A Regulatory Requirement Non Interventional Study to Monitor the Safety and Effectiveness of JARDIANCE® (Empagliflozin, 10mg, 25mg, q.d.) in Korean Patients With Type 2 Diabetes Mellitus
Conditions: Diabetes Mellitus, Type 2
Sponsor: Boehringer Ingelheim

ABCD
TITLE PAGE
NON-INTERVENTIONAL STUDY PROTOCOL
TITLE PAGE
Document Number:
c09963608-06
BI Study Number:
1245.116
BI Investigational
Product:
JARDIANCE® (empagliflozin)
Title:
A regulatory requirement non interventional study to monitor the 
safety and effectiveness of JARDIANCE® (empagliflozin 10mg, 
25mg) in Korean patients with type 2 diabetes mellitus
Brief lay title
JARDIANCE® rPMS in Korean patients with type 2 diabetes
mellitus
Protocol version 
identifier:
6.0
Date of last version of 
protocol:
21 Aug 2017
PASS:
Yes
EU PAS register 
number:
EUPAS13627
Active substance:
empagliflozin
Medicinal product:
JARDIANCE® film-coated tablets 10mg, 25mg
Product reference:
Not applicable
Procedure number:
Not applicable
Marketing authorisation 
holder:
Boehringer Ingelheim Korea
Joint PASS:
Not applicable
Research question and 
objectives:
To monitor the safety profile and effectiveness of JARDIANCE®
in Korean patients with type 2 diabetes mellitus in a routine 
clinical practice setting
Country of study:
Multi-Centre study conducted in Korea

Boehringer Ingelheim
Page 2 of 43
Non-Interventional Study Protocol 
BI Study Number 1245.116
c09963608-06
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
tmAuthor:
NIS Specialist
Phone: 
   Fax: 
Marketing authorisation 
holder:
MAH contact person:
EU-QPPV:
Signature of EU-
QPPV:
Not applicable
Date:
23 Nov 2017
Page 1 of 43
Proprietary confidential information
© 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission

Boehringer Ingelheim
Page 3 of 43
Non-Interventional Study Protocol 
BI Study Number 1245.116
c09963608-06
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
TABLE OF CONTENTS
1.
TITLE PAGE ................................................................................................................ 1
1.
TABLE OF CONTENTS .................................................................................... 3
2.
LIST OF ABBREVIATIONS ............................................................................. 6
3.
RESPONSIBLE PARTIES ................................................................................. 8
4.
ABSTRACT.......................................................................................................... 9
4.1
FLOW CHART............................................................................................. 12
5.
MILESTONES................................................................................................... 13
6.
RATIONALE AND BACKGROUND ............................................................. 14
6.1
RATIONALE ................................................................................................ 14
6.2
BACKGROUND ........................................................................................... 14
6.3
DRUG PROFILE .......................................................................................... 15
7.
RESEARCH QUESTION AND OBJECTIVES ............................................. 16
7.1
PRIMARY OBJECTIVE ............................................................................. 16
7.2
SECONDARY OBJECTIVE ....................................................................... 16
8.
RESEARCH QUESTION AND OBJECTIVES ............................................. 17
8.1
STUDY DESIGN........................................................................................... 17
8.1.1
Method of assigning patients to treatment groups............................. 17
8.1.2
Dosage and Administration.................................................................. 17
8.1.3
Concomitant therapy, Restrictions, And rescue................................. 18
8.1.3.1
Rescue medication, emergency procedures, and additional treatments18
8.2
SETTING....................................................................................................... 18
8.2.1
Study sites............................................................................................... 18
8.2.2
Study population ................................................................................... 19
8.2.2.1
Main diagnosis for study entry......................................................... 19
8.2.2.2
Inclusion criteria: ............................................................................. 19
8.2.2.3
Exclusion criteria: ............................................................................ 19
8.2.2.4
Subjects of special investigation ...................................................... 19
8.2.3
Study visits ............................................................................................. 19
8.2.3.1
Screening and run-in periods ........................................................... 19
8.2.3.2
Visit 1; Baseline Visit ...................................................................... 19
8.2.3.3
Visit 2; 12 weeks from Visit 1 ......................................................... 20
8.2.3.4
Visit 3; 24 weeks from Visit 1 ......................................................... 21

Boehringer Ingelheim
Page 4 of 43
Non-Interventional Study Protocol 
BI Study Number 1245.116
c09963608-06
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
8.2.3.5
End of study ..................................................................................... 21
8.2.3.6
Follow-up period.............................................................................. 21
8.2.4
Study discontinuation ........................................................................... 22
8.3
VARIABLES ................................................................................................. 22
8.3.1
Analysis sets ........................................................................................... 22
8.3.1.1
Number of cases subject who entered the study .............................. 22
8.3.1.2
Number of cases subject to CRF collection ..................................... 22
8.3.1.3
Number of cases subject to safety evaluation .................................. 22
8.3.1.4
Number of cases subject to efficacy evaluation............................... 23
8.3.2
Endpoints ............................................................................................... 23
8.3.2.1
Endpoints of safety........................................................................... 23
8.3.2.2
Endpoints of effectiveness ............................................................... 23
8.3.3
Assessment criteria................................................................................ 24
8.3.3.1
Assessment of safety........................................................................ 24
8.3.3.2
Assessment of efficacy..................................................................... 24
8.3.4
Items of Investigation............................................................................ 25
8.3.4.1
Demographic data ............................................................................ 25
8.3.4.2
Medical/Surgical history and pre-treatment experience .................. 25
8.3.4.3
Concomitant medication .................................................................. 26
8.3.4.4
Drug administration status ............................................................... 26
8.3.4.5
Information on the site ..................................................................... 26
8.4
DATA SOURCES ......................................................................................... 26
8.5
STUDY SIZE................................................................................................. 26
8.6
DATA MANAGEMENT .............................................................................. 27
8.7
DATA ANALYSIS ........................................................................................ 27
8.7.1
Analysis of demographic data.............................................................. 27
8.7.2
Safety analysis........................................................................................ 27
8.7.2.1
Adverse Events by preferred Terms (AEs/ADRs/SAEs)................. 28
8.7.3
Efficacy analysis .................................................................................... 29
8.7.4
Interim analyses..................................................................................... 29
8.7.5
Handling of missing data...................................................................... 29
8.8
QUALITY CONTROL................................................................................. 29
8.9
LIMITATIONS OF THE RESEARCH METHODS ................................ 30
8.9.1
Loss to follow-up.................................................................................... 30
8.9.2
Channeling bias ..................................................................................... 30

Boehringer Ingelheim
Page 5 of 43
Non-Interventional Study Protocol 
BI Study Number 1245.116
c09963608-06
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
8.9.3
Confounding .......................................................................................... 30
8.10
DATA PROTECTION, STUDY RECORDS ............................................. 30
8.10.1
Data quality assurance.......................................................................... 31
8.10.2
Study records......................................................................................... 31
8.10.2.1
Source documents ............................................................................ 31
8.10.2.2
Direct access to source data and documents .................................... 32
8.10.2.3
Storage period of records ................................................................. 32
9.
PROTECTION OF HUMAN SUBJECTS ...................................................... 33
9.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ..................................................................................................... 33
9.2
STATEMENT OF CONFIDENTIALITY.................................................. 33
10.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ..................................................................................................... 34
10.1
DEFINITIONS OF ADVERSE EVENTS................................................... 34
10.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION 
AND REPORTING....................................................................................... 36
10.3
REPORTING TO HEALTH AUTHORITIES .......................................... 39
11.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY 
RESULTS........................................................................................................... 40
12.
REFERENCES................................................................................................... 41
12.1
PUBLISHED REFERENCES...................................................................... 41
12.2
UNPUBLISHED REFERENCES................................................................ 41
13.
APPENDICES.................................................................................................... 42
13.1
ELECTRONIC CASE REPORT FORM ................................................... 42
13.2
SAE/ NON-SERIOUS ADVERSE REACTION REPORT....................... 42
13.3
PREGNANCY MONITORING FORM ..................................................... 42
13.4
JARDIANCE® PRESCRIPTION INFORMATION FOR KOREA........ 42
14.
AMENDMENTS AND UPDATES................................................................... 43

Boehringer Ingelheim
Page 6 of 43
Non-Interventional Study Protocol 
BI Study Number 1245.116
c09963608-06
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
LIST OF ABBREVIATIONS
2.
ACR
Albumin Creatinine Ratio 
ADR
Adverse Drug Reaction 
AE
Adverse Event 
AESI
Adverse Event of Special Interest
ASAE
Always Serious Adverse Events
ASD
Absolute Standardized Differences 
BI
Boehringer Ingelheim 
BP
Blood Pressure 
CA
Competent Authority 
CML
Local Clinical Monitor 
CRA
Clinical Research Associate 
CRO
Contract Research Organization 
CTP
Clinical Trial Protocol 
CTR
Clinical Trial Report 
DKA
Diabetic Ketoacidosis
DMP
Data Management Plan 
eCRF
Electronic Case Report Form 
EDC
Electronic Data Capture 
eGFR
Estimated Glomerular Filtration Rate 
EU
European Union 
EU PAS
European Union electronic register of post-authorization studies 
EU-QPPV
European Union-Qualified Person for Pharmacovigilance 
FPG
Fasting Plasma Glucose 
GCP
Good Clinical Practice 
GLUT
Glucose Transporter 
GPP
Good Pharmacy Practice 
HbA1c
Glucosylated Hemoglobin 
HDL-C
High Density Lipoprotein Cholesterol 
IC50
Inhibitory Concentration  
ICH
International Conference on Harmonisation 
IEC
Independent Ethics Committee 

