Post Marketing Surveillance on Long Term Drug Use of JARDIANCE® Tablets in Patients With Chronic Heart Failure in Japan
Conditions: Heart Failure
Sponsor: Boehringer Ingelheim

ABCD
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TITLE PAGE
Non-Interventional Study (NIS) Protocol
TITLE PAGE
Document Number:
c37302912-04
BI Study Number:
1245.286
BI Investigational
Product(s):
Empagliflozin 
Title:
Post Marketing Surveillance on Long Term Drug Use of 
JARDIANCE® Tablets in Patients with chronic heart failure in 
Japan.
Brief lay title:
PMS of JARDIANCE in CHF
Protocol version 
identifier:
Version 4.0
Date of last version of 
protocol:
5 October 2023
PASS:
Yes
EU PAS register 
number:
EUPAS44340
Active substance:
Empagliflozin 
Medicinal product:
JARDIANCE® Tablets
Product reference:
Not applicable
Procedure number:
Not applicable
Marketing authorisation 
holder(s):
Joint PASS:
No
Research question and 
objectives:
Study objective is to investigate the safety and effectiveness of long-
term daily use of JARDIANCE® Tablets in patients with chronic 
heart failure under real-world use.
Country(-ies) of study:
Japan
Author:

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Marketing authorisation 
holder(s):
MAH contact person:
EU-QPPV:
Signature of EU-QPPV:
e-signature is on BIRDS
Date:
1 April 2024
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© 2024 Boehringer Ingelheim Group of 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
TITLE PAGE.................................................................................................................. 1
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 ................................................. 13
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
9.2.2.1
Patient registration method .............................................................. 14
9.2.3
Study visits .............................................................................................. 14
9.2.4
Study discontinuation.............................................................................. 14
9.3
VARIABLES .................................................................................................. 14
9.3.1
Exposures ................................................................................................ 14
9.3.2
Outcomes................................................................................................. 15
9.3.2.1
Primary outcomes............................................................................. 15
9.3.2.2
Secondary outcomes......................................................................... 15
9.3.3
Covariates................................................................................................ 16
9.4
DATA SOURCES........................................................................................... 18
9.5
STUDY SIZE.................................................................................................. 18
9.6
DATA MANAGEMENT................................................................................ 21
9.7
DATA ANALYSIS......................................................................................... 21
9.7.1
Main analysis........................................................................................... 22
9.7.3
Safety analysis......................................................................................... 22

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9.8
QUALITY CONTROL................................................................................... 23
9.9
LIMITATIONS OF THE RESEARCH METHODS...................................... 23
9.10
OTHER ASPECTS ......................................................................................... 23
9.10.1
Data quality assurance............................................................................. 23
9.10.2
Study records........................................................................................... 23
9.10.2.1
Source documents ............................................................................ 23
9.10.2.2
Direct access to source data and documents .................................... 24
9.10.3
Completion of study................................................................................ 24
10.
PROTECTION OF HUMAN SUBJECTS .......................................................... 25
10.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ...................................................................................................... 25
10.2
STATEMENT OF CONFIDENTIALITY...................................................... 25
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS....................................................................................................... 26
11.1
DEFINITIONS OF ADVERSE EVENTS...................................................... 26
11.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION AND 
REPORTING .................................................................................................. 28
11.3
REPORTING TO HEALTH AUTHORITIES................................................ 30
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
............................................................................................................................. 31
13.
REFERENCES .................................................................................................... 32
13.1
PUBLISHED REFERENCES......................................................................... 32
13.2
UNPUBLISHED REFERENCES................................................................... 32
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.............................................. 33
ANNEX 2. FLOW CHARTS OF VARIABLES.......................................................... 34
ANNEX 3. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .............................. 35

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2.
LIST OF ABBREVIATIONS
ADR
Adverse Drug Reaction
AE
Adverse Event
BIcMQ
Boehringer Ingelheim 
CHF
Chronic Heart Failure
CI
Confidence Interval
CRF
Case Report Form
eCRF
Electronic Case Report Form
CV
CardioVascular
EDC
Electronic Data Capture
EU-QPPV
European Union – Qualified Person for Pharmacovigilance
GPSP
Good Post- marketing Study Practice
HF
Heart Failure
HFrEF
Heart Failure with reduced Ejection Fraction
J-PMD Act
Japanese pharmaceuticals and Medical Devices Act
J-RMP
Japan Risk Management Plan
MedDRA
Medical Dictionary for Drug Regulatory Activities
MHLW
Ministry of health, Labour and Welfare
PMDA
Pharmaceuticals and Medical Devices Agency
PMS
Post Marketing Surveillance
SAE
Serious Adverse Event
SOP
Standard Operating Procedures
T2DM
Type 2 Diabetes mellitus

