Post Marketing Surveillance in Japan on Long Term Drug Use of TRADIANCE® Combination Tablets AP and BP in Patients With Type 2 Diabetes Mellitus
Conditions: Diabetes Mellitus, Type 2
Sponsor: Boehringer Ingelheim

ABCD
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TITLE PAGE
Non-interventional Study Protocol
TITLE PAGE
Document Number:
c20025178-02
BI Study Number:
1275.0026 
BI Investigational
Product(s):
Empagliflozin + linagliptin
Title:
Post Marketing Surveillance in Japan on Long Term Drug Use 
of TRADIANCE® Combination Tablets AP and BP in Patients 
with type 2 Diabetes Mellitus
Brief lay title
A long-term study on the side effects of TRADIANCE® in 
Japanese patients with type 2 diabetes
Protocol version 
identifier:
Version 2.0
Date of last version of 
protocol:
8 December 2017
PASS:
Yes
EU PAS register 
number:
EUPAS26442
Active substance:
Empagliflozin + linagliptin
Medicinal product:
TRADIANCE® Combination Tablets AP, BP
Product reference:
Not applicable
Procedure number:
Not applicable
Marketing authorisation 
holder(s):
Joint PASS:
No
Research question and 
objectives:
Study objective is to investigate the safety of long-term daily use 
of TRADIANCE® Combination Tablets AP and BP in Japanese
patients with type 2 Diabetes Mellitus under real-world use.
Country(-ies) of study:
Japan
Author:
 (Trial Clinical Monitor,
 
 
Marketing authorisation 
holder(s):

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MAH contact person:
EU-QPPV:
Signature of EU-
QPPV:
e-signature is on BIRDS
Date:
20 November 2018
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© 2018 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................................................................................ 5
3.
RESPONSIBLE PARTIES.................................................................................... 6
4.
ABSTRACT........................................................................................................... 7
5.
AMENDMENTS AND UPDATES..................................................................... 10
6.
MILESTONES..................................................................................................... 11
7.
RATIONALE AND BACKGROUND................................................................ 12
8.
RESEARCH QUESTION AND OBJECTIVES ................................................. 14
9.
RESEARCH METHODS .................................................................................... 15
9.1
STUDY DESIGN............................................................................................ 15
9.2
SETTING........................................................................................................ 15
9.2.1
Study sites ............................................................................................... 15
9.2.2
Study population ..................................................................................... 15
9.2.2.1
Inclusion/ exclusion criteria ............................................................. 15
9.2.2.2
Registration period........................................................................... 15
9.2.2.3
Patient registration method .............................................................. 16
9.2.3
Discontinuation of the study by the sponsor ........................................... 16
9.3
VARIABLES .................................................................................................. 16
9.3.1
Exposures ................................................................................................ 16
9.3.2
Outcomes................................................................................................. 17
9.3.2.1
Primary outcome .............................................................................. 17
9.3.2.2
Secondary outcomes......................................................................... 17
9.3.3
Covariates................................................................................................ 17
9.4
DATA SOURCES........................................................................................... 19
9.5
STUDY SIZE.................................................................................................. 19
9.6
DATA MANAGEMENT................................................................................ 20
9.7
DATA ANALYSIS......................................................................................... 20
9.7.1
Analyses of Safety................................................................................... 20
9.7.3
Interim analyses....................................................................................... 21
9.8
QUALITY CONTROL................................................................................... 22

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9.9
LIMITATIONS OF THE RESEARCH METHODS...................................... 22
9.10
OTHER ASPECTS ......................................................................................... 22
9.10.1
Data quality assurance............................................................................. 22
9.10.2
Study records........................................................................................... 22
9.10.2.1
Source documents ............................................................................ 22
9.10.2.2
Direct access to source data and documents .................................... 22
9.10.3
Completion of study................................................................................ 23
10.
PROTECTION OF HUMAN SUBJECTS .......................................................... 24
10.1
Study approval, patient information, and informed consent........................... 24
10.2
Statement of confidentiality............................................................................ 24
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS....................................................................................................... 25
11.1
Definitions of adverse events.......................................................................... 25
11.2
Adverse event and serious adverse event reporting........................................ 26
11.3
Reporting to health Authorities....................................................................... 28
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
............................................................................................................................. 29
13.
REFERENCES .................................................................................................... 30
13.1
PUBLISHED REFERENCES......................................................................... 30
13.2
UNPUBLISHED REFERENCES................................................................... 30
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.............................................. 31
ANNEX 2. flow chart of variableS............................................................................... 32

