The Drug Use-results Survey (All-Case Surveillance) on Prizbind® for Intravenous Solution 2.5 g in Japan
Conditions: Hemorrhage
Sponsor: Boehringer Ingelheim

ABCD
NON-INTERVENTIONAL STUDY PROTOCOL
Document Number:
c10292519-03
BI Study Number:
1321.15
BI Investigational
Product(s):
Idarucizumab
Title:
The drug use-results survey (All-Case Surveillance) on 
Prizbind® for Intravenous Solution 2.5 g in Japan
Brief lay title
All-Case surveillance of Prizbind®
Protocol version 
identifier:
3.0
Date of last version of 
protocol:
25 March 2019
PASS:
Yes
EU PAS register 
number:
EUPAS15981
Active substance:
Idarucizumab (V03AB37)
Medicinal product:
Prizbind® for Intravenous Solution 2.5 g
Product reference:
Not applicable
Procedure number:
Not applicable
Marketing authorisation 
holder(s):
Joint PASS:
No
Research question and 
objectives:
To evaluate safety and effectiveness of Prizbind® for 
Intravenous Solution 2.5 g under Japanese clinical condition
Country(-ies) of study:
Japan
Author:
Phone: 
Fax: 
 

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Marketing authorisation 
holder(s):
MAH contact person:
EU-QPPV:
Signature of EU-
QPPV:
The signature of EU-QPPV is provided electronically
Date:
25 March 2019
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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
TITLE PAGE.................................................................................................................. 1
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 ............................................................................................... 14
9.2.2
Study population ..................................................................................... 15
9.2.2.1
Inclusion / exclusion criteria ................................................................ 15
9.2.2.2
Registration period ............................................................................... 15
9.2.2.3
Patient registration method................................................................... 15
9.2.3
Study visits .............................................................................................. 15
9.2.4
Study discontinuation.............................................................................. 15
9.3
VARIABLES .................................................................................................. 16
9.3.1
Exposures ................................................................................................ 16
9.3.2
Outcomes................................................................................................. 16
9.3.2.1
Primary outcomes................................................................................. 16
9.3.2.2
Secondary outcomes............................................................................. 16
9.3.3
Covariates................................................................................................ 17
9.4
DATA SOURCES........................................................................................... 18
9.5
STUDY SIZE.................................................................................................. 18
9.6
DATA MANAGEMENT................................................................................ 19
9.7
DATA ANALYSIS......................................................................................... 20
9.7.1
Main analysis........................................................................................... 20
9.8
QUALITY CONTROL................................................................................... 21

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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
9.10.2.1 Source documents................................................................................. 22
9.10.2.2 Direct access to source data and documents ........................................ 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....................................................................................................... 24
11.1
DEFINITIONS OF ADVERSE EVENTS...................................................... 24
11.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION AND 
REPORTING .................................................................................................. 25
11.3
REPORTING TO HEALTH AUTHORITIES................................................ 27
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
............................................................................................................................. 28
13.
REFERENCES .................................................................................................... 29
13.1
PUBLISHED REFERENCES......................................................................... 29
13.2
UNPUBLISHED REFERENCES................................................................... 29
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.............................................. 30

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2.
LIST OF ABBREVIATIONS
ADR
Adverse Drug Reaction
AE
Adverse Event
AESI
Adverse Event of Special Interest
CRF
Case Report Form
CTP
Clinical Trial Protocol
ENCePP 
European Network of Centres for Pharmacoepidemiology and 
Pharmacovigilance 
EU-QPPV
European Union-Qualified Person for Pharmacovigilance
GPSP
Good Post-marketing Study Practice
J-RMP
Japanese Risk Management Plan
MedDRA
Medical Dictionary for Regulatory Activities
PMDA
Pharmaceuticals and Medical Devices Agency
PMS
Post Marketing Surveillance
PSUR
Periodic Safety Update Report
SAE
Serious Adverse Event
TSAP
Trial Statistical Analysis Plan

