A Regulatory Requirement Non-interventional Study to Monitor the Safety and Effectiveness of Esgliteo (Empagliflozin/Linagliptin, 10/5mg, 25/5mg) in Korean Patients With Type 2 Diabetes Mellitus
Conditions: Diabetes Mellitus, Type 2
Sponsor: Boehringer Ingelheim

001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
TITLE PAGE 
Non-Interventional Study (NIS) Protocol             
 
TITLE PAGE 
 
Document Number: 
c37168579-01 
BI Study Number: 
1275-0028 
BI Investigational 
Product(s): 
Esgliteo® (empagliflozin/linagliptin, 10/5mg, 25/5mg) 
Title: 
A regulatory requirement non-interventional study to monitor the 
safety and effectiveness of Esgliteo (empagliflozin/linagliptin, 10/5mg, 
25/5mg) in Korean patients with type 2 diabetes mellitus 
Brief lay title: 
Esgliteo PMS in Korean patients with type 2 diabetes mellitus 
Protocol version 
identifier: 
5.0 
Date of last version of 
protocol: 
23 May 2022 
PASS: 
Yes 
EU PAS register 
number: 
EUPAS44579 
Active substance: 
empagliflozin/linagliptin 
Medicinal product: 
Esgliteo Tablet 
10/5mg, 25/5mg 
Product reference: 
Not applicable 
Procedure number: 
Not applicable 
Marketing authorisation 
holder(s): 
 
Joint PASS: 
Not applicable 

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Non-interventional Study Protocol 
BI Study Number 1275-0028                                                                              c37168579-01 
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Research question and 
objectives: 
To monitor the safety profile and effectiveness of Esgliteo in Korean 
patients with type 2 diabetes mellitus in a routine clinical practice 
setting 
Country(-ies) of study: 
South Korea 
Author: 
Phone:
  Fax:
Marketing authorisation 
holder(s): 
MAH contact person: 
EU-QPPV: 
Signature of EU-QPPV: 
Not applicable 
Date: 
28 Oct 2022 
 
Page 1 of 43 
 
Proprietary confidential information 
© 2022 Boehringer Ingelheim Group of companies. All rights reserved. 
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission 
 
 
 
 
 
 
 

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Boehringer-Ingelheim 
Non-interventional Study Protocol 
BI Study Number 1275-0028                                                                              c37168579-01 
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1. 
TABLE OF CONTENTS 
TITLE PAGE .................................................................................................................. 1 
1. 
TABLE OF CONTENTS ....................................................................................... 3 
2. 
LIST OF ABBREVIATIONS ................................................................................ 6 
3. 
RESPONSIBLE PARTIES .................................................................................... 8 
4. 
ABSTRACT ........................................................................................................... 9 
5. 
AMENDMENTS AND UPDATES ..................................................................... 11 
6. 
MILESTONES ..................................................................................................... 14 
7. 
RATIONALE AND BACKGROUND ................................................................ 15 
7.1 
RATIONALE .................................................................................................. 15 
7.2 
BACKGROUND ............................................................................................ 15 
8. 
RESEARCH QUESTION AND OBJECTIVES ................................................. 17 
8.1 
PRIMARY OBJECTIVE ................................................................................ 17 
8.2 
SECONDARY OBJECTIVE .......................................................................... 17 
9. 
RESEARCH METHODS .................................................................................... 18 
9.1 
STUDY DESIGN ............................................................................................ 18 
9.1.1 
Method of Assigning Patients to Treatment Groups ............................... 18 
9.1.2 
Dosage and Administration ..................................................................... 18 
9.1.3 
Concomitant Therapy, Restrictions, Rescue ........................................... 19 
9.2 
SETTING ........................................................................................................ 19 
9.2.1 
Study Sites ............................................................................................... 19 
9.2.2 
Study Population ..................................................................................... 19 
9.2.2.1 
Main diagnosis for study entry ......................................................... 20 
9.2.2.2 
Inclusion criteria: ............................................................................. 20 
9.2.2.3 
Exclusion criteria: ............................................................................ 20 
9.2.2.4 
Subjects of special investigation ...................................................... 20 
9.2.3 
Study Visits ............................................................................................. 20 
9.2.3.1 
Screening and run-in periods ........................................................... 20 
9.2.3.2 
Visit 1; Baseline Visit ...................................................................... 20 
9.2.3.3 
Visit 2; 12 weeks from Visit 1 ......................................................... 21 
9.2.3.4 
Visit 3; 24 weeks from Visit 1 ......................................................... 22 
9.2.3.5 
End of study and follow-up period ................................................... 22 
9.2.4 
Study Discontinuation ............................................................................. 22 

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BI Study Number 1275-0028                                                                              c37168579-01 
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9.2.5 
Flow Chart ............................................................................................... 23 
9.3 
VARIABLES .................................................................................................. 24 
9.3.1 
Analysis Sets ........................................................................................... 24 
9.3.1.1 
Number of cases subject who entered the study .............................. 24 
9.3.1.2 
Number of cases subject to CRF collection ..................................... 24 
9.3.1.3 
Number of cases subject to safety evaluation .................................. 24 
9.3.1.4 
Number of cases subject to effectiveness evaluation ....................... 24 
9.3.2 
Endpoints ................................................................................................. 25 
9.3.2.1 
Endpoints of safety ........................................................................... 25 
9.3.2.2 
Endpoints of effectiveness ............................................................... 25 
 
9.3.2.2.1 Primary endpoints ..................................................................................... 25 
 
9.3.2.2.2 Secondary endpoints ................................................................................. 25 
 
9.3.2.2.3 The final effectiveness evaluation ............................................................. 25 
9.3.3 
Assessment Criteria ................................................................................. 26 
9.3.3.1 
Assessment of safety ........................................................................ 26 
9.3.3.2 
Assessment of effectiveness ............................................................. 26 
9.4 
DATA SOURCES ........................................................................................... 27 
9.5 
STUDY SIZE .................................................................................................. 27 
9.6 
DATA MANAGEMENT ................................................................................ 27 
9.7 
DATA ANALYSIS ......................................................................................... 27 
9.7.1 
Analysis of Demographic Data ............................................................... 27 
9.7.2 
Analysis of Safety ................................................................................... 28 
9.7.3 
Analysis of Effectiveness ........................................................................ 28 
9.7.4 
Interim Analyses ..................................................................................... 29 
9.7.5 
Handling of Missing Data ....................................................................... 29 
9.8 
QUALITY CONTROL ................................................................................... 29 
9.9 
LIMITATIONS OF THE RESEARCH METHODS ...................................... 29 
9.9.1 
Loss to Follow-up .................................................................................... 29 
9.9.2 
Channeling Bias ...................................................................................... 30 
9.9.3 
Confounding ............................................................................................ 30 
9.10 
OTHER ASPECTS ......................................................................................... 30 
9.10.1 
Data Quality Assurance ........................................................................... 30 
9.10.2 
Study Records ......................................................................................... 31 
9.10.2.1 
Source documents ............................................................................ 31 
9.10.2.2 
Direct access to source data and documents .................................... 31 