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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 Post Marketing Surveillance (PMS) tracking system which 
manage the contracts with site and investigators name.
Co-sponsor
Medical advisor
Task:
1. Providing medical advice and comments on the study results
2. Providing medical advice on risk minimisation
3. Reviewing the contents of publication for the study results

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4.
ABSTRACT
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
JARDIANCE® Tablets
Name of active ingredient:
Empagliflozin
Protocol date:
Study
number:
Version/Revision:
Version/Revision date:
1 November 2021
1245.286
Version 4.0
1 April 2024
Title of study:
Post Marketing Surveillance on Long Term Drug Use of JARDIANCE®
Tablets in Patients with chronic heart failure (CHF) in Japan.
Rationale and 
background:
In Japan, post-approval execution of Post Marketing Surveillance is 
requested by the Japanese Pharmaceuticals and Medical Devices Act (J-
PMD Act) in order to accumulate safety and effectiveness data for re-
examination. Re-examination period is defined by J-PMD Act. Four years 
after approval of additional indication, results of PMS need to be submitted 
as a part of re-examination dossier to the Japanese regulatory authority, the 
Ministry of Health, Labour and Welfare (MHLW). 
Collected data from PMS will be included in the Japanese periodic safety 
reports and submitted to MHLW on designated dates until the end of re-
examination period.
Research question 
and objectives:
Study objective is to investigate the safety and effectiveness of long-term 
daily use of JARDIANCE® Tablets in patients with CHF under real-world 
use.
Study design:
Cohort study
Non-interventional, single arm study based on newly collected data
Patients will be observed for up to 52 weeks after start of the treatment with 
JARDIANCE® Tablets or until discontinuation of administration.
Population:
Inclusion criteria
-
Patients with chronic heart failure who are prescribed with 
JARDIANCE® Tablets in Japan. 
-
Patients who have never been treated with Empagliflozin (including 
treatment for T2DM) before enrolment.
Exclusion criteria
None

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Variables:
Outcomes:
Primary outcome:
-
Incidence of adverse drug reactions (ADR) (focus on hypoglycaemia, 
the events relevant volume depletion, influence of ketone body 
increased / ketoacidosis, renal impairment)
Secondary outcomes:
-
Incidence of all-cause death
-
Incidence of CV death
-
Incidence of hospitalizations for heart failure
Further outcomes:
      Other safety outcomes;
-
Incidences of serious adverse events 
-
Time to all-cause death, CV death and hospitalization for heart failure
-
Change from baseline in eGFR over time
-
Baseline characteristics 
Data sources:
Patients’ data will be collected by electronic Case Report Form on 
Electronic Data Capture system
Study size:
1000 (safety set)
Data analysis:
Descriptive statistics will be summarised for safety and effectiveness. 
Milestones:
Planned start of data collection: 1 APR 2022
Planned end of data collection: 30 JUN 2024
Study Report planned to be archived in 1-2Q 2025

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5.
AMENDMENTS AND UPDATES
Number
Date
Section of 
study 
protocol
Amendment or update
Reason
1
16 December 
2021
3
Updated Medical 
adviser
Administrative 
update
6
Added registration in 
the EU PAS register
Registration to
EU PAS
9.3.1
Added the rationale 
for observation period
Directions
from PMDA
9.3.3, Annex 
2
Added covariate items 
(patient status,
hospitalization 
history, device usage, 
underlying disease, 
exercise, diet therapy, 
water intake 
management, BNP)
Directions
from PMDA
2
5 October 2023
Annex 3
Amendment (non-
substantial)
Attached ENCePP 
checklist due to 
CAPA corrective 
action. This 
amendment is non-
substantial and 
categorized as 
unnecessary to be 
submitted to 
PMDA
3
1 April 2024
9.6
Amendment (non-
substantial)
Contract 2 of 9.6 
DATA 
MANAGEMENT
was changed from 
1 April 2024. This 
amendment is non-
substantial and 
categorized as 
unnecessary to 
submit to PMDA

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6.
MILESTONES
Milestone
Planned Date
Start of data collection
1 April 2022
End of data collection
30 June 2024
Registration in the EU PAS 
register
22 November 2021
Final report of study results:
1-2Q 2025