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3.
RESPONSIBLE PARTIES
Marketing authorization
Study Site Contact details and the list of all investigators will be kept in a stand-alone 
document. This document will be managed in the drug use-results survey tracking system 
which manages the contracts with site and investigators name.
Biostatistics
Trial Statistician (TSTAT) assigned to 1321.15 is responsible for overall biostatistics. 
Programming
Trial statistical programmer (TPROG) assigned to 1321.15 is responsible for overall SAS 
statistical programming. 
Data Management
     Trial Data Manager (TDM) assigned to 1321.15 is responsible for overall data 
management
Medical adviser

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4.
ABSTRACT
Name of company:
Boehringer Ingelheim 
Name of finished medicinal 
product:
Prizbind® for Intravenous Solution 
2.5 g
Name of active ingredient:
Idarucizumab (V03AB37)
Protocol date:
Study 
number:
Version/Revision:
Version/Revision 
date:
23 Sep 2016
1321.15
3.0
25 Mar 2019
Title of study:
The drug use-results survey (All-Case Surveillance) on Prizbind® for 
Intravenous Solution 2.5 g in Japan
Rationale and 
background:
The Japanese Law for Ensuring the Quality, Efficacy, and Safety of 
Drugs and Medical Devices requires accumulating safety and 
effectiveness data of launched products in Japan for re-examination. 
Since there are a limited number of Japanese subjects treated in clinical 
trial, All-Case Surveillance is planned to collect safety and 
effectiveness data of Prizbind® for Intravenous Solution 2.5 g.
The PMS plan is a part of the local Risk Management Plan in Japan (J-
RMP). The J-RMP was submitted to the Japanese regulatory authority, 
the PMDA as a part of J-CTD and need to be approved by PMDA as 
approval condition. After 8years from approval, the results of the PMS 
are needed to be submitted to the PMDA, as a part of the re-
examination dossier.
Research question 
and objectives:
This PMS is designed to investigate the safety and effectiveness of 
Prizbind® for Intravenous Solution 2.5 g in patients under Japanese 
clinical condition according to the Japanese package insert.
Study design:
Non-interventional study based on newly collected data.
All patients administrated Prizbind® for Intravenous Solution 2.5 g 
after the approval at the sites contracted with the sponsor will be 
registered. This study permits the contract with the sites both before 
and after patient's administration of Prizbind® to collect the data 
retrospectively. The study will consist of data from baseline visit to 
4weeks follow-up for patients who initiate Prizbind® for Intravenous 
Solution 2.5 g. The patient registration should continue until the 
approval condition will be removed. CRF will not be collected after 
the number of cases reaches target number.
Population:
Inclusion criteria
-
Patients who are prescribed with Prizbind® for Intravenous 
Solution 2.5 g by the discretion of investigators
Exclusion criteria
-
None

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Name of company:
Boehringer Ingelheim 
Name of finished medicinal 
product:
Prizbind® for Intravenous Solution 
2.5 g
Name of active ingredient:
Idarucizumab (V03AB37)
Protocol date:
Study 
number:
Version/Revision:
Version/Revision 
date:
23 Sep 2016
1321.15
3.0
25 Mar 2019
Variables:
Primary outcomes
Any suspected ADRs (primary outcome), Serious AEs, and AEs for 
important potential risks(hypersensitivity, thrombotic event）
Secondary outcomes
Effectiveness will be assessed with a focus on the following variable 
as secondary outcome.
Reversal of anticoagulation as measured by coagulation test (aPTT, 
activated partial thromboplastin time)(secondary outcome)
Data sources:
Case Report Forms (CRFs) for individual patients will be provided by 
the sponsor.
After the medical examination and observation at the specified points
(Baseline, up to Week 4, or discontinuation) are completed, the 
investigator needs to immediately enter data of the registered patients 
(including withdrawals and dropouts) in CRF. In case that any adverse 
events occur, the data should be as soon as possible entered into CRF.
Study size:
300
Data analysis:
Due to the nature of the observational study, no confirmatory statistical 
testing is foreseen in this study. Analyses are descriptive in nature 
including means, standard deviation, min, Q1, medians, Q3, max, 
frequency and percentages.
Milestones:
Start of data collection: 28 September 2016
End of data collection: March 2020 (in plan)
Final report of study results: 4Q 2020 (in plan)

