Post-Marketing Surveillance on the Use of Prazaxa® Capsules in Japanese Patients With Nonvalvular Atrial Fibrillation After the Availability of Idarucizumab
Conditions: Atrial Fibrillation
Sponsor: Boehringer Ingelheim

ABCD
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PAGE
Non-interventional Study Protocol
Document Number:
c15727707-01
BI Study Number:
1160.0284
BI Investigational
Product(s):
Dabigatran etexilate
Title:
Post-Marketing Surveillance on the Use of Prazaxa® 
Capsules in Japanese patients with nonvalvular atrial 
fibrillation after the availability of idarucizumab
Brief lay title
Japanese Prazaxa PMS, second
Protocol version 
identifier:
Version 1.0
Date of last version of 
protocol:
Initial
PASS:
Yes
EU PAS register 
number:
NA
Active substance:
Dabigatran etexilate
Medicinal product:
Prazaxa® Capsules 75 mg 110 mg
Product reference:
Not applicable
Procedure number:
Not applicable
Marketing authorisation 
holder(s):
Joint PASS:
No
Research question and 
objectives:
To confirm appropriate use and safety profile of Prazaxa® 
Capsules with prospective investigation in the routine 
medical practice after the availability of idarucizumab
Country(-ies) of study:
Japan
Author:
(Trial Clinical Monitor,
 
 

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Marketing authorisation 
holder(s):
MAH contact person:
EU-QPPV:
Signature of EU-
QPPV:
The signature of the EU-QPPV is provided electronically
Date:
22 February 2017
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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....................................................................... 9
6.
MILESTONES..................................................................................................... 10
7.
RATIONALE AND BACKGROUND................................................................ 11
8.
RESEARCH QUESTION AND OBJECTIVES ................................................. 12
9.
RESEARCH METHODS .................................................................................... 13
9.1
STUDY DESIGN............................................................................................ 13
9.2
SETTING........................................................................................................ 13
9.2.1
Study sites ............................................................................................... 13
9.2.2
Study population ..................................................................................... 13
9.2.3
Study visits .............................................................................................. 13
9.2.4
Study discontinuation.............................................................................. 14
9.3
VARIABLES .................................................................................................. 14
9.3.1
Exposures ................................................................................................ 14
9.3.2
Outcomes................................................................................................. 14
9.3.2.1
Primary outcomes............................................................................. 14
9.3.2.2
Secondary outcomes......................................................................... 15
9.3.3
Covariates................................................................................................ 16
9.4
DATA SOURCES........................................................................................... 17
9.5
STUDY SIZE.................................................................................................. 18
9.6
DATA MANAGEMENT................................................................................ 18
9.7
DATA ANALYSIS......................................................................................... 18
9.7.1
Main analysis........................................................................................... 19
9.7.3
Interim analyses....................................................................................... 19
9.8
QUALITY CONTROL................................................................................... 20
9.9
LIMITATIONS OF THE RESEARCH METHODS...................................... 20
9.10
OTHER ASPECTS ......................................................................................... 20
9.10.1
Data quality assurance............................................................................. 20

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9.10.2
Study records........................................................................................... 20
9.10.2.1
Source documents ............................................................................ 20
9.10.2.2
Direct access to source data and documents .................................... 20
9.10.3
Completion of study................................................................................ 20
10.
PROTECTION OF HUMAN SUBJECTS .......................................................... 21
10.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED
CONSENT ...................................................................................................... 21
10.2
STATEMENT OF CONFIDENTIALITY...................................................... 21
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS....................................................................................................... 22
11.1
DEFINITIONS OF ADVERSE EVENTS...................................................... 22
11.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION AND
REPORTING .................................................................................................. 23
11.3
REPORTING TO HEALTH AUTHORITIES................................................ 25
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
............................................................................................................................. 26
13.
REFERENCES .................................................................................................... 27
13.1
PUBLISHED REFERENCES......................................................................... 27
13.2
UNPUBLISHED REFERENCES................................................................... 27
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.............................................. 28
ANNEX 2. FLOW CHART OF VARIABLES ............................................................ 29