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7.
RATIONALE AND BACKGROUND
Heart failure (HF) is a progressive and potentially fatal condition that is affecting over 60 
million people worldwide and expected to increase as the population ages. HF is a major and 
growing public health problem in the developed countries.  In Japan, approximately 1.2 
million individuals have HF with an estimated prevalence of 1% (R20-3363, R20-0158).
Empagliflozin outcome trial in patients with CHF with reduced ejection fraction 
(EMPEROR-Reduced; BI trial number 1245.121 (P20-07681)) 3 compared empagliflozin 10 
mg once daily treatment with placebo as add-on to standard of care treatment in patients with 
HFrEF (left ventricular ejection fraction (LVEF) ≤40%), regardless of baseline diabetes 
status. The risk of cardiovascular death or hospitalisation for heart failure (primary endpoint) 
was significantly reduced with empagliflozin treatment. As shown in the testing hierarchy for 
the two key secondary endpoints, empagliflozin was also superior to placebo in reducing the 
risk of recurrent hospitalisation for heart failure and in slowing renal function decline as 
assessed by eGFR slope of change, the latter accompanied by less frequent renal outcome 
events. These benefits were consistent for patients with and without type 2 diabetes mellitus. 
The results from the adverse events and safety laboratory analyses were similar to the known 
safety profile of empagliflozin. Of the 3730 patients enrolled in EMPEROR-Reduced, 144 
patients in the empagliflozin group were enrolled from Japan. As there is limited number of 
Japanese patients with NYHA III (15 patients) or IV (0 patient), eGFR <45 mL/min/1.73m2
(37 patients) and without type 2 diabetes (74 patients) in EMPEROR-Reduced, PMDA 
requested to collect more safety information of those patients.
This Post Marketing Surveillance (PMS) with 1,000 patients has been planned to collect the 
safety data (especially hypoglycaemia, the events relevant volume depletion, influence of 
ketone body increased / ketoacidosis, renal impairment ) according to the Safety 
Specification on the J-RMP and PMDA’s request. PMDA also required to collect information 
on effectiveness related survey items (all-cause death, CV death, hospitalizations for heart 
failure) in this study. They asked us to confirm the occurrence of all-cause death and CV 
death in real world because the number of all-cause death in the empagliflozin group was 
higher than in placebo group in Japanese patients in 1245.121. However, they thought the 
effectiveness related survey items were not considered to be serious issue and control group 
(comparator) was not necessary. We estimate that the study will collect the safety data from 
patients with NYHA III-IV (50 patients), eGFR <45 mL/min/1.73m2 (more than 100 patients) 
and without type 2 diabetes (500 patients) referring to the epidemiological surveys in Japan 
(R20-3363, R21-3494, R20-3355, R21-3495, R21-3496) and Japanese patients of 
EMPEROR-Reduced (P20-07681).
In Japan, post-approval execution of Post Marketing Surveillance (PMS) is requested by the 
Japanese Pharmaceuticals and Medical Devices Act (J-PMD Act) in order to accumulate 
safety and efficacy data for re-examination. Re-examination period is defined by J-PMD Act. 
Four years after approval of combination drugs, results of PMS need to be submitted as a part 
of re-examination dossier to the Japanese regulatory authority, the Ministry of Health, Labour 
and Welfare (MHLW). 

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Collected data from PMS will be included in the Japanese periodic safety reports and 
submitted to MHLW on designated dates until the end of re-examination period.
The protocol may be revised because of new information or knowledge obtained in the course 
of conducting PMS. When a change of the approved label such as in dosage and 
administration or indications is made during the re-examination period of JARDIANCE®
Tablets (except that for this change a re-examination period is newly designated by MHLW) 
and
 finds it necessary to revise this protocol, 
handling each matter should be discussed and the protocol may be revised. If any issue or 
concern arises (e.g. suggestion of a potential for clinically significant adverse reaction, 
remarkable increase in incidence of an adverse reaction, or any issue or concern on safety or 
efficacy assessment made prior to the approval of JARDIANCE® Tablets) in the course of 
PMS, implementation of additional special surveillance or post-marketing clinical trial should 
be discussed to identify or confirm a cause or estimated cause of such issue. Special 
surveillance is defined by J-PMD Act. It means surveillance for long-term use or special 
patient population (elderly, renal/hepatic dysfunction etc.). 

