Non-Interventional, Cross-sectional Study to Describe Health-related Quality of Life Among Controlled and Uncontrolled Patients With Nonvalvular Atrial Fibrillation on Anticoagulants. RE-QUOL Study.
Conditions: Atrial Fibrillation
Sponsor: Boehringer Ingelheim

ABCD
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TITLE PAGE
Non-interventional Study Protocol
Document Number:
c14460058-01
BI Study Number:
1160-0280
BI Investigational
Product(s):
Dabigatran etexilate (Pradaxa®)
Title:
Non-Interventional, cross-sectional study to describe health-
related quality of life among controlled and uncontrolled patients 
with nonvalvular atrial fibrillation on anticoagulants. RE-QUOL 
study.
Brief lay title
Health related quality of life in patients on anticoagulants
Protocol version 
identifier:
1.0
Date of last version of 
protocol:
05 January 2017
PASS:
No
EU PAS register 
number:
EU PAS 16988
Active substance:
B01AE07 - Dabigatran etexilate
Medicinal product:
Dabigatran etexilate
Product reference:
EU/1/08/442
Procedure number:
EMEA/H/C/829
Marketing authorisation 
holder(s):
Boehringer Ingelheim International GmbH
Binger Str. 173
D-55216 Ingelheim am Rhein
Germany
Joint PASS:
No
Research question and 
objectives:
There is a dearth of evidence regarding Health Related Quality 
of Life (HRQoL) in controlled and uncontrolled patients on oral 
anticoagulants. 
The present study has been designed to describe the HRQoL in 
patients with non valvular atrial fibrillation (NVAF) receiving 
conventional vitamin K antagonist (VKA) but no controlled and 
those controlled who received VKA or direct oral anticoagulant 

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(DOAC).
Primary objective: The primary objective of the study is to 
describe the HRQoL in uncontrolled patients treated with VKA 
and controlled patients treated with VKA or DOAC.
Secondary objective: The secondary objective is to describe the 
profile of uncontrolled patients
Country(-ies) of study:
Spain
Author:
(Outsourced Trial Clinical Monitor)
Mobile: 
Marketing authorisation 
holder(s):
Boehringer Ingelheim International GmbH
Binger Str. 173
D-55216 Ingelheim am Rhein
Germany
Date:
05 January 2017
Page 2 of 39
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© 2017 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.................................................................................... 6
4.
ABSTRACT........................................................................................................... 7
5.
AMENDMENTS AND UPDATES..................................................................... 10
6.
MILESTONES..................................................................................................... 11
7.
RATIONALE AND BACKGROUND................................................................ 12
8.
RESEARCH QUESTION AND OBJECTIVES ................................................. 13
9.
RESEARCH METHODS .................................................................................... 14
9.1
STUDY DESIGN............................................................................................ 14
9.2
SETTING........................................................................................................ 14
9.2.1
Study sites ............................................................................................... 15
9.2.2
Study population ..................................................................................... 15
9.2.3
Study visits .............................................................................................. 16
9.2.4
Study discontinuation.............................................................................. 16
9.3
VARIABLES .................................................................................................. 16
9.3.1
Exposures ................................................................................................ 17
9.3.2
Outcomes................................................................................................. 18
9.3.2.1
Primary outcomes............................................................................. 18
9.3.2.2
Secondary outcomes......................................................................... 18
........................................................................... 18
9.3.3
Covariates................................................................................................ 18
9.4
DATA SOURCES........................................................................................... 18
9.5
STUDY SIZE.................................................................................................. 19
9.6
DATA MANAGEMENT................................................................................ 19
9.7
DATA ANALYSIS......................................................................................... 20
9.7.1
Main analysis........................................................................................... 20
9.7.2
Further analysis ....................................................................................... 20
9.8
QUALITY CONTROL................................................................................... 20
9.9
LIMITATIONS OF THE RESEARCH METHODS...................................... 21
9.10
OTHER ASPECTS ......................................................................................... 21
9.10.1
Data quality assurance............................................................................. 21
9.10.2
Study records........................................................................................... 21

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9.10.2.1
Source documents ............................................................................ 21
9.10.2.2
Direct access to source data and documents .................................... 22
9.10.3
Completion of study................................................................................ 22
10.
PROTECTION OF HUMAN SUBJECTS .......................................................... 23
10.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ...................................................................................................... 23
10.2
STATEMENT OF CONFIDENTIALITY...................................................... 23
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS....................................................................................................... 25
11.1
DEFINITIONS OF ADVERSE EVENTS...................................................... 25
11.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION AND
REPORTING .................................................................................................. 26
11.3
REPORTING TO HEALTH AUTHORITIES................................................ 28
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
............................................................................................................................. 29
13.
REFERENCES .................................................................................................... 30
13.1
PUBLISHED REFERENCES......................................................................... 30
13.2
UNPUBLISHED REFERENCES................................................................... 30
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.............................................. 31
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .............................. 32
ANNEX 3. ADDITIONAL INFORMATION.............................................................. 38