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BI Study Number 1275-0028                                                                              c37168579-01 
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9.10.2.3 
Storage period of records ................................................................. 32 
10. 
PROTECTION OF HUMAN SUBJECTS .......................................................... 33 
10.1 
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ...................................................................................................... 33 
10.2 
STATEMENT OF CONFIDENTIALITY ...................................................... 33 
11. 
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ....................................................................................................... 34 
11.1 
DEFINITIONS OF ADVERSE EVENTS ...................................................... 34 
11.2 
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION AND 
REPORTING .................................................................................................. 36 
11.3 
REPORTING TO HEALTH AUTHORITIES AND IEC/IRB ....................... 39 
12. 
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
 ............................................................................................................................. 40 
13. 
REFERENCES .................................................................................................... 41 
13.1 
PUBLISHED REFERENCES ......................................................................... 41 
13.2 
UNPUBLISHED REFERENCES ................................................................... 41 
14. 
APPENDICES ..................................................................................................... 42 
14.1 
ELECTRONIC CASE REPORT FORM ........................................................ 42 
14.2 
NON-INTERVENTIONAL STUDY (NIS) ADVERSE EVENT FORM ..... 42 
14.3 
PREGNANCY MONITORING FORM ......................................................... 42 
14.4 
ESGLITEO PRESCRIPTION INFORMATION FOR KOREA .................... 42 
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS .............................................. 43 
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .............................. 44 
 
 
 

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BI Study Number 1275-0028                                                                              c37168579-01 
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2. 
LIST OF ABBREVIATIONS 
ACR 
Albumin Creatinine Ratio 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine Aminotransferase 
 
 
AST 
Aspartate Aminotransferase 
CA 
Competent Authority 
CCDS 
Company Core Data Sheet 
CI 
Confidence Interval 
CML 
Local Clinical Monitor  
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTP 
Clinical Trial Protocol 
DMP 
Data Management Plan 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
eGFR 
Estimated Glomerular Filtration Rate 
ENCePP  
European Network of Centres for Pharmacoepidemiology and 
Pharmacovigilance  
FDA 
Food and Drug Administration 
FPG 
Fasting Plasma Glucose 
GCP 
Good Clinical Practice 
GEP 
Good Epidemiological Practice 
GPP 
Good Pharmacoepidemiology Practice 
GVP 
Good Pharmacovigilance Practices 
HbA1c 
Glucosylated Hemoglobin 
IB 
Investigator’s Brochure 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ISF 
Investigator Site File 
KIMS 
Korea Index of Medical Specialties 
LPVM 
Local PV Manager 
MAH 
Marketing Authorization Holder 
MedDRA 
Medical Dictionary for Regulatory Activities 
MFDS 
The Ministry of Food and Drug Safety 
NCE 
New Chemical Entity 

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BI Study Number 1275-0028                                                                              c37168579-01 
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NIS 
Non-Interventional Study 
NSADR 
Non Serious Adverse Drug Reaction 
OPU 
Operative Unit 
PASS 
Post-Authorization Safety Study 
SADR 
Serious Adverse Drug Reaction 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SGLT2 
Sodium-dependent Glucose Co-transporter 2  
SOP 
Standard Operating Procedure  
T2DM 
Type 2 Diabetes Mellitus 
TCM 
Trial Clinical Monitor 
TMF 
Trial Master File 

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BI Study Number 1275-0028                                                                              c37168579-01 
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3. 
RESPONSIBLE PARTIES 
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 participating countries. 
 
Data Management and Statistical Evaluation will be done by CRO according to CRO’s SOPs. 
 
The organization of the study in the participating countries will be done by the respective 
local BI- operative unit (OPU) or 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. In each local BI OPU participating in this 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 BI or 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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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BI Study Number 1275-0028                                                                              c37168579-01 
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4. 
ABSTRACT  
Name of company: 
 
 
Boehringer Ingelheim 
Name of finished medicinal 
product:  
ESGLITEO®. 
 
Name of active ingredient: 
empagliflozin/linagliptin 
 
Protocol date: 
Study 
number: 
Version/Revision: 
Version/Revision 
date: 
26 Apr2021  
1275-0028 
5.0 
28 Oct 2022 
Title of study: 
A regulatory requirement non-interventional study to monitor the 
safety and effectiveness of Esgliteo (empagliflozin/linagliptin, 10/5mg, 
25/5mg) 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) should be 
conducted. Such NIS can provide supplementary data to monitor the 
safety of NCEs in a real-world situation. Data collected in randomized 
clinical study with strict inclusion/exclusion criteria and rigorous 
monitoring schemes have limitations. This is a non-interventional, 
multi-centre single national study. It will provide additional safety 
information of Esgliteo in Korean patients with type 2 diabetes 
mellitus in a routine clinical practice setting. 
Research question 
and objectives: 
The objectives of this study are to monitor the safety and effectiveness 
of Esgliteo in Korean patients with type 2 diabetes mellitus in a routine 
clinical practice setting. 
Study design: 
Non-interventional, multi-center and single national study based on 
newly collected data 
Population: 
Patients diagnosed with type 2 diabetes mellitus in Korea. 
Esgliteo is indicated as an adjunct to diet and exercise to improve 
glycemic control in patients with type 2 diabetes mellitus. 
 
Inclusion criteria: 
 
Patients who have started at first time on Esgliteo 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: 
 
Patients with previous exposure to Esgliteo 
 
Patients with hypersensitivity to the empagliflozin and/or 
linagliptin or any of the excipients 
 
Patients with type 1 diabetes or diabetic ketoacidosis 

Page 10 of 43 
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BI Study Number 1275-0028                                                                              c37168579-01 
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001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020 
 
Name of company: 
 
 
Boehringer Ingelheim 
Name of finished medicinal 
product:  
ESGLITEO®. 
 
