A Regulatory Requirement Non Interventional Study to Monitor the Safety and Effectiveness of JARDIANCE DUO® (Empagliflozin/Metformin, 5/500mg, 5/850mg, 5/1000mg, 12.5/500mg, 12.5/850mg, 12.5/1000mg) in Korean Patients With Type 2 Diabetes Mellitus
Conditions: Diabetes Mellitus, Type 2
Sponsor: Boehringer Ingelheim

TITLE PAGE
NON-INTERVENTIONAL STUDY PROTOCOL
TITLE PAGE
Document Number:
c10880816-03
BI Study Number:
1276.39
BI Investigational
Product:
JARDIANCE DUO® (empagliflozin/metformin)
Title:
A regulatory requirement non interventional study to monitor the 
safety and effectiveness of JARDIANCE DUO®
(empagliflozin/metformin, 5/500mg, 5/850mg, 5/1000mg, 
12.5/500mg, 12.5/850mg, 12.5/1000mg) in Korean patients with 
type 2 diabetes mellitus
Brief lay title
JARDIANCE DUO® rPMS in Korean patients with type 2 
diabetes mellitus
Protocol version 
identifier:
3.0
Date of last version of 
protocol:
25 Apr 2018
PASS:
Yes
EU PAS register 
number:
EUPAS 24004
Active substance:
empagliflozin/metformin
Medicinal product:
JARDIANCE DUO® film-coated tablet
5/500mg, 5/850mg, 5/1000mg, 
12.5/500mg, 12.5/850mg, 12.5/1000mg
Product reference:
Not applicable
Procedure number:
Not applicable
Marketing authorisation 
holder:
Joint PASS:
Not applicable
Research question and 
objectives:
To monitor the safety profile and effectiveness of JARDIANCE 
DUO® in Korean patients with type 2 diabetes mellitus in a 
routine clinical practice setting

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Country of study:
Multi-Centre study conducted in Korea
Author:
Phone:
  Fax:
Marketing authorisation 
holder:
MAH contact person:
EU-QPPV:
Signature of EU-
QPPV:
Not applicable
Date:
31 Jan 2019
Page 1 of 53
Proprietary confidential information
© 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission

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1.
TABLE OF CONTENTS
TITLE PAGE ................................................................................................................ 1
1.
TABLE OF CONTENTS .................................................................................... 3
2.
LIST OF ABBREVIATIONS ............................................................................. 6
3.
RESPONSIBLE PARTIES ................................................................................. 8
4.
ABSTRACT.......................................................................................................... 9
4.1
FLOW CHART............................................................................................. 14
5.
MILESTONES................................................................................................... 15
6.
RATIONALE AND BACKGROUND ............................................................. 16
6.1
RATIONALE ................................................................................................ 16
6.2
BACKGROUND ........................................................................................... 16
7.
RESEARCH QUESTION AND OBJECTIVES ............................................. 18
7.1
PRIMARY OBJECTIVE ............................................................................. 18
7.2
SECONDARY OBJECTIVE ....................................................................... 18
8.
RESEARCH METHODS.................................................................................. 19
8.1
STUDY DESIGN........................................................................................... 19
8.1.1
Method of assigning patients to treatment groups............................. 19
8.1.2
Dosage and Administration.................................................................. 19
8.1.3
Concomitant therapy, Restrictions, And rescue................................. 20
8.1.3.1
Restrictions....................................................................................... 20
8.2
SETTING....................................................................................................... 21
8.2.1
Study sites............................................................................................... 21
8.2.2
Study population ................................................................................... 21
8.2.2.1
Main diagnosis for study entry......................................................... 21
8.2.2.2
Inclusion criteria: ............................................................................. 22
8.2.2.3
Exclusion criteria: ............................................................................ 22
8.2.2.4
Subjects of special investigation ...................................................... 23
8.2.3
Study visits ............................................................................................. 24
8.2.3.1
Screening and run-in periods ........................................................... 24
8.2.3.2
Visit 1; Baseline Visit ...................................................................... 24
8.2.3.3
Visit 2; 12 weeks from Visit 1 ......................................................... 24
8.2.3.4
Visit 3; 24 weeks from Visit 1 ......................................................... 25
8.2.3.5
End of study ..................................................................................... 25