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8.
RESEARCH QUESTION AND OBJECTIVES
Study objective is to investigate the safety and effectiveness of long-term daily use of 
JARDIANCE® Tablets in patients with CHF under real-world use.
The primary outcome of this study is the incidence of any adverse drug reactions (ADRs) 
(focus on hypoglycaemia, the events relevant volume depletion, influence of ketone body 
increased / ketoacidosis, renal impairment) (see section 9.3.2).
9.
RESEARCH METHODS
9.1
STUDY DESIGN
This is a non-interventional study based on newly collect data of patients under routine care
to confirm safety and effectiveness of JARDIANCE® Tablets in real-world setting in 
Japanese patients with CHF.
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 JARDIANCE® Tablets are available for prescription.
Planned number of site: Approximately 200 Sites (including CV internal medicine)
A medical representative will explain the objective and design of this study to investigators at 
each study site and conclude a written contract with the head of the study site (e.g., hospital 
director).  
9.2.2
Study population
As this is a non-interventional study, no specific treatment is mandated or withheld from the 
patients. No limitations are set up on background factors and their concomitant drugs in use 
of actual medical practice. 
Inclusion criteria
-
Patients with CHF failure who are prescribed with JARDIANCE® Tablets in Japan. 
-
Patients who have never been treated with Empagliflozin (including treatment for T2DM) 
before enrolment.
Exclusion criteria
None

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Registration period
From April 2022 to March 2023
9.2.2.1
Patient registration method
The registration method will be a central registration system. Patients who begin treatment 
with JARDIANCE® Tablets after the conclusion of the contract will be registered by entering 
necessary information in the Electronic Data Capture (EDC) system within 14 days from the 
day of treatment initiation (inclusive).
Patient registration will be stopped when the overall target number of patients for the study is 
reached. 
9.2.3
Study visits
The study will consist of a baseline visit and further visits in a 52-week follow-up for patients 
who have initiated JARDIANCE® Tablets treatment. The follow-up data (safety and 
administration of JADRIANCE®) from patients who change hospital and continue taking 
JADRIANCE® will be collected by participating investigators if possible.
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 overall goals or goals at a particular study site. 
2.
Emergence of any effectiveness/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 Non-interventional 
Study protocol, or the contract by 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 JARDIANCE® Tablets is estimated as time from the day JARDIANCE® Tablets 
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 JARDIANCE® Tablets will be followed up to 52 weeks.
For the Japanese  population of Study 1245.121, the estimated cumulative incidence 
functions (all-cause death being taken into consideration as competing risk) at approximately 

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one year (360 days) and last assessment or censored after treatment were approximately 0.7% 
and 2.0% for hypoglycemic events and approximately 8% and 14% for volume depletion  in 
the empagliflozin group. No estimated cumulative incidence function was calculated for the 
effect of increased ketone body/ketoacidosis or acute renal failure (For acute renal failure, the 
estimated cumulative incidence functions [all-cause death being taken into consideration as 
competing risk] at approximately one year [360 days] and last assessment or censored after 
treatment were approximately 7% and 16% in the empagliflozin group for the entire 
population of Study 1245.121. In addition, in empagliflozin group for Japanese population, 
13 patients occurred acute renal failure). For these events, there was no tendency for an 
increase in the estimated cumulative incidence function between at approximately one year 
[360 days] after treatment and at last assessment or censored from approximately one year 
[360 days] after treatment. In the empagliflozin group of the Japanese population of Study 
1245.121, the incidences of adverse events of hypoglycemia, volume depletion and acute 
renal failure were 1.54, 9.35, and 6.95 (/100 patient-years), respectively. The incidences of 
all-cause death, CV death, and hospitalizations for heart failure at Year 1 was 3.1%, 2.3%, 
and 6.2%, respectively. Assuming that the proportions of these events for this study are the 
same as in 1245.121 described above, the estimated incidences of events of hypoglycemia, 
volume depletion, acute renal failure, all-cause death, CV death, and hospitalizations for heart 
failure at 1 year are 10, 94, 70, 30, 23,62 patients, respectively in this study. The incidence of 
ketoacidosis is very low so that collected cases will be individually examined.
If the number of events for the analysis is sufficient, a subpopulation analysis will be 
performed and considered as much as possible. For events in which the number of collected 
patients is small, the patients with events will be examined individually.
Based on these considerations, setting the observation period to one year in this study is 
found to be appropriate because the applicant assumes that the one-year observation period 
enables to sufficiently collect adverse drug reactions requiring additional pharmacovigilance 
activities in the Japanese population.
9.3.2
Outcomes
9.3.2.1
Primary outcomes
The primary endpoint of this study is the incidence of ADRs (focus on hypoglycaemia, the 
events relevant volume depletion, influence of ketone body increased / ketoacidosis, renal 
impairment).
ADRs definition and reporting is described in section 11.
There is no primary outcome for effectiveness as the primary objective of a PMS is 
evaluating safety.
9.3.2.2
Secondary outcomes
-
Incidence of all-cause death
-
Incidence of CV death
-
Incidence of hospitalizations for heart failure 