Name of active ingredient: 
empagliflozin/linagliptin 
 
Protocol date: 
Study 
number: 
Version/Revision: 
Version/Revision 
date: 
06 Apr 2021 
1275-0028 
5.0 
28 Oct 2022 
 
 
Patients with eGFR < 45 mL/min/1.73m2, end stage renal 
disease, or patient on dialysis 
Patients for whom empagliflozin/linagliptin is contraindicated 
according local label of Esgliteo 
Variables: 
Endpoints of safety 
All reported adverse events in patients who take at least one dose of 
Esgliteo 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 effectiveness evaluation at the end of the last 
visit will be noted. 
Data sources: 
Field study with new data collection 
Study size: 
Single arm (N=600 approximately) 
Data analysis: 
In this non-interventional study, all statistical analyses will be 
descriptive. Data of characteristics and other status of patients will be 
described and proportions including the confidence intervals will be 
provided. 
Milestones: 
As per regulation, the re-examination period extends from 31 March 
2017 until 30 March 2023. However, active enrolment is to be initiated 
in 2021 before finalizing the re-imbursement agreement with the 
authority. Actual study period will be for about 2 years. 
 
 
 
 
 
 
 
 
 
 

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BI Study Number 1275-0028                                                                              c37168579-01 
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5. 
AMENDMENTS AND UPDATES 

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BI Study Number 1275-0028                                                                              c37168579-01 
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Number 
Date 
Section of  
study protocol 
Amendment or update 
Reason 
1 
11 May 
2021 
9.2.2.3 Exclusion 
criteria 
• 
Patients with eGFR < 30 
mL/min/1.73m2, end stage renal 
disease, or patient on dialysis  
• 
Patients with moderate renal 
impairment  (eGFR >/= 30 and 
< 60 mL/min/1.73m2) not yet 
treated with empagliflozin at 
time of enrolment 
Changed and Added eGFR 
cut-off criteria for 
Contraindication and 
Renal Impairment Patient 
according to local label 
2 
12 Oct 2021 
9.2.2.3 Exclusion 
criteria 
• 
Patients with eGFR < 3045 
mL/min/1.73m2, end stage renal 
disease, or patient on dialysis  
• 
Patients with moderate renal 
impairment  (eGFR >/= 30 and 
< 60 mL/min/1.73m2) not yet 
treated with empagliflozin at 
time of enrolment 
Comment from  Korea HA 
(MFDS) : Amend the 
exclusion criteria 
according to Korea LPI. 
3 
23 May 
2022 
9.2.3.3 Visit 2; 12 
weeks from Visit 1 
• 
Effectiveness assessment: 
HbA1c, FPG (Within 1month 
prior to Visit 2) 
Add assessment period  
 
4 
23 May 
2022 
9.2.3.4 Visit 3; 24 
weeks from Visit 1 
• 
Effectiveness assessment: 
HbA1c, FPG (Within 1month 
prior to Visit 3) 
Add assessment period  
 
5 
23 May 
2022 
9.7.1Analysis of 
Demographic Data 
① Basic information and disease 
information 
Age, Gender, Pregnancy, Family 
history of T2DM, Allergy, 
Smoking status, Body weight, 
Diabetes mellitus complications 
(if available), Other medical 
history, Disease period, Elderly 
(Age ≥ 65 years), Renal 
impairment and Hepatic 
impairment, Long term use(over 
24 weeks) 
Collect data if available 
6 
28 Oct 2022 
9.1.2 Dosage and 
Administration 
In patients tolerating this drug 10 
mg/5 mg once daily and requiring 
additional glycaemic control, the 
dose can be increased to 
empagliflozin 25 mg/linagliptin 5 
mg once daily.  
Update in accordance with 
the product label updated 
on September 28, 2022. 
7 
28 Oct 2022 
11.1 
 DEFINITIONS OF 
ADVERSE EVENTS 
Delete the Always Serious Adverse 
Events 
Not applicable for NIS 
studies including local 
PMS studies 
8 
28 Oct 2022 
11.1 
 DEFINITIONS OF 
ADVERSE EVENTS 
Update definitions for AESI hepatic 
injury  
In accordance with the 
changes concerning the 
hepatic injury definition as 
AESI. 

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BI Study Number 1275-0028                                                                              c37168579-01 
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9 
28 Oct 2022 
11.2 ADVERSE 
EVENT AND 
SERIOUS 
ADVERSE EVENT 
COLLECTION AND 
REPORTING 
Delete the report timeline of ASAE 
Not applicable for NIS 
studies including local 
PMS studies 
 

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BI Study Number 1275-0028                                                                              c37168579-01 
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6. 
MILESTONES 
Milestone 
Planned Date 
Start of data collection 
30 Oct 2021 
End of data collection 
30 Nov 2022 
Interim report 
30 May 2022 
Final report of study results: 
30 Jun 2023 
 
 
 
 

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BI Study Number 1275-0028                                                                              c37168579-01 
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7. 
RATIONALE AND BACKGROUND 
7.1 
RATIONALE 
According to the local regulations, when a new chemical entity (NCE) is registered, a 
regulatory non-interventional study (NIS) should be conducted. Such NIS can provide 
supplementary data to monitor the safety of NCEs in a real-world situation. Data collected in 
randomized clinical study with strict inclusion/exclusion criteria and rigorous monitoring 
schemes have limitations. 
 
This is a non-interventional, multi-centre single national study. It will provide additional 
safety information of Esgliteo (empagliflozin/linagliptin) in Korean patients with type 2 
diabetes mellitus in a routine clinical practice setting. 
 
7.2 
BACKGROUND 
Diabetes mellitus is an increasingly prevalent disease. Recent estimates suggest that the 
number of people worldwide with diabetes is currently 382 million and is expected to reach 
at least 592 million within the next 25 years [R14-1408]. The most common form is type 2 
diabetes, which is characterized by insulin resistance, impaired insulin secretion, and 
increased blood glucose levels. Type 2 diabetes is also associated with microvascular 
complications [R09-6405, R09-6406] and elevated cardiovascular risks [R12-2906]. 
 