Boehringer Ingelheim
Page 7 of 43
Non-Interventional Study Protocol 
BI Study Number 1245.116
c09963608-06
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
IRB
Institutional Review Board 
ISF
Investigator Site File 
LDL-C
Low Density Lipoprotein Cholesterol 
LPVM
Local PV Manager 
MAH
Marketing Authorisation Holder Activities 
MedDRA
Medical Dictionary for Drug Regulatory Activities 
MFDS
The Ministry of Food and Drug Safety 
NCE
New Chemical Entity 
NIS
Non-Interventional Study 
NSADR
Non Serious Adverse Drug Reaction 
OPU
Operative Unit 
PASS
Post Authorization Safety Studies 
SADR
Serious Adverse Drug Reaction 
SAE
Serious Adverse Event 
SAP
Statistical Analysis Plan 
SGLT2
Sodium-dependent Glucose Co-transporter 2 
SOP
Standard Operating Procedure 
SUSAR
Suspected Unexpected Serious Adverse Reactions 
T2DM
Type 2 Diabetes Mellitus 
TC
Triglycerides 
T-Chol
Total Cholesterol 
TCM
Trial Clinical Monitor  
TMF
Trial Master File 
TMM
Team Member Medicine 
UTI
Urinary Tract Infection 

Boehringer Ingelheim
Page 8 of 43
Non-Interventional Study Protocol 
BI Study Number 1245.116
c09963608-06
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
RESPONSIBLE PARTIES
3.
Boehringer Ingelheim (BI) has appointed a Trial Clinical Monitor (TCM), responsible for 
coordinating all required activities, in order to

manage the study in accordance with applicable regulations and internal standard 
operating procedures (SOPs).

direct the study team in the preparation, conduct, and reporting of the trial,

order the materials as needed for the study,

ensure appropriate training and information of Local Clinical Monitors (CMLs), 
Clinical Research Associate (CRAs), and Investigators of Korea.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
The organization of the study will be done by a Contract Research Organization (CRO) with 
which the responsibilities and tasks will have been agreed and a written contract filed before 
initiation of the study. A CML will be appointed responsible for coordinating the activities 
required in order to manage the study in accordance with applicable regulations and internal 
SOPs in the countries covered by the respective BI OPU. On-site monitoring will be 
performed by a CRO appointed by BI.
An Investigator Site File (ISF) containing all relevant study related documentation will be
maintained according to local regulations and BI SOPs at each study site. A copy of the ISF 
documents will also be kept as an electronic Trial Master File (TMF) at BI according to BI 
SOPs. Documents related to participating physician and other important participants,
especially their curricula vitae, will be filed in the TMF.

Boehringer Ingelheim
Page 9 of 43
Non-Interventional Study Protocol 
BI Study Number 1245.116
c09963608-06
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
ABSTRACT
4.
Name of company:
Boehringer Ingelheim Korea
Name of finished medicinal 
product:
JARDIANCE®
Name of active ingredient:
empagliflozin
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
27 May 2016
1245.116
6.0
23 Nov 2017
Title of study:
A regulatory requirement non interventional study to monitor the 
safety and effectiveness of JARDIANCE® (empagliflozin, 10mg, 
25mg) in Korean patients with type 2 diabetes mellitus
Rationale and 
background:
According to the local regulations, when a new chemical entity (NCE) 
is registered, a regulatory non interventional study (NIS) of an 
extended period (6 years) should be conducted. A rNIS can provide 
supplementary data to monitor the safety of NCEs in a real-life 
situation. Data collected in randomized clinical study with strict 
inclusion/exclusion criteria and rigorous monitoring schemes have 
limitations.
Research question 
and objectives:
To monitor the safety profile and efficacy of JARDIANCE®
(empagliflozin, 10mg, 25mg) in Korean patients with type 2 diabetes
mellitus in a routine clinical practice setting
Study design:
Observational prospective, non-interventional, open-label, multi-centre 
study
Population:
Patients diagnosed with type 2 diabetes mellitus in Korea
Inclusion criteria:

Patients who have started at first time on JARDIANCE® in 
accordance with the approved label in Korea

Age ≥19 years at enrolment

Patients who have signed on the data release consent form
Exclusion criteria:

Known hypersensitivity to empagliflozin or any of its 
excipients

Patients with type 1 diabetes or for the treatment of diabetic 
ketoacidosis

Patients with persistent eGFR<60 mL/min/1.73 m2,end stage 
renal disease or on dialysis

Patients with rare hereditary conditions of galactose 
intolerance, the Lapp lactase deficiency or glucose-
galactosemalabsorption

Patients for whom empagliflozin is contraindicated according 
local label of JARDIANCE®
Variables:
Endpoints of safety

Boehringer Ingelheim
Page 10 of 43
Non-Interventional Study Protocol 
BI Study Number 1245.116
c09963608-06
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim Korea
Name of finished medicinal 
product:
JARDIANCE®
Name of active ingredient:
empagliflozin
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
27 May 2016
1245.116
6.0
23 Nov 2017
All reported adverse events in patients who take at least one dose of 
JARDIANCE® will be noted.
Endpoints of effectiveness
Change from baseline in HbA1c, fasting plasma glucose (FPG), body 
weight, blood pressure (SBP, DBP) after 12weeks and/or 24 weeks of 
treatment and the final efficacy evaluation at the end of the last visit
will be noted.
Data sources:
Field study with new data collection
Study size:
Single arm (N=3,000 approximately)
A total of 3000 patients will be entered in this study, and each patient 
will be followed for total three times (baseline, short term 12 weeks 
follow up, long term 24 weeks follow up). Since T2DM is chronic 
disease it might be restrictive to collect safety and effectiveness data in 
short-term (12weeks) period, all patients will be enrolled for long-term 
(24weeks) surveillance.
Study sites:
A total of 3,000 patients will be enrolled at approximately 70 sites by 
as many as 70 or more NIS physicians. To minimize the selection bias 
at the site level, the goal is to have participating centers reflect a 
balance between general hospitals and clinics for surveillance. The 
treating physicians will mainly be internists. To minimize the selection 
bias, consecutive patients from each site who meet inclusion criteria 
will be enrolled in this study.
Data analysis:
1) Analysis of demographic data:
Demographic data and the health status of subjects for the safety 
evaluation will be analysed descriptively. For continuous data, mean, 
standard deviation, minimum value, and maximum value will be 
described, while for categorical data, frequency will be shown.
2) Safety analysis : 
In the safety assessment population, the number of subjects to whom 
AE occurred and the number of AEs will be calculated. Also, the 
incidence proportion of AEs will be estimated with its 95% 
confidence interval.
3) Efficacy analysis: 
Mean, standard deviation, minimum value, maximum value, and 
median of changes in glycosylated hemoglobin(HbA1c) and fasting 

Boehringer Ingelheim
Page 11 of 43
Non-Interventional Study Protocol 
BI Study Number 1245.116
c09963608-06
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim Korea
Name of finished medicinal 
product:
JARDIANCE®
Name of active ingredient:
empagliflozin
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
27 May 2016
1245.116
6.0
23 Nov 2017
plasma glucose(FPG), body weight, and blood pressure (SBP, DBP), 
which were measured at the last visit versus baseline, should be 
presented, and if there is difference before administration versus after 
administration should be analyzed using paired t-test. The number 
and percentage of subjects for final efficacy evaluation should be 
mentioned. The final effectiveness evaluation of “Improved” will be 
classified as “Effective”. “Unchanged” and “Aggravated” will be 
classified as “Ineffective”. The effectiveness rate and its 95% 
confidence intervals will be estimated with exact method.
Milestones:
Study duration: 6 years (MFDS set JARDIANCE® re-examination 
period from 12 August 2014 to 11 August 2020). Interim reports:
biannually for the first two years and annually thereafter by November 
2020.