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8.2.3.6
Follow-up period.............................................................................. 26
8.2.4
Study discontinuation ........................................................................... 26
8.3
VARIABLES ................................................................................................. 26
8.3.1
Analysis sets ........................................................................................... 26
8.3.1.1
Number of cases subject who entered the study .............................. 26
8.3.1.2
Number of cases subject to CRF collection ..................................... 26
8.3.1.3
Number of cases subject to safety evaluation .................................. 26
8.3.1.4
Number of cases subject to effectiveness evaluation....................... 27
8.3.2
Endpoints ............................................................................................... 27
8.3.2.1
Endpoints of safety........................................................................... 27
8.3.2.2
Endpoints of effectiveness ............................................................... 27
8.3.2.2.1 Main endpoint................................................................................ 27
8.3.3
Assessment criteria................................................................................ 28
8.3.3.1
Assessment of safety........................................................................ 28
8.3.3.2
Assessment of effectiveness............................................................. 29
8.3.4
Items of Investigation............................................................................ 29
8.3.4.1
Demographic data ............................................................................ 29
8.3.4.2
Medical/Surgical history and pre-treatment experience .................. 29
8.3.4.3
Concomitant medication .................................................................. 30
8.3.4.4
Drug administration status ............................................................... 30
8.3.4.5
Information on the site ..................................................................... 30
8.4
DATA SOURCES ......................................................................................... 30
8.5
STUDY SIZE................................................................................................. 30
8.6
DATA MANAGEMENT .............................................................................. 31
8.7
DATA ANALYSIS ........................................................................................ 31
8.7.1
Analysis of demographic data.............................................................. 31
8.7.2
Safety analysis........................................................................................ 31
8.7.2.1
Adverse Events by preferred Terms (AEs/ADRs/SAEs)................. 32
8.7.3
Effectiveness analysis............................................................................ 33
8.7.4
Interim analyses..................................................................................... 33
8.7.5
Handling of missing data...................................................................... 33
8.8
QUALITY CONTROL................................................................................. 33
8.9
LIMITATIONS OF THE RESEARCH METHODS ................................ 34
8.9.1
Loss to follow-up.................................................................................... 34

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8.9.2
Channeling bias ..................................................................................... 34
8.9.3
Confounding .......................................................................................... 34
8.10
DATA PROTECTION, STUDY RECORDS ............................................. 34
8.10.1
Data quality assurance.......................................................................... 35
8.10.2
Study records......................................................................................... 35
8.10.2.1
Source documents ............................................................................ 35
8.10.2.2
Direct access to source data and documents .................................... 36
8.10.2.3
Storage period of records ................................................................. 36
9.
PROTECTION OF HUMAN SUBJECTS ...................................................... 37
9.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ..................................................................................................... 37
9.2
STATEMENT OF CONFIDENTIALITY.................................................. 37
10.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ..................................................................................................... 38
10.1
DEFINITIONS OF ADVERSE EVENTS................................................... 38
10.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION 
AND REPORTING....................................................................................... 40
10.3
REPORTING TO HEALTH AUTHORITIES .......................................... 43
11.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY 
RESULTS........................................................................................................... 44
12.
REFERENCES................................................................................................... 45
12.1
PUBLISHED REFERENCES...................................................................... 45
12.2
UNPUBLISHED REFERENCES................................................................ 45
13.
APPENDICES.................................................................................................... 46
13.1
ELECTRONIC CASE REPORT FORM ................................................... 46
13.2
SAE/ NON-SERIOUS ADVERSE REACTION REPORT....................... 47
13.3
PREGNANCY MONITORING FORM ..................................................... 52
13.4
JARDIANCE DUO® PRESCRIPTION INFORMATION FOR KOREA52
14.
AMENDMENTS AND UPDATES................................................................... 53

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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
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 
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 
IRB
Institutional Review Board 

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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 

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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 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.