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2.
LIST OF ABBREVIATIONS
ADR
Adverse Drug Reaction
AE
Adverse Event
CRF
Case Report Form
eCRF
Electronic Case Report Form
DPP-4
Dipeptidyl-peptidase IV
ECG
Electrocardiogram
EDC
Electronic Data Capture
EU-QPPV
European Union – Qualified Person for Pharmacovigilance
GPSP
Good Post- marketing Study Practice
J-PMD Act
Japanese pharmaceuticals and Medical Devices Act
J-RMP
Japan Risk Management Plan
MedDRA
Medical Dictionary for Drug Regulatory Activities
MHLW
Ministry of health, Labour and Welfare
PMDA
Pharmaceuticals and Medical Devices Agency
PMS
Post Marketing Surveillance
SAE
Serious Adverse Event
SOP
Standard Operating Procedures
T2DM
Type 2 Diabetes mellitus

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3.
RESPONSIBLE PARTIES
Contact details and the list of all investigators will be kept in a stand-alone document. This 
document will be managed in the Post Marketing Surveillance (PMS) tracking system which 
manage the contracts with site and investigators name.
Co-sponsor
Medical advisor
Task:
1．Providing medical advice and comments on the study results
2．Providing medical advice on risk minimisation
3．Reviewing the contents of publication for the study results

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4.
ABSTRACT
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
TRADIANCE® Combination Tablets 
AP, BP
Name of active ingredient:
Empagliflozin, Linagliptin
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
8 December 2017
1275.0026
Version 2.0
20 November 2018
Title of study:
Post Marketing Surveillance in Japan on Long Term Drug Use of 
TRADIANCE® Combination Tablets AP and BP in Patients with type 
2 Diabetes Mellitus
Rationale and 
background:
In Japan, post-approval execution of Post Marketing Surveillance is 
requested by the Japanese Pharmaceuticals and Medical Devices Act 
(J-PMD Act) in order to accumulate safety and efficacy data for re-
examination. Re-examination period is defined by J-PMD Act. Four 
years after approval of combination drugs, results of PMS need to be 
submitted as a part of re-examination dossier to the Japanese 
regulatory authority, the Ministry of Health, Labour and Welfare 
(MHLW). 
Collected data from PMS will be included in the Japanese periodic 
safety reports and submitted to MHLW on designated dates until the 
end of re-examination period.
Research question 
and objectives:
Study objective is to investigate the safety of long-term daily use of 
TRADIANCE® Combination Tablets AP and BP in Japanese patients 
with type 2 Diabetes Mellitus under real-world use.
Study design:
Cohort study
Non-interventional, single arm study based on newly collected data
Patients will be observed for up to 52 weeks after start of the treatment 
with TRADIANCE® Combination Tablets AP or BP or until 
discontinuation of administration.
Population:
Inclusion criteria
-  Japanese patients with type 2 Diabetes mellitus who are prescribed 
with TRADIANCE® Combination Tablets AP or BP
-  Patients who have never been treated with TRADIANCE®
Combination Tablets AP or BP before enrolment
Exclusion criteria
None

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Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
TRADIANCE® Combination Tablets 
AP, BP
Name of active ingredient:
Empagliflozin, Linagliptin
Protocol date:
Study 
number:
Version/Revision:
Version/Revision 
date:
8 December 2017
1275.0026
Version 2.0
20 November 2018
Variables:
Outcomes:
Primary outcome:
Incidences of adverse drug reactions (ADRs)
Secondary outcomes:
None
Data sources:
Patients’ data will be collected by electronic Case Report Form on 
Electronic Data Capture system
Study size:
1000 (safety set)

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Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
TRADIANCE® Combination Tablets 
AP, BP
Name of active ingredient:
Empagliflozin, Linagliptin
Protocol date:
Study 
number:
Version/Revision:
Version/Revision 
date:
8 December 2017
1275.0026
Version 2.0
20 November 2018
Data analysis:
Descriptive statistics will be summarised for safety and efficacy. 
A mixed model repeated measures analysis will be performed for 
HbA1c and FPG over time.
Milestones:
Planned start of data collection: 15 JAN 2019
Planned end of data collection: 30 APR 2021
Study Report planned to be archived in 1Q 2022