Boehringer Ingelheim
Page 12 of 43
Non-Interventional Study Protocol 
BI Study Number 1245.116
c09963608-06
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
4.1
FLOW CHART
Data points
Baseline
Follow-up 1
Follow-up 2
Visit Number
1
2
3
Week/s
0
12
24
Informed consent
X
Diagnosis
X
Inclusion / exclusion criteria
X
Demographics
X
Family history of T2DM
X
Diabetes mellitus complications
X
Medical history
X
Physical examination
X
X
X
Anti-hyperglycemic agents
X
X
X
Concomitant medications
X
X
X
JARDIANCE® administration status
X
X
X
Renal function
  X A
X A
X A
Effectiveness endpoints
X
X
X
The final efficacy evaluation
X
Changes in lab tests
X A
X A
Adverse events
X
X
Study completion
X
X
A : If available

Boehringer Ingelheim
Page 13 of 43
Non-Interventional Study Protocol 
BI Study Number 1245.116
c09963608-06
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
MILESTONES
5.
Milestone
Planned Date
Start of data collection
01 Aug 2016
End of data collection
11 Aug 2020
Interim report 1
11 Oct 2016
Interim report 2
11 Oct 2017
Interim report 3
11 Oct 2018
Interim report 4
11 Oct 2019
Registration in the EU PAS register
TBD
Final report of study results:
11 Nov 2020

Boehringer Ingelheim
Page 14 of 43
Non-Interventional Study Protocol 
BI Study Number 1245.116
c09963608-06
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
RATIONALE AND BACKGROUND
6.
6.1
RATIONALE
According to the local regulations, when a new chemical entity (NCE) is registered, a 
regulatory non interventional study (NIS) of an extended period (6 years) should be 
conducted. Such rNIS can provide supplementary data to monitor the safety of NCEs in a 
real-life situation. Data collected in randomized clinical study with strict inclusion/exclusion 
criteria and rigorous monitoring schemes have limitations.
This is an observational prospective, non-interventional, open-label, multi-centre national 
study. It will provide additional safety information of JARDIANCE® (empagliflozin) in 
Korean patients with type 2 diabetes mellitus in a routine clinical practice setting.
6.2
BACKGROUND
Type 2 diabetes mellitus (T2DM) is characterized by increased peripheral insulin resistance
and an insulin-secretory defect that varies in severity leading to raised blood glucose levels.
T2DM constitutes 90% to 95% of the diabetic population with an estimated 387 million
people affected worldwide. It is now a common and serious global health problem, which for
most countries has evolved in association with rapid cultural and social changes, ageing
populations, increasing urbanization, dietary changes, reduced physical activity and other
unhealthy lifestyle and behavioural patterns. The incidence of T2DM is expected to increase
to approximately 592 million patients over the next 20 years [R14-4616].
The prevalence of type 2 diabetes mellitus (T2DM) in Korea is estimated to be 7.3% (in those 
over 20 years of age), and it has increased about 5-fold over the past 30 years according to a 
report of the Korea National Health and Nutrition Examination Survey (KNHNES III, 2005) 
[R13-1653]. The number of patients with T2DM is expected to increase dramatically from 
about 3.2 million in 2011 (8.8% of the national population) to about 4.25 million (11.1%) by 
2030 [R12-1019].
JARDIANCE® is a reversible, highly potent and selective competitive inhibitor of SGLT2 
with an IC50 of 1.3 nM. It has a 5000-fold selectivity over human SGLT1 (IC50 of 6278 nM), 
responsible for glucose absorption in the gut. Furthermore high selectivity could be shown 
toward other glucose transporters (GLUTs) responsible for glucose homeostasis in the 
different tissues. [P11-13842]
Empagliflozin improves glycemic control in patients with type 2 diabetes mellitus by
reducing renal glucose reabsorption. The amount of glucose removed by the kidney through
this glucuretic mechanism is dependent upon the blood glucose concentration and GFR
[P12-00692, R11-4288]. Through inhibition of SGLT2 in patients with T2DM and 
hyperglycemia, excess glucose is excreted in the urine.

Boehringer Ingelheim
Page 15 of 43
Non-Interventional Study Protocol 
BI Study Number 1245.116
c09963608-06
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
SGLT2 is highly expressed in the kidney, whereas expression in other tissues is absent or 
very low [P11-13842]. It is responsible as the predominant transporter for reabsorption of 
glucose from the glomerular filtrate back into the circulation [P12-00692]. In patients with 
type 2 diabetes mellitus and hyperglycaemia a higher amount of glucose is filtered and 
reabsorbed. [ra00656956]
The phase III studies have shown that treatment with empagliflozin 10 mg or 25 mg once
daily for up to 24 weeks results in a reduction of HbA1c up to 0.85%, body weight up to 2.2
kg and SBP up to 4.8 mmHg compared to placebo. This was consistently observed with
empagliflozin as monotherapy, add on to metformin, to metformin + sulphonylurea, to
pioglitazone with or without metformin, to multiple daily insulin injection with or without
metformin, and to basal insulin with metformin and/or sulphonylurea.
Empagliflozin was well tolerated in patients with T2DM up to maximum treatment duration 
of 104 weeks in completed studies. Treatment with empagliflozin resulted in a similar 
percentage of overall AEs, severe AEs, and serious AEs compared to placebo and/or active 
comparators. Treatment with empagliflozin showed a higher frequency of genital infections 
and increased urination. In general a small increase in overall urinary tract infections 
frequency was observed with empagliflozin compared to comparators, especially in females. 
The overall hypoglycaemic events were similar with empagliflozin compared to placebo. 
There was a reduction in eGFR which gradually returned toward baseline values over the 
treatment period in the trials. Furthermore, eGFR returned to baseline when empagliflozin 
was discontinued. [c01838761-15]
6.3
DRUG PROFILE
JARDIANCE® is a novel antidiabetic drug that induces dose-dependent glucose excretion by 
inhibiting re-uptake of glucose by the sodium-dependent glucose co-transporter 2 in renal 
proximal tubules.
Treatment with JARDIANCE® as monotherapy and in combination with metformin, 
pioglitazone, sulfonylurea, and insulin lead to clinically relevant improvements in HbA1c, 
fasting plasma glucose, body weight, systolic and diastolic blood pressure (SBP, DBP). 
For a more detailed description of the drug profile refer to the local prescribing information 
of JARDIANCE®.

Boehringer Ingelheim
Page 16 of 43
Non-Interventional Study Protocol 
BI Study Number 1245.116
c09963608-06
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
RESEARCH QUESTION AND OBJECTIVES
7.
7.1
PRIMARY OBJECTIVE
The primary objective of this study is to monitor the safety profile of JARDIANCE® in 
Korean patient with type 2 diabetes mellitus (T2DM) in a routine clinical setting. 
7.2
SECONDARY OBJECTIVE
The secondary objective of this study is to monitor the effectiveness of JARDIANCE® by 
evaluation of the change from baseline after 12 weeks and/or 24 weeks in the glycosylated 
hemoglobin (HbA1c), fasting plasma glucose (FPG), body weight, blood pressure (SBP, DBP)
and the final efficacy evaluation at the end of the last visit in Korean T2DM patients.

Boehringer Ingelheim
Page 17 of 43
Non-Interventional Study Protocol 
BI Study Number 1245.116
c09963608-06
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
RESEARCH QUESTION AND OBJECTIVES
8.
This rNIS is an observational prospective, non-interventional, open-label, multi-centre 
national study. As per regulation, the re-examination period extends from 12 August 2014 
until 11 August 2020. However, active enrolment is to be initiated in 2016 after finalizing the 
re-imbursement agreement with the authority. Before initiation of the study, any newly 
reported adverse events collected from other sources such as spontaneous cases, literature 
cases etc will be closely monitored. The last patient follow up is expected in Aug 2020.
This study will be carried out in the manner of successive survey that the investigator will be 
asked to successively write in the case report forms (CRFs) from the subject who was 
initially administered the drug following the study start date to the requested number of 
subjects without omission. Prior to initiation of the study, a written contract shall be 
concluded, and this contract shall be executed among BI OPU, CRO with the head of the site 
or the investigator with his/her consent. 
Patients will be managed according to the local practice guidelines. The choice of treatment 
will be solely at the discretion of the participating physician. JARDIANCE® will be 
administered according to the approved label in Korea. Hence there are no additional risks to 
patients by participating in this rNIS.
8.1
STUDY DESIGN
This is a single arm study with JARDIANCE®.
JARDIANCE® will be prescribed according to the local label and at the discretion of the 
treating physician. Since this is a non-interventional study, the drug will not be supplied by 
the sponsor. Furthermore, the sponsor will not cover the expenses related to other 
medications taken by the patient, interventions, procedures, or diagnostic test.
8.1.1
Method of assigning patients to treatment groups
The choice of treatment is fully at the discretion of the physician and the patient. There is no 
treatment assignment by a third party.
8.1.2
Dosage and Administration 
The starting dose and the dose escalation schedule are based on the current authorized label 
in Korea.
The recommended dose of JARDIANCE® is 10 mg once daily. In patients tolerating 
JARDIANCE® 10 mg once daily and requiring additional glycemic control, the dose can be 
increased to 25 mg once daily. 
When JARDIANCE® is used in combination with a sulphonylurea or with insulin, a lower 
dose of the sulphonylurea or insulin may be considered to reduce the risk of hypoglycaemia.

