employed methods are described in the 
data analysis section.

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9.10
OTHER ASPECTS
9.10.1
Informed Consent, Data Protection, Study Records
The study will be carried out in compliance with the protocol, the principles laid down in 
the Declaration of Helsinki, and as close as possible to the standards of the International 
Conference of Harmonisation (ICH) Tripartite Guideline, Good Clinical Practice (GCP), 
Guidelines for Good Epidemiological Practice (GEP) [R10-4560], Good 
Pharmacoepidemiology Practice (GPP) [R09-0182]and relevant BI Standard Operating 
Procedures (SOPs). Standard medical care (prophylactic, diagnostic and therapeutic 
procedures) remains in the responsibility of the treating physician of the patient.
The investigator should inform the sponsor immediately of any urgent safety measures 
taken to protect the study subjects against any immediate hazard, and also of any serious
breaches of the protocol/ICH GCP.
The rights of the investigator and of the sponsor with regard to publication of the results of 
this trial are described in the investigator contract. As a general rule, no trial results should 
be published prior to finalization of the Study Report.
9.10.2
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.
Prior to patient participation in the study, written informed consent must be 
obtained from each patient (or the patient’s legally accepted representative) 
according to ICH GCP and to the regulatory and legal requirements of the 
participating country. Each signature must be personally dated by each signatory
and the informed consent and any additional patient- information form retained 
by the investigator as part of the trial records. A signed copy of the informed 
consent and any additional patient information must be given to each patient or 
the patient’s legally accepted representative. ICH-GCP will be used as guidance 
where applicable.
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 

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Ingelheim, by appropriate IRB / IEC members, and by inspectors from regulatory
authorities.
9.10.3
Data quality assurance
A quality assurance audit/inspection of this study may be conducted by the sponsor or 
sponsor’s designees or by Institutional Review Board (IRBs) / Independent Ethics Committee 
(IECs) or by regulatory authorities. The quality assurance auditor will have access to all 
medical records, the investigator’s study-related files and correspondence, and the informed 
consent documentation of this study.
9.10.4
Study records
Case Report Forms (CRFs) for individual patients will be provided by the sponsor via 
remote data capture. All of the clinical data and site/investigator characteristics will be 
captured via a web-based EDC 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 Investigator will approve the data using an electronic signature that is 21 CFR Part 11 
compliant.
Patients must not be identified on the eCRF by name. Appropriately coded identification 
(i.e. Patient numbers) must be used. The Investigator must make a separate confidential 
record of these details (Patient enrolment log) to permit the identification of all patients 
enrolled in the study in case follow-up is required.  Any supporting documentation must be 
redacted of any patient identifying information and the patient ID number must be clearly
written on the documents.
9.10.4.1
Source documents
  Source documents provide evidence for the existence of the patient and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s 
site.
Data entered in the eCRFs that are transcribed from source documents must be consistent
with the source documents or the discrepancies must be explained. The investigator may
need to request previous medical records or transfer records, depending on the trial; also 
current medical records must be available.
For eCRFs all data must be derived from source documents:

Patient identification (gender, date of birth)

Patient participation in the study (substance, study number, patient number, date 
patient was informed) 

Dates of Patient’s visits, including prescription of study medication

Medical history (including study indication and concomitant diseases, if applicable)

Medication history

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
PACT-Q 1 and 2 questionnaires: the original paper questionnaires completed by
the patients

Adverse drug reactions (non-serious) (onset date (mandatory), and end date 
(if available))

Serious adverse drug reactions (onset date (mandatory), and end date (if available))

Fatal adverse events (onset date (mandatory), and end date (if available))

Pregnancy

Concomitant therapy (start date, changes)

Originals or copies of laboratory results (in validated electronic format, if available)

Conclusion of Patient’s Participation in the study
9.10.4.2
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. eCRFs and all source documents, including progress notes and copies of 
laboratory and medical test results must be available at all times for review by the 
sponsor’s clinical study monitor, auditor and inspection by health authorities (e.g. FDA). 
The Clinical Research Associate (CRA) / on site monitor and auditor may review all 
eCRFs, and written informed consents. The accuracy of the data will be verified by
reviewing the documents described in Section 9.10.2.1.

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10.
PROTECTION OF HUMAN SUBJECTS
Safeguards in order to comply with national and European Union requirements for ensuring 
the well-being and rights of participants in non-interventional post-authorisation (safety)
studies.
The study will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for 
Good Clinical Practice (GCP) (to the extent applicable to the NIS setting and required by 
local regulations), Good Epidemiological Practice (GEP), Guidelines for Good 
Pharmacoepidemiology Practice (GPP), and relevant BI Standard Operating Procedures 
(SOPs). Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains 
in the responsibility of the treating physician of the patient.
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches 
of the protocol/ICH GCP.
The rights of the investigator and of the sponsor with regard to publication of the results of 
this study are described in the investigator contract. As a general rule, no study results should 
be published prior to finalisation of the Study Report.
10.1
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.
Prior to patient participation in the study, written informed consent must be obtained from 
each patient (or the patient’s legally accepted representative) according to ICH GCP and to 
the regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the investigator as part of the study records. A signed copy of 
the informed consent and any additional patient information must be given to each patient or 
the patient’s legally accepted representative.
The patient must be informed that his/her personal study-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of 
disclosure must also be explained to the patient.
The patient must be informed that his / her medical records may be examined by authorised 
monitors (CML/CRA) or Quality Medicine auditors appointed by Boehringer Ingelheim, by 
appropriate IRB / IEC members, and by inspectors from regulatory authorities.