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4.
ABSTRACT
Name of company:
Boehringer Ingelheim Korea
Name of finished medicinal 
product:
JARDIANCE DUO®
Name of active ingredient:
empagliflozin/metformin
Protocol date:
Study
number:
Version/Revision:
Version/Revision date:
18 Aug 2016
1276.39
3.0
31 Jan 2019
Title of study:
A regulatory requirement non interventional study to monitor the safety 
and effectiveness of JARDIANCE DUO® (empagliflozin/metformin, 
5/500mg, 5/850mg, 5/1000mg, 12.5/500mg, 12.5/850mg, 12.5/1000mg) 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 (4 or 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.
Research question 
and objectives:
To monitor the safety profile and effectiveness of JARDIANCE DUO®
(empagliflozin/metformin, 5/500mg, 5/850mg, 5/1000mg, 12.5/500mg, 
12.5/850mg, 12.5/1000mg) 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.
JARDIANCE DUO® is indicated as an adjunct to diet and exercise to 
improve glycaemic control in adult patients with type 2 diabetes mellitus 
who are appropriate to take a combination of empagliflozin and metformin.

When the patients never experienced prior treatments and 
monotherapy would not provide appropriate glycaemic control, or

When metformin monotherapy does not provide adequate glycemic 
control, or

As add-on therapy to sulphonylurea in patients with insufficient 
glycemic control despite treatment with metformin in combination 
with SU, or

As add-on therapy to pioglitazone in patients with insufficient 
glycemic control despite treatment with metformin in combination 
with pioglitazone, or

As add-on therapy to linagliptin in patients with insufficient 
glycemic control despite treatment with metformin in combination 
with linagliptin

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Name of company:
Boehringer Ingelheim Korea
Name of finished medicinal 
product:
JARDIANCE DUO®
Name of active ingredient:
empagliflozin/metformin
Protocol date:
Study
number:
Version/Revision:
Version/Revision date:
18 Aug 2016
1276.39
3.0
31 Jan 2019

As add-on therapy to insulin in patients with insufficient glycemic 
control despite treatment with insulin in combination with 
metformin, or

As add-on therapy to insulin in combination with sulphonylurea in 
patients with insufficient glycemic control despite treatment with 
insulin in combination with metformin plus sulphonylurea, or

As replacement therapy of empagliflozin plus metformin (Patients 
switching from separate tablets of empagliflozin (10 mg or 25 mg 
total daily dose) and metformin to JARDIANCE DUO® should 
receive the same daily dose of empagliflozin and metformin already 
being taken.)
Inclusion criteria:

Patients who have started at first time on JARDIANCE DUO® 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 JARDIANCE DUO®

Hypersensitivity to active ingredients empagliflozin and/or 
metformin or to any of the excipients

Moderate (stage 3b) and severe renal failure (CrCl < 45 ml/min or 
eGFR < 45 ml/min/1.73m2)

Acute conditions with the potential to alter renal function such as: 
dehydration, severe infection, cardiovascular collapse (shock), 
acute myocardial infarction, sepsis

Type 1 diabetes, acute or chronic metabolic acidosis, including 
diabetic ketoacidosis with or without coma, history of a 
ketoacidosis (type 1 diabetes and diabetic ketoacidosis should be 
treated with insulin).

Congestive heart failure requiring pharmacologic management, in 
particular those with unstable or acute congestive heart failure

Radiologic studies involving the use of intravascular iodinated 
contrast materials (for example, intravenous urogram, intravenous 
cholangiography, angiography, and computed tomography (CT) 

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Name of company:
Boehringer Ingelheim Korea
Name of finished medicinal 
product:
JARDIANCE DUO®
Name of active ingredient:
empagliflozin/metformin
Protocol date:
Study
number:
Version/Revision:
Version/Revision date:
18 Aug 2016
1276.39
3.0
31 Jan 2019
scans with intravascular contrast materials) - Intravascular 
administration of iodinated contrast media may lead to acute renal 
failure and has been associated with lactic acidosis in patients 
receiving metformin. Therefore, in patients with eGFR > 
60ml/min/1.73m2, JARDIANCE DUO® must be discontinued prior 
to, or at the time of the test and not be reinstituted until 48 hours 
afterwards, and only after renal function has been re-evaluated and 
has not deteriorated further. In patients with moderate renal 
impairment (eGFR 45-60 ml/min/1.73m2), JARDIANCE DUO®
must be discontinued 48 hours before administration of iodinated 
contrast media and not be reinstituted until at least 48 hours 
afterwards, and only after renal function has been re-evaluated and 
has not deteriorated further.