Boehringer Ingelheim
Page 18 of 43
Non-Interventional Study Protocol 
BI Study Number 1245.116
c09963608-06
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
JARDIANCE® can be taken with or without food and tablets should be swallowed whole. If a 
dose is missed, it should be taken as soon as the patient remembers. A double dose should not 
be taken on the same day.
Please refer to the current local label for about Special populations (Patients with renal 
impairment, Patients with hepatic impairment, Elderly patients). 
8.1.3
Concomitant therapy, Restrictions, And rescue
Additional drugs are allowed as considered necessary for the patient’s welfare to be 
prescribed at the discretion of the treating physician. It is required, however, to record the 
details in the eCRF of all concomitant medication administered to the patient during the 
course of treatment. This includes concomitant therapies started one month prior to 
JARDIANCE® initiation until the patient completes the final follow-up visit.
8.1.3.1
Rescue medication, emergency procedures, and additional treatments
Please refer to the current local label.(13.4)
8.2
SETTING
As per regulations, enrolled patients will be followed up for 12 or/and 24 weeks treatment 
period.
8.2.1
Study sites
A total of 3,000 patients will be enrolled at approximately 70 sites by as many as 70 or more 
NIS physicians. To minimize the selection bias at the site level, the goal is to have 
participating centers reflect a balance between general hospitals and clinics for surveillance. 
The treating physicians will mainly be internists. To minimize the selection bias, consecutive 
patients from each site who meet inclusion criteria will be enrolled in this study.
As provided in the 『Standards for Re-examination of New Drugs』of the Ministry of Food 
and Drug Safety Notification, BI OPU should select study site according to the following 
requirements; 
①
Equipment/facility, and manpower capable of fully achieving the goal of 
investigation should be held;  
②
The investigator should have specialized knowledge of the drug subject to 
investigation and the indication, have completed education/training necessary for 
performing the investigation, or have practical experience; 
③
Study site and the investigator should strictly keep confidential the record of 
subject’s personal data
④
The investigator should be fully aware of the『Standards for Re-examination of 
New』and study protocol.

Boehringer Ingelheim
Page 19 of 43
Non-Interventional Study Protocol 
BI Study Number 1245.116
c09963608-06
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
8.2.2
Study population
8.2.2.1
Main diagnosis for study entry
Patients diagnosed with T2DM will be included.
8.2.2.2
Inclusion criteria:

Patients who have started at first time on JARDIANCE® in accordance with the 
approved label in Korea

Age ≥19 years at enrolment

Patients who have signed on the data release consent form
8.2.2.3
Exclusion criteria:

Known hypersensitivity to empagliflozin or any of its excipients

Patients with type 1 diabetes or for the treatment of diabetic ketoacidosis (DKA)

Patients with persistent eGFR<60 mL/min/1.73 m2, end stage renal disease or on 
dialysis

Patients with rare hereditary conditions of galactose intolerance, the Lapp lactase 
deficiency or glucose-galactosemalabsorption

Patients for whom empagliflozin is contraindicated according local label of 
JARDIANCE®
8.2.2.4
Subjects of special investigation
The patient who have signed on the data release consent form, subjects of special 
investigation (Geriatric(Older than 65 years), Pregnant Women, renal impairment, hepatic 
impairment and other special population) among the patients who conducted investigation for 
safety assessment after the administration of JARDIANCE® can be further investigation into 
cases collected from this study may be taken into account according to the outcome of 
retrospective analysis.
8.2.3
Study visits
8.2.3.1
Screening and run-in periods
This section is not applicable as this is a non-interventional study.
8.2.3.2
Visit 1; Baseline Visit 
Upon patient enrolment, the following will be recorded on the patient’s eCRF.

Information on the site (Hospital name, Department, Physician name, Contract date)

Visit date

Boehringer Ingelheim
Page 20 of 43
Non-Interventional Study Protocol 
BI Study Number 1245.116
c09963608-06
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Diagnosis: date of the diagnosis of T2DM, Family history of T2DM

Inclusion / Exclusion criteria

Informed consent form: Date of Informed consent

Demographic data: Age, gender, pregnancy, height, smoking status 

Diabetes mellitus related complication (Retinopathy, Neuropathy, Nephropathy, 
Vasculopathy, etc)

Medical history: Hypertension, Dislipidemia, Coronary artery disease, Stroke, Liver 
disease, Renal failure, Allergy, Nephropathy, etc (history of concomitant disease 
within 6 months)

Physical examination: body weight, blood pressure (SBP, DBP)

Renal Function: record Serum creatinine, eGFR, urin ACR if blood test result is 
available (the most recent data prior to baseline)

Effectiveness endpoints: HbA1c, FPG (Lab data should be collected within 1month 
prior to baseline)

Concomitant anti-hyperglycemic agent : record any anti-hyperglycemic agents have 
been taken prior to the baseline visit (within 1 month prior to baseline)

Concomitant medications: record all medications have been taken at least once since 
one month prior to the baseline visit.

Dose of JARDIANCE® given(Daily dose(Dosage/Administration), Start date)
At visit 1, the patient will be requested to contact the treating physician in the event of any 
adverse events noted after initiating JARDIANCE® treatment.
8.2.3.3
Visit 2; 12 weeks from Visit 1
After 12 weeks from Visit 1, the patients will return for follow-up. The followings will be 
noted and recorded in the eCRF.

Visit date

Physical examination: body weight, blood pressure (SBP, DBP)

Any change of JARDIANCE® given(Daily dose(Dosage/Administration), Start date, 
Date of discontinuation or continuation, Action taken, Causality)

Effectiveness endpoints: HbA1c, FPG

Renal Function: record Serum creatinine, eGFR, urine ACR if blood test result is 
available (The most recent data since last visit, except previously entered data)

Concomitant anti-hyperglycemic agent including new medications taken since last 
visit : any change in the concomitant medications (dose and dosing intervals)

Concomitant medications including new medications taken since last visit : any 
change in the concomitant medications (dose and dosing intervals)

Boehringer Ingelheim
Page 21 of 43
Non-Interventional Study Protocol 
BI Study Number 1245.116
c09963608-06
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Any changes in laboratory tests if there is any lab result which was clinically 
significant compared to data before JARDIANCE® therapy (This data is collected on 
the basis of medical need, i.e. independent of the NIS) 

Any adverse events noted, AESI (Adverse Event of Special interest)

Study completion status
8.2.3.4
Visit 3; 24 weeks from Visit 1
After 24 weeks from Visit 1, the patients will return for follow-up. The followings will be 
noted and recorded in the eCRF.

Visit date

Physical examination: body weight, blood pressure (SBP, DBP)

Any change of JARDIANCE® given(Daily dose(Dosage/Administration), Start date, 
Date of discontinuation or continuation, Action taken, Causality)

Effectiveness endpoints : HbA1c, FPG

Renal Function: record Serum creatinine, eGFR, urine ACR if blood test result is 
available (The most recent data since last visit, except previously entered data)

Concomitant anti-hyperglycemic agent including new medications taken since last 
visit : any change in the concomitant medications (dose and dosing intervals)

Concomitant medications including new medications taken since last visit : any 
change in the concomitant medications (dose and dosing intervals)

Any changes in laboratory tests if there is any lab result which was clinically 
significant compared to data before JARDIANCE® therapy (This data is collected on 
the basis of medical need, i.e. independent of the NIS) 

Any adverse events noted, AESI (Adverse Event of Special interest)

Study completion status
8.2.3.5
End of study 

Visit date

Discontinuation or continuation (if interruption, date of last administration, reason
for interruption)

The final efficacy evaluation

NIS physician’s electronic signature for data integrity
8.2.3.6
Follow-up period
Patients with adverse events noted at the final follow-up visit or upon premature 
discontinuation of JARDIANCE® will be monitored further until the resolution of those 
adverse events. Alternatively, those patients will be followed up until the NIS physician and 
sponsor agree that no further follow-up is necessary.

Boehringer Ingelheim
Page 22 of 43
Non-Interventional Study Protocol 
BI Study Number 1245.116
c09963608-06
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
8.2.4
Study discontinuation
Boehringer Ingelheim Korea reserves the right to discontinue the study overall or at a 
particular study site at any time for the following reasons:
•
Emergence of any effectiveness/safety information that could significantly affect 
continuation of the study
•
Violation of applicable local regulations, the NIS protocol, or the contract by a study 
site or participating physician, disturbing the appropriate conduct of the study.
8.3
VARIABLES
8.3.1
Analysis sets
A total of 3000 patients will be entered in this study, and each patient will be followed for 
total three times (baseline, short term 12weeks follow up, long term 24weeks follow up).
Since T2DM is chronic disease it might be restrictive to collect safety and effectiveness data 
in short-term (12weeks) period, all patients will be enrolled for long-term (24weeks) 
surveillance.
8.3.1.1
Number of cases subject who entered the study
This number means the planned number of cases as specified in the contract concluded with 
the investigator (physician) prior to initiation of the study.
8.3.1.2
Number of cases subject to CRF collection
This number means the number of cases who signed the informed consent form to participate 
in the study as subject, with a record of taking JARDIANCE® once at least.
8.3.1.3
Number of cases subject to safety evaluation
These include those who signed the informed consent form to participate in this study as 
subject, took JARDIANCE® once at least, and were followed up by the physician once or 
more.
Reflecting Ministry of Food & Drug Safety (MFDS) guideline, the cases below shall be 
excluded from safety analysis (defined below) set in the following order:
a.
Patients who signed on the data release consent form of JARDIANCE® rPMS prior 
to the contract date
b.
Patients administrated JARDIANCE® prior to the contract date
c.
Patients administrated JARDIANCE® prior to the signed on the data release consent 
form
d.
Patients who have not taken JARDIANCE®
e.
Follow-up failure: Patients whose safety information can not be obtained due to 
follow-up Loss
f.
Patients who were prescribed for other indications except indications in the local
label