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2.
LIST OF ABBREVIATIONS
ADR
Adverse Drug Reaction
AE
Adverse Event
aPTT
Activated Partial Thromboplastin Time
BI
Boehringer Ingelheim
CABG
Coronary Artery Bypass Graft
CML
Local Clinical Monitor 
CrCL
Creatinine Clearance
CRF
Case Report Form
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
eGFR
Estimated Glomerular Filtration Rate
EU-QPPV
European Union – Qualified Person for Pharmacovigilance
GPSP
Good Post- marketing Study Practice
GVP
Good Pharmacovigilance Practices
IRB
Institutional Review Board
J-PAL
Japanese Law for Ensuring the Quality, Efficacy, and Safety of
Drugs and Medical Devices
LAA
Left Atrial Appendage
MAH
Marketing Authorisation Holder
MedDRA
Medical Dictionary for Drug Regulatory Activities
NIS
Non-Interventional Study
NVAF
Non-Valvular Atrial Fibrillation 
PASS
Post-Authorization Safety Study
PCI
Percutaneous Coronary Intervention
PMDA
Pharmaceuticals and Medical Devices Agency
PMD Act
Act on Pharmaceuticals and Medical Devices
PMS
Post Marketing Surveillance
PSR
Periodic safety report
PT
Prothrombin Times
PT-INR
Prothrombin Time-International Normalized Ratio
SAE
Serious Adverse Event
SOP
Standard Operating Procedure

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3.
RESPONSIBLE PARTIES
Contact details and the list of all investigators will be kept in a stand-alone document. This 
document will be managed in the PMS tracking system which manage the contracts with site 
and investigators name.

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4.
ABSTRACT
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Prazaxa® Capsules
Name of active ingredient:
Dabigatran etexilate
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
22 February 2017
1160.0284
Version 1.0
Not applicable
Title of study:
Post-Marketing Surveillance on the Long-Term Use of Prazaxa® 
Capsules in Japanese patients with nonvalvular atrial fibrillation after 
the availability of idarucizumab
Rationale and 
background:
Even after the availability of idarucizumab in real clinical practice, 
appropriate use of Prazaxa® Capsules will continue. The patient 
population who receive Prazaxa® Capsules and the safety profile of 
Prazaxa® Capsules is not expected to change.
This study can confirm appropriate use with prospective investigation 
in the routine medical practice.
Research question 
and objectives:
The study objective is to confirm appropriate use and safety profile of 
Prazaxa® Capsules in real-world setting after the availability of 
idarucizumab.
Study design:
Observational study based on newly collected data for 52 weeks.
Population:
- Inclusion criteria
Male and female patients with nonvalvular atrial fibrillation who have 
never received Prazaxa® Capsules / dabigatran etexilate for preventing 
the occurrence of ischemic stroke and systemic embolism before 
enrolment in Japan
- Exclusion criteria
None

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Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Prazaxa® Capsules
Name of active ingredient:
Dabigatran etexilate
Protocol date:
Study 
number:
Version/Revision:
Version/Revision 
date:
22 February 2017
1160.0284
Version 1.0
Not applicable
Variables:
Outcomes:
Safety
Primary outcomes:
Incidences of adverse drug reactions
 
Others: baseline characteristics
Demographics, duration and medical condition of indication, medical 
history/ concomitant disease, history of bleeding events, concomitant/ 
past medications and therapy, vital signs and safety laboratory tests, 
pregnancy
Data sources:
Patients’ data will be collected by electronic Case Report Form
on Electronic Data Capture system
Study size:
5000 (safety set)
Data analysis:
Analyses are descriptive in nature, incidence rates and corresponding 
confidence intervals, absolute and relative frequencies will be given.
Milestones:
Planned start of data collection: 1 JUL 2017
Planned end of data collection: 30 SEP 2020
Interim results will be submitted in the re-examination dossier to 
PMDA in APR 2019.
Study Report planned to be archived in 3Q 2021
Study result based on study report is submitted additionally as a part 
of the re-examination dossier to PMDA in 4Q 2021.