Diabetes and its complications have become a major cause of morbidity and mortality in 
Korea. Although diabetes-related mortality has recently decreased from 25.1 per 100,000 
persons in 2002 to 19.6 per 100,000 persons in 2009, diabetes is still the fifth-leading cause 
of death in Korea. Diabetic complications such as renal failure, neuropathy, retinopathy, 
coronary and cerebral artery diseases, and amputations are associated with increased medical 
costs and reduced life expectancy [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]. 
 
Treatment of type 2 diabetes usually involves lifestyle interventions, such as diet and 
exercise, as well as the administration of antidiabetic drugs. Although initially effective, 
currently available oral antidiabetic agents often fail to maintain long-term glycemic control 
or are associated with side effects that may limit their use. Hence, there is an ongoing need 
for new therapeutic options to provide sustained improvements in glycemic control. 
[c03606501-02] 
 
In the EMPA-REG OUTCOME trial (1245.25), empagliflozin demonstrated significant 
benefit in patients with T2DM with established cardiovascular (CV) disease by reducing 
overall mortality mostly due to CV death and hospitalisation for heart failure. Furthermore, 
empagliflozin significantly reduced the risk for the combined endpoint of new onset or 
worsening of nephropathy (new onset of macroalbuminuria, 2x serum creatinine 
accompanied by eGFR(Estimated Glomerular Filtration Rate) ≤45 mL/min/1.73 m2, initiation 

Page 16 of 43 
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BI Study Number 1275-0028                                                                              c37168579-01 
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of continuous renal replacement therapy, and death due to renal disease) compared to placebo 
[c02695839-01]. 
 
In the CARMELINA trial, linagliptin did not increase the risk of the combined endpoint of 
CV death, non-fatal myocardial infarction or non-fatal stroke (3-point MACE), or the risk of 
combined endpoint of renal death, ESRD, 40% or more sustained decrease in eGFR, when 
added to standard of care in adult patients with T2DM with increased CV risk evidenced by a 
history of established macrovascular or renal disease. In addition, linagliptin did not increase 
the risk of hospitalisation for heart failure. No increased risk of CV death or all-cause 
mortality was observed [c22196815-01]. 
 
Thus, the FDC of linagliptin with empagliflozin provides clinically meaningful treatment 
benefits by lowering glucose and reducing HbA1c further than monotherapy with either 
component at corresponding doses. Combining linagliptin with empagliflozin simplifies the 
antidiabetic therapy by decreasing the number of tablets to be taken and is expected to 
improve patients’ compliance with medication; FDC therapy has resulted in improved 
compliance in patients previously treated with oral antidiabetics [s00083671-01]. 
 
For a detailed description of the drug profile refer to the local prescribing information of 
Esgliteo. 
 

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BI Study Number 1275-0028                                                                              c37168579-01 
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8. 
RESEARCH QUESTION AND OBJECTIVES 
8.1 
PRIMARY OBJECTIVE 
The primary objective of this study is to monitor the safety profile of Esgliteo in Korean 
patient with type 2 diabetes mellitus (T2DM) in a routine clinical setting. 
 
8.2 
SECONDARY OBJECTIVE 
The secondary objective of this study is to monitor the effectiveness of Esgliteo 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 effectiveness evaluation at the end of the last visit in Korean T2DM patients. 
 
 
 

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BI Study Number 1275-0028                                                                              c37168579-01 
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9. 
RESEARCH METHODS 
This study is a national multi-centre non-interventional study (NIS). As per regulation, the re-
examination period extends from 31 March 2017 until 30 March 2023. However, active 
enrolment is to be initiated in 2021 before 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. 
 
This study will be carried out by enrolling patients in a consecutive manner into the study 
requiring completion of 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. 
 
Patients will be managed according to the local practice guidelines. The choice of treatment 
will be solely at the discretion of the participating physician. Esgliteo will be administered 
according to the approved label in Korea. Hence there are no additional risks to patients by 
participating in this NIS. 
 
9.1 
STUDY DESIGN 
This is a NIS based on single arm with Esgliteo. Esgliteo 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. 
9.1.1 
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.  
9.1.2 
Dosage and Administration  
The starting dose and the dose escalation schedule are based on the current authorized label 
in Korea. 
 
The recommended dose is one tablet once daily as follows; 
 In patients tolerating this drug 10 mg/5 mg once daily and requiring additional 
glycaemic control, the dose can be increased to empagliflozin 25 mg/linagliptin 5 mg 
once daily.  
 In patients switching from separate tablets of empagliflozin and linagliptin to Esgliteo 
should receive the same dose already being taken. 
 
The tablets can be taken with or without food, swallowed whole. If a dose is missed, it should 
be taken as soon as the patient remembers. If a dose is missed, and it is less than 12 hours 

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BI Study Number 1275-0028                                                                              c37168579-01 
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until the next dose, the dose should be skipped and the next dose should be taken at the usual 
time. A double dose should not be taken at once. 
9.1.3 
Concomitant Therapy, Restrictions, Rescue 
The protocol will allow additional drugs 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 of all concomitant medication administered to the patient during the course of 
treatment in eCRF. This includes concomitant therapies started one month prior to Esgliteo 
initiation until the patient completes the final follow-up visit. 
For more detailed information, please refer to the current local label. 
 
9.2 
SETTING 
Enrolled patients will be followed up after 12 or/and 24 weeks of treatment period. 
 
9.2.1 
Study Sites 
Approximately 20 sites by as many as 20 or more NIS investigators will participate. 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. 
 
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 
Drugs』and study protocol. 
 
9.2.2 
Study Population 
A total of 600 patients will be enrolled at approximately 20 sites by as many as 20 or more 
NIS physicians. To minimize the selection bias, consecutive patients from each site who meet 
inclusion criteria will be enrolled in this study. 

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BI Study Number 1275-0028                                                                              c37168579-01 
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9.2.2.1 
Main diagnosis for study entry 
Patients diagnosed with type 2 diabetes mellitus in Korea. Esgliteo is indicated as an adjunct 
to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus who 
are appropriate to take a combination of empagliflozin and linagliptin. 
9.2.2.2 
Inclusion criteria: 
 Patients who have started at first time on Esgliteo in accordance with the approved 
label in Korea 
 Age ≥19 years at enrolment 
 Patients who have signed on the data release consent form 
9.2.2.3 
Exclusion criteria: 
 Patients with previous exposure to Esgliteo 
 Patients with hypersensitivity to the empagliflozin and/or linagliptin or any of the 
excipients 
 Patients with type 1 diabetes or diabetic ketoacidosis 
 Patients with eGFR < 45 mL/min/1.73m2, end stage renal disease, or patient on 
dialysis 
 Patients for whom empagliflozin/linagliptin is contraindicated according to the local 
label of Esgliteo 
9.2.2.4 
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 Esgliteo can be further investigation into cases 
collected from this study may be taken into account according to the outcome of retrospective 
analysis. 
 