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2.
LIST OF ABBREVIATIONS
ADR
Adverse Drug Reaction
AE
Adverse Event
AESI
Adverse Event of Special interest
AF
Atrial Fibrillation
CA
Competent Authority
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(4*)764, F1*-4*-8 #/- G>'=H8 &-I 
!40-/+,9
CI
Confidence Interval
CML
Local Clinical Monitor 
CRA
Clinical Research Associate
CTCAE
Common Terminology Criteria for Adverse Events
DMP
%404 J4.4/-A-.0 
K64.
DOAC
%1,-)0 L,46 #.01)+4/764.0
eCRF
Electronic Case Report Form
ENCePP 
European Network of Centres for Pharmacoepidemiology and 
Pharmacovigilance 
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GEP
Good Epidemiological Practice
GPP
Good Pharmacoepidemiology Practice
GVP
Good Pharmacovigilance Practices
MK( !D!
M6+@46 K34,A4)+21/164.)- !61.1)46 D,146 !++,F1.40+,
"#& 'NOP%
"9:-,0-.*1+.8 #@.+,A46 ,-.46 4.F 612-, 57.)01+.8 &0,+B- ;Q :+1.0?8 
N6--F1./ 31*0+,9 +, :,-F1*:+*101+.8 O4@16- ERS8 P6F-,69
;<G> 9-4,*?8 
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E!&S
E.F121F746 
!4*- &45-09 S-:+,0
EP!
E.F-:-.F-.0 P031)* !+AA100--
ERS
E.0-,.401+.46 R+,A461V-F S401+
E&W
E.2-*01/40+, &10- W16-
OK(J
O+)46 K34,A4)+21/164.)- J4.4/-,
O(PW
Left Ventricular Ejection Fraction
J#"
J4,B-01./ #703+,1V401+. "+6F-,
R(#W
R+. ' (462764, #0,146 W1@,166401+. 
L#!
L,46 4.01)+4/76401+.
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D1A- 1. D3-,4:-701) S4./-
(X#
(104A1. X #.04/+.1*0

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3.
RESPONSIBLE PARTIES
D3-,4:-701) #,-4 
 !4,F1+24*)764, J-F1)1.- 
D-4A J-A@-, J-F1)46 #5541,*
D,146 !61.1)46 J+.10+,
;L70*+7,)-F?
D,146 &0401*01)14.
OK(J
!++,F1.40+, E.2-*01/40+,

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4.
ABSTRACT
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Pradaxa®
Name of active ingredient:
B01AE07 - Dabigatran etexilate
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
05 Jan 2017
1160-0280
Title of study:
Non-Interventional, cross-sectional study to describe health-related 
quality of life among controlled and uncontrolled patients with 
nonvalvular atrial fibrillation on anticoagulants. RE-QUOL study
Rationale and 
background:
The present study has been designed to describe the HRQoL in patients 
with non valvular AF receiving conventional VKA but no controlled 
and those controlled who received VKA or DOAC. 
The type of patients to be included in this study are those seen in 
Internal Medicine, i.e. elderly patients, chronically ill, mostly 
hospitalized, polymedicated, and at high thromboembolic and bleeding 
risk. The present study will provide valuable data about the HRQoL of 
these patients regarding their anticoagulation status (controlled or non-
controlled).
Research question 
and objectives:
There is a dearth of evidence regarding HRQoL in controlled and 
uncontrolled patients on oral anticoagulants. 
The present study has been designed to describe the HRQoL in patients 
with non valvular AF receiving conventional VKA but no controlled 
and those controlled who received VKA or DOAC.
Primary objective: to describe the HRQoL in uncontrolled patients 
treated with VKA and controlled patients treated with VKA or DOAC. 
Secondary objective: to describe the profile of uncontrolled patients
Study design:
This observational multicenter and cross-sectional study will be 
conducted in Departments of Internal Medicine from approximately 50 
centers in Spain 
Approximately 500 patients seen in internal medicine are planned to be 
included in the study. To minimize selection bias at the patient level, 
consecutive patients from each site who meet entry criteria will be 
enrolled. The 3 participating autonomous communities planned are 
Madrid, Valencia and Andalucía. Patients should be included in a ratio 
2:1, 2 patients controlled (VKA patients with a Time in Therapeutic 
range TTR ≥ 65% and all DOAC patients) per 1 patient uncontrolled 
(VKA patients with a TTR < 65%), due to the controlled patients 
comprise more treatments. 
Control will be considered when INR values are between 2 and 3. 
The design of the study impose an only visit to be performed that will 

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coincide with one of those performed by the patients as part of routine 
follow-up of their disease, without interfering with usual clinical 
practice of the investigator. A specific therapeutic strategy has already 
been assigned based on routine practice, and without interference with 
the physician’s prescription habits. The observational nature of the 
study is ensured as no diagnostic or therapeutic intervention outside of 
routine clinical practice will be applied.
Population:
Patients with non-valvular atrial fibrillation who are on the same 
anticoagulant therapy (VKA or DOAC) during at least 6 months and 
maximum 2 years will be included.
The patient will be considered included when he/she agrees to 
participate in the study by signing the informed consent. 
The patient will be classified between controlled or uncontrolled group 
depending on the %TTR if VKA patients. If the %TTR collected from 
the analytical records was obtained by the Rosendaal method, VKA 
patients with a TTR < 65% will be allocated to the uncontrolled group 
and VKA patients with a TTR ≥ 65% will be allocated to the 
controlled group). If the %TTR was obtained by the direct method, the 
patient will be considered uncontrolled or controlled depending on 
whether the TTR value is < 60%. All DOAC patients will be allocated 
to the controlled group.
Variables:
Quality of life: HRQoL will be based on the patients’ ratings on 
Sawicki questionnaire completed during the only study visit. This 
questionnaire includes 32 items grouped in 5 dimensions – treatment 
satisfaction, self-efficacy, strained social network, daily hassles and 
distress. Higher scores indicate lower HRQoL.  
Uncontrolled patient profile: demographic characteristics (age, gender, 
work status, life status, etc), CHA2DS2-VASc, HAS-BLED, AF
diagnosis  date, VKA treatment, time since treatment initiation, time 
since patient is uncontrolled (if assessable) left ventricular ejection 
fraction, Kidney function (creatinine clearance), concomitant diseases, 
concomitant treatments, frequency of visits to the physician, and 
history of thromboembolic and bleeding events
Data sources:
Data collection will be limited to those available in the medical records 
of selected patients and the questionnaire necessary to evaluate the 
primary objective of the study, of patients in whom a specific 
therapeutic strategy has already been assigned based on routine 
practice, and without interference with the physician’s prescription 
habits
Study size:
It is planned that a total of approximately 330 patients will be recruited 
for the controlled group and 170 patients will be recruited for the 
uncontrolled group.
Based on such sample size estimates, categorical variables of binomial 
proportions (e.g. gender) will be estimated with the precision (i.e. 
width of descriptive 95% confidence interval) described in Table 9.5: 
1, according to the prevalence of the attribute.
Data analysis:
To describe the quality of life among patients controlled and 
uncontrolled: The primary outcome of the study is the health-related 