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10.2
STATEMENT OF CONFIDENTIALITY
Individual patient medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the 
study need to be available for inspection on request by the participating physicians, the 
sponsor’s representatives, by the IRB / IEC and the regulatory authorities 
10.3
COMPLETION OF STUDY
The EC/competent authority in each participating country needs to be notified about the end 
of the study (last patient out) or early termination of the study.

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11.
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS
11.1
DEFINITIONS OF ADVERSE EVENTS
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have a 
causal relationship with this treatment. An adverse event can therefore be any unfavourable 
and unintended sign (e.g. an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility. Adverse reactions may arise 
from use of the product within or outside the terms of the marketing authorisation or from 
occupational exposure. Conditions of use outside the marketing authorization include off-
label use, overdose, misuse, abuse and medication errors.
Serious adverse event
A serious adverse event is defined as any AE which
-
results in death, 
-
is life-threatening, 
-
requires in-patient hospitalization, or
-
prolongation of existing hospitalisation, 
-
results in persistent or significant disability or incapacity, or 
-
is a congenital anomaly/birth defect 
Life-threatening in this context refers to a reaction in which the patient was at risk of death at 
the time of the reaction; it does not refer to a reaction that hypothetically might have caused 
death if more severe.
Medical and scientific judgement should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalisation but might jeopardise the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or 
development of dependency or abuse. Any suspected transmission via a medicinal product of 
an infectious agent is also considered a serious adverse reaction.

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Adverse Event of Special Interest (AESI)
The term Adverse Event of Special Interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this study, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. 
No AESIs have been defined for this study.
11.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION 
AND REPORTING
The investigator shall maintain and keep detailed records of all AEs in their patient files. 
Collection of AEs
The study design is of non-interventional nature and the study is conducted within the 
conditions of the approved marketing authorisation. Sufficient data from controlled 
interventional trials are available to support the evidence on the safety and efficacy of the 
studied BI drug. For this reason the following AE collection and reporting requirements have 
been defined.
The following must be collected by the investigator in the (e)CRF from signing the informed 
consent onwards until the end of the study: 
-
all adverse drug reaction (ADRs) (serious and non-serious), 
-
all AEs with fatal outcome, 
-
all pregnancies
Note: For all patients on Pradaxa® these data must be recorded on the AE pages in the 
eCRF. The separate NIS AE form or Pregnancy Monitoring Form must be used for 
Pradaxa® patient only (see ‘Expedited Reporting’ below).
All ADRs , including those persisting after study completion must be followed up until they 
are resolved, have been sufficiently characterized, or no further information can be obtained.
The investigator carefully assesses whether an AE constitutes an ADR using the information 
below.
Causal relationship of adverse event
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an adverse event. An adverse 
reaction, in contrast to an adverse event, is characterised by the fact that a causal relationship 
between a medicinal product and an occurrence is suspected. 
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 

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Arguments that may suggest a reasonable causal relationship could be:
•
The event is consistent with the known pharmacology of the drug 
•
The event is known to be caused by or attributed to the drug class.
•
A plausible time to onset of the event relative to the time of drug exposure.
•
Evidence that the event is reproducible when the drug is re-introduced
•
No medically sound alternative etiologies that could explain the event (e.g. 
preexisting or concomitant diseases, or co-medications).
•
The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).
•
An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:
•
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days/weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)
•
Continuation of the event despite the withdrawal of the medication, taking into
account the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.
•
Additional arguments amongst those stated before, like alternative explanation (e.g.
situations where other drugs or underlying diseases appear to provide a more likely
explanation for the observed event than the drug concerned).
•
Disappearance of the event even though the study drug treatment continues or remains 
unchanged.
Intensity of adverse event
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) which is/are easily tolerated
Moderate:
Enough discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Pregnancy:
In rare cases, pregnancy might occur in a study. Once a subject has been enrolled into the 
study, after having taken Pradaxa®, the investigator must report any drug exposure during 
pregnancy, which occurred in a female subject or in a partner to a male subject to the Sponsor 
by means of Part A of the Pregnancy Monitoring Form. The outcome of the pregnancy 
associated with the drug exposure during pregnancy must be followed up and reported by 
means of Part B of the Pregnancy Monitoring Form. 
In the absence of a reportable AE, only the Pregnancy Monitoring Form must be completed, 
otherwise the NIS AE form is to be completed and forwarded as well within the respective 
timelines. 