Boehringer Ingelheim
Page 23 of 43
Non-Interventional Study Protocol 
BI Study Number 1245.116
c09963608-06
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
8.3.1.4
Number of cases subject to efficacy evaluation
These cases include those who signed the informed consent form to participate in this study 
as subject, visited as per the study schedule, took JARDIANCE®, and were evaluated for the 
efficacy.
Reflecting Ministry of Food & Drug Safety (MFDS) guideline, the cases below shall be 
excluded from efficacy analysis (defined below) set in the following order:
a.
Patients excluded from safety analysis set listed in section 8.3.1.3
b.
Patients with missing information of assessment of efficacy set listed in section 
8.3.2.2 at visit 2, visit 3.
8.3.2
Endpoints
8.3.2.1
Endpoints of safety
All reported adverse events in patients who take at least one dose of JARDIANCE® will be 
noted.
Endpoints pertaining to safety will be presented as incidence rates of adverse events and will 
include:
•
Adverse events
•
Unexpected adverse events
•
Serious adverse events
•
Drug-related adverse events
•
Non serious adverse drug reaction
•
Adverse event of special interest
•
Adverse events leading to discontinuation
8.3.2.2
Endpoints of effectiveness
8.3.2.2.1
Main endpoint
Change from baseline in HbA1c after 12 weeks and/or 24 weeks of treatment
8.3.2.2.2
Other endpoints
•
Occurrence of treat to target effectiveness response that is an HbA1c under treatment 
of < 7% after 12 weeks and/or 24 weeks of treatment 
•
Occurrence of relative effectiveness response (HbA1c lowering by at least 0.5% after 
12 weeks and/or 24 weeks)
•
Change from baseline in fasting plasma glucose (FPG) after 12 weeks and/or 24 
weeks of treatment
•
Change from baseline in body weight after 12 weeks and/or 24 weeks of treatment.
•
Change from baseline in blood pressure (SBP, DBP) after 12 weeks and/or 24 weeks 
of treatment.

Boehringer Ingelheim
Page 24 of 43
Non-Interventional Study Protocol 
BI Study Number 1245.116
c09963608-06
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
8.3.2.2.3
The final efficacy evaluation
Records by performing the final efficacy evaluation at the end of the last visit 
①
Improved: If determined as there is any effect of maintaining or improving disease 
related factors.
②
Unchanged: If disease related factors have not been changed compared with before 
administration, and not determined as there is any effect of maintaining symptoms.
③
Aggravated: If disease related factors are worse than before administration.
④
Unassessable: If it cannot be determined due to insufficient information collected. 
(Even though there are any objective indicators present, it is possible to belong to 
this grade.)
'Improved' is assessed as "Effective", "Unchanged" and "Aggravated "are assessed 
as "Invalid".
8.3.3
Assessment criteria
8.3.3.1
Assessment of safety
•
Adverse events (event name/ symptoms/ sign/ identify hypoglycemia symptoms)
•
Onset date, End date 
•
Intensity (Mild/ Moderate/ Severe)
•
Serious (Serious/ Non-Serious)
•
Outcome of the event (Recovered/ Recovering/ Not yet recovered/ Sequela/ 
Unknown)
•
Causality (Certain/ Probable·Likely/ Probable/ Possible/ Unlikely/ Conditional· 
Unclassified/ Unaccessible·Unclassifiable) 
•
Factors other than JARDIANCE® (None/ Concomitant medication/ Concomitant 
disease/ etc)
•
Action taken with study drug due to AE (Discontinued/ Reduced/ Increased/ 
Continue/ Unknown/ Not applicable)
•
Recurrence in reintroduced (Recurrence/ Do not recur/ Unknown/ Not applicable)
•
Adverse Event of Special interest (Not applicable/Vaginal moniliasis, vulvovaginitis, 
balanitis and other genital infection/Increased urination/Urinary tract 
infection/Volume depletion/ Diabetic Ketoacidosis, Decreased renal function, 
Hepatic injury defined by the alterations of liver parameters/Lower limb amputation)
•
Investigator’s comments(if needed) 
8.3.3.2
Assessment of efficacy
①
HbA1c:

Boehringer Ingelheim
Page 25 of 43
Non-Interventional Study Protocol 
BI Study Number 1245.116
c09963608-06
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
HbA1c should be collected within 1 month prior to baseline and after 12 weeks and 
24 weeks of treatment.
②
Fasting Plasma Glucose (FPG):
FPG should be collected within 1 month prior to baseline and after 12 weeks and 24 
weeks of treatment.
③
Body Weight: 
Body weight should be collected within 1 month prior to baseline and after 12 weeks 
and 24 weeks of treatment.
④
Blood Pressure (SBP, DBP) : 
Blood pressure(SBP, DBP) should be collected within 1 month prior to baseline and 
after 12 weeks and 24 weeks of treatment.
⑤
Final efficacy evaluation: Final efficacy evaluation should be accessed and recorded 
at the end of the last visit. 
8.3.4
Items of Investigation
8.3.4.1
Demographic data
For demographic evaluation, following background information of subjects shall be recorded:  

Subject signed date 

Subject study number

Age

Gender

Pregnancy (current status)

Height

Body weight

Smoking status
8.3.4.2
Medical/Surgical history and pre-treatment experience
The medical/surgical history to be collected and the treatment experience prior to 
administration of this drug includes:  

Date of diagnosis

Family history of T2DM

Diabetes mellitus related complication (including but not limited to Retinopathy, 
Neuropathy, Nephropathy, Vasculopathy, etc.)

Boehringer Ingelheim
Page 26 of 43
Non-Interventional Study Protocol 
BI Study Number 1245.116
c09963608-06
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Medical history : Hypertension, Dislipidemia, Coronary artery disease, Stroke, Liver 
disease, Renal failure, Allergy, Nephropathy, etc.
8.3.4.3
Concomitant medication
Information on concomitant medication that is to be collected includes:   

Brand name or generic name 

Daily dose 

Unit

Indication 

Start date

Date of discontinuation or continuation 
8.3.4.4
Drug administration status
Information on the study drug administration status includes:   

Dose

Unit

Start date

Date of discontinuation or continuation
8.3.4.5
Information on the site
Information on the site includes:  

Hospital name 

Department 

Physician name 
8.4
DATA SOURCES
This study will be carried out in the manner of successive survey that the investigator will be
asked to successively write in the case report forms(CRFs) from the subject who was initially 
administered the drug following the study start date to the requested number of subjects 
without omission. Prior to initiation of the study, written contract shall be concluded, and this 
contract shall be concluded with the head of the site or the investigator with his/her consent.
8.5
STUDY SIZE
The sample size of 3,000 patients is based on the requirement of the local regulatory authority 
(MFDS). As per regulation, long-term surveillance is necessary for the T2DM indication. 
Since T2DM is chronic disease it might be restrictive to collect safety and effectiveness data 
in short-term (12weeks) period, all patients will be enrolled for long-term (24weeks) 
surveillance.

Boehringer Ingelheim
Page 27 of 43
Non-Interventional Study Protocol 
BI Study Number 1245.116
c09963608-06
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
8.6
DATA MANAGEMENT
Patients’ data will be gathered by eCRF. The data management procedures to ensure the 
quality of the data are described in detail in the data management plan (DMP) available in 
TMF. Data management and statistics will be outsourced to a qualified contract research 
organization (CRO).
8.7
DATA ANALYSIS
8.7.1
Analysis of demographic data
Demographic data and the health status of subjects for the safety evaluation will be analysed
descriptively. For continuous data, mean, standard deviation, minimum value, and maximum 
value will be described, while for categorical data, frequency will be shown. 
Parameters corresponding to demographic data are as mentioned below. 
①
Basic information and disease information 
Age, gender, pregnancy, body weight, smoking status,  diabetes mellitus 
complications, other medical history, disease period, Family history of T2DM, 
elderly (Age ≥65 years), renal impairment and hepatic impairment, allergy, long 
term use(over 24 weeks)
②
Medication information
Concomitant medication, study drug administration status (total period of drug use, 
average of daily dose), reason for early interruption, any anti-diabetic agents
To assess the extent of preferential prescribing and the potential for channeling bias, data 
from the TRAJENTA® (linagliptin) rPMS will be used as a comparator. The baseline 
characteristics of patients starting JARDIANCE® for the first time will be compared to the 
baseline characteristics of patients who started  TRAJENTA® for the first time. Proportions 
and means (SD) of the baseline characteristics will be compared using absolute standardized 
differences (ASD), where an ASD of at least 10% will be considered a meaningful difference.
p-values will also be calculated.
8.7.2
Safety analysis
①Among the subjects of safety evaluation, the number of subjects with adverse event 
incurred and the number of adverse events incurred should be calculated, and the 
incidence rate of adverse events and the 95% confidence interval should be presented.  
②The number and percentage of adverse events by type and category should be 
presented.  
③Analysis should be made using Chi-square test or Fisher’s Exact test on the adverse 
event onset status by demographic data of subjects of safety evaluation.