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quality of life as measured by the Sawicki questionnaire. The scores of 
each individual question will be summarized descriptively in the 
controlled and uncontrolled patients. In addition, the summary score 
for each dimension of the questionnaire will be calculated for each 
patient by dividing the total score by the number of items included in 
that dimension and summarized in the same way as the individual 
questions.
To describe the profile of uncontrolled patients treated with vitamin K 
antagonists: The specified variables in Section 9.3.2.2 [demographic 
characteristics (age, gender, work status, life status, etc), CHA2DS2-
VASc, HAS-BLED, AF diagnosis date, VKA treatment, time since 
treatment initiation, time since patient is uncontrolled (if assessable) 
left ventricular ejection fraction, Kidney function (creatinine 
clearance), concomitant diseases, concomitant treatments, frequency of 
visits to the physician, and history of thromboembolic and bleeding 
events] will be summarized descriptively.
Missing data will not be imputed and will be left as lost. 
Milestones:
Note that the times described below may be modified by the 
administrative processing periods for study initiation
-
Final Protocol: January 2017
-
start of data collection: March 2017
-
end of data collection: September 2017
-
final study report: December 2017

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5.
AMENDMENTS AND UPDATES
None. 

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6.
MILESTONES
Milestone
Planned Date
IEC approval
January 2017
Start of data collection
March 2017
End of data collection
September 2017
Registration in the EU PAS 
register
December 2016
Final report of study results:
December 2017

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7.
RATIONALE AND BACKGROUND
Atrial fibrillation (AF) affects 1-2% of general population, but specially persons between 80 -
85 years, in whom the prevalence can reach 16% [1-3]. The first oral anticoagulants to 
prevent the risk of thromboembolic events in AF were the vitamin K antagonists (VKA) 
warfarin and acenocoumarol. The management of these agents remains problematic because 
they need routine coagulation monitoring, clinical surveillance and continuous patient 
education, affecting to their daily habits and in consequence to their quality of life [4]. Also, 
data show that 80% of patients continue receiving acenocoumarol in Spain, with a percentage 
of International Normalized Ratio (INRs) in therapeutic range between 44%-59% [5,6], and 
mean time in therapeutic range (TTR) of 64% [5]. 
The direct oral anticoagulants (DOAC) maintain the benefits of anticoagulant therapy and 
may increase perception of quality of life among patients because they not necessitate the 
strict monitoring required for VKA. On the other hand maintaining a stable level of 
anticoagulation with DOACs prevents uncontrolled patients as well as the increased number 
of monitoring visits for this reason. Theoretically, this fact would have positive implications 
in quality of life. However, the available evidence from the study of quality of life, does not 
suggest that patients have large decrements in their quality of life because of suffering from 
FA. In this sense, the study of Roalfe et al., cross sectional in 1762 patients over 75 years and 
suffering AF, concluded that in absence of comorbidity, chronic AF has little impact on 
generic QoL [7]. This suggests that treatment strategies should focus on the prevention of 
complications such as stroke, so it is necessary to go depth in the study of the anticoagulant 
therapy and the impact in QoL.
HRQoL was assessed in a sub-group of the overall RE-LY population to measure the effect 
of the choice of anticoagulant during a stable phase of treatment in the first year of the study, 
in patients without outcome events, such as strokes or major bleedings [8] . HRQoL was 
assessed using the EQ-5D, a generic measure of health outcome. Over the course of one year, 
all anticoagulated patients without outcome events had stable HRQoL. Scores between 
dabigatran and warfarin were comparable. There is a dearth of evidence regarding HRQoL in 
controlled and uncontrolled patients on oral anticoagulants. 
The present study has been designed to describe the HRQoL in patients with non valvular AF 
receiving conventional VKA but no controlled and those controlled who received VKA or 
DOAC. 
Since the type of patients to be included in this study is that seen in Internal Medicine, i.e. 
elderly patients, chronically ill, mostly hospitalized, polymedicated, and at high 
thromboembolic and bleeding risk, the present study will provide valuable data about the 
HRQoL of these patients regarding their anticoagulation status (controlled or non-controlled).

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8.
RESEARCH QUESTION AND OBJECTIVES
The present study has been designed to describe the HRQoL in patients with non valvular AF 
receiving conventional VKA but no controlled and those controlled who received VKA or 
DOAC.
The primary objective of the study is to describe the HRQoL in uncontrolled patients treated 
with VKA and controlled patients treated with VKA or DOAC. 
The secondary objective is to describe the profile of uncontrolled patients