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Expedited Reporting of AEs and Drug Exposure During Pregnancy
The following must be reported by the investigator on the NIS AE form from signing the 
informed consent onwards until the end of the study: 
Type of Report
Timeline
All serious ADRs associated with Pradaxa®
immediately within 24 hours
All AEs with fatal outcome in patients 
exposed to Pradaxa®
immediately within 24 hours
All non-serious ADRs associated with 
Pradaxa®
7 calendar days
All pregnancy monitoring forms
associated with Pradaxa®
7 calendar days
Note: the NIS AE form or Pregnancy Monitoring Form is required only for Pradaxa®
patients, not for VKA patients.
The same timelines apply if follow-up information becomes available for the respective 
events. In specific occasions the Investigator could inform the Sponsor upfront via telephone. 
This does not replace the requirement to complete and fax the NIS AE form.
Information required
For each reportable adverse event, the investigator should provide the information requested 
on the appropriate (e)CRF pages and the NIS AE form.
Reporting of related Adverse Events associated with any other BI drug
The investigator is encouraged to report all adverse events related to any BI drug other than 
Pradaxa® according to the local regulatory requirements for spontaneous AE reporting at the 
investigator’s discretion by using the locally established routes and AE report forms. The 
term AE includes drug exposure during pregnancy, and, regardless of whether an AE 
occurred or not, any abuse, off-label use, misuse, medication error, occupational exposure, 
lack of effect, and unexpected benefit.
11.3
REPORTING TO HEALTH AUTHORITIES
Adverse event reporting to regulatory agencies will be done by the MAH according to local
and international regulatory requirements.

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12.
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS
The rights of the investigator and of the sponsor with regard to publication of the results of 
this study are described in the investigator contract. As a general rule, no study results should 
be published prior to finalisation of the Study Report.
Results of this non-interventional study will be disclosed on external websites according to
BI SOP.
In addition, a study specific publication plan will be developed to describe planned 
publications per country and for overall study results.

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13.
REFERENCES
13.1
PUBLISHED REFERENCES
P13-05668    Monz BU, Connolly SJ, Korhonen M, Noack H, Pooley J Assessing the 
impact of dabigatran and warfarin on health-related quality of life: results 
from an RE- LY sub-study. Int J Cardiol 168 (3), 2540 - 2547 (2013).
R09-0182
Guidelines for Good Pharmacoepidemiology Practices (GPP).
Pharmacoepidemiology and Drug Safety 17, 200 - 208 (2008).
R10-4560
Good Epidemiological Practice (GEP). IEA Guidelines for Proper Conduct of
Epidemiological Reseach (2007).
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).
R10-6394
Pisters R, Lane DA, Nieuwlaat R, Vos CB de, Crijns HJGM, Lip GYH 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 138 
(5), 1093 -
1100 (2010).
R15-1312
Caterina R de, Brueggenjuergen B, Darius H, Heuzey JY le, Renda G, 
Schilling RJ, Schmitt J, Zamorano JL, Kirchhof P Quality of life and 
patient satisfaction data in atrial fibrillation patients stably treated with a 
VKA vs patients switched from a VKA to NOAC. The PREFER in AF 
registry.
ESC 2014, 36th Cong of the European Society of Cardiology
(ESC), Barcelona, 30 Aug - 3 Sep 2014 (Poster)
R15-1314
Prins MH, Guillemin I, Gilet H, Gabriel S, Essers B, Raskob G, Kahn 
SR Scoring and psychometric validation of the Perception of 
Anticoagulant Treatment Questionnaire (PACT-Q).
Health Qual Life Outcomes 7, 30 (2009)
R15-1316
Prins MH, Marrel A, Carita P, Anerson D, Bousser MG, Crijns H, Consoli 
S, Arnould B
Multinational development of a questionnaire assessing patient 
satisfaction with anticoagulant treatment: the 'Perception of 
Anticoagulant Treatment Questionnaire' (PACT-Q).
Health Qual Life Outcomes 7, 9 (2009)
R15-1359
Heidorn K, Haenschke J, Lindner T, Mittelmeier W, Skripitz R
Health economic analysis of thromboprophylaxis with rivaroxaban 
and certoparin-sodium in patients after total hip or knee replacement.
Int J Orthop 1 (1), 15 - 18 (2014)

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13.2
UNPUBLISHED REFERENCES
None

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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
The following stand-alone documents have not been finalized at the time of protocol 
finalization. The final version of these documents will be archived in the Trial Master File 
(TMF)

Statistical and Epidemiological Analysis Plan (SEAP)

List of participating investigators

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ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS
Not applicable

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ANNEX 3. ADDITIONAL INFORMATION
The Perception of Anticoagulant Treatment Questionnaires (PACT-Q®) will be shown on 
the next pages (in English). Validated translations of these PACT-Q1 and PACT-Q2 
questionnaires will be provided to the patients participating in this study (in their local 
language).

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ANNEX 3.1  PERCEPTION OF ANTICOAGULANT TREATMENT 
QUESTIONNAIRE, PART 1 (PACT-Q1)

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ANNEX 3.2  PERCEPTION OF ANTICOAGULANT TREATMENT 
QUESTIONNAIRE, PART 2 (PACT-Q2)

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001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015