Boehringer Ingelheim
Page 28 of 43
Non-Interventional Study Protocol 
BI Study Number 1245.116
c09963608-06
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
④To estimate any factors that are thought to influence the analyzed incidence rate of 
adverse events, logistic regression analysis should be conducted, and for statistically 
significant parameters, the meaning should be described. 
8.7.2.1
Adverse Events by preferred Terms (AEs/ADRs/SAEs)
All AEs recorded in the CRF will be classified by body organs and terms under the 
classification standard of MedDRA terms, and all AEs excluding the AEs whose ‘Causality’ 
is “Unlikely” will be treated as AEs whose causality cannot be excluded (hereafter “Adverse 
Drug Reaction (ADR)”). The study database will not be locked until coding is complete.
①
The number of AE according to Severity (Mild, Moderate, Severe), Outcome of the 
event (Recovered, Not yet recovered, Sequelae, Fatal, Unknown), Action taken with 
trial drug due to AE (Continue, Reduced, Discontinued, Increased, Discontinued and 
reintroduced, Not applicable), Causality (Certain/ Probable·Likely/ Probable/ 
Possible/ Unlikely/ Conditional· Unclassified/ Unaccessible·Unclassifiable),Therapy 
for the event (Yes, No) will be calculated.
②
All AEs will be classified into the preferred terms according to Severity (Mild, 
Moderate, Severe), Outcome of the event, (Recovered, Not yet recovered, Sequelae, 
Fatal, Unknown), Action taken with trial drug due to AE (Continue, Reduced, 
Discontinued, Increased, Discontinued and reintroduced, Not applicable), Causality 
(Certain, Probable/Likely, Possible, Unlikely), Therapy for the event (Yes, No). 
Also, the number of each AE will be calculated.
③
The number of patients and the number of Serious AE/Serious ADR (SADR), 
unexpected AE/ADR, unexpected Serious AE/unexpected Serious ADR, AE/ADR 
will be calculated according to the preferred terms. Also, the incidence proportion 
and its 95% confidence interval will be estimated.
④
For subjects excluded from safety analysis set ‡, the number of patients and the 
number of Serious AE/Serious ADR (SADR), unexpected AE/unexpected ADR, 
unexpected Serious AE/unexpected Serious ADR, AE/ADR will be calculated 
according to the preferred terms. Also, the incidence proportion and its 95% 
confidence interval will be estimated.
‡Patients excluded from safety analysis sets: ‘Patients who have not taken 
JARDIANCE®’ and ‘Follow-up failure’ of patients excluded from safety analysis 
sets will be excluded (This term reflects the Ministry of Food & Drug Safety 
(MFDS) guideline).
Safety analyses will be based on all patients treated, i.e. all patients who received at least one 
dose of JARDIANCE® except those who are found to have no observation after enrolment, 
invalid registration, or invalid contract with the site. However, if data for patients who have 
been treated with JARDIANCE® beyond the scope of approved label are collected, separate 

Boehringer Ingelheim
Page 29 of 43
Non-Interventional Study Protocol 
BI Study Number 1245.116
c09963608-06
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
safety analyses will be performed. Patients lost to follow up will be characterized compared
to the remaining patients and reason and time point of loss to follow up will be evaluated.
8.7.3
Efficacy analysis
①
Mean, standard deviation, minimum value, maximum value, and median of changes 
in glycosylated hemoglobin(HbA1c) and fasting plasma glucose(FPG), body weight, 
and blood pressure (SBP, DBP), which were measured at the last visit versus baseline, 
should be presented, and if there is difference before administration versus after 
administration should be analyzed using paired t-test.
②
If there is difference in the change of glycosylated hemoglobin(HbA1c) according to 
demographic parameters mentioned in 8.7.1 should be analyzed using t-test or
ANOVA(Analysis of Variance).
③
The frequency and percentage of patients who had glycosylated hemoglobin(HbA1c)
reaching less than 7% (target efficacy response rate) at the last visit should be 
calculated, and the frequency and percentage of patients with glycosylated 
hemoglobin(HbA1c) decreased by at least 0.5% at the last visit should be calculated.
④
For final efficacy evaluation (improved, unchanged, aggravated, unassessable) and 
‘effective(improved)’/‘ineffective(unchanged, aggravated)’, the number and 
percentage of subjects should be mentioned. The final effectiveness evaluation of 
“Improved” will be classified as “Effective”, “Unchanged” and “Aggravated” will be 
classified as “Ineffective”. The effectiveness rate and its 95% confidence intervals 
will be estimated with exact method.
⑤
To estimate any factors that are thought to influence an effective ratio, logistic 
regression analysis should be conducted, and for statistically significant parameters, 
the meaning should be described.  
8.7.4
Interim analyses
In accordance with local regulation for rNIS, interim analyses are planned biannually for the 
initial two years and annually thereafter.
8.7.5
Handling of missing data
Maximum attempt will be made to ensure the completeness of data collection. All available 
data will be used in the data analysis. 
8.8
QUALITY CONTROL
All entries in the eCRF and the existing codings will be stored in a database. The structure of 
the database is based on the division into sections and entry fields defined in the eCRF. To 
improve and ensure data quality, data checks will be performed automatically in the eCRF 
directly on electronic entry at the study site.

Boehringer Ingelheim
Page 30 of 43
Non-Interventional Study Protocol 
BI Study Number 1245.116
c09963608-06
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Plausible value ranges for numerical data entries and logical data and list entries will be filed 
in the eCRF. The tests for consistency and completeness based on this will be performed 
during entry in the eCRF. The validity of the recorded data will therefore be ensured by the 
validations incorporated in the documentation system, which highlight incorrect or 
implausible entries to the data entry clerk/doctor.
If corrections are necessary after the data are saved, these will be documented in an audit 
trail.
For the further quality assurance of the documented patient observations, a sample-based 
source data comparison will be performed on about 10% of the sites. An additional 
inspection/quality assurance check of this NIS can be performed in case of any deviation.
8.9
LIMITATIONS OF THE RESEARCH METHODS
8.9.1
Loss to follow-up
All efforts will be made to minimize loss to follow up, particularly in the tracking of lost 
patients. To the extent possible, occurrence of adverse event, at minimum, for patients lost to 
follow up will be obtained via patient visit/telephone/letter/email etc. This allows assessing 
the impact of informative censoring due to treatment discontinuation. Also, patients lost to 
follow up will be characterized compared to the remaining patients and reason and time point 
of loss to follow up will be evaluated.
8.9.2
Channeling bias
Channeling bias can occur due to preferential prescribing in relation to different risks for the 
events of interest: e.g., if empagliflozin would be more often prescribed to higher risk
patients compared to other treatments, higher incidences of outcome events were then 
expected in the empagliflozin group. To assess the extent of preferential prescribing of 
JARDIANCE® and the potential for channeling bias, baseline data from the TRAJENTA®
(linagliptin) rPMS will be used to provide context for the JARDIANCE® rPMS data.
8.9.3
Confounding
As in any observational study, confounding may affect the estimation of associated between 
drug exposure and outcome of interest and statistical techniques. However, as only major 
confounders for selected research questions can be captured, residual (unmeasured) 
confounding may remain.
8.10
DATA PROTECTION, STUDY RECORDS
The International Conference on Harmonization/Harmonized Tripartite Guideline for Good 
Clinical Practice (ICH/GCP) does not often apply to NIS as most elements are relevant for 
controlled clinical trials. However, in this NIS, all attempts will be made to adhere, as close 
as possible, to the standards of ICH/GCP. 
The protocol of this regulatory requisite NIS will be submitted to the Ministry of Food And 
Drug Safety (MFDS) for notification. It is not a local requirement in Korea to obtain 
Institutional Review Board (IRB) approval for the conduct of regulatory requisite NIS. 