9.2.3 
Study Visits 
9.2.3.1 
Screening and run-in periods 
This section is not applicable as this is a non-interventional study. 
9.2.3.2 
Visit 1; Baseline Visit  
Upon patient enrolment, the following will be recorded on the patient’s eCRF. 
 
Visit date 
 
Diagnosis: date of the diagnosis of T2DM, Family history of T2DM 
 
Inclusion / Exclusion criteria 
 
Data release consent form: Date of data release consent form 

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 
Demographic data: Year of birth(age), Gender, Pregnancy, Previous allergy, Height, 
Smoking status 
 
Diabetes mellitus related complication(Retinopathy, Neuropathy, Nephropathy, 
Vasculopathy, Others) 
 
Medical history: Renal impairment, Hepatic impairment, Others. (history of 
concomitant disease within 6 months prior to baseline) 
 
Physical examination: Body weight, Blood pressure (SBP, DBP) 
 
Renal function test: Serum creatinine, eGFR, Urine ACR if blood test result is 
available(the most recent data prior to baseline) 
 
Effectiveness assessment: HbA1c, FPG (within 1 month prior to baseline) 
 
Concomitant anti-hyperglycemic agent: record any anti-hyperglycemic agents that 
have been taken at least once (within 1 month prior to baseline) 
 
Concomitant medications: record all medications that have been taken at least once 
(within 1 month prior to baseline) 
 
Dose of Esgliteo given (Daily dose, 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 Esgliteo treatment. 
9.2.3.3 
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 changes of Esgliteo given 
 
Effectiveness assessment: HbA1c, FPG (Within 1month prior to Visit 2) 
 
Renal function test: 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 changes in the concomitant medications (dose and dosing intervals) 
 
Concomitant medications including new medications taken since last visit: any 
changes 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 Esgliteo 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 (if necessary) 

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 
The final effectiveness evaluation(if necessary) 
 
NIS physician’s electronic signature for data integrity (if necessary) 
9.2.3.4 
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 changes of Esgliteo given 
 
Effectiveness endpoints: HbA1c, FPG (Within 1month prior to Visit 3) 
 
Renal function test: 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 changes in the concomitant medications (dose and dosing intervals) 
 
Concomitant medications including new medications taken since last visit: any 
changes 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 Esgliteo 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(if necessary) 
 
The final effectiveness evaluation 
 
NIS physician’s electronic signature for data integrity 
 
9.2.3.5 
End of study and follow-up period 
Patients with adverse events noted at the final follow-up visit or upon premature 
discontinuation of Esgliteo will be monitored further until the study completion. 
Alternatively, those patients will be followed up until the NIS physician and sponsor agree 
that no further follow-up is necessary. 
 
 
9.2.4 
Study Discontinuation 
Boehringer Ingelheim reserves the right to discontinue the study overall or at a particular 
study site at any time for the following reasons: 
 
1. Failure to meet expected enrolment goals overall or at a particular study site 

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BI Study Number 1275-0028                                                                              c37168579-01 
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2. Emergence of any effectiveness/safety information that could significantly affect 
continuation of the study 
3. Violation of Good Pharmacoepidemiology Practice (GPP), the study protocol, or the 
contract by a study site, investigator or research collaborator, disturbing the appropriate 
conduct of the study 
 
The investigator/the study site/research collaborator will be reimbursed for reasonable 
expenses incurred in case of study/site termination (except in case of the third reason). 
 
9.2.5 
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-diabetic agents 
X 
X 
X 
Concomitant medications 
X 
X 
X 
Esgliteo administration status 
X 
X 
X 
Renal function 
  X A 
X A 
X A 
Effectiveness endpoints 
X 
X 
X 
Overall effectiveness evaluation 
 
 
X 
Changes in lab tests 
 
X A 
X A 
Adverse events 
 
X 
X 
Study completion 
 
X 
X 
A: If applicable 
 
 

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BI Study Number 1275-0028                                                                              c37168579-01 
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9.3 
VARIABLES 
9.3.1 
Analysis Sets 
A total of 600 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 too restrictive to collect safety and effectiveness data in 
short-term (12weeks) period, all patients will be enrolled for long-term (24weeks) 
surveillance. 
9.3.1.1 
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. 
9.3.1.2 
Number of cases subject to CRF collection 
This number means the number of cases who signed the data release consent form to 
participate in the study as subject, with a record of taking Esgliteo once at least. 
9.3.1.3 
Number of cases subject to safety evaluation 
These include those who signed the data release consent form to participate in this study as 
subject, took Esgliteo 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 did not signed or signed on the data release consent form of Esgliteo 
PMS prior to the contract date 
b. Patients administrated Esgliteo prior to the contract date 
c. Patients administrated Esgliteo prior to the signed on the data release consent form 
d. Patients who have not taken Esgliteo 
e. Follow-up failure: Patients whose safety information cannot be obtained due to 
follow-up Loss 
f. 
Patients who were prescribed for other indications except indications in the local 
label 
9.3.1.4 
Number of cases subject to effectiveness evaluation 
These cases include those who signed the data release consent form to participate in this 
study as subject, visited as per the study schedule, took Esgliteo, and were evaluated for the 
effectiveness. 
Reflecting Ministry of Food & Drug Safety (MFDS) guideline, the cases below shall be 
excluded from effectiveness analysis (defined below) set in the following order: 
 
a. Patients excluded from safety analysis set listed in section 9.3.1.3 
b. Patients with missing information of assessment of effectiveness set listed in section 
9.3.2.2 at visit 2, visit 3 

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BI Study Number 1275-0028                                                                              c37168579-01 
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9.3.2 
Endpoints 
9.3.2.1 
Endpoints of safety 
All reported adverse events in patients who take at least one dose of Esgliteo will be noted.  
Endpoints pertaining to safety will be presented as frequency 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 
• 
Adverse events by intensity, outcome of the events, causality 
9.3.2.2 
Endpoints of effectiveness 
9.3.2.2.1 
Primary endpoints 
• 
Change from baseline in HbA1c after 12 weeks and/or 24 weeks of treatment 
9.3.2.2.2 
Secondary 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. 
9.3.2.2.3 
The final effectiveness evaluation 
Records by performing the final effectiveness 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. 