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5.
AMENDMENTS AND UPDATES
Number
Date
Section of 
study 
protocol
Amendment or 
update
Reason
None

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6.
MILESTONES
Milestone
Planned Date
Start of data collection
1 July 2017
End of data collection
30 September 2020
Study progress report
None
Study interim report 1
17 December 2017 (J-PSR)
Study interim report 2
17 December 2018 (J-PSR)
Study interim report 3
20 April 2019 (J-PSR)
Study interim report 4
20 April 2019 (re-examination dossier for Prazaxa 
Capsules)
Registration in the EU 
PASS register
To be registered
Final report of study results:
3Q 2021

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7.
RATIONALE AND BACKGROUND
This PMS study is planned additionally to the requirement by the Act on Pharmaceuticals and 
Medical Devices (PMD Act) in Japan. The regulatory required PMS (BI trial number: 
1160.130) has been completed in January 2017. 
The data collected in the PMS study are required to be submitted to the Pharmaceuticals and 
Medical Devices Agency (PMDA), the local regulatory agency in Japan, according to the 
process of re-examination which will take place 8 years after approval of registration. 
In Japan, idarucizumab (Prizbind®), a specific reversal agent of dabigatran, launched in 
November 2016, and the treatment environment of stroke prevention in patient with NVAF 
has changed. Even after the availability of idarucizumab in real clinical practice, the safety 
profile of dabigatran is not changed, and patients who recommend dabigatran also will not 
change. Also, appropriate use of dabigatran will continue as before. 
Contraindication as per Japanese Package Insert should be respected.
However, we considered that the prospective investigation such as special drug use survey 
regarding the status of appropriate use of dabigatran under real clinical practice including 
whether idarucizumab influences to safety profile of dabigatran is necessary. Meanwhile, the 
previous regulatory required PMS (BI trial number: 1160.130) has already been completed, 
so it is unable to evaluate the influence on appropriate use of dabigatran under real clinical 
practice with the impact of idarucizumab launch as this rate. Therefore, we decided to 
conduct this newly planned PMS study (BI trial number: 1160.0284).
As for the survey items, evaluation points of this PMS study are consistent with previous 
regulatory required PMS because of taking into consideration descriptive differences.
With regard to the data obtained in this PMS study, we will provide interim analysis results to 
the clinical sites for the purpose of promoting further appropriate use of dabigatran.

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8.
RESEARCH QUESTION AND OBJECTIVES
The study objective is to confirm appropriate use and safety profile of Prazaxa® Capsules in 
real-world setting after the availability of idarucizumab.

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9.
RESEARCH METHODS
9.1
STUDY DESIGN
This is an observational study based on newly collect real-world data (i.e., data under real-
world practice) to confirm appropriate use and safety of Prazaxa® Capsules in real-world 
setting in patients with nonvalvular atrial fibrillation.
The study will consist of a baseline visit and further visits in a 52-week follow-up for patients 
who have initiated the Prazaxa® Capsules treatment.
9.2
SETTING
9.2.1
Study sites
Sites throughout entire country will be equally listed according the size of the hospitals or 
general clinics at which Prazaxa® Capsules are available for prescription.
Planned number of site: Approximately 800 Sites
A medical representative will explain the objective and design of this study to investigators at 
each study site and exchange a written contract with the head of the study site (e.g., hospital 
director).
9.2.2
Study population
As this is an observational study, no specific treatment is mandated or withheld from the 
patients. The choice of maintenance treatment for nonvalvular atrial fibrillation must be 
according to regular medical practice and at discretion of physician (i.e., no randomised 
assignment of patient to treatment [Prazaxa® Capsules or other treatment] is performed).
Inclusion criteria
Male and female patients with nonvalvular atrial fibrillation who have never received 
Prazaxa® Capsules / dabigatran etexilate for preventing the occurrence of ischemic stroke 
and systemic embolism before enrolment in Japan
Exclusion criteria
None
9.2.3
Study visits
Registration periods: From July 2017 to June 2019
The registration method will be a continuous investigation system. Patients who begin 
treatment with Prazaxa® Capsules after the conclusion of the contract will be registered by 
entering necessary information in the EDC within 14 days whenever possible from the day of 
treatment initiation (inclusive).