In patients with severe infections or severe traumatic systemic 
disorders, JARDIANCE DUO® should be temporarily suspended, 
and should not be restarted until the patient’s oral intake has 
resumed and renal function has been evaluated as normal.

JARDIANCE DUO® should be temporarily suspended for any 
surgical procedure (except minor procedures not associated with 
restricted intake of food and fluids) before 48 hours, and not be 
reinstituted until 48 hours afterwards, after renal function has been 
evaluated as normal.

Patients with malnutrition, starvation, hypostheniam pituitary or 
adrenal insufficiency

Impaired hepatic function (since impaired hepatic function has been 
associated with some cases of lactic acidosis, JARDIANCE DUO®
should generally be avoided in patients with clinical or laboratory 
evidence of hepatic disease), pulmonary infarction, severe 
respiratory impairment, any condition associated with hypoxemia, 
excessive alcohol intake, GI disorders such as dehydration, 
diarrhoea or vomiting

Pregnant women, women who may be pregnant, nursing women

Disease which may cause tissue hypoxia (especially acute disease, 
or worsening of chronic disease) such as: decompensated heart 
failure, respiratory failure, recent myocardial infarction, shock

Patients for whom empagliflozin/metformin is contraindicated 
according local label of JARDIANCE DUO®

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Name of company:
Boehringer Ingelheim Korea
Name of finished medicinal 
product:
JARDIANCE DUO®
Name of active ingredient:
empagliflozin/metformin
Protocol date:
Study
number:
Version/Revision:
Version/Revision date:
18 Aug 2016
1276.39
3.0
31 Jan 2019

Current participation in other clinical trials
Variables:
Endpoints of safety
All reported adverse events in patients who take at least one dose of 
JARDIANCE DUO® will be noted.
Endpoints of effectiveness
Change from baseline in HbA1c, 
 
Data sources:
Field study with new data collection
Study size:
Single arm (N=600 approximately)
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 
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 600 patients will be enrolled at approximately 20 sites by as 
many as 20 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) Effectiveness analysis: 
Mean, standard deviation, minimum value, maximum value, and median 
of changes in glycosylated hemoglobin(HbA1c)
 

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Name of company:
Boehringer Ingelheim Korea
Name of finished medicinal 
product:
JARDIANCE DUO®
Name of active ingredient:
empagliflozin/metformin
Protocol date:
Study
number:
Version/Revision:
Version/Revision date:
18 Aug 2016
1276.39
3.0
31 Jan 2019
Milestones:
Study duration: MFDS set JARDIANCE DUO® re-examination period 
from 21 January 2016 to 11 August 2020. The study period is granted as 
the remaining period of JARDIANCE® (empagliflozin) according to the 
Standards for Re-examination of New Drugs.

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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 DUO® administration status
X
X
X
Renal function
  X A
X A
X A
Effectiveness endpoints
X
X
X
 
Changes in lab tests
X A
X A
Adverse events
X
X
Study completion
X
X
A : If available

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5.
MILESTONES
Milestone
Planned Date
Start of data collection
30 Jan 2018
End of data collection
11 Aug 2020
Interim report 1
11 Oct 2017
Interim report 2
11 Oct 2018
Interim report 3
11 Oct 2019
Registration in the EU PAS register
TBD
Final report of study results:
11 Nov 2020

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6.
RATIONALE AND BACKGROUND
6.1
RATIONALE
According to the local regulations, when a new chemical entity (NCE) is registered, a 
regulatory non interventional study (rNIS) of an extended period (4 or 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 DUO®
(empagliflozin/metformin) in Korean patients with type 2 diabetes mellitus in a routine 
clinical practice setting.
6.2
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]
The benefits of empagliflozin in combination with metformin have been shown in 3 main
studies in patients with T2DM not adequately controlled by metformin, alone or combined
with other antidiabetic agents (pioglitazone or SU). The main measure of effectiveness was
the change in HbA1c after 24 weeks of treatment [s00039827-01].
The studies showed a clinically relevant reduction in HbA1c with empagliflozin compared