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BI Study Number 1275-0028                                                                              c37168579-01 
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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”.  
9.3.3 
Assessment Criteria 
9.3.3.1 
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/ Not yet recovered/ Sequela/ Fatal/ Unknown) 
• 
Causality (Certain/ Probable·Likely/ Possible/ Unlikely/ Conditional· Unclassified/ 
Unassessable·Unclassifiable)  
• 
Action taken with study drug due to AE (Dose not changed/ Dose reduced/ Dose 
increased/ Drug withdrawn/ Not applicable) 
• 
Adverse Event of Special interest (Hepatic injury/ Decreased renal function/ 
Metabolic acidosis, ketoacidosis and diabetic ketoacidosis (DKA)/ Lower limb 
amputation) 
9.3.3.2 
Assessment of effectiveness 
①  HbA1c(%):  
HbA1c should be collected within 1 month prior to baseline and after 12 weeks, 24 
weeks of treatment. 
②  Fasting Plasma Glucose (FPG)(mg/dL):  
FPG should be collected within 1 month prior to baseline and after 12 weeks, 24 
weeks of treatment. 
③ Body Weight(kg):  
Body weight should be collected within 1 month prior to baseline and after 12 
weeks, 24 weeks of treatment. 
④ Blood Pressure (SBP, DBP)(mmHg):  
Blood pressure(SBP, DBP)  should be collected within 1 month prior to baseline 
and after 12 weeks, 24 weeks of treatment. 
⑤ Final effectiveness evaluation: Final effectiveness evaluation should be accessed 
and recorded at the end of the last visit.  
 

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BI Study Number 1275-0028                                                                              c37168579-01 
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9.4 
DATA SOURCES 
This study will be carried out by enrolling patients in a consecutive manner into the study 
requiring completion of 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. 
 
9.5 
STUDY SIZE 
The sample size of 600 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. 
 
9.6 
DATA MANAGEMENT 
Patients’ data will be collected 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). 
 
9.7 
DATA ANALYSIS 
9.7.1 
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, Family history of T2DM, Allergy, Smoking status, Body 
weight, Diabetes mellitus complications (if available), Other medical history, Disease 
period, Elderly (Age ≥ 65 years), Renal impairment and Hepatic impairment, Long 
term use(over 24 weeks) 
② Medication information 
Concomitant medication, Any anti-diabetic agents, Study drug administration status 
(total period of drug use, average of daily dose), Reason for early interruption 

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BI Study Number 1275-0028                                                                              c37168579-01 
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9.7.2 
Analysis of Safety 
① Among 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 
frequency of adverse events and the 95% confidence interval should be presented. 
② The number and percentage of adverse events by type and category should be 
presented. 
③ Analysis 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. 
④ To estimate any factors that are thought to influence the analyzed frequency of 
adverse events, logistic regression analysis should be conducted, and for statistically 
significant parameters, the meaning should be described. 
 
Adverse Events (AEs) excluding the AEs whose ‘Causality’ is “Unlikely” will be treated as 
AEs whose causality cannot be excluded (hereafter “Adverse Drug Reaction (ADR)”). 
 
AEs will be coded according to the latest version of Medical Dictionary for Drug Regulatory 
Affairs (MedDRA) coding system. Concomitant medications will be coded according to the 
latest version of KIMS(Korea Index of Medical Specialties) coding system. The study 
database will not be locked until coding is complete. 
 
Safety analyses will be based on all patients treated, i.e. all patients who received at least one 
dose of Esgliteo. However, if data for patients who have been treated with Esgliteo beyond 
the scope of approved label are collected, separate 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. 
9.7.3 
Analysis of Effectiveness 
① Mean, standard deviation, minimum value, maximum value, and median of changes 
in glycosylated hemoglobin(HbA1c) and fasting plasma glucose(FPG), weight, and 
blood pressure, which were measured at the last visit versus baseline, should be 
presented, and if there is a 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 9.7.1 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 effectiveness 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 effectiveness evaluation (improved, unchanged, aggravated, unassessable) 
and ‘effective(improved)’/‘ineffective(unchanged, aggravated)’, the number and 

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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.   
9.7.4 
Interim Analyses 
In accordance with local regulation for NIS, interim analyses are planned biannually for the 
initial two years and annually thereafter. 
9.7.5 
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. 
 
9.8 
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. 
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. 
All changes after initial data entry will be documented in an audit trail. An additional 
inspection/quality assurance check of the data collected within this NIS can be performed in 
case of any deviation. 
 
9.9 
LIMITATIONS OF THE RESEARCH METHODS 
9.9.1 
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 and others. Also, patients 
lost to follow up will be characterized compared to the completed patients and reason and 
time point of loss to follow up will be evaluated. 

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BI Study Number 1275-0028                                                                              c37168579-01 
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9.9.2 
Channeling Bias 
Channeling bias can occur due to access to product depending on reimbursement 
circumstances or preferential prescribing in relation to different risks for the events of 
interest: e.g., if Esgliteo would be more often prescribed to higher risk patients compared to 
other treatments, higher frequency of outcome events were then expected in the Esgliteo 
group. To assess the extent of preferential prescribing of Esgliteo and the potential for 
channeling bias, baseline data from the Jardiance Duo (empagliflozin /metformin) PMS 
would be used to provide context for the Esgliteo PMS data. 
 
9.9.3 
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. 
 
9.10 
OTHER ASPECTS 
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 required NIS will be submitted to the Ministry of Food and 
Drug Safety (MFDS) for notification. Also, the protocol of this NIS will be submitted to 
Institutional Review Board (IRB) 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). 
 
 will submit periodic reports during re-examination period, and 
the final report to MFDS upon study completion. The periodic 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. 
9.10.1 
Data Quality Assurance 
A quality assurance audit/inspection of this study may be conducted by the sponsor or 
sponsor’s designees or by Institutional Review Board (IRBs) / Independent Ethics Committee 
(IECs) or by regulatory authorities. The quality assurance auditor will have access to all 
medical records, the investigator’s study-related files and correspondence, and the data 
release consent form documentation of this study. 