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Patient registration will be stopped when the target number of the study is reached. After the 
end of the registration period, investigators use a signed form to confirm that patients have 
been registered continuously at the site. A log of all patients included into the study will be 
maintained at the site.
After start of the treatment with Prazaxa® Capsules, each patient will be observed for 52 
weeks or at premature discontinuation from the PMS. Observations are made at the following 
time points: before first administration of Prazaxa® Capsules (this visit is defined as 
baseline), 4, 8, 12, 26 and 52 weeks after the start of treatment, or at discontinuation.
9.2.4
Study discontinuation
 reserves the right to discontinue the PMS 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 PMS, or any other administrative reasons.
3. Violation of Good Post-marketing Study Practice (GPSP), the NIS protocol, or the 
contract by a study site or investigator, disturbing the appropriate conduct of the PMS
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
9.3.1
Exposures
Exposure to Prazaxa® Capsules is estimated as time from the day Prazaxa® Capsules is 
initiated until the day the drug is last administrated on a patient-level (or the final contact 
with the patient during the regular observation period).
Patients newly initiating Prazaxa® Capsules will be followed up to 52 weeks.
9.3.2
Outcomes
9.3.2.1
Primary outcomes
The primary Outcome is the absolute and relative (%) frequency of patients with suspected
adverse drug reactions (ADRs).
There is no primary outcome for effectiveness as the primary objective of a PMS is
evaluating safety.

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9.3.2.2
Secondary outcomes
None

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9.3.3
Covariates
At least the following variables based on physician’s report will be considered important 
baseline characteristics and potential risk factors for the outcomes of interest.

gender, date of birth, indication, pregnancy status, patient status (inpatient/outpatient), 
body weight, height, hypersensitive disposition, alcohol status, smoking status

atrial fibrillation (date of onset, disease type, electric cardioversion status, 
pharmacological cardioversion status, ablation treatment status, pace maker status, LAA 
occlusion status, LAA amputation status)

concomitant disease/medical history (cardiac failure congestive, left ventricular 
hypertrophy, hypertension, diabetes mellitus, stroke, transient ischemic attack, systemic 
embolism, pulmonary embolism, deep-vein thrombosis, peripheral arterial disease, 
aortic plaque, thyrotoxicosis, hyperlipidemia, ischemic heart disease, myocardial 
infarction, valvular disease, hepatic function disorder, renal impairment [including 
CrCL and eGFR if applicable], gastro intestinal disorder, cancer, dementia and others)

history of bleeding events

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
antithrombogenic drugs administered before the day of first administration of Prazaxa® 
Capsules

concomitant / past medications and therapy

Administration of Prazaxa® Capsules (dose, daily frequency, in the first administration-
reason to prescribe lower dose (other than 150mg bid), start and end date, primary 
reason of discontinuation, use of idarucizumab)

blood pressure and pulse rate (if applicable)