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with placebo, both on metformin background. Similar benefits were seen in the studies
regardless of the other antidiabetic agent being taken.
In addition, the results indicated that treatment empagliflozin on top of metformin
background was associated with a decrease in body weight and blood pressure. The
combination of empagliflozin and metformin also showed a clinically meaningful efficacy
profile in treatment-naïve patients with T2DM.
Supportive evidence was provided from several further studies. Some of these were
continuations of the main studies that showed the benefits of empagliflozin and metformin
continued with longer therapy [s00039827-01].
Data for cardiovascular safety of empagliflozin from the EMPA REG OUTCOME® study
1245.25 [c02695839-01] showed that with regard to cardiovascular endpoints, treatment with
empagliflozin significantly reduced the risk for the combined endpoint of CV death, MI, or
stroke compared to placebo in patients with T2DM and high CV risk on standard of care
treatment. Further, empagliflozin significantly reduced overall mortality, heart failure
requiring hospitalisation, and the combined endpoint of heart failure requiring hospitalisation
or CV death, compared to placebo; and significantly reduced the risk for the combined
nephropathy endpoints. The effects on CV outcomes in the subgroup of patients who were on 
metformin treatment at baseline were consistent with the overall population [s00039827-01].
Thus, the clinical development programme for the FDC empagliflozin plus metformin has
demonstrated the efficacy of empagliflozin in the establishment and maintenance of
glycaemic control with additional beneficial effects of reducing weight and blood pressure in
patients with T2DM [s00039827-01]. 
For a detailed description of the drug profile refer to the local prescribing information of 
JARDIANCE DUO®.

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7.
RESEARCH QUESTION AND OBJECTIVES
7.1
PRIMARY OBJECTIVE
The primary objective of this study is to monitor the safety profile of JARDIANCE DUO® 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 DUO®
by evaluation of the change from baseline after 12 weeks and/or 24 weeks in the glycosylated 
hemoglobin (HbA1c), 
 
 
 in Korean T2DM patients.

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8.
RESEARCH METHODS
This rNIS is an observational prospective, non-interventional, open-label, multi-centre 
national study. As per regulation, the re-examination period extends from 21 January 2016
until 11 August 2020. However, active enrolment is to be initiated in 2018 after finalizing the 
re-imbursement agreement with the authority. The last patient follow up is expected in Aug
2020 and the final report of study results will be submitted to MFDS in Nov 2020. 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 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 DUO® 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 DUO®.
JARDIANCE DUO® 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 recommended dose is one tablet twice daily. The dosage should be individualised on the 
basis of the patient’s current regimen, effectiveness, and tolerability while not exceeding the 
maximum recommended daily dose of 25 mg of empagliflozin and 2000 mg of metformin.

In patients not adequately controlled on metformin alone or in combination with other 
products, including insulin, the recommended starting dose of JARDIANCE DUO®
should provide empagliflozin 5 mg twice daily (10 mg total daily dose) and the dose 
of metformin similar to the dose already being taken. In patients tolerating a total 
daily dose of empagliflozin 10 mg and requiring additional glycaemic control, the 
dose can be increased to a total daily dose of empagliflozin 25 mg. 

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
Patients switching from separate tablets of empagliflozin (10 mg or 25 mg total daily 
dose) and metformin to JARDIANCE DUO® should receive the same daily dose of 
empagliflozin and metformin already being taken.
When JARDIANCE DUO® is used in combination with a sulphonylurea and/or insulin, a 
lower dose of sulphonylurea and/or insulin may be required to reduce the risk of 
hypoglycaemia (see section on 4. Adverse Events and 6. Interactions on the 13.4 Korean 
label).
JARDIANCE DUO® should be given with meals to reduce the gastrointestinal undesirable 
effects associated with metformin.
Missed dose
If a dose is missed, it should be taken as soon as the patient remembers. However, a double 
dose should not be taken at the same time. In that case, the missed dose should be skipped.
Elderly patients
In patients 75 years and older, renal function and risk of volume depletion should be taken 
into account. In patients aged 85 years and older, initiation of JARDIANCE DUO® is not 
recommended due to the limited therapeutic experience of empagliflozin.
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 DUO® initiation until the patient completes the final follow-up visit.
8.1.3.1
Restrictions

Radiologic studies involving the use of intravascular iodinated contrast materials (for 
example, intravenous urogram, intravenous cholangiography, angiography, and 
computed tomography (CT) scans with intravascular contrast materials) -
Intravascular administration of iodinated contrast media may lead to acute renal 
failure and has been associated with lactic acidosis in patients receiving metformin. 
Therefore, in patients with eGFR > 60ml/min/1.73m2, JARDIANCE DUO® must be 
discontinued prior to, or at the time of the test and not be reinstituted until 48 hours 
afterwards, and only after renal function has been re-evaluated and has not 
deteriorated further. In patients with moderate renal impairment (eGFR 45-60 
ml/min/1.73m2), JARDIANCE DUO® must be discontinued 48 hours before 
administration of iodinated contrast media and not be reinstituted until at least 48 
hours afterwards, and only after renal function has been re-evaluated and has not 
deteriorated further.