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BI Study Number 1275-0028                                                                              c37168579-01 
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9.10.2 
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. 
9.10.2.1 
Source documents 
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
 
Data entered in the eCRFs that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may need 
to request previous medical records or transfer records, depending on the study; also current 
medical records must be available. 
 
For the eCRF, the following data need to be derived from source documents: 
• 
Patient identification (gender, age) 
• 
Patient participation in the study (study number, patient number, date patient was 
informed) 
• 
Dates of Patient’s visits, including dispensing of study medication 
• 
Medical history (including study indication and concomitant diseases, if applicable) 
• 
Medication history 
• 
Physical examination (body weight, blood pressure (SBP, DBP)) 
• 
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 available) 
• 
Completion of Patient’s Participation in the study 
9.10.2.2 
Direct access to source data and documents 
The investigator/institution will permit study-related monitoring, audits, IRB/IEC review and 
regulatory inspection, providing direct access to all related source data/documents. 
CRFs/eCRFs and all source documents, including progress notes and copies of laboratory and 
medical test results must be available at all times for review by the sponsor’s clinical study 
monitor, auditor and inspection by health authorities (e.g. US Food and Drug Administration 

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BI Study Number 1275-0028                                                                              c37168579-01 
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(FDA)). BI study staff and auditor may review all CRFs/eCRFs, and written informed 
consents. The accuracy of the data will be verified by reviewing the documents described in 
Section 9.10.2.1. 
9.10.2.3 
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. 
 
 

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BI Study Number 1275-0028                                                                              c37168579-01 
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10. 
PROTECTION OF HUMAN SUBJECTS 
The study will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, Guidelines for Good Pharmacoepidemiology Practice (GPP), and the 
relevant BI Standard Operating Procedures (SOPs). Standard medical care (prophylactic, 
diagnostic and therapeutic procedures) remains the responsibility of the treating physician of 
the patient. 
 
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches 
of the protocol. 
 
 
10.1 
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT 
This NIS will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and Competent Authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments. 
 
Prior to patient participation in the study, written data release 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 data release consent retained by the investigator as part of the study 
records. A signed copy of the data release 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. 
 
 
10.2 
STATEMENT OF CONFIDENTIALITY 
Individual patient medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers. 
 
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the 
study need to be available for inspection on request by the participating physicians, the 
sponsor’s representatives, by the IRB/IEC and the regulatory authorities. 

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BI Study Number 1275-0028                                                                              c37168579-01 
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11. 
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS 
11.1 
DEFINITIONS OF ADVERSE EVENTS 
Adverse event 
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have a 
causal relationship with this treatment. An adverse event can therefore be any 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 drug reaction 
An adverse drug reaction (ADR) 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 authorization 
or from occupational exposure. Conditions of use outside the marketing authorization include 
off-label use, overdose, misuse, abuse and medication errors. 
 
Serious adverse event 
A serious adverse event is defined as any AE which 
- results in death,  
- is life-threatening,  
- requires in-patient hospitalization, or 
- prolongation of existing hospitalization,  
- results in persistent or significant disability or incapacity, or  
- is a congenital anomaly/birth defect  
 
Life-threatening in this context refers to a reaction in which the patient was at risk of death at 
the time of the reaction; it does not refer to a reaction that hypothetically might have caused 
death if more severe. 
 
Medical and scientific judgement should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize 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. 
 
 
Adverse Event of Special Interest (AESI) 

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BI Study Number 1275-0028                                                                              c37168579-01 
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The term Adverse Event of Special Interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this study, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the
within the same timeframe that applies to SAEs. 
 
The following are considered as AESIs: 
 
• 
Hepatic injury 
- An elevation of AST and/or ALT ≥3-fold ULN combined with an elevation of 
total bilirubin ≥2-fold ULN measured at the same visit, or in samples drawn with
in 30 days of each other, OR 
- 
An elevation of AST and/or ALT ≥3-fold ULN and INR ≥1.5-fold ULN measur
ed at the same visit, or in samples drawn within 30 days of each other, OR 
- 
An elevation of AST and/or ALT ≥3-fold ULN with new onset, or worsening of 
fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, an
d/or eosinophilia (>5%), OR 
- An isolated elevation of AST and/or ALT ≥5-fold ULN  
 
• 
Decreased renal function 
- Creatinine value shows a >2-fold increase from baseline and is above the ULN 
• 
Metabolic acidosis, ketoacidosis and diabetic ketoacidosis (DKA) 
• 
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). 
Each lower limb amputation, disarticulation, or auto-amputation should be report
ed separately. The SAE report should include the date of the procedure, the level 
of amputation or disarticulation, the medical condition(s) leading to the procedur
e and if the patient had some of the known risk factor(s) for lower limb amputati
on. 
 
 
 

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BI Study Number 1275-0028                                                                              c37168579-01 
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11.2 
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION 
AND REPORTING 
The investigator shall maintain and keep detailed records of all AEs in their patient files.  
 
Collection of AEs 
The study is a non-interventional study in real-world situation and will be conducted within 
the conditions of the approved marketing authorization. For this reason, the following AE 
collection and reporting requirements have been defined. 
 
All adverse events occurred from the signing date on data release consent form to last visit 
date of monitoring period need to be collected, documented and reported to the sponsor using 
the AE page of eCRF(14.1).  
 
The investigator carefully assesses whether an AE constitutes an ADR using the information 
below.  
 
Causal relationship of adverse event 
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an adverse event. An adverse 
reaction, in contrast to an adverse event, is characterized by the fact that a causal relationship 
between a medicinal product and an occurrence is suspected. 
 
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.  
 