laboratory tests (blood biochemistry and urinalysis) (if applicable)
Haematology: Leukocyte count (WBC), Haemoglobin (Hb), Erythrocyte count (RBC), 
Platelet count, Haematocrit
Blood chemistry: AST (aspartate transaminase, SGOT), ALT (alanine transaminase, 
SGPT), -GTP (gamma-glutamyl-transferase), Total bilirubin (T-BIL), 
Total cholesterol (T-CHO), HDL cholesterol (HDL), 
LDL cholesterol (LDL), Triglycerides (TG), Fasting blood glucose, 
HbA1c, Blood urea nitrogen (BUN), Creatinine (CRE), Uric acid (UA),
Sodium (Na), Potassium (K), Chlorine (Cl),
Alkaline Phosphatase (Al-P)
Urinalysis:
Protein, Glucose, Urobilinogen, Uric blood
Blood coagulation test: aPTT, PT-INR, PT (baseline only)
To calculate eCCR, the Cockcroft-Gault formula will be used.
eCCR = 
(	
)×[]
× [/]
× 0.85(if female)
To calculate eGFR, the following formula will be used.
eGFR = 194 × SCR.- × AGE.1 × 0.739 (if female)
WT: body weight, SCR: serum creatinine
See ANNEX 2 for more 
details.
9.4
DATA SOURCES
Case Report Forms (CRFs) for individual patients will be provided by the sponsor via the
Electronic Data Capture (EDC) system.
In EDC system, two casebooks will be set up.:
Book 1 includes baseline, 4 weeks, 8 weeks and 12 weeks. 
Book 2 includes 26 weeks and 52 weeks.

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The data are to be transmitted immediately after being entered into EDC at 12 weeks (Book 
1) and 52 weeks (Book 2) after the start of treatment or at discontinuation.
For any adverse events, the data should be immediately entered into EDC and transmitted.
9.5
STUDY SIZE
In order to consider with the PMS study (1160.130) (December 2011-March 2016) in 
descriptive manner after obtaining the results from this PMS, sample size of this survey is 
planned as same as the study 1160.130 for the patients with nonvalvular atrial fibrillation. 
From the interim results (cut-off date: 17 September 2016) of PMS 1160.130, the rate of 
major bleeding event was 0.37 per 100 patient-year (30/6443, 95%CI: 0.26-0.53). However, 
since follow-up duration is reduced by half compared with 1160.130. This might lead to a 
decreased precision in the estimation of outcome incidence rates.
9.6
DATA MANAGEMENT
Patients’ data will be gathered by EDC system provided by external vendor below.
Contract 1
Contract 2
Company Name
To be determined.
Outsourced work
EDC system setting
Patient registration
Clinical Data Management
Document management of 
contract with site.
9.7
DATA ANALYSIS
This is an observational study to collect real-world data (i.e., data under routine medical 
practice) on safety and appropriate use of Prazaxa® Capsules treatment. Analyses are 
descriptive in nature, including confidence intervals. Due to the nature of the observational 
study, no confirmatory statistical testing is foreseen in this study. Subgroup analyses are 
also performed if sample size allows.
Per local regulation, any patient who meets one of the following criteria is treated as 
ineligible for all analyses:
•
No safety observation was documented after registration.
•
No required registration procedure was followed.
•
No valid site contract was available.

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9.7.1
Main analysis
The analysis of outcome events will include all patients registered in the study and 
receiving the Prazaxa® Capsules treatment. All outcome events are based on reported AE 
data which will be handled according to BI standards.
The safety analysis will include all patients registered in the study and receiving the 
Prazaxa® Capsules treatment except for patients who meet the ineligible criteria (see 
section 9.7). In general, safety analyses will be descriptive in nature, be based on BI 
standards, and focus on AEs related to the Prazaxa® Capsules treatment.
AEs will be coded using the current version of the Medical Dictionary for Drug Regulatory 
Activities (MedDRA) and will be based on the concept of treatment emergent AEs. To this 
end, all AEs occurring between the initiation of Prazaxa® Capsules prescribed at baseline 
visit and  6 days (inclusive) after the last administration will be considered ‘treatment 
emergent’. An AE is considered to be an ADR if either the physician/investigator who has 
reported the AE or the sponsor assesses its causal relationship as ‘related’.
The incidence (n and % in treatment group) and treatment exposure time adjusted incidence 
rate (n in 100 patient years) of AEs in patients treated with Prazaxa® Capsules (treatment 
emergent including 6 days after discontinuation of Prazaxa® Capsules medication) will be
tabulated by MedDRA SOC and PT for overall and for subgroups based on the important 
baseline characteristics, if sample size allows.
No imputation is planned for missing AE data except for missing onset dates which will be
handled according to BI standard.
The safety data will be assessed by using demographic data (e.g. indication for use, CrCL) 
in terms of appropriate use.
9.7.3
Interim analyses
Several interim analyseswill be performed for the purpose of submission of periodic safety
reports to PMDA in project (status update of using Prazaxa® Capsules not only with this 
trial but all usage, every 6 month in two years after approval and every 12 months 
afterward. The submission date is depending on the time from the approval).
Interim results will be submitted in the re-examination dossier to PMDA by 20 April 2019.