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9.3.3
Covariates
The following variables based on physician’s report will be considered important baseline 
characteristics and potential risk factors for the outcomes of interest.
Demographics:
Patient status (inpatient/outpatient), Gender, year of birth, indication, pregnancy status, 
height, body weight, Body Mass Index (derived), hypersensitivity factor (pick up from 
medical history and concomitant disease data), diagnosed date of HF, NYHA 
classification, NT-proBNP, LVEF, alcohol habit, smoking history, degree of renal/hepatic 
functions at baseline, T2DM (diagnosed date) , dates of previous hospitalisations for heart 
failure, device usage (cardiac pacemaker, implantable cardioverter defibrillator, cardiac 
resynchronization therapy, other)
Medical history / Concomitant disease:
Underlying disease (ischemic heart disease (angina pectoris, myocardial infarction, other) / 
non-ischemic heart disease (hypertensive, valvular, idiopathic cardiomyopathy, other), 
hypertension, stroke, atrial fibrillation, hyperlipidemia, hyperuricemia, malignancy, 
hypersensitivity factor, others
Previous / Concomitant drugs and therapies: 
Previous drugs (in the 3 months before newly starting JARDIANCE® Tablets):
HF, T2DM, others
Dose, daily frequency, start and end date
Concomitant drugs and therapies:
HF, T2DM, others
Dose, daily frequency, start and end date, reason for use, route of administration
Exercise, diet therapy and water intake management  
Start and end date, compliance
Administration of JARDIANCE® Tablets: 
Dose, daily frequency, start and end date, primary reason of discontinuation, reason for 
changing hospital, compliance
Echocardiography:

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Left ventricular ejection rate, left ventricular end-diastolic diameter (LVEDD), left 
ventricular end-systolic diameter (LVESD), left atrial dimension, early diastolic left 
ventricular filling velocity (E peak), peak atrial filling velocity (A peak), Early-diastolic 
mitral annular velocity (e’)
Blood pressure and pulse rate (if applicable):
Systolic / diastolic blood pressure, pulse rate
Physical examination:
Body weight, grip strength
Laboratory tests (blood biochemistry and urinalysis) (if applicable):
Haematology: 
Erythrocyte count (RBC), haemoglobin (Hb), haematocrit (Hct),
leukocyte counts (WBC), leukocyte fraction (Neutrophil count, 
lymphocyte count), platelet count
Blood chemistry: HbA1c (NGSP), fasted blood glucose, creatinine (CRE), 
                              aspartate transaminase (AST, SGOT), alanine transaminase (ALT, 
                              SGPT), alkaline phosphatase (ALP), gamma-glutamyl-transferase
                             (-GTP), albumin, total bilirubin (T-BIL), blood urea nitrogen (BUN), 
                             total cholesterol (T-CHO), HDL cholesterol (HDL), LDL cholesterol
                            (LDL), Triglycerides (TG), uric acid (UA), ketone, BNP, NT-proBNP
Urinalysis:
Glucose, protein, albumin, ketone, creatinine.
Body Mass Index (BMI):
BMI（kg/m2）=  weight(kg) / height2 (m2)
Grades for renal dysfunction are as follows. eGFR will be derived from serum 
creatinine.
Normal: 
eGFR ≥90 mL/min/1.73m2
Mild: 
eGFR ≥60 mL/min/1.73m2 and <90 mL/min/1.73m2
Moderate: 
eGFR ≥30 mL/min/1.73m2 and <60 mL/min/1.73m2
Severe: 
eGFR <30 mL/min/1.73m2
Investigator should judge the grade for hepatic dysfunction by using lab data category
as described below and symptoms/concomitant diagnoses.
Normal: 
Normal AST/ALT
Mild: 
AST/ALT >ULN and <3x ULN
Moderate:
AST/ALT≥3xULN and <5x ULN + total Bil<= 2xULN
Severe:
AST/ALT≥5 xULN, or AST/ALT≥3xULN and <5x ULN + total Bil>
2xULN
ULN is taken from the corporate standard reference range (BI-KMED-BDS-HTG-
0042 Handling, Display and Analysis of Laboratory Data).