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9.
RESEARCH METHODS
9.1
STUDY DESIGN
This observational multicenter and cross-sectional study will be conducted in Departments of 
Internal Medicine from approximately 50 centers in Spain.
The design of the study impose an only visit to be performed that will coincide with one of 
those performed by the patients as part of routine follow-up of their disease, without 
interfering with usual clinical practice of the investigator. A specific therapeutic strategy has 
already been assigned based on routine practice, and without interference with the 
physician’s prescription habits. The observational nature of the study is ensured as no 
diagnostic or therapeutic intervention outside of routine clinical practice will be applied. 
Figure 1 shows the design of the study.
Figure 1. Design of the study
9.2
SETTING
Approximately 500 patients seen in internal medicine are planned to be included in the study. 
To minimize selection bias at the patient level, consecutive patients from each site who meet 
entry criteria will be enrolled. Patients should be included in a ratio 2:1, 2 patients controlled 
(VKA patients with a TTR ≥ 65% and all DOAC patients) per 1 patient uncontrolled (VKA 
patients with a TTR < 65%), due to the controlled patients comprise more treatments. 
The patient will be classified between controlled or uncontrolled group depending on the 
%TTR if VKA patients. If the %TTR collected from the analytical records was obtained by 
the Rosendaal method, VKA patients with a TTR < 65% will be allocated to the uncontrolled 
group and VKA patients with a TTR ≥ 65% will be allocated to the controlled group. If the 
%TTR was obtained by the direct method, the patient will be considered uncontrolled or 
controlled depending on whether the TTR value is < 60%. All DOAC patients will be 
allocated to the controlled group. See figure 2 below.

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Figure 2. Patient allocation
If %TTR is not available on analytical records, investigator will calculate it using the last 6 
months INR values (at least 4 INR values during the last 6 months). To perform the 
calculation, it is recommended to avoid periods of anticoagulation initiation and periods with 
treatment interruptions due to surgery or bleedings.  
9.2.1
Study sites
Internal medicine specialists from Hospital sites regularly prescribing DOACs and VKA for 
stroke prevention in non-valvular atrial fibrillation according to the respective Summary of 
Product Characteristics will participate.
The study will be performed among 3 autonomous communities in Spain: Madrid, 
Comunidad Valenciana and Andalucía. 
9.2.2
Study population
To be eligible to participate in the study, patients must meet the following selection criteria:
Inclusion criteria
Patients will be included in the study if all of the following criteria are met:
1. The patient is willing and provides written informed consent to participate in this 
study.
2. The patient is at least 18 years of age
3. The patient has a diagnosis of non-valvular atrial fibrillation
4. The patient is on the same anticoagulant therapy (VKA or DOAC) during at least 6 
months and maximum 2 years.   
5. If treated with VKA, availability of %TTR in past analytical records or enough 
amount of INR measures to calculate it.

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Exclusion criteria:
Patients will be excluded from participating in this study if 1 or more of the following criteria 
are met:
1. Current participation in any clinical trial of a drug or device
2. Contraindication to the use of DOAC or VKA as described in the Summary of 
Product Characteristics (SmPC).
A log of all patients included into the study (having given informed consent) will be 
maintained in the study file at the study site.
9.2.3
Study visits
The design of the study impose an only visit to be performed that will coincide with one of 
those performed by the patients as part of routine follow-up of their disease, without 
interfering with usual clinical practice of the investigator. A specific therapeutic strategy has 
already been assigned based on routine practice, and without interference with the 
physician’s prescription habits.
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. Emergence of any efficacy/safety information that could significantly affect continuation 
of the study 
3. Violation of the study protocol, or the contract by a study site or investigator, disturbing 
the appropriate conduct of the study
The investigator / the study site will be reimbursed for reasonable expenses incurred in case 
of study termination (except in case of the third reason).
9.3
VARIABLES
The following variables will be obtained at the unique study visit if available in patient 
medical records:
Variables
Study visit
Informed consent
X
Selection criteria
X
Date of visit
X
Demographic data: age, sex, race, work status, life status, weight, 
height
X

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Variables
Study visit
Non Valvular Atrial Fibrilation (NVAF) history: age at diagnosis, 
disease duration 
X
Concomitant diseases 
X
Physical examination: height, weight and BMI
X
Creatinine clearance calculated via Cockcroft-Gault Formula / 
Creatinine values if available from already existing lab report (to be
calculated in eCRF)
X
Left Ventricular Ejection Fraction (LVEF)-quantitative
X
LVEF-qualitative Normal (≥50%), slightly depressed (49-31%), 
moderately (40-31%), severely (≤30%)
X
TTR
X
CHA2DS2VASc score (to be calculated in the eCRF)
X
HAS-BLED score (to be calculated in the eCRF)
X
VKA treatment
X
Time since treatment initiation 
X
Time since patient is uncontrolled
X
Concomitant treatments
X
Frequency of visits to the physician
X
History of thromboembolic and bleeding events
X
HRQoL questionnaire (Sawicki)
X
9.3.1
Exposures
Patients in this study will have been prescribed a specific anticoagulant treatment for their 
NVAF at least 6 months prior to study initiation.  Prescription of the treatments will have 
been done under the sole responsibility of the healthcare professional. The study population 
will be treated with VKA or DOAC according to the approved local Summary of Product 
Characteristics (SmPC). 
As this is a non-interventional observational study, designed to reflect as faithfully as 
possible real-life clinical practice, the decision to start treatment with VKA or DOAC is prior 

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to and independent of the participation of the patient in the study and based on medical 
judgment criteria and routine clinical practice. In addition, no intervention, either diagnostic 
or therapeutic, will be applied to patients other than that used for routine clinical practice.
9.3.2
Outcomes
9.3.2.1
Primary outcomes
The primary outcome is the health-related quality of life and will be obtained with the results 
of the sawicki questionnaire at study visit. The questionnaire to be used is the validated 
spanish adaptation [9] of the original questionnaire [10]. The questionnaire includes 32 items 
grouped in 5 dimensions. Patients will estimate the impact of each item on their self-
perceived treatment-related quality of life on a scale of 1 (total disagreement) to 6 (total 
agreement). The 5 dimensions are general treatment satisfaction, self-efficacy, strained social 
network, daily hassles and distress. A lower score indicates greater higher quality of life and 
a higher score indicates lower quality of life. The questionnaire is self-completed (see annex 
no 3).
9.3.2.2
Secondary outcomes
The secondary outcome is the uncontrolled patient profile and will be defined by the 
following variables collected from patient medical records: demographic characteristics (age, 
gender, work status, life status, etc), CHA2DS2-VASc, HAS-BLED, AF diagnosis date, 
VKA treatment, time since treatment initiation, time since patient is uncontrolled (if 
assessable) left ventricular ejection fraction, Kidney function (creatinine clearance), 
concomitant diseases, concomitant treatments, frequency of visits to the physician, and 
history of thromboembolic and bleeding events.
9.3.3
Covariates
Not applicable.
9.4
DATA SOURCES
Data collection will be limited to those available in the medical records of selected patients. 
Patients will be asked to answer the questionnaire necessary to evaluate the primary objective 
of the study at the unique study visit. 
Patient demographic data, concomitant therapies and concomitant diseases will be completed 
based on patient’s medical records. Creatinine clearance for assessment of kidney function 
will be calculated within the electronic Case Report Form (eCRF), by entering creatinine 
values from existing lab reports, if available.