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Table 1
Flow chart
Observation / Evaluation time points are approximate. Collected data should be reported as 
those to the closest available time.
Time
Item
Observation period
Baseline
before treatment
Drug 
administration
48 hours
after 
administrat
ion
4weeks/or 
discontinuation
Patient registration*1
X
Patient demographics
X
Medical history
X
Dabigatran use
X
Bleed assessment Surgery/Procedure
X (to be reported throughout the observation period)
Prizbind® administration
X
Coagulation tests*2
X (to be reported throughout the period)
Concomitant medications /therapy
X (to be reported throughout the observation period)
Blood pressure, pulse rate
(X )(to be reported throughout the period)
(X )(to be 
reported)
Laboratory tests
(X) (to be reported throughout the period)
(X )(to be 
reported )
Adverse events
X (to be reported throughout the period)
Re-start anticoagulant therapy
X
*1: Patients administered Prizbind® for Intravenous Solution 2.5 g after approval will be registered
regardless of date of contract for this study.
*2: All aPTT values monitored during the observation period should be entered.
(X): If applicable

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5.
AMENDMENTS AND UPDATES
Number
Date
Section of 
study 
protocol
Amendment or 
update
Reason
2.0
6 Jun 2018
9.3.3
Amendment
In order to 
harmonize the 
CTP and the 
CRF
3.0
12 Mar 2019
9.1, 11.2
Update
In order to 
transfer to the 
only-
enrollment 
phase

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6.
MILESTONES
Milestone
Planned Date
Start of data collection
28 September 2016
End of data collection
March 2020 (in plan)
Registration in the EU 
PASS register
Registered
Final report of study results
4Q 2020 (in plan)

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7.
RATIONALE AND BACKGROUND
The reversal of the anticoagulant effects of dabigatran by idarucizumab, a humanised 
monoclonal antibody fragment, has been demonstrated in volunteers (studies 1321.1, 1321.2 
and 1321.5) and patients from the Study 1321.3(about 500 patients were enrolled in Q2 2016).
participated in Global phase III study (1321.3) after phase I study (1321.5) in Japanese 
subjects (60 cases)was finished. For the application for marketing approval in Japan, an 
interim analysis of 1321.3 was conducted by using data in 243 patients (including 4 Japanese 
patients) as of October 26, 2015. These clinical study results showed that idarucizumab was 
effective for neutralizing the anticoagulant effect of dabigatran and a favorable safety profile
of idarucizumab.
On the other hand, a limited number of Japanese subjects were treated in clinical trials.
MHLW may require All-Case Surveillance of idarucizumab as an approval condition. 
Therefore,
plans All-Case Surveillance to collect safety and efficacy data of 
idarucizumab (Prizbind® for Intravenous Solution 2.5 g) after its marketing launch in Japan.
Japanese regulation related to Post Marketing Surveillance (PMS)
This PMS is planned according to the Japanese Law for Ensuring the Quality, Efficacy, and 
Safety of Drugs and Medical Devices. The law requires in principle that data on the safety 
and effectiveness of all launched products to be accumulated under Japanese clinical 
condition. The PMS is a part of the local Risk Management Plan in Japan (J-RMP) to be 
submitted to the Pharmaceuticals and Medical Devices Agency (PMDA), the local 
regulatory agency in Japan at New Drug Application. After 8years from approval of 
registration, the data collected in the PMS are required to be submitted to PMDA according 
to the process of re-examination.
Japanese regulation related to All-Case Surveillance
The All-Case Surveillance means a use-results survey that is conducted to collect 
information on all patients who have used the product since its launch until a data from 
certain number of cases have been accumulated. The All-Case Surveillance is required for
products that needs the background information of patients treated with the product as well 
as safety and effectiveness issues related to the product for reaffirming approval details and 
collecting information which is essential for proper use at the earliest possible stage, 
thoroughly.
For example, the regulatory agency may require the implementation of the All-Case 
Surveillance for a pharmaceutical product as an approval condition when there are only a 
small number, or even no cases existing in clinical trials in Japan and when there are any 
concerns about the pharmaceutical product regarding the occurrence of serious adverse drug 
reactions. Necessity for the All-Case Surveillance is determined by the following steps: 
review in PMDA, subsequent discussion by the Pharmaceutical Affairs and Food Sanitation 
Council, and the final decision by MHLW.