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Enzymatic method:
eGFR（mL/min/1.73 m2）= 194×Creatinine (mg/dL) - 1.094×Age-0.287
For female, ×0.739
Jaffe rate assay:
eGFR（mL/min/1.73 m2）= 175×Creatinine (mg/dL) 
－1.154×Age
－0.203
For female, ×0.742
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
EDC system.
In EDC system, two casebooks will be set:
Book 1 includes baseline, 12 weeks and 26 weeks. 
Book 2 includes 40 weeks and 52 weeks.
The data are to be transmitted immediately after being entered into EDC at 26 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
1000 patients will be included in the study. 1200 patients will be enrolled.
Because there is no hypothesis for this study, no sample size calculation is conducted based 
on the statistical test. The observed proportions of confirmed hypoglycaemia, ketoacidosis 
(narrow BIcMQ), fluid volume depletion (narrow BIcMQ), and acute renal failure (narrow 
SMQ) in the empagliflozin group in the Japanese population of the EMPEROR-Reduced 
study were 1.4% (2/144), 0% (0/144), 11.8% (17/144), and 9% (13/144), respectively.  Also, 
the proportions of patients with heart failure in the empagliflozin group in the Japanese 
population in the EMPEROR-Reduced study who had NYHA III or IV and eGFR <45 
mL/min/1.73m2, and no type 2 diabetes were 10.4% (15/144), 25.7% (37/144), and 51.4%, 
respectively. The proportions of adverse events in the empagliflozin group observed in the 
Japanese population in the EMPEROR-Reduced study described above are assumed to be the 
true proportions of adverse events, while to be conservative, the proportions of risk factors 
(NYHA III or IV, eGFR <45 mL/min/1.73m2, no type 2 diabetes) of 5% (50/1000), 10% 
(100/1000), and 50% (500/1000) based on the epidemiological surveys in Japan (R20-3363, 
R21-3494, R20-3355, R21-3495, R21-3496) are assumed to be the true proportions of risk 
factors in this study.

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Assuming that the odds ratio of "yes" to "no" is 2, the power to detect a difference in a 
specific risk factor at a two-sided significance level of 5% when 1000 Japanese patients are 
included in the study is given by the values in Table 1. In calculating the power, we used the 
normal approximation formula of the two-sample binomial test for the difference in the 
proportions of the risk factors "yes" and "no" considered as two independent samples.

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Table 1
Power to detect a difference in a specific risk factor at a two-sided 
significance level of 5% when 1000 Japanese patients are included in 
the study is given by the values
The true proportions of adverse events
1.4% 
(hypoglycaemia)
9%
(acute renal failure)
11.8%
(fluid volume 
depletion)
The true 
proportions 
of risk factor 
“yes”
5%
0.190
0.442
0.499
10%
0.242
0.641
0.717
50%
0.325
0.946
0.979
In addition, the upper limits of the 95% confidence intervals (CI) for confirmed 
hypoglycaemia, fluid volume loss, and acute renal failure in the empagliflozin group 
observed in the Japanese population of the EMPEROR-Reduced study were calculated by 
normal approximation to be 0.033, 0.137, and 0.171, respectively (since ketoacidosis are not 
observed in the EMPEROR-Reduced study, the upper limits of the 95% for the ketoacidosis 
was not calculated). In this study, the upper limits of the 95%CI will be less than 0.033, 0.137, 
and 0.171, respectively, when the number of patients with each adverse event was 23, 116, 
and 148 for the total of 1000 cases in this study, indicating that it can be explained that 
incidence rates are not much higher than those observed in the EMPEROR-Reduced study 
with a certain accuracy. Furthermore, in EMPEROR-Reduced study, since limited number of 
patients were exposed by treatment drug, it was difficult to find signal of risk regarding to 
rare adverse events. Therefore, it is meaningful to show probabilities observing at least one 
adverse event. Table 2 shows the probabilities that one or more cases of confirmed 
hypoglycaemia, fluid volume depletion, or acute renal failure will occur, assuming that the 
number of cases with risk factors "Yes" is 50, 100, and 500, respectively, in addition to the 
total of 1000 cases in this study (since ketoacidosis are not observed in the EMPEROR-
Reduced study, the probability for the ketoacidosis was not calculated). For example, if true 
proportion of an AE is 1.4% (hypoglycaemia) and 500 patients who have a specific risk 
factor “Yes” are enrolled into study, probability observing such AE in this study is 99.9%, 
that is almost certainly it can be observed such AE in this study.