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9.5
STUDY SIZE
It is planned that a total of approximately 330 patients will be recruited for the controlled 
group and 170 patients will be recruited for the uncontrolled group.
Based on such sample size estimates, categorical variables of binomial proportions (e.g. 
gender) will be estimated with the precision (i.e. width of descriptive 95% confidence 
interval) described in Table 9.5: 1, according to the prevalence of the attribute.
Table 9.5: 1 Width of 95% confidence interval by prevalence of attribute
Prevalence of attribute
Sample size
170
330
10% Expected n
17
33
95% CI width
9.60
6.78
20% Expected n
34
66
95% CI width
12.54
8.91
30% Expected n
51
99
95% CI width
14.27
10.16
40% Expected n
68
132
95% CI width
15.20
10.84
50% Expected n
85
166
95% CI width
15.50
11.05
* Calculations are based on the Clopper-Pearson method.
9.6
DATA MANAGEMENT
The data will be entered by the investigators themselves and/or authorized personnel directly 
in the electronic case report form (eCRF). A data management plan (DMP) will be created to 
describe all functions, processes, and specifications for data collection, cleaning and 
validation. The eCRFs will include programmable edits to obtain immediate feedback if data 
are missing, out of range, illogical or potentially erroneous. 
When data management is outsourced, the designated contract organization will be 
responsible for the development and implementation of the data management plan and 
preparation of the data handling report according to the sponsor´s standards.

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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
Analyses will be performed by Boehringer Ingelheim’s designees. The analysis population 
will consist of all eligible patients (i.e. all patients fulfilling all inclusion criteria and no 
exclusion criteria).
In this non-interventional study, cross-sectional data at study visit will be collected for non-
valvular AF patients with a VKA or DOAC therapy. Once the study has been completed and 
all data from the last patient have been recorded, the database will be closed and statistical 
analysis will be performed.
The proposed methods for statistical analysis presented below are a summary of the methods 
that will be applied in the study to analyze the data collected and to answer the study 
objectives. Missing data will not be imputed and will be left as lost. 
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 for the variables of interest. Additional details of the planned analysis 
will be provided in the statistical analysis plan (SAP).
9.7.1
Main analysis
The primary outcome of the study is the health-related quality of life as measured by the 
Sawicki questionnaire. The scores of each individual question will be summarized 
descriptively in the controlled and uncontrolled patients. In addition, the summary score for 
each dimension of the questionnaire will be calculated for each patient by dividing the total 
score by the number of items included in that dimension and summarized in the same way as 
the individual questions.
9.7.2
Further analysis
To describe the profile of uncontrolled patients treated with vitamin K antagonists, the 
specified variables in Section 9.3.2.2 will be summarized descriptively.
9.8
QUALITY CONTROL
The 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 

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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. 
Strict and continuous quality control will be maintained to ensure the accuracy and scientific 
rigor of the data obtained, maintaining uniform conditions for collecting the information. 
Quality control will be carried out by qualified personnel designated for this purpose.
A quality assurance audit/inspection of his study may be conducted by the sponsor or 
sponsor’s designees or by 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 document of this study.
9.9
LIMITATIONS OF THE RESEARCH METHODS
This study is only descriptive and is not designed to allow for causal inference regarding the 
impact of OAC control on HRQoL.
Apart from inherent limitations of observational studies, a criticism could be the use of a 
specific questionnaire of HRQoL originally designed for patients receiving oral 
anticoagulation with vitamin K and that could ignore other aspects related to quality of life in 
atrial fibrillation as previously reported
9.10
OTHER ASPECTS
Not applicable
9.10.1
Data quality assurance
A quality assurance audit/inspection of this study may be conducted by the sponsor or 
sponsor’s designees or by 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.
9.10.2
Study records
Case Report Forms (CRFs) for individual patients will be provided by the sponsor, via 
remote data capture. 
9.10.2.1
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 study; also current 
medical records must be available.
For eCRFs all data must be derived from source documents.

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9.10.2.2
Direct access to source data and documents
The investigator / institution will permit study-related monitoring, audits, 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. The Clinical Research Associate (CRA) / 
Clinical Monitor Local (CML) and auditor may review all eCRFs, and written informed 
consents. The accuracy of the data may be verified by reviewing source documents.
9.10.3
Completion of study
The EC/competent authority in Spain needs to be notified about the end of the study (last 
patient out) or early termination of the study. 

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10.
PROTECTION OF HUMAN SUBJECTS
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.
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 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. 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 IEC members, and by inspectors from regulatory authorities.
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 

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study need to be available for inspection on request by the participating physicians, the 
sponsor’s representatives, by the IEC and the competent authorities.