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5.
AMENDMENTS AND UPDATES
Number
Date
Section of 
study 
protocol
Amendment or update
Reason
1
20
November 
2018
Title page, 
abstract, 8, 
9.1, 9.3.2, 
9.7.2, 11.2
Delete objective 
“investigate 
effectiveness”.
Change outcomes:
- “secondary outcome” was 
transferred to “other 
outcomes“.
- delete identified and 
potential risks and added 
“priority survey items” for 
safety outcomes.  
Results of 
discussion with 
PMDA
Abstract, 6, 
9.2.2.2
Milestone update
Change 
initiation date
Title page, 3, 
abstract, 6, 
9.6
Update person in charge, 
Co-sponsor, medical 
advisor, CRO, timelines
Administrative 
updates
9.8
Delete local SOP 
Administrative 
updates
Annex 2
Delete “Compliance”
Results of 
discussion with 
PMDA
The 
compliance is 
included in the 
“Administratio
n status of 
TRADIANCE®
Combination 
Tablets AP or 
BP”.

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6.
MILESTONES
Milestone
Planned Date
Start of data collection
15 January 2019
End of data collection
30 April 2021
Registration in the EU PAS
register
7 November 2018
Final report of study results:
1Q 2022

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7.
RATIONALE AND BACKGROUND
Treatment Guide for Diabetes 2014-2015 (R14-4302) in Japan recommends to achieve the 
glycaemic goal of HbA1c to <7.0% in preventing the onset of microangiopathy and inhibiting 
its progress, while it states that suitable current treatment aims should be established 
according to age and complications on a case-by-case basis. If good control cannot be 
achieved with one type of oral antidiabetic agent, combination therapy with another drug 
having a different mode of action should be recommended.
TRADIANCE® Combination Tablets are the fixed dose combination of two oral antidiabetic 
agents for the treatment of type 2 Diabetes mellitus (T2DM). Empagliflozin is an inhibitor of 
the sodium-glucose co-transporter 2 (SGLT-2) and linagliptin is an inhibitor of the enzyme 
dipeptidyl-peptidase IV (DPP-4) both of which decrease blood glucose concentrations in 
patients with T2DM.
Empagliflozin received its first worldwide marketing approval in Australia on 17 Apr 2014. 
To this day, marketing approval has been received in many countries including European 
countries and US. In Japan, empagliflozin has received marketing approval on 26 Dec 2014.
Linagliptin received its first worldwide marketing approval, from the US Food and Drug 
Administration (FDA) on 02 May 2011. To this day, marketing approval has been received in 
many countries including European countries. In Japan, linagliptin has received marketing 
approval on 01 Jul 2011.
TRADIANCE® Combination Tablets received its first worldwide marketing approval, from 
the US Food and Drug Administration (FDA) on 30 Jan 2015.
Based on the complementary mechanisms of action of SGLT-2 inhibitors and DPP-4 
inhibitors TRADIANCE® Combination Tablets have the potential to show additional 
efficacy, in terms of optimised glucose control, than its individual components in patients 
with T2DM. In addition, with use of a fixed dose combination formulation, the required 
number of tablets will be decreased, which is expected to improve adherence of the patient to 
the recommended treatment, compared to treatment combining single agents.
In Japan, post-approval execution of Post Marketing Surveillance (PMS) is requested by the 
Japanese Pharmaceuticals and Medical Devices Act (J-PMD Act) in order to accumulate 
safety and efficacy data for re-examination. Re-examination period is defined by J-PMD Act. 
Four years after approval of combination drugs, results of PMS need to be submitted as a part 
of re-examination dossier to the Japanese regulatory authority, the Ministry of Health, Labour 
and Welfare (MHLW). 
Collected data from PMS will be included in the Japanese periodic safety reports and 
submitted to MHLW on designated dates until the end of re-examination period.
The protocol may be revised because of new information or knowledge obtained in the course 
of conducting PMS. When a change of the approved label such as in dosage and 
administration or indications is made during the re-examination period of TRADIANCE® 
Combination Tablets AP and BP (except that for this change a re-examination period is 
newly designated by MHLW) and
finds it 
necessary to revise this protocol, handling each matter should be discussed and the protocol 

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may be revised. If any issue or concern arises (e.g. suggestion of a potential for clinically 
significant adverse reaction, remarkable increase in incidence of an adverse reaction, or any 
issue or concern on safety or efficacy assessment made prior to the approval of 
TRADIANCE® Combination Tablets AP and BP) in the course of PMS, implementation of 
additional special surveillance or post-marketing clinical trial should be discussed to identify 
or confirm a cause or estimated cause of such issue. Special surveillance is defined by J-PMD 
Act. It means surveillance for long-term use or special patient population (elderly, 
renal/hepatic dysfunction etc.). 