Boehringer Ingelheim
Page 31 of 43
Non-Interventional Study Protocol 
BI Study Number 1245.116
c09963608-06
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
However, the protocol of this NIS will be submitted to IRBs whenever required or requested 
by these institutions. This study will be conducted in accordance with the Standards for Re-
examination of New Medicines notified by MFDS, Korean Pharmaceutical Affairs Code 
(KPAC), Enforcement Regulation of KPAC and other applicable local laws and industry 
code (including but not limited to the Regulations on Fair Competition in the Trade of 
Medicines of KPMA and KRPIA). 
Boehringer Ingelheim Korea will submit interim reports during the re-examination period, 
and the final report to MFDS upon study completion. The interim report for the final year 
will be substituted with the final report. When required, the interim reports and the final 
report will be submitted to the IRBs as well.
8.10.1
Data quality assurance
A quality assurance audit/inspection of this study may be conducted by the sponsor or 
sponsor’s designees or by IRBs/IECs or by regulatory authorities. The quality assurance 
auditor will have access to all medical records, the investigator’s study-related files and 
correspondence, and the informed consent documentation of this non-interventional study.
8.10.2
Study records
All of the clinical data will be captured via a web-based EDC (Electronic Data Capture) 
System. The site staff will enter and edit the data via a secure network, with secure access 
features (username, password and secure identification – an electronic password system). A 
complete electronic audit trail will be maintained. The treating physician will approve the 
data using an electronic signature.
Patients will not be identified on the eCRF by name. Appropriate code identification (i.e., 
patient number) will be used. The treating physician will make a separate confidential record 
of these details (patient identification code list) to permit identification of all patients enrolled 
in this study in case follow-up is required. Likewise, any supporting documentation will be 
redacted of any patient identifying information, and the patient ID number clearly written on 
the documents. 
8.10.2.1
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site.
Data reported on the eCRFs must be consistent with the source data or the discrepancies must 
be explained. The Investigator may need to request previous medical records or transfer 
records, depending on the study; current medical records must also be available.
For the eCRF, the following data need to be derived from source documents:

Patient participation in the study (study number, patient number, date patient was 
informed)

Patient identification (gender, age)

Physical examination (body weight, blood pressure(SBP, DBP))

Boehringer Ingelheim
Page 32 of 43
Non-Interventional Study Protocol 
BI Study Number 1245.116
c09963608-06
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Dates of Patient’s visits, including dispensing of study medication

Medical history (including study indication and concomitant diseases, if applicable)

Medication history

Adverse events and outcome events (onset date (mandatory), and end date (if available))

Serious adverse events (onset date (mandatory), and end date (if available))

Concomitant therapy (start date, changes)

Laboratory results (if If available)

Completion of Patient’s Participation in the study
8.10.2.2
Direct access to source data and documents
The Investigator / institution will permit study-related monitoring, audits, IRB review and 
regulatory inspection, providing direct access to all related source data / documents. eCRF 
and all source documents must be available at all times for review by the Sponsor’s Medical 
Project Manager(MPM), auditor and inspection by health authorities (e.g. MFDS). The MPM 
and auditor may review all eCRF, and written informed consents. The accuracy of the data 
will be verified by reviewing the documents described in section 8.10.2.1.
8.10.2.3
Storage period of records
The NIS physician and the site are jointly responsible for maintaining essential study 
documents for 3 years after completion of the study (defined as termination date of re-
examination period) by the Pharmaceutical Affairs Law and shall take measures to prevent 
accidental or premature destruction of these documents.

Boehringer Ingelheim
Page 33 of 43
Non-Interventional Study Protocol 
BI Study Number 1245.116
c09963608-06
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
PROTECTION OF HUMAN SUBJECTS
9.
The study will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the applicable sections of GCP, relevant BI 
Standard Operating Procedures and local regulations. 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/International Conference on Harmonization (ICH) GCP / GPP if applicable.
The rights of the investigator and of the sponsor with regard to publication of the results of 
this study are described in the investigator contract.
9.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT
Prior to patient participation in the study, written informed consent must be obtained from 
each patient (or the patient’s legally accepted representative) according to the regulatory and 
legal requirements of the participating country. Each signature must be personally dated by 
each signatory and the informed consent retained by the investigator as part of the study 
records. A signed copy of the informed consent and any additional patient information must 
be given to each patient or the patient’s legally accepted representative.
The patient must be informed that his/her personal study-related data will be used by BI in 
accordance with the local data protection law. The level of disclosure must also be explained 
to the patient.
The patient must be informed that his / her medical records may be examined by authorised 
monitors (MPMs) or Clinical Quality Assurance auditors appointed by BI, by appropriate 
IRB / IEC members, and by inspectors from regulatory authorities.
9.2
STATEMENT OF CONFIDENTIALITY
Individual patient medical information obtained as a result of this study will be considered 
confidential and disclosure to third parties will be prohibited with the exceptions noted 
below. Patient confidentiality will be ensured by using patient identification code numbers.
Treatment data will be made available to the patient’s personal physician or to other 
appropriate medical personnel responsible for the patient’s welfare. Data generated from the 
study will be made available for inspection on request by the participating physicians, the 
sponsor and/or its representatives and/or designees, by the IRBs/IECs and the regulatory 
authorities.

Boehringer Ingelheim
Page 34 of 43
Non-Interventional Study Protocol 
BI Study Number 1245.116
c09963608-06
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
MANAGEMENT AND REPORTING OF ADVERSE 
10.
EVENTS/ADVERSE REACTIONS
10.1
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 unfavorable 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 (SAE) is defined as any AE which:
•
results in death,
•
is life-threatening,
•
requires inpatient hospitalization or 
•
prolongation of existing hospitalization,
•
results in persistent or significant disability or incapacity,
•
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 hospitalization 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 hospitalization or 
development of dependency or abuse. Any suspected transmission via a medicinal product of 
an infectious agent is also considered a serious adverse reaction.
Non Serious Adverse Drug Reaction
Non Serious Adverse Drug Reaction (NSADR) is defined as any adverse reaction which does 
not meet the SAE criteria.

Boehringer Ingelheim
Page 35 of 43
Non-Interventional Study Protocol 
BI Study Number 1245.116
c09963608-06
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
ASAE (Always Serious Adverse Events)
BI has defined a list of adverse events that are considered as “always serious” by fulfilling the 
criterion “medically important event” by definition and are therefore judged as serious. If a 
non-serious AE meets this definition, a query will be raised. The investigator must verify the 
description and seriousness of the event. If the event description is correct, the item “serious” 
needs to be ticked and an SAE has to be reported in expedited fashion. The list of these 
adverse events can be found via the eCRF system.
AESI (Adverse Event of Special interest)
The term Adverse Event of Special Interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this study, e.g. the potential for AEs based on knowledge from 
other compounds in the same class.  The adverse events below reported from patients who 
were administered this drug in a placebo-controlled study in accordance with the approved 
labeling fall under any adverse events of special interest.  The following are considered as 
AESIs:

Vaginal moniliasis, vulvovaginitis, balanitis and other genital infection 

Increased urination

Urinary tract infection (UTI)

Volume depletion

Diabetic Ketoacidosis (DKA)

Decreased renal function:
-
Creatinine value shows a >2-fold increase from baseline and is above the ULN

Hepatic injury defined by the following alterations of liver parameters: 
-
An elevation of AST and/or ALT >3-fold ULN combined with an elevation of to
tal bilirubin >2-fold ULN measured in the same blood draw sample. 
-
An isolated elevation of AST and/or ALT >5-fold ULN (without an elevation of 
total bilirubin >2-fold ULN)

Lower limb amputation
-
Amputation (i.e. resection of a limb through a bone)
-
Disarticulation (i.e. resection of a limb through a joint)
-
Auto-amputations (i.e. spontaneous separation of non-viable portion of the lower 
limb)
Not included in this definition are debridement (removal of callus or dead tissue), 
procedures on a stump (like stump revision, drainage of an abscess, wound revision 
etc.) and other procedures (e.g., nail resection or removal) without a concomitant 
resection of a limb (amputation or disarticulation).

Boehringer Ingelheim
Page 36 of 43
Non-Interventional Study Protocol 
BI Study Number 1245.116
c09963608-06
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Besides, Diabetic Ketoacidosis, which may be observed in patients treated with SGLT-2 
inhibitors, also corresponds to an adverse event of special interest in this investigation, and 
these adverse events of special interest should be closely monitored and reported during the 
investigation period.
10.2
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 studies are available to support the evidence on the safety and efficacy of the 
studied JARDIANCE®. For this reason the following AE collection and reporting requirements 
have been defined.
All adverse events occurred from the signing date on ICF to 30 days after last administration 
date of medication need to be collected, documented and reported to the sponsor using the 
AE reporting form of eCRF (13.1). 
All SAEs, ASAEs and AESIs must be reported with details of relevant non serious AEs,
occurring at the same time, within 24 hours of occurrence and via telephone/fax to the Local 
PV Manager (LPVM) of BI Korea using the NIS AE form (13.2). All non-serious Adverse 
Reactions associated with JARDIANCE® (empagliflozin) and pregnancy monitoring forms 
must be reported within 7 calendar days of occurrence and via telephone/fax to the LPVM of 
BI Korea. If any new or further information to these events is available, a follow-up NIS AE 
report has to be sent to BI. All SAEs and non-serious AEs must include a causal relationship 
assessment from the physician.
All ADRs (serious and non-serious), 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.
Contact details:
Local PV Manager (LPVM)
Address: BoehringerIngelheim Korea, Medical Dept.
15F, Yonsei Severance Bldg.10, Tongil-ro, Jung-gu, Seoul, Korea (Postal code : 04527)
The investigator carefully assesses whether an AE constitutes an Adverse Reaction using the 
information below. 