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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.
Adverse Event of Special Interest (AESI)

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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. 
The following are considered as AESIs:
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 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. 
Arguments that may suggest a reasonable causal relationship could be:
•
The event is consistent with the known pharmacology of the drug 

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•
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
The intensity of adverse events should be classified and recorded according to the Common 
Terminology Criteria for Adverse Events (CTCAE) criteria, version 4.0, in the (e)CRF.
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. 
Expedited Reporting of AEs and Drug Exposure During Pregnancy

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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
7 calendar days
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 
the 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.
The results of this study may be published in a national journal and presented in regional or
national congresses.

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13.
REFERENCES
13.1
PUBLISHED REFERENCES
[1]
Barrios V, Calderon A, Escobar C, de la Figuera M. Patients with atrial fibrillation in 
a primary care setting: Val-FAAP study. Rev Esp Cardiol (Engl Ed) 2012;65:47-53.
[2]
Cea-Calvo L, Redon J, Lozano JV, et al. [Prevalence of atrial fibrillation in the 
Spanish population aged 60 years or more. The PREV-ICTUS study]. Rev Esp 
Cardiol 2007;60:616-24.
[3]
Gomez-Doblas JJ, Muniz J, Martin JJ, et al. Prevalence of atrial fibrillation in Spain. 
OFRECE study results. Rev Esp Cardiol (Engl Ed) 2014;67:259-69.
[4]
Alegret JM, Vinolas X, Arias MA, et al. New oral anticoagulants vs vitamin K 
antagonists: benefits for health-related quality of life in patients with atrial fibrillation. 
Int J Med Sci 2014;11:680-4.
[5]
Ansell J, Hollowell J, Pengo V, Martinez-Brotons F, Caro J, Drouet L. Descriptive 
analysis of the process and quality of oral anticoagulation management in real-life 
practice in patients with chronic non-valvular atrial fibrillation: the international study 
of anticoagulation management (ISAM). J Thromb Thrombolysis 2007;23:83-91.
[6]
Clua Espuny JL, Dalmau Llorca MR, Aguilar MC. [Characteristics of oral anti-
coagulation treatment in high-risk chronic auricular fibrillation]. Aten Primaria 
2004;34:414-9.
[7]
Roalfe AK, Bryant TL, Davies MH, et al. A cross-sectional study of quality of life in 
an elderly population (75 years and over) with atrial fibrillation: secondary analysis of 
data from the Birmingham Atrial Fibrillation Treatment of the Aged study. Europace 
2012;14:1420-7.
[8]
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 2013;168:2540-7.
[9]
Sanchez GR, Yanes BM, Cabrera MA, Ferrer Garcia-Borras JM, Alvarez NR, Barrera 
LE. [Cross-cultural adaptation of a questionnaire for measuring the quality of life of 
patients taking oral anticoagulants]. Aten Primaria 2004;34:353-9.
[10]
Sawicki PT. A structured teaching and self-management program for patients 
receiving oral anticoagulation: a randomized controlled trial. Working group for the 
Study of Patient Self-Management of Oral Anticoagulation. JAMA 1999; 281: 145-
50.
13.2
UNPUBLISHED REFERENCES
Not applicable

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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
Number
Title
<1>
Patient information and Informed Consent Form
<2>
Investigator  List
<3>
Statistical Analysis Plan (SAP)
<4>
Data Management Plan (DMP)
<5>
Serious Adverse Event Report in Non-Interventional Studies (NIS (S)AE Form)
<6>
Pregnancy Monitoring Form

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ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS
Study title:
Non-Interventional, cross-sectional study to describe health-related quality of life 
among controlled and uncontrolled patients with nonvalvular atrial fibrillation on 
anticoagulants. RE-QUOL study.
Study reference number:
1160-0280
Section 1: Milestones
Yes
No
N/A
Section
Number
1.1
Does the protocol specify timelines for 
1.1.1 Start of data collection1
6
1.1.2 End of data collection2
6
1.1.3 Study progress report(s)
1.1.4 Interim progress report(s)
1.1.5 Registration in the EU PAS register
6
1.1.6 Final report of study results.
6
Comments:
Study progress reports to Ethics committee and health authorities will be done annually
according to spanish regulations.
Section 2: Research question
Yes
No
N/A
Section
Number
2.1
Does the formulation of the research question 
and objectives clearly explain: 
8
2.1.1 Why the study is conducted? (e.g. to address 
an important public health concern, a risk identified in 
the risk management plan, an emerging safety issue)
7
2.1.2 The objective(s) of the study?
8
2.1.3 The target population? (i.e. population or 
subgroup to whom the study results are intended to be 
generalised)
7
2.1.4 Which hypothesis(-es) is (are) to be 
tested?
2.1.5 If applicable, that there is no a priori
hypothesis?
Comments:
Exploratory study
                                                
1 Date from which information on the first study is first recorded in the study dataset or, in the case of 
secondary use of data, the date from which data extraction starts.
2 Date from which the analytical dataset is completely available.

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Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Section 3: Study design
Yes
No
N/A
Section 
Number
3.1
Is the study design described? (e.g. cohort, case-
control, cross-sectional, new or alternative design) 
9.1
3.2
Does the protocol specify whether the study is 
based on primary, secondary or combined data 
collection?
9.4
3.3
Does the protocol specify measures of 
occurrence? (e.g. incidence rate, absolute risk)
3.4
Does the protocol specify measure(s) of 
association? (e.g. relative risk, odds ratio, excess risk, 
incidence rate ratio, hazard ratio, number needed to harm 
(NNH) per year)
3.5
Does the protocol describe the approach for the 
collection and reporting of adverse 
events/adverse reactions? (e.g. adverse events that 
will not be collected in case of primary data collection)
11
Comments:
Descriptive study. No measures of occurrence or measures of association are performed
Section 4: Source and study populations
Yes
No
N/A
Section 
Number
4.1
Is the source population described?
9.2
4.2
Is the planned study population defined in terms 
of:
4.2.1 Study time period?
9.1
4.2.2 Age and sex?
9.2
4.2.3 Country of origin?
9.2
4.2.4 Disease/indication?
9.2
4.2.5 Duration of follow-up?
4.3
Does the protocol define how the study 
population will be sampled from the source 
population? (e.g. event or inclusion/exclusion criteria)
9.2
Comments:
Cross-sectional study. No follow-up is carried out
Section 5: Exposure definition and measurement
Yes
No
N/A
Section
Number
5.1
Does the protocol describe how the study 
exposure is defined and measured?
(e.g. operational details for defining and categorising 
exposure, measurement of dose and duration of drug 
exposure)
9.3
5.2
Does the protocol address the validity of the 
exposure measurement? (e.g. precision, accuracy, use 
of validation sub-study)