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9.8
QUALITY CONTROL
All processes are conducted according to GPSP SOPs and GPSP working instruction. 
Appropriate records and documents are stored based on the GPSP SOPs and these 
processes are checked by internal self-check.
9.9
LIMITATIONS OF THE RESEARCH METHODS
The general scientific objective of this non-interventional study is to obtain an estimate of the
occurrence of the adverse events in the population under study. Due to the nature of a single
cohort observational study, however, there are issues that may impose limitations in
particular on the validity of the assessment based on the study data such as selection bias, loss
to follow up, channeling bias and information and recall bias. Thus, comparisons and causal
conclusions cannot be made, except for the investigator reported drug-related AEs.
9.10
OTHER ASPECTS
9.10.1
Data quality assurance
This PMS is to be conducted in accordance with both the in-house SOP and working 
instructions which are in compliance with GPSP.
9.10.2
Study records
Case Report Forms (CRFs) for individual patients will be provided by the sponsor via
Electronic Data Capture (EDC) system.
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 reported on 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.
9.10.2.2
Direct access to source data and documents
Direct access to source data and documents for PMS study is not allowed in Japan.
9.10.3
Completion of study
Completion of the PMS will be notified to PMDA when the re-examination document is 
applied to in accordance with J-PAL and GPSP.

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10.
PROTECTION OF HUMAN SUBJECTS
There is no regulation or requirement for ensuring the well-being and rights of participants in
a non-interventional observational study.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient.
10.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT
The review by IRB is not mandatory for conducting PMS in Japanese GPSP. The sponsor
will enter into a contract with a representative (e.g., head of hospital) in accordance with
GPSP. Written informed consent prior to patient participation in the trial is not a regulatory or
legal requirement in accordance with GPSP.
10.2
STATEMENT OF CONFIDENTIALITY
Individual patient medical information obtained as a result of this PMS 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.
Data generated as a result of the PMS needs to be available for inspection on request by the
regulatory authorities.

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11.
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS
Procedures for the collection, management and reporting of individual cases of adverse 
events/adverse reactions (see 001-MCS-05-501-RD-01 for collection requirements) and of 
any new information that might influence the evaluation of the benefit-risk balance of the 
product while the study is being conducted. 
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 

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development of dependency or abuse. Any suspected transmission via a medicinal product of 
an infectious agent is also considered a serious adverse reaction.
An AE which possibly leads to disability will be reported as an SAE.
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 eCRF. When any adverse events
occur, the data should be immediately entered into eCRF and transmitted.: 
-
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 
•
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).

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•
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 Prazaxa® Capsules, 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 as soon as possible. 
Information required
For each reportable adverse event, the investigator should provide the information requested 
on the appropriate eCRF pages.
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 
Prazaxa® Capsules, according to the local regulatory requirements for spontaneous AE 
reporting at the investigator’s discretion by using the locally established routes and AE report 

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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 progress reports and final reports will be submitted to PMDA in Japan PSR (Periodic
safety report). And also the interim report for this PMS is included in re-examination
documents.
This study is planned for the publication based on the final report.
The rights of the physician and of the sponsor with regard to publication of the results of this 
PMS are described in the contract. As a general rule, no PMS results should be published 
prior to finalisation of the Study Report.
In addition, further interim analysis might be performed for the scientific presentations and 
publications for the purposes of promoting appropriate use of Prazaxa® Capsules.