In patients with severe infections or severe traumatic systemic disorders, 
JARDIANCE DUO® should be temporarily suspended, and should not be restarted 

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until the patient’s oral intake has resumed and renal function has been evaluated as 
normal.

JARDIANCE DUO® should be temporarily suspended for any surgical procedure 
(except minor procedures not associated with restricted intake of food and fluids) 
before 48 hours, and not be reinstituted until 48 hours afterwards, after renal function 
has been evaluated as normal.
Please refer to the current local label for more detailed information (13.4).
8.2
SETTING
As per regulations, enrolled patients will be followed up for 12 or 24 weeks treatment period. 
8.2.1
Study sites
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 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
Drugs』and study protocol.
8.2.2
Study population
8.2.2.1
Main diagnosis for study entry
Patients diagnosed with type 2 diabetes mellitus in Korea.
JARDIANCE DUO® is indicated as an adjunct to diet and exercise to improve glycaemic 
control in adult patients with type 2 diabetes mellitus who are appropriate to take a 
combination of empagliflozin and metformin.

When the patients never experienced prior treatments and monotherapy would not 
provide appropriate glycaemic control, or

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
When metformin monotherapy does not provide adequate glycemic control, or

As add-on therapy to sulphonylurea in patients with insufficient glycemic control 
despite treatment with metformin in combination with SU, or

As add-on therapy to pioglitazone in patients with insufficient glycemic control 
despite treatment with metformin in combination with pioglitazone, or

As add-on therapy to linagliptin in patients with insufficient glycemic control despite 
treatment with metformin in combination with linagliptin

As add-on therapy to insulin in patients with insufficient glycemic control despite 
treatment with insulin in combination with metformin, or

As add-on therapy to insulin in combination with sulphonylurea in patients with 
insufficient glycemic control despite treatment with insulin in combination with 
metformin plus sulphonylurea, or

As replacement therapy of empagliflozin plus metformin (Patients switching from 
separate tablets of empagliflozin (10 mg or 25 mg total daily dose) and metformin to 
JARDIANCE DUO® should receive the same daily dose of empagliflozin and 
metformin already being taken.)
8.2.2.2
Inclusion criteria:

Patients who have started at first time on JARDIANCE DUO® 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:

Patients with previous exposure to JARDIANCE DUO®

Hypersensitivity to active ingredients empagliflozin and/or metformin or to any of 
the excipients

Moderate (stage 3b) and severe renal failure (CrCl < 45 ml/min or eGFR < 45 
ml/min/1.73m2)

Acute conditions with the potential to alter renal function such as: dehydration, 
severe infection, cardiovascular collapse (shock), acute myocardial infarction, sepsis

Type 1 diabetes, acute or chronic metabolic acidosis, including diabetic ketoacidosis 
with or without coma, history of a ketoacidosis (type 1 diabetes and diabetic 
ketoacidosis should be treated with insulin).

Congestive heart failure requiring pharmacologic management, in particular those 
with unstable or acute congestive heart failure

Radiologic studies involving the use of intravascular iodinated contrast materials (for 
example, intravenous urogram, intravenous cholangiography, angiography, and 
computed tomography (CT) scans with intravascular contrast materials) -
Intravascular administration of iodinated contrast media may lead to acute renal 
failure and has been associated with lactic acidosis in patients receiving metformin. 
Therefore, in patients with eGFR > 60ml/min/1.73m2, JARDIANCE DUO® must be 

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discontinued prior to, or at the time of the test and not be reinstituted until 48 hours 
afterwards, and only after renal function has been re-evaluated and has not 
deteriorated further. In patients with moderate renal impairment (eGFR 45-60 
ml/min/1.73m2), JARDIANCE DUO® must be discontinued 48 hours before 
administration of iodinated contrast media and not be reinstituted until at least 48 
hours afterwards, and only after renal function has been re-evaluated and has not 
deteriorated further.