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Section 5: Exposure definition and measurement
Yes
No
N/A
Section
Number
5.3
Is exposure classified according to time 
windows? (e.g. current user, former user, non-use)
9.3
5.4
Is exposure classified based on biological 
mechanism of action and taking into account the 
pharmacokinetics and pharmacodynamics of the 
drug?
Comments:
Observational study. Patients treated as per routine clinical practice.
Section 6: Outcome definition and measurement
Yes
No
N/A
Section 
Number
6.1
Does the protocol specify the primary and 
secondary (if applicable) outcome(s) to be 
investigated?
9.3
6.2
Does the protocol describe how the outcomes
are defined and measured? 
9.3
6.3
Does the protocol address the validity of 
outcome measurement? (e.g. precision, accuracy, 
sensitivity, specificity, positive predictive value, prospective 
or retrospective ascertainment, use of validation sub-study)
6.4
Does the protocol describe specific endpoints 
relevant for Health Technology Assessment? 
(e.g. HRQoL, QALYs, DALYS, health care services utilisation, 
burden of disease, disease management)
9.3
Comments:
Descriptive outcomes
Section 7: Bias
Yes
No
N/A
Section
Number
7.1
Does the protocol describe how confounding will 
be addressed in the study?
7.1.1. Does the protocol address confounding by 
indication if applicable?
7.2
Does the protocol address:
7.2.1. Selection biases (e.g. healthy user bias)
9.2
7.2.2. Information biases (e.g. misclassification of 
exposure and endpoints, time-related bias)
7.3
Does the protocol address the validity of the 
study covariates?
Comments:
This study is only descriptive
Section 8: Effect modification
Yes
No
N/A
Section
Number

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Non-interventional Study Protocol
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Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Section 8: Effect modification
Yes
No
N/A
Section
Number
8.1
Does the protocol address effect modifiers?
(e.g. collection of data on known effect modifiers, sub-group 
analyses, anticipated direction of effect) 
Comments:
This study is only descriptive
Section 9: Data sources
Yes
No
N/A
Section 
Number
9.1
Does the protocol describe the data source(s) 
used in the study for the ascertainment of:
9.1.1 Exposure? (e.g. pharmacy dispensing, general 
practice prescribing, claims data, self-report, face-to-face 
interview)
9.4
9.1.2 Outcomes? (e.g. clinical records, laboratory 
markers or values, claims data, self-report, patient 
interview including scales and questionnaires, vital 
statistics)
9.3
9.1.3 Covariates?
9.2
Does the protocol describe the information 
available from the data source(s) on:
9.2.1 Exposure? (e.g. date of dispensing, drug quantity, 
dose,  number of days of supply prescription, daily 
dosage,  prescriber)
9.3
9.2.2 Outcomes? (e.g. date of occurrence, multiple 
event, severity measures related to event)
9.3
9.2.3 Covariates? (e.g. age, sex, clinical and drug use 
history, co-morbidity, co-medications, lifestyle)
9.3
Is a coding system described for: 
9.3.1 Exposure? (e.g. WHO Drug Dictionary, Anatomical 
Therapeutic Chemical (ATC) Classification System)
9.3.2 Outcomes? (e.g. International Classification of 
Diseases (ICD)-10, Medical Dictionary for Regulatory 
Activities (MedDRA))
9.3.3 Covariates?
9.4
Is a linkage method between data sources
described? (e.g. based on a unique identifier or other)
9.2
Comments:
Coding system for exposure and outcomes will be described in SAP
Section 10: Analysis plan
Yes
No
N/A
Section
Number
10.1 Is the choice of statistical techniques described? 
9.7
10.2 Are descriptive analyses included?
9.7
10.3 Are stratified analyses included?

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Non-interventional Study Protocol
BI Study Number 1160-0280
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001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Section 10: Analysis plan
Yes
No
N/A
Section
Number
10.4 Does the plan describe methods for adjusting for 
confounding?
10.5 Does the plan describe methods for handling 
missing data?
9.7
10.6 Is sample size and/or statistical power 
estimated?
9.5
Comments:
This study is only descriptive
Section 11: Data management and quality 
control
Yes
No
N/A
Section
Number
11.1 Does the protocol provide information on data 
storage? (e.g. software and IT environment, database 
maintenance and anti-fraud protection, archiving)
9.6
11.2 Are methods of quality assurance described?
9.8
11.3 Is there a system in place for independent 
review of study results? 
Comments:
Observational study of routine clinical practice.
Section 12: Limitations
Yes
No
N/A
Section
Number
12.1 Does the protocol discuss the impact on the 
study results of:
12.1.1 Selection bias?
9.2
12.1.2 Information bias?
12.1.3 Residual/unmeasured confounding?
(e.g. anticipated direction and magnitude of such biases, 
validation sub-study, use of validation and external data, 
analytical methods)
12.2 Does the protocol discuss study feasibility?
(e.g. study size, anticipated exposure, duration of follow-up 
in a cohort study, patient recruitment)
9.2
Comments:
This study is only descriptive
Section 13: Ethical issues
Yes
No
N/A
Section
Number
13.1 Have requirements of Ethics Committee/ 
Institutional Review Board been described?
10.1
13.2 Has any outcome of an ethical review procedure 
been addressed?
13.3 Have data protection requirements been 
described?
10.1