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8.
RESEARCH QUESTION AND OBJECTIVES
This PMS is designed to investigate the safety and effectiveness of Prizbind® for Intravenous 
Solution 2.5 g in patients under Japanese clinical condition according to the Japanese package 
insert.

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9.
RESEARCH METHODS
9.1
STUDY DESIGN
This is a non-interventional study based on new data collection to gather data on safety and 
effectiveness of the Prizbind® for Intravenous Solution 2.5g under Japanese clinical condition. 
Patients who have been treated with dabigatran etexilate and required rapid reversal of the 
anticoagulant effects of dabigatran enter the study. Prizbind® is given intravenously, as 
idarucizumab at 5 g/dose (2 x 2.5 g/50 mL).
The study will consist of data from baseline visit to 4 weeks follow-up for patients who 
initiate Prizbind® for Intravenous Solution 2.5 g.
The study will be initiated after the approval of Prizbind® for Intravenous Solution 2.5 g in 
Japan. All patients administrated Prizbind® for Intravenous Solution 2.5 g after the approval
at the sites contracted with the sponsor will be registered. The study permits the contract with 
the sites both before and after patient's administration of Prizbind to collect the data 
retrospectively. CRFs of 300 patients will be collected. However the patient registration 
continues until the approval condition has been removed.
Information will be collected via CRFs for patients who have been administered Prizbind up 
to and including 14 April 2019. For patients administered Prizbind after the time point, no 
pre-specified information will be collected via CRFs. Following the time point, patients will 
only be registered in order to count the number of patients being administered Prizbind at 
every site, for so long as it is required by PMDA.
The primary outcome of this study is the frequency of patients with any suspected 
adverse drug reactions (ADRs)
The secondary outcome of this study is reversal of anticoagulation as measured by aPTT
9.2
SETTING
9.2.1
Study sites
All sites that Prizbind® for Intravenous Solution 2.5 g administered to patients will 
participate in this study. The sites will be contracted with 
A medical representative (MR) will explain the objectives and design of this study to the 
investigators at study sites and exchange a written contract with the head of the study site 
(e.g., hospital director).The sites which do not exchange a contract beforehand will be 
requested, when MR provides Prizbind® material including documents for this study and 
the package insert etc.to the sites, to inform of patient who administered Prizbind® to 

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9.2.2
Study population
9.2.2.1
Inclusion / exclusion criteria
Inclusion criteria
•
Patients who are prescribed with Prizbind® for Intravenous Solution 2.5 g by the 
discretion of investigators 
Exclusion criteria
•
None
9.2.2.2
Registration period
From the 28 September 2016 until until the approval condition will be removed.
9.2.2.3
Patient registration method
At each study site, all patients who initiate treatment with Prizbind® for Intravenous Solution 
2.5 g after the approval will be registered into this study.
Paper registration form will be used to collect necessary information and will be sent to the 
sponsor by fax.
End of registration
Patient registration will be stopped after the approval condition will be removed.
Only patient registration will be continued and CRF data will not be collected after the 
number of cases reaches target number.
9.2.3
Study visits
Collected data should be reported as those to the closest available time
(see Table 1).
9.2.4
Study discontinuation
reserves the right to discontinue the study overall or at a particular study site at any time 
for the following reasons:
1. Emergence of any effectiveness/safety information that could significantly affect 
continuation of the study 
2. 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 study
The study site will be reimbursed for reasonable expenses incurred in case of study 
termination (except in case of the second reason).