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13.
REFERENCES
13.1
PUBLISHED REFERENCES
R11-1250
Schulman S, Angerås U, Bergqvist D, Eriksson B, Lassen MR, Fisher W; 
Subcommittee on Control of Anticoagulation of the Scientific and 
Standardization Committee of the International Society on Thrombosis and 
Haemostasis. Definition of major bleeding in clinical investigations of 
antihemostatic medicinal products in surgical patients. J Thromb Haemost 
2010;8:202-4.
P11-05406
Lip GYH, Andreotti F, Fauchier L, Huber K, Hylek E, Knight E, Lane DA, 
Levi M, Marin F, Palareti G, Kirchhof P, Bleeding risk assessment and 
management in atrial fibrillation patients: a position document from the 
European Heart Rhythm Association, endorsed by the European Society of 
Cardiology Working Group on Thrombosis.
Europace 13, 723 - 746 (2011)
13.2
UNPUBLISHED REFERENCES
Not applicable

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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
Number
Document 
Reference Number
Date
Title
None
None

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ANNEX 2. FLOW CHART OF VARIABLES
Time point
Item
Observation period *1
Before 
first 
administr
ation of
Prazaxa®
Capsules
Week 4
Week 8
Week 12
Week 26
Week 52 or at 
discontinuation
Patient enrolment
X*2
Surveillance items:
• Patient demographic
X
• Atrial fibrillation  
characteristics
X
• Concomitant disease/
medical history
X
• History of bleeding events
X
• Prior Anti-thrombotic 
therapy 
X
• Administration status of 
Prazaxa® Capsules
X (Record throughout the observation period)
• Concomitant drug /
Concomitant therapy
X (Record throughout the observation period)
• Blood pressure/pulse rate
(X)
(X)
(X)
(X)
(X)
(X)
• Pregnancy status
X (confirm throughout the observation 
period)
X (confirm throughout the 
observation period)
• Laboratory tests*3
(X)
(X)
(X)
(X)
(X)
(X)
• Stroke/SEE, Haemorrhage, 
myocardial infarction and 
gastrointestinal disorder
X (Examine throughout the observation period)
• Adverse events
X (Examine throughout the observation period)
*1: Time points during the observation period are approximate. Collected data should be reported as of the 
closest available visit.
*2:
Patients administered Prazaxa® Capsules will be registered within 14 days from whenever the day of first 
administration is possible.
*3:
All aPTT and PT-INR data measured at any time during the observation period should be completely 
entered into eCRF.
(X): If applicable
eCRF (electronic case report form): At 12 weeks, 52 weeks, and each time an adverse event has occurred, data
in corresponding observation period should be entered into the eCRF and transmitted using the EDC system.

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c15727707
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1160-0284-nis-protocol
Post-Marketing Surveillance on the Use of Prazaxa® Capsules in Japanese patients
with nonvalvular atrial fibrillation after the availability of idarucizumab
Approval-Trial Clinical Monitor
22 Feb 2017 11:04 CET
Approval-Team Member Medical
Affairs
22 Feb 2017 12:39 CET
Approval-
 Medicine
23 Feb 2017 02:49 CET
Author-Trial Statistician
23 Feb 2017 04:33 CET
Approval-EU Qualified Person
Pharmacovigilance
23 Feb 2017 17:14 CET
Approval-
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Therapeutic Area
24 Feb 2017 07:23 CET
Approval-Pharmacovigilance
Representative
24 Feb 2017 09:47 CET
Approval-Therapeutic Area 
26 Feb 2017 18:42 CET

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 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c15727707
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Approval-
 Pharmacovigilance
27 Feb 2017 00:50 CET