In patients with severe infections or severe traumatic systemic disorders, 
JARDIANCE DUO® should be temporarily suspended, and should not be restarted 
until the patient’s oral intake has resumed and renal function has been evaluated as 
normal.

JARDIANCE DUO® should be temporarily suspended for any surgical procedure 
(except minor procedures not associated with restricted intake of food and fluids) 
before 48 hours, and not be reinstituted until 48 hours afterwards, after renal function 
has been evaluated as normal.

Patients with malnutrition, starvation, hypostheniam pituitary or adrenal 
insufficiency

Impaired hepatic function (since impaired hepatic function has been associated with 
some cases of lactic acidosis, JARDIANCE DUO® should generally be avoided in 
patients with clinical or laboratory evidence of hepatic disease), pulmonary infarction, 
severe respiratory impairment, any condition associated with hypoxemia, excessive 
alcohol intake, GI disorders such as dehydration, diarrhoea or vomiting

Pregnant women, women who may be pregnant, nursing women

Disease which may cause tissue hypoxia (especially acute disease, or worsening of 
chronic disease) such as: decompensated heart failure, respiratory failure, recent 
myocardial infarction, shock

Patients for whom empagliflozin/metformin is contraindicated according local label 
of JARDIANCE DUO®

Current participation in other clinical trials
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 DUO® can be further 
investigation into cases collected from this study may be taken into account according to the 
outcome of retrospective analysis.

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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

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 in sitting position (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, 
 (Lab data should be collected within 1 month 
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 DUO® 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 DUO® 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 in sitting position (SBP, DBP)

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
Any change of JARDIANCE DUO® given (Daily dose(Dosage/Administration), 
Start date, Date of discontinuation or continuation, Action taken, Causality)

Effectiveness endpoints: HbA1c, 

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 DUO® 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 in sitting position (SBP, DBP)

Any change of JARDIANCE DUO® given (Daily dose(Dosage/Administration), 
Start date, Date of discontinuation or continuation, Action taken, Causality)

Effectiveness endpoints : HbA1c, 

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 DUO® 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)

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
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 DUO® 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.
8.2.4
Study discontinuation
reserves the right to discontinue the study overall or at a 
particular study site at any time for the following reasons:
•
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 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 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 DUO® 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 DUO® 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 DUO® rPMS 
prior to the contract date
b.
Patients administrated JARDIANCE DUO® prior to the contract date

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c.
Patients administrated JARDIANCE DUO® prior to the signed on the data release 
consent form
d.
Patients who have not taken JARDIANCE DUO®
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
8.3.1.4
Number of cases subject to effectiveness 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 DUO®, 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 8.3.1.3
b.
Patients with missing information of assessment of effectiveness 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 DUO®
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

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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/ Not yet recovered/ Sequela/ Fatal/ Unknown)
•
Causality (Certain/ Probable·Likely/ Probable/ Possible/ Unlikely/ Conditional· 
Unclassified/ Unassessable·Unclassifiable) 
•
Factors other than JARDIANCE DUO® (None/ Concomitant medication/ 
Concomitant disease/ etc.)
•
Action taken with study drug due to AE (Discontinued/ Reduced/ Increased/ 
Continue/ Discontinued and reintroduced/ Unknown/ Not applicable)
•
Recurrence in reintroduced (Recurrence/ No-recurrence/ 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)

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•
Investigator’s comments(if needed) 
8.3.3.2
Assessment of effectiveness
①
HbA1c:
HbA1c should be collected within 1 month prior to baseline and after 12 weeks and 
24 weeks of treatment.
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

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
Family history of T2DM

Diabetes mellitus related complication (including but not limited to Retinopathy, 
Neuropathy, Nephropathy, Vasculopathy, etc)

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 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 

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in short-term (12weeks) period, all patients will be enrolled for long-term (24weeks) 
surveillance.
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 DUO® (linagliptin/metformin) rPMS will be used as a comparator. The 
baseline characteristics of patients starting JARDIANCE DUO® for the first time will be 
compared to the baseline characteristics of patients who started TRAJENTA DUO® 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
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 
incidence rate 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.  