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9.3
VARIABLES
9.3.1
Exposures
Dosage and administration: Prizbind® (2 x 2.5 g/50 mL) is administered intravenously, as two 
consecutive infusions over 5 to 10 minutes each or as a bolus injection in adults.
Exposure to Prizbind®: The total dose is 5 g (two 2.5g vials). 
9.3.2
Outcomes
9.3.2.1
Primary outcomes
Safety will be assessed with a focus on the following variables, frequencies and percentages.

Any suspected ADRs (primary outcome)

Serious AEs

AEs for important potential risks*; hypersensitivity, thrombotic event (ischemic 
stroke, myocardial infarction, pulmonary embolism, deep vein thrombosis, systemic 
embolism) *: Immunogenicity will be assessed by clinical signs and symptoms of 
hypersensitivity.
How to assess and report AEs including the definitions are described in section 11.
9.3.2.2
Secondary outcomes
Effectiveness will be assessed with a focus on the following variable as secondary outcome.

Reversal of anticoagulation as measured by coagulation tests( aPTT)
The maximum effect on the anticoagulant activity within 4 hours after the completion of 
administration:
Maximum Reversal：｛（predose aPTT − minimum postdose aPTT）/
（predose aPTT −  ULN）｝× 100%
ULN: upper limit of normal in each site

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9.3.3
Covariates
Baseline characteristics and observation items
After the medical The following items will be considered as the baseline characteristics.  For 
all interventions/measures dates will be recorded. (see Table 1).
Demographics:
Dabigatran Use(start date, daily dose, times/day, date and time of last intake)
Prizbind® purpose of use(life-threatening or uncontrolled bleeding, emergency 
surgery/urgent procedures, other)
Bleeding location, severity, start date and time, bleeding related to trauma
Type of surgery/urgent procedure
In/out patient
Gender
Age (birth year)
Height
Weight
hypersensitive disposition
Pregnancy
Medical history/concomitant diseases
History of bleeding events
Department (emergency, cardiovascular, Neurosurgery, Neurology, Gastroenterolog,
other)
Participation of dabigatran clinical trial
Administration of Prizbind® :
Treatment (dose/an injection, Start date and time, end date and time, consecutive 
infusions or as bolus injection)
Primary reason of discontinuation for the survey
Bleeding / Surgery:
Bleeding Status (Stopped, Reduced, No change, worsened, Temporarily stopped and 
re-bleeding,Not assessable, time and date)
Volume of lost Blood (if applicable)
Surgery/urgent procedures (indication, start date and time, end date and time)
Coagulation test values (if applicable):
aPTT, PT-INR, Fibrinogen, FDP, D-dimer
All aPTT values monitored during the observation period should be entered.
Concomitant medications:

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  Treatment period (Start date, end date)
Reason for use
Concomitant therapies (use of blood products)
blood products/transfusion (Product, Number of Unit, Treatment period)
FFP, packed RBCs, platelets, whole blood, volume expanders, tranexamic acid, 
cryoprecipitate, PCCs, Factor VIIa and any other hemostatic agents
Dialysis(Yes/no)
Blood pressure, pulse rate:
Systolic/ diastolic blood pressure, Pulse rate
Re-start anticoagulant therapy
Re-Start date and time
Name of medication, dose
Laboratory tests (if applicable):
Liver function test (ALT, AST, Total Bilirubin, Alkaline Phosphatase (ALP))
Renal function test (BUN, Creatinine)
Na+, K+, Cl-
Albumin
Plasma glucose
Creatine kinase (CK-MB:if increased )
Triglyceride,Cholesterol (Total)
Hematology(White blood Cell Count, Red blood Cell Count, Hemoglobin, 
Hematocrit, Platelet Count)
9.4
DATA SOURCES
Case Report Forms (CRFs) for individual patients will be provided by the sponsor.
After the medical examination and observation at the specified points (Baseline, up to 4
weeks, or discontinuation) are completed, the investigator needs to immediately enter data of 
the registered patients (including withdrawals and dropouts) in CRF. In case that any adverse 
events occur, the data should be immediately entered into CRF.
9.5
STUDY SIZE
It is planned to collect 300 patients.
A sample size of 300 patients was planned in consideration of post-marketing occurrence of 
haemorrhagic events observed for Prazaxa® (based on the periodic safety update reports) and 
on the basis of feasibility.
Important potential risks (thrombosis and hypersensitivity) are considered as the key survey 
items. If real incidence rates of thrombosis and hypersensitivity in Japanese patients are same 

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as shown in the interim data in Study 1321.3 (5.3% and 12.3%) [c03666927-01], 95% 
confidence interval of their incidence rate is shown in the Table 2.
To ensure the same accuracy of the estimation (95% confidence interval: 2.8% to 9.0% 
(thrombosis), 8.4% -17.1% (hypersensitivity) in this study, about 250-300 cases is required
with conservative estimation. Further, with a sample size of 300 patients, any ADR with 
frequency of 1% or higher can be detected with probability of 95% or greater in at least one 
patient.
Table 2
95% confidence interval of the incidence rate
N
Incidence rate
95% confidence interval
Upper-Lower
Lower
Upper
Thrombosis
100
5.30%
1.7%
11.8%
10.1%
150
5.30%
2.2%
10.3%
8.1%
200
5.30%
2.6%
9.4%
6.8%
250
5.30%
2.9%
8.9%
6.0%
300
5.30%
3.0%
8.5%
5.5%
350
5.30%
3.2%
8.2%
5.0%
400
5.30%
3.3%
8.0%
4.7%
Hypersensitivity
100
12.30%
6.5%
20.5%
13.9%
150
12.30%
7.5%
18.7%
11.2%
200
12.30%
8.1%
17.7%
9.6%
250
12.30%
8.5%
17.0%
8.6%
300
12.30%
8.8%
16.6%
7.8%
350
12.30%
9.0%
16.2%
7.2%
400
12.30%
9.2%
15.9%
6.7%
9.6
DATA MANAGEMENT
Data management is going to be outsourced to CRO(s). Detailed data management process
with the CRO(s) will be described as data management procedure (or plan) which will be 
approved by BI-TDM and the CRO(s) before the initiation of DM operations. Data 
management and statistical software(s) are to be determined with the CRO(s) and described 
in the procedure (or plan). 
Paper-based case report form is used for 1321.15 and monitoring is not applicable for PMS in 
Japan. 
Contract research organizations 
Name

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9.7
DATA ANALYSIS
This is a non-interventional study based on new data collection to gather data on safety and 
effectiveness of the Prizbind® for Intravenous Solution 2.5 under Japanese clinical condition. 
Analyses for safety, effectiveness and baseline characteristics are descriptive in nature 
including means, standard deviation, min, Q1, medians, Q3, max, frequency and percentages.
Per local regulation, any patient who meets at least one of the following criteria is treated as 
ineligible for all analyses: 