Arguments that may suggest a reasonable causal relationship could be: 
• 
The event is consistent with the known pharmacology of the drug  
• 
The event is known to be caused by or attributed to the drug class 
• 
A plausible time to onset of the event relative to the time of drug exposure 
• 
Evidence that the event is reproducible when the drug is re-introduced 
• 
No medically sound alternative etiologies that could explain the event (e.g. 
preexisting or concomitant diseases, or co-medications). 
• 
The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome). 
• 
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) 

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BI Study Number 1275-0028                                                                              c37168579-01 
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• 
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 eCRF 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 
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 
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 adverse event 
The intensity of the AE should be judged based on the following: 
Mild: 
Awareness of sign(s) or symptom(s) which is/are easily tolerated 
Moderate: 
Enough discomfort to cause interference with usual activity 
Severe: 
Incapacitating or causing inability to work or to perform usual activities 

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BI Study Number 1275-0028                                                                              c37168579-01 
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Expedited Reporting of AEs and Drug Exposure during Pregnancy to BI 
Pharmacovigilance 
The following must be reported by the investigator on the NIS AE form and/or Pregnancy 
Monitoring Form(14.3) from signing the data release consent onwards until the end of the 
study and provide to the LPVM of
 
Contact details: 
Local PV Manager (LPVM) 
Tel:
Fax:
Address:
 
 
Type of Report 
Timeline 
All Serious Adverse Events (SAEs) 
immediately within 24 hours 
All AEs with fatal outcome 
immediately within 24 hours 
All protocol specified Adverse Event of 
Special Interest (AESIs) 
Immediately within 24 hours 
All non-serious adverse events 
7 calendar days 
Drug exposure during pregnancy 
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 the AE page of the eCRF and/or the NIS 
AE form. 
 
Pregnancy: 
In rare cases, pregnancy might occur in a NIS. Once a patient has been enrolled in the study 
and has taken study medication, the investigator must report any drug exposure during 
pregnancy in a study participant within 7 days by means of Part A of the Pregnancy 
Monitoring Form (14.3) to the LPVM of 
 
 
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the LPVM of 
 on the Pregnancy Monitoring Form (Part 
B).  
 
The ISF will contain the Pregnancy Monitoring Form (Part A and B). As pregnancy itself is 
not to be reported as an AE, in the absence of an accompanying serious ADR and/or AESI, 
only the Pregnancy Monitoring Form and not the NIS AE form is to be completed. If there is 
a serious ADR and/or AESI associated with the pregnancy a NIS AE form must be completed 
in addition. 
 
Information required 

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BI Study Number 1275-0028                                                                              c37168579-01 
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For each reportable adverse event, the investigator should provide the information requested 
on the appropriate eCRF page and the NIS AE form. 
 
For each AE, the investigator will provide the onset, end, intensity, outcome, seriousness and 
action taken with Esgliteo. The investigator will determine the relationship of Esgliteo to all 
AEs as defined in the 'Adverse Event Reporting' section of the investigator 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 
Esgliteo according to the local regulatory requirements for spontaneous AE reporting at the 
investigator’s discretion by using the locally established routes and AE report forms. The 
term AE includes drug exposure during pregnancy, and, regardless of whether an AE 
occurred or not, any abuse, off-label use, misuse, medication error, occupational exposure, 
lack of effect, and unexpected benefit. 
 
 
11.3 
REPORTING TO HEALTH AUTHORITIES AND IEC/IRB 
Adverse event reporting to regulatory agencies and IEC/IRB will be done by the Marketing 
Authorization Holder (MAH) according to local and international regulatory requirements.  
 
 
 

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BI Study Number 1275-0028                                                                              c37168579-01 
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12. 
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS 
The rights of the investigator and of the sponsor with regard to publication of the results of 
this study are described in the investigator contract. As a general rule, no study results should 
be published prior to finalization of the Study Report. 
 
 

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BI Study Number 1275-0028                                                                              c37168579-01 
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13. 
REFERENCES 
13.1 
PUBLISHED REFERENCES 
R14-1408 
Guariguata L, Whiting DR, Hambleton I, Beagley J, Linnenkamp U, Shaw 
JE. Global estimates of diabetes prevalence for 2013 and projections for 
2035. Diabetes Res Clin Pract 2014;103: 137-149. 
R09-6405 
UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive 
blood glucose control with metformin on complications in overweight 
patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854-865. 
R09-6406 
Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HAW. 10-Year 
follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 
2008 359(15): 1577-1589 
R12-2906 
International Diabetes Federation (IDF). Diabetes and cardiovascular 
disease: time to act: diabetes: a major risk factor. website: 
cvd.idf.org/Risk_Factors/Diabetes_A_Major_Risk_Factor/index.html 
(access date: 29 June 2012) ; Brussels: International Diabetes Federation 
(IDF); 2005. 
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 
ClinPract 2011;94:311-21. 
 
13.2 
UNPUBLISHED REFERENCES 
c03606501-02 
Empagliflozin/metformin hydrochloride Clinical Overview, 13 January 
2016 
 
c02695839-01 
A Phase III, multicentre, international, randomised, parallel group, double 
blind cardiovascular safety study of BI 10773 (10 mg and 25 mg 
administered orally once daily) compared to usual care in type 2 diabetes 
mellitus patients with increased cardiovascular risk. 1245.25. 12 Oct 2015. 
 
c22196815-01 
A multicenter, international, randomized, parallel group, double-blind, 
placebo-controlled Cardiovascular Safety & Renal Microvascular 
outcome study with LINAgliptin, 5 mg once daily in patients with type 2 
diabetes mellitus at high vascular risk. CARMELINA. 03 Aug 2018. 
 
s00083671-01 
Empagliflozin/linagliptin Periodic Benefit-Risk Evaluation Report, 13 
Dec 2019 

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BI Study Number 1275-0028                                                                              c37168579-01 
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14. 
APPENDICES 
14.1 
ELECTRONIC CASE REPORT FORM 
Please refer to “ELECTRONIC CASE REPORT FORM” in site file or in electronic CRF 
web page for the latest version. 
 
14.2 
NON-INTERVENTIONAL STUDY (NIS) ADVERSE EVENT FORM 
Please refer to “Non-Interventional Study (NIS) Adverse Event Form” in site file or in 
electronic CRF web page for the latest version. 
 
14.3 
PREGNANCY MONITORING FORM 
Please refer to “PREGNANCY MONITORING FORM” in site file or in electronic CRF web 
page for the latest version. 
 
14.4 
ESGLITEO PRESCRIPTION INFORMATION FOR KOREA 
Please refer to “ESGLITEO PRESCRIPTION INFORMATION FOR KOREA” in site file or 
in electronic CRF web page for the latest version. 
 

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BI Study Number 1275-0028                                                                              c37168579-01 
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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS 
Number 
Document 
Reference Number 
Date 
Title 
None 
None 
None 
None 
 
 
 

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BI Study Number 1275-0028                                                                              c37168579-01 
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ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS 
Please refer to “ENCePP Checklist for Study Protocols” in separate file