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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 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/ Unaccessable·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 DUO®’ 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 DUO® 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 DUO® beyond the scope of approved label are 

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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.
8.7.3
Effectiveness analysis
①
Mean, standard deviation, minimum value, maximum value, and median of changes 
in glycosylated hemoglobin(HbA1c)
 
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.

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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.
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/metformin would be more often prescribed to higher 
risk patients compared to other treatments, higher incidences of outcome events were then 
expected in the empagliflozin/metformin group. To assess the extent of preferential prescribing 
of JARDIANCE DUO® and the potential for channeling bias, baseline data from the 
TRAJENTA DUO® (linagliptin/metformin) rPMS will be used to provide context for the 
JARDIANCE DUO® 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. 
However, the protocol of this NIS will be submitted to IRBs whenever required or requested 

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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 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))

Dates of Patient’s visits, including dispensing of study medication

Medical history (including study indication and concomitant diseases, if applicable)

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
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.

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9.
PROTECTION OF HUMAN SUBJECTS
The study will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the 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.

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10.
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS
10.1
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 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.

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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).

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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 effectiveness of 
the studied JARDIANCE DUO®. 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 (CRF13.1). 
All SAEs, ASAEs and AESIs must be reported within 24 hours of occurrence and via 
telephone/fax to the Local PV Manager (LPVM) of
using the NIS AE form (13.2). 
All non-serious Adverse Reactions associated with JARDIANCE DUO® 
(empagliflozin/metformin) and pregnancy monitoring forms must be reported within 7 calendar 
days of occurrence and via telephone/fax to the LPVM of 
 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:
The investigator carefully assesses whether an AE constitutes an Adverse Reaction using the 
information below. 
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 

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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 
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,

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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 DUO®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: 
Type of Report
Timeline
All Serious Adverse Events (SAEs), Always 
Serious Adverse Events (ASAEs) and Adverse 
immediately within 24 hours

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Event of Special interest
* 13.2 SAE/ Non-Serious Adverse Reaction Report
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 DUO® (empagliflozin/metformin)
* 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 DUO® tablets. The investigator will determine the relationship 
of JARDIANCE DUO® 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 DUO®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.

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11.
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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12.
REFERENCES
12.1
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.
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.
R13-1653
Kim DJ. The epidemiology of diabetes in Korea. Diabetes Metab J 2011, 
35: 303-308;
12.2
UNPUBLISHED REFERENCES
c03606501-02
Empagliflozin/metformin hydrochloride Clinical Overview, 13 January 
2016
s00039827-01
Empagliflozin/metformin hydrochloride Periodic Benefit-Risk Evaluation 
Report, 14 Jun 2016

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13.
APPENDICES
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.

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13.2
SAE/ NON-SERIOUS ADVERSE REACTION REPORT

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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 DUO® PRESCRIPTION INFORMATION FOR KOREA
Please refer to “JARDIANCE DUO® Prescription Information for Korea” in site file or in 
electronic CRF web page for the latest version.

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14.
AMENDMENTS AND UPDATES
Number
Date
Section of 
study protocol
Amendment or update
Reason
1
25 Apr 2018
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
- Attached 
appendix  
separately
2
31 Jan 2019
8.2.2 Study 
population
8.2.2.1 Add-on therapy 
to ‘linagliptin’
- Updates 
indication 
according to  
approved local 
label

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
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Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c10880816
3.0
clinical-trial-protocol
A regulatory requirement non interventional study to monitor the safety and
effectiveness of JARDIANCE DUO (empagliflozin/metformin, 5/500mg, 5/850mg,
5/1000mg, 12.5/500mg, 12.5/850mg, 12.5/1000mg) in Korean patients with type 2
diabetes mellitus
Author-Clinical Trial Manager
15 Mar 2019 07:38 CET
Approval-Pharmacovigilance
15 Mar 2019 08:16 CET
Approval-EU Qualified Person
Pharmacovigilance
15 Mar 2019 09:56 CET
Approval-Medical 
15 Mar 2019 10:36 CET
Approval-
Safety Evaluation
Therapeutic Area
15 Mar 2019 11:05 CET
Approval-Team Member Medicine
18 Mar 2019 11:05 CET

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Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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