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8.
RESEARCH QUESTION AND OBJECTIVES
Study objective is to investigate the safety of TRADIANCE® Combination Tablets AP and 
BP in patients with T2DM used in routine care. The primary outcome of this study is the 
incidence of any adverse drug reactions (ADRs) (see section 9.3.2).

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9.
RESEARCH METHODS
9.1
STUDY DESIGN
This is a non-interventional study based on newly collect data of patients under routine care
to confirm safety of TRADIANCE® Combination Tablets AP and BP in real-world setting in 
Japanese patients with T2DM.
The study will consist of a baseline visit and further visits in a 52-week follow-up for patients 
who have initiated TRADIANCE® Combination Tablets AP or BP treatment.
9.2
SETTING
9.2.1
Study sites
Sites throughout entire country will be equally listed according the size of the hospitals or 
general clinics at which TRADIANCE® Combination Tablets AP or BP are available for 
prescription.
Planned number of site: Approximately 200 Sites
A medical representative will explain the objective and design of this study to investigators at 
each study site and conclude a written contract with the head of the study site (e.g., hospital 
director). 
9.2.2
Study population
As this is a non-interventional study, no specific treatment is mandated or withheld from the 
patients. No limitations are set up on background factors and their concomitant drugs in use 
of actual medical practice. 
9.2.2.1
Inclusion/ exclusion criteria
Inclusion criteria

Japanese patients with T2DM who are prescribed with TRADIANCE® Combination 
Tablets AP or BP

Patients who have never been treated with TRADIANCE® Combination Tablets AP or BP 
before enrolment
Exclusion criteria
None
9.2.2.2
Registration period
From January 2019 to January 2020

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9.2.2.3
Patient registration method
The registration method will be a continuous investigation system. Patients who begin 
treatment with TRADIANCE® Combination Tablets AP or BP after the conclusion of the 
contract will be registered by entering necessary information in the Electronic Data Capture 
(EDC) system within 14 days whenever possible from the day of treatment initiation 
(inclusive).
Patient registration will be stopped when the overall target number of patients for the study is 
reached. After the end of the registration period, investigators use a signed form to confirm 
that patients have been registered continuously at the site. A log of all patients included in the 
study will be maintained at the site.
9.2.3
Discontinuation of the study by the sponsor 
 reserves the right to discontinue the PMS overall or at a particular study site at any time 
for the following reasons:
1.
Failure to meet expected enrolment overall goals or goals at a particular study site.
2.
Emergence of any efficacy/safety information that could significantly affect
continuation of the PMS or any other administrative reasons.
3.
Violation of Good Post- marketing Study Practice (GPSP), the Non-interventional 
Study protocol, or the contract by study site or investigator, disturbing the
appropriate conduct of the PMS.
The study site will be reimbursed for reasonable expenses incurred in case of study 
termination (except in case of the third reason).
9.3
VARIABLES
9.3.1
Exposures
Exposure to TRADIANCE® Combination Tablets AP or BP is estimated as time from the day 
TRADIANCE® Combination Tablets AP or BP is initiated until the day the drug is last 
administrated on a patient-level (or the final contact with the patient during the regular 
observation period).
Patients newly initiating TRADIANCE® Combination Tablets AP or BP will be followed up 
to 52 weeks.

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9.3.2
Outcomes
9.3.2.1
Primary outcome
The primary endpoint of this study is the incidence of adverse drug reactions (ADRs).
ADRs definition and reposrting is described in section 11.
There is no primary outcome for effectiveness as the primary objective of a PMS is 
evaluating safety.
9.3.2.2
Secondary outcomes
None
9.3.3
Covariates
The following variables based on physician’s report will be considered important baseline 
characteristics and potential risk factors for the outcomes of interest.
Demographics:
Gender, date of birth, indication, pregnancy status, height, body weight, Body Mass Index 
(derived), waist circumference, hypersensitivity factor (pick up from medical history and 
concomitant disease data), diagnosed date of T2DM, alcohol habit, smoking history, 
degree of renal/hepatic functions at baseline