No follow-up visit data are available

No required registration procedure is followed

No valid site contract is available
9.7.1
Main analysis
All outcome events are based on reported AE data which will be handled according to BI 
standards (see the section below).
The safety analysis will include all patients who registered, received the Prizbind® for 
Intravenous Solution 2.5 g treatment and collected CRF except for who meet the ineligible 
criteria (see Section 9.7).
AEs will be coded using the current version of the Medical Dictionary for Regulatory 
Activities (MedDRA). Based on the concept of treatment emergent AEs, all AEs occurring 
between first intake of Prizbind® for Intravenous Solution 2.5 g prescribed at baseline visit up 
to 5 days after the last intake will be considered ‘treatment period’. In addition, AEs with 
onset date before start of the trial treatment but with worsening in intensity during the 
treatment will also be assigned to the on-treatment period. Other AEs will be assigned to the 
screening or post-treatment period, respectively.
An AE is considered to be an ADR if either the physician who has reported the AE or the 
sponsor assesses its causal relationship as ‘related’.
The frequency and percentages of ADRs, SAEs, and other AEs occurred in treatment period 
as well as treatment + post-treatment period will be tabulated by system organ class and 
preferred term for all patients and for subgroups based on the important baseline 
characteristics (details will be described in the TSAP). 
No imputation is planned for missing AE data except for missing onset dates which will be 
handled according to BI standard.

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9.8
QUALITY CONTROL
All processes are conducted according to GPSP SOPs <102-MLS-90-119>. 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. For 
patients enrolled in sites with the contract implemented after administration of Prizbind the 
information is limited to the information included in the medical chart which might lead to 
missing information.
9.10
OTHER ASPECTS
9.10.1
Data quality assurance
This PMS is to be conducted in accordance with both the in-house PMS SOP and working 
instructions which are in compliance with GPSP.
9.10.2
Study records
Paper CRFs for individual patients will be provided by the sponsor. 

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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 CRFs 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 CRFs, 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 is not allowed in Japan.

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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.
10.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT
The review by Institutional Review Board (IRB) is not mandatory for conducting the PMS in 
Japanese GPSP.  The sponsor will enter into a contract with a representative (i.e., 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 study is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the 
study need to be available for inspection on request by the participating physicians, the 
sponsor’s representatives by the regulatory 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.
An AE which possible leads to disability will be reported as an SAE.
Adverse Event of Special Interest (AESI)
The term 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 

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study, e.g. the potential for AEs based on knowledge from other compounds in the same 
class. 
No AESIs have been defined for this study.
11.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION 
AND REPORTING
The investigator shall maintain and keep detailed records of all AEs in their patient files. 
Collection of AEs
The study design is of non-interventional nature and the study is conducted within the 
conditions of the approved marketing authorisation. Sufficient data from controlled 
interventional trials are available to support the evidence on the safety and efficacy of the 
studied BI drug. For this reason the following AE collection and reporting requirements have 
been defined.
The following must be collected by the investigator in the CRF: 
-
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).
•
The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).

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•
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 Prizbind®, 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
The investigator will report the Pregnancy Monitoring Forms as soon as possible via the 
unique entry point described in the Site Materials.
Information required
For each reportable adverse event, the investigator should provide the information requested 
on the appropriate CRF 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 
the Prizbind® 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 

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occurred or not, any abuse, off-label use, misuse, medication error, occupational exposure, 
lack of effect, and unexpected benefit.
AEs occurring from the patients whom used Prizbind after 15 April 2019 will not be 
collected in the CRF. These events will be reported spontaneously according to local 
regulations.
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 interim and final results will be submitted to PMDA in Japanese Periodic Safety Update 
Report (PSUR) and re-examination documents. And the interim and final results including 
case reports are also planned to be used for related publications.

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13.
REFERENCES
13.1
PUBLISHED REFERENCES
   Not applicable
13.2
UNPUBLISHED REFERENCES
c03666927-01   Clinical trial report – interim analysis. Idarucizumab (BI 655075). 
1321.3. A
Phase III, case series clinical study of the reversal of the 
anticoagulant effects of dabigatran by intravenous administration 
of 5.0 g idarucizumab (BI655075) in patients treated with 
dabigatran etexilate who have uncontrolled bleeding or require 
emergency surgery or procedures. RE-VERSE-AD (A study of 
the RE-VERSal Effects of Idarucizumab on Active Dabigatran) 
trial.Interim analysis based on request from Japanese regulatory 
authorities.15 Jan 2016.

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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
Not applicable