Boehringer Ingelheim
Page 37 of 43
Non-Interventional Study Protocol 
BI Study Number 1245.116
c09963608-06
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Causal relationship of AEs
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 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).
•
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.
The causal relationship must be provided by the Investigator for all potential study drugs, i.e. 
the BI study drug and for all other study drugs.
The reason for the decision on causal relationship needs to be provided in the (e)CRF and on 
the NIS AE form (if applicable).
Related
a.
Certain : An event occurring in a plausible time relationship to drug administration 
and that cannot be explained by concurrent disease or other drugs or chemicals. The 

Boehringer Ingelheim
Page 38 of 43
Non-Interventional Study Protocol 
BI Study Number 1245.116
c09963608-06
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
response to withdrawal of the drug (dechallenge) should be clinically plausible. The 
event must be definitive pharmacologically or phenomenologically, using a 
satisfactory rechallenge procedure if necessary,
b.
Probable/Likely : An event with a reasonable time sequence to administration of the 
drug, unlikely to be attributed to concurrent disease or other drugs or chemicals, and 
which follows a  clinically reasonable response on withdrawal (dechallenge). 
Rechallenge information is not required to fulfill this definition.
c.
Possible: An event with a reasonable time sequence to administration of the drug, but 
which could also be explained by concurrent disease or other drugs or chemicals. 
Information on drug withdrawal may be lacking or unclear.
d.
Conditional/Unclassified: Case of requiring more data or reviewing the additional 
data for the appropriate assessment
e.
Unassessable/Unclassifiable: Case that it cannot be judged and complemented or 
confirmed due to the insufficient or contradictory information 
Unrelated
a.
Unlikely : An event with a temporal relationship to drug administration which makes 
a causal relationship improbable, and in which other drugs, chemicals or underlying 
disease provide plausible explanations.
Intensity of AE
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 study medication, JARDIANCE®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’s LPVM 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/AESI, only the Pregnancy Monitoring Form must be 
completed, otherwise the NIS AE form is to be completed and forwarded as well within the 
respective timelines. 
The ISF will contain the Pregnancy Monitoring Form (Part A and B).
Expedited Reporting of AEs and Drug Exposure During Pregnancy
The following must be reported by the investigator on the NIS AE form from signing the 
informed consent onwards until the end of the study: 

Boehringer Ingelheim
Page 39 of 43
Non-Interventional Study Protocol 
BI Study Number 1245.116
c09963608-06
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Type of Report
Timeline
All Serious Adverse Events (SAEs), Always 
Serious Adverse Events (ASAEs) and Adverse 
Event of Special interest and non-serious AEs 
relevant to the SAEs/ASAEs/AESI
* 13.2 SAE/ Non-Serious Adverse Reaction Report
immediately within 24 hours
All AEs with fatal outcome
* 13.2 SAE/ Non-Serious Adverse Reaction Report
immediately within 24 hours
All non-serious Adverse Reactions associated with
JARDIANCE® (empagliflozin)
* 13.2 SAE/ Non-Serious Adverse Reaction Report 
7 calendar days
All pregnancy monitoring forms
* 13.3 Pregnancy Monitoring Form A, B
7 calendar days
The same timelines apply if follow-up information becomes available for the respective 
events. In specific occasions the Investigator could inform the Sponsor upfront via telephone. 
This does not replace the requirement to complete and fax the NIS AE form.
All other Adverse Events must be reported using eCRF within 2weeks to the Sponsor.
Information required
For each reportable AE, the investigator should provide the information requested on the 
appropriate (e)CRF pages and the NIS AE form.
For each AE, the investigator will provide the onset, end, intensity, outcome, seriousness and
action taken with JARDIANCE® tablets. The investigator will determine the relationship of
JARDIANCE® tablets to all AEs as defined in the 'Adverse Event Reporting' section of the 
physician binder.
Reporting of related AEs associated with any other BI drug
The investigator is encouraged to report all adverse events related to any BI drug other than
JARDIANCE®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.
10.3
REPORTING TO HEALTH AUTHORITIES
Adverse event reporting to regulatory agencies will be done by the MAH according to local 
and international regulatory requirements.

Boehringer Ingelheim
Page 40 of 43
Non-Interventional Study Protocol 
BI Study Number 1245.116
c09963608-06
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
PLANS FOR DISSEMINATING AND COMMUNICATING 
11.
STUDY RESULTS
The rights of the investigator and of the sponsor with regard to publication of the results of 
this study are described in the investigator contract. As a general rule, no study results should 
be published prior to finalization of the Study Report.

Boehringer Ingelheim
Page 41 of 43
Non-Interventional Study Protocol 
BI Study Number 1245.116
c09963608-06
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
REFERENCES
12.
12.1
PUBLISHED REFERENCES
R13-1653
Kim DJ. The epidemiology of diabetes in Korea. Diabetes Metab J 2011; 
35: 303-308
R12-1019
Whiting DR, Guariguata L, Weil C, Shaw J. IDF diabetes atlas: global 
estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res 
Clin Pract 2011;94:311-21.
R06-0179
Stumvoll M, Goldstein BJ, Haeften TW van. Type 2 diabetes: principles 
of pathogenesis and therapy. Lancet 2005;365:1333-1346.
R14-4616 
International Diabetes Federation (IDF). IDF diabetes atlas 6th ed. (2014)
P11-13842
Grempler R, Thomas L, Eckhardt M, Himmelsbach F, Sauer A, Sharp DE, 
et al. Empagliflozin, a novel selective sodium glucose cotransporter-2 
(SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 
inhibitors. Diabetes Obesity and Metabolism, Article first published 
online: 13 NOV 2011, DOI: 10.1111/j.1463-1326.2011.01517.xDiabetes 
Obes Metab 2012;14(1):83-90
P12-00692
DeFronzo RA, Davidson JA, Prato S del. The role of the kidneys in 
glucose homeostasis: a new path towards normalizing glycaemia.Diabetes 
Obes Metab 2012;14(1):5-14.
R11-4288
Gerich JE. Role of the kidney in normal glucose homeostasis and in the 
hyperglycaemia of diabetes mellitus: therapeutic implications.
Diabetic Med 27, 136 - 142 (2010)
12.2
UNPUBLISHED REFERENCES
ra00656956
JARDIANCE®  Company Core Data Sheet, 09 January 2015
c01838761-15
empagliflozin Investigator’s Brochure, 23 July 2015

Boehringer Ingelheim
Page 42 of 43
Non-Interventional Study Protocol 
BI Study Number 1245.116
c09963608-06
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
APPENDICES
13.
13.1
ELECTRONIC CASE REPORT FORM
Please refer to “ELECTRONIC CASE REPORT FORM” in site file or in electronic CRF 
web page for the latest version.
13.2
SAE/ NON-SERIOUS ADVERSE REACTION REPORT
Please refer to “SAE/ NON-SERIOUS ADVERSE REACTION REPORT” in site file or in 
electronic CRF web page for the latest version.
13.3
PREGNANCY MONITORING FORM
Please refer to “PREGNANCY MONITORING FORM” in site file or in electronic CRF web 
page for the latest version.
13.4
JARDIANCE® PRESCRIPTION INFORMATION FOR KOREA
Please refer to “JARDIANCE® Prescription Information for Korea” in site file or in 
electronic CRF web page for the latest version.

Boehringer Ingelheim
Page 43 of 43
Non-Interventional Study Protocol 
BI Study Number 1245.116
c09963608-06
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
AMENDMENTS AND UPDATES
14.
Number
Date
Section of 
study protocol
Amendment or update
Reason
1
30 May 2016
Version number 
and date
Update of version number 
and date 
Change of 
protocol 
version 
2
12 Jul 2016
8.7.2 Safety 
analysis
8.7.3 Efficacy 
analysis
8.7.2 Safety analysis 
was added to; 
Logistic regression analysis 
8.7.3 Efficacy analysis
regression analysis 
was changed to;
logistic regression analysis
MFDS 
comments
3
06 Feb 2017
Version number 
and date
Update of version number 
and date 
Change of 
protocol 
version 
4
21 Aug 2017
8.2.3.2
Visit 1; 
Baseline Visit
8.2.3.3 Visit 2
8.2.3.4 Visit 3
10.1 Definitions 
of adverse 
events
13.Appendices
8.2.3.2 Change of data 
collection period
8.2.3.3, 8.2.3.4 Addition of 
Renal function test on 
Follow up visit
10.1 Addition of ‘Always 
Serious Adverse Events’
10.1 Addition of ‘AESI’
case (Lower limb 
amputation)
- Period 
adjustment for 
completeness 
of data 
collection
- Follow up for 
renal function
- Addition of  
AE collection 
and method 
classification 
method 
according to 
BI PV process
5
23 Nov 2017
Abstract
8.2.3.2
Visit 1; 
Baseline Visit
Addition to Study size and 
study sites, Final 
effectiveness evaluation
8.2.3.2 Change of data 
collection period
13. Appendices are attached 
separately
- Period 
adjustment for 
completeness 
of data 
collection
- Attached 
appendix  
separately

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c09963608
6.0
clinical-trial-protocol
A regulatory requirement non interventional study to monitor the safety and
effectiveness of JARDIANCE® (empagliflozin 10mg, 25mg) in Korean patients with
type 2 diabetes mellitus
Author-Clinical Monitor
29 Nov 2017 06:05 CET
Approval-Pharmacovigilance
29 Nov 2017 06:22 CET
Approval-Safety
29 Nov 2017 07:48 CET
Approval-Medical Monitor
29 Nov 2017 08:04 CET
Approval-EU Qualified Person
Pharmacovigilance
29 Nov 2017 08:22 CET
Approval-Team Member Medicine
29 Nov 2017 12:31 CET

Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c09963608
6.0