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Table 2
Probabilities that one or more cases of confirmed hypoglycaemia, 
fluid volume depletion, or acute renal failure will occur, assuming 
that the number of cases with risk factors "Yes" is 50, 100, and 500, 
respectively, in addition to the total of 1000 cases in this study
The true proportions of adverse events
1.4% 
(hypoglycaemia)
9%
(acute renal 
failure)
11.8%
(fluid volume depletion)
Sample size
50
0.506
0.991
0.998
100
0.756
1
1
500
0.999
1
1
1000
1
1
1
9.6
DATA MANAGEMENT
The data management plan is summarized below. Full details of the data management plan 
are documented in a separate NIS-Data Management and Review Plan (NIS-DMRP).
Patients’ data will be gathered by EDC system provided by external vendor below. 
Contract 1
Contract 2
Company Name
Outsourced work
EDC system setting
Patient registration
Clinical Data Management
Document management of 
contract with site.
9.7
DATA ANALYSIS
This is a non-interventional study to collect data on patients under routine medical practice on 
safety, effectiveness and appropriate use of JARDIANCE® Tablets treatment. The analyses in 
this PMS are descriptive and exploratory by nature. No formal hypotheses tests will be made. 
All analyses will be performed on the “safety set” that will include all patients who have 
received treatment of JARDIANCE® Tablet at least one time except those who are found to 
have no observation after registration, invalid registration, or invalid contract with the site.

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Subgroup analyses will be performed if sample size allows.
The statistical analysis plan for the study is summarized below. Full details of the statistical 
analysis will be documented in the separate statistical analysis plan, which will be finalized 
before the end of data collection.
9.7.1
Main analysis
In this PMS, since the primary endpoint is the incidence of ADRs (focus on hypoglycaemia, 
the events relevant volume depletion, influence of ketone body increased / ketoacidosis, renal 
impairment), the main analysis is to show frequency, proportion and its corresponding 
confidence interval (CI). The details are given in Section 9.7.3.
9.7.3
Safety analysis
The safety analysis will include all patients who registered in the study and receiving the 
JARDIANCE® Tablets treatment at least one time except those who are found to have no 
observation after enrolment, invalid registration, or invalid contract with the site (see section 
9.7). In general, safety analyses will be descriptive, based on BI standards, and focus on AEs 
related to the JARDIANCE® Tablets 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 JARDIANCE® Tablets prescribed at baseline
visit and 7 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 frequency of ADRs will be tabulated by system organ class and preferred term according
to the current MedDRA version. The frequency of SAEs will also be tabulated likewise.
The incidence of ADRs stratified based on patient demographics will also be displayed.

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No imputation is planned for missing AE data except for missing onset dates which will be 
handled according to BI standard.
9.8
QUALITY CONTROL
All processes are conducted according to GPSP Standard Operating Procedures (SOP). 
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 design which uses 
a single cohort in this observational safety study, a potential limitation is the absence of 
comparator groups, such as active treatments or natural progression of disease. Moreover, 
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 and information and recall 
bias.
9.10
OTHER ASPECTS
9.10.1
Data quality assurance
This PMS study 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
CRFs for individual patients will be provided by the sponsor via 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 study 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
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-PMD Act 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 the 
responsibility of the patient’s treating physician.
10.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT
The review by Institutional Review Board 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 BI-VQD-12562_05-501_AD-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 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 AE 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 AE 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 SAE 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. Every new occurrence 
of cancer or an exacerbation of an existing cancer will be reported as a SAE regardless of the 
duration between discontinuation of the drug and the occurrence of the cancer.
No AESIs have been defined for this study.

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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 authorization. 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 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 AE. An adverse reaction, in 
contrast to an AE, is characterized 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 JARDIANCE® Tablets, 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 Non-interventional Study AE form is to be completed and forwarded as well as 
soon as possible. 
Priority survey items:
Hypoglycaemia, the events relevant volume depletion, influence of ketone body increased / 
ketoacidosis, renal impairment
Information required
For each reportable adverse event, the investigator should provide the information requested
on the appropriate (e)CRF pages.

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Reporting of related Adverse Events associated with any other BI drug
The investigator is encouraged to report all AEs related to any BI drug other than
JARDIANCE® Tablets, 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 the 
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 Periodic
safety report. And also the final 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 study are described in the contract. As a general rule, no PMS study results should be 
published prior to finalization 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 JARDIANCE® Tablets.