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Non-interventional Study Protocol
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001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Comments:
Section 14: Amendments and deviations
Yes
No
N/A
Section
Number
14.1 Does the protocol include a section to document 
amendments and deviations? 
5
Comments:
Section 15: Plans for communication of study 
results
Yes
No
N/A
Section
Number
15.1 Are plans described for communicating study 
results (e.g. to regulatory authorities)?
12
15.2 Are plans described for disseminating study
results externally, including publication?
12

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Non-interventional Study Protocol
BI Study Number 1160-0280
c14460058-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
ANNEX 3. ADDITIONAL INFORMATION
Spanish adaptation of the Sawicki questionnaire:
1. Su tratamiento le hace sentir preocupado o estresado
  1
  2
  3
  4
  5
  6
2. El esfuerzo por controlar su coagulación sanguínea le 
produce molestias cuando está fuera de casa
  1
  2
  3
  4
  5
  6
3. Su tratamiento le limita para organizar su tiempo libre 
como quiere
  1
  2
  3
  4
  5
  6
4. Está insatisfecho con la cantidad de tiempo que 
invierte en controlar su coagulación
  1
  2
  3
  4
  5
  6
5. Cree que ha aprendido a controlar su tratamiento
  1
  2
  3
  4
  5
  6
6. El riesgo de hacerse heridas le limita para llevar a cabo 
sus tareas domésticas
  1
  2
  3
  4
  5
  6
7. Evita realizar ciertas actividades (p. ej. Montar en 
bicicleta) por el riego de accidentes
  1
  2
  3
  4
  5
  6
8. Su tratamiento preocupa a sus familiares
  1
  2
  3
  4
  5
  6
9. Puede afrontar los problemas que surgen relacionados 
con su tratamiento
  1
  2
  3
  4
  5
  6
1. Le preocupa su salud en el futuro
  1
  2
  3
  4
  5
  6
11. Tiene miedo de realizar ejercicio por el miedo de 
hacerse una herida
  1
  2
  3
  4
  5
  6
12. Está insatisfecho con el tiempo que le lleva conseguir 
los resultados
  1
  2
  3
  4
  5
  6
13. Le preocupa que su tratamiento pudiera acortar su 
vida
  1
  2
  3
  4
  5
  6
14. Le disgusta tener que planear sus actividades con 
antelación
  1
  2
  3
  4
  5
  6
15. Le preocupa la incertidumbre que siente mientras 
espera los resultados
  1
  2
  3
  4
  5
  6
16. Ve menos a sus amigos desde que sigue este 
tratamiento
  1
  2
  3
  4
  5
  6
17. Evita salir de vacaciones porque es incapaz de 
conocer los efectos negativos que tienen los diferentes 
alimentos en su tratamiento
  1
  2
  3
  4
  5
  6
18. Está bien informado de lo que debe hacer para 
conseguir unos resultados dentro de los límites 
adecuados
  1
  2
  3
  4
  5
  6
19.       Se siente dependiente de su medicación 
anticoagulante
  1
  2
  3
  4
  5
  6
2. Evita viajar porque tiene miedo de no recibir 
tratamiento adecuado en el caso de que sus resultados 
estén demasiado altos o bajos 
  1
  2
  3
  4
  5
  6

Boehringer Ingelheim
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21. Está harto de la cantidad de tiempo que pierde en el médico
  1
  2
  3
  4
  5
  6
22. Practicaría más deporte si no tomara anticoagulantes
  1
  2
  3
  4
  5
  6
23. Tiene problemas en el trabajo por sus frecuentes faltas a
causa del tratamiento
  1
  2
  3
  4
  5
  6
24. Está seguro de poder controlar su tratamiento
  1
  2
  3
  4
  5
  6
25. Tiende a preocuparse por las cosas
  1
  2
  3
  4
  5
  6
26. A pesar de las visitas habituales al médico, cómo se siente 
de limitado
  1
  2
  3
  4
  5
  6
27. Le molesta que mucha gente no comprenda los problemas
relacionados con su tratamiento
  1
  2
  3
  4
  5
  6
28. Cuando va al dentista o a otros médicos. Está preocupado
por si no saben lo suficiente sobre la anticoagulación
  1
  2
  3
  4
  5
  6
29. Su tratamiento ha afectado a su vida sexual
  1
  2
  3
  4
  5
  6
3. Le molesta ser tratado como un inválido
  1
  2
  3
  4
  5
  6
31. Está preocupado por los efectos secundarios de su
tratamiento anticoagulante
  1
  2
  3
  4
  5
  6
32. Le preocupa la reacción de otras personas ante su 
tratamiento
  1
  2
  3
  4
  5
  6
Puntuación:
Satisfacción
Autoeficacia
Estrés
Limitaciones diarias
Alteraciones sociales
Opciones de respuesta
1=Nada
2=Muy poco
3=Poco
4=Algo
5=Bastante
6=Mucho

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
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c14917649
1.0
clinical-trial-protocol-version-01
Non-Interventional, cross-sectional study to describe health-related quality of life
among controlled and uncontrolled patients with nonvalvular atrial fibrillation on
anticoagulants. RE-QUOL study.
Approval-Team Member Medical
Affairs
10 Jan 2017 10:01 CET
Approval-Medical 
10 Jan 2017 10:51 CET
Approval-
 Safety Evaluation
Therapeutic Area
10 Jan 2017 13:37 CET
Author-Trial Statistician
10 Jan 2017 19:06 CET
Approval-Therapeutic Area 
13 Jan 2017 11:18 CET

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Document Number: 
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