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13.
REFERENCES
13.1
PUBLISHED REFERENCES
R20-3363 Japan Circulation Society. Guidelines for Diagnosis and Treatment of Acute and 
Chronic Heart Failure. 2017
R20-0158 Okura Y, Ramadan MM, Ohno Y, et al. Impending Epidemic: Future Projection 
of Heart Failure in Japan to the Year 2055. Circ J 2008; 72:489-491.
P20-07681 Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with 
empagliflozin in heart failure. New Engl J Med 2020;383(15):1413-1424.
R21-3494 Tsuchihashi-Makaya M, Hamaguchi S, Kinugawa S, et al. and for the JCARE-
CARD Investigators. Characteristics and Outcome of Hospitalized Patients With 
Heart Failure and Reduced vs Preserved Ejection Fraction - A Report From the 
Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) -. Circ 
J 2009; 73: 1893-1900.
R20-3355 Shiba N, Nochioka K, Miura M, et al. on behalf of the CHART-2 Investigators. 
Trend of Westernization of Etiology and Clinical Characteristics of Heart Failure 
Patients in Japan - First Report From the CHART-2 Study -. Circ J 2011; 75: 823-
833. 
R21-3495 Hamaguchi S, Tsuchihashi-Makaya M, Kinugawa S, et al. for the JCARE-CARD 
Investigators. Chronic Kidney Disease as an Independent Risk for Long-Term 
Adverse Outcomes in Patients Hospitalized With Heart Failure in Japan -Report 
From the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-
CARD)-. Circ J 2009; 73: 1442-1447.
R21-3496 Shiba N, Matsuki M, Takahashi J, et al. Prognostic Importance of Chronic 
Kidney Disease in Japanese Patients With Chronic Heart Failure -Implications of 
the CHART Study-. Circ J 2008; 72: 173-178.
13.2
UNPUBLISHED REFERENCES
BI-KMED-BDS-HTG-0042 “Handling, Display and Analysis of Laboratory Data”, current 
version, KMED.
BI-VQD-12562_05-501_AD-01
Individual Case Safety Report (ICSR) collection,         
processing and reporting by Source, current version.

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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 CHARTS OF VARIABLES
Time point
Item
Observation period *1
Before first 
administration of
JARDIANCE®
Tablets
Week 12
Week26
Week 40
Week 52 or at 
discontinuation
Registration
X*2
Demographics
X
Physical examination
(Body weight, height, grip 
strength)
(X)
(X*3)
(X*3)
(X*3)
(X*3)
Concomitant disease/
medical history
X
Prior HF / T2DM drugs
X*4
Administration status of
JARDIANCE® Tablets
X (Record throughout the observation period)
Concomitant drug and 
therapy
X*
X (Record throughout the observation period)
Blood pressure, pulse rate
and Echocardiography
(X)
(X)
(X)
(X)
(X)
Pregnancy status*5
X (confirm throughout the observation period)
X (confirm throughout the 
observation period)
Laboratory tests
(X)
(X)
(X)
(X)
(X)
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 JARDIANCE® Tablets should be registered within 14 days from the day of first 
administration.
*3: Body weight and grip strength
*4: From 3 month before first administration of JARDIANCE® Tablets
*5: Only for female patients
(X): If applicable
eCRF (electronic case report form): At 26 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.

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ANNEX 3. ENCEPP CHECKLIST FOR STUDY PROTOCOLS

BOEHRINGER INGELHEIM Group of Companies
NIS Protocol
Page 36 of 40
BI Study Number 1245.286
c37302912-04
Proprietary confidential information © 2024 Boehringer Ingelheim Group of companies
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020

BOEHRINGER INGELHEIM Group of Companies
NIS Protocol
Page 37 of 40
BI Study Number 1245.286
c37302912-04
Proprietary confidential information © 2024 Boehringer Ingelheim Group of companies
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020

BOEHRINGER INGELHEIM Group of Companies
NIS Protocol
Page 38 of 40
BI Study Number 1245.286
c37302912-04
Proprietary confidential information © 2024 Boehringer Ingelheim Group of companies
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020

BOEHRINGER INGELHEIM Group of Companies
NIS Protocol
Page 39 of 40
BI Study Number 1245.286
c37302912-04
Proprietary confidential information © 2024 Boehringer Ingelheim Group of companies
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020

BOEHRINGER INGELHEIM Group of Companies
NIS Protocol
Page 40 of 40
BI Study Number 1245.286
c37302912-04
Proprietary confidential information © 2024 Boehringer Ingelheim Group of companies
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c37302912
4.0
1245-0286-non-interventional-study-protocol
Post Marketing Surveillance on Long Term Drug Use of JARDIANCE® Tablets in
Patients with chronic heart failure in Japan.
Approval-Clinical Trial Leader
04 Apr 2024 07:37 CEST

Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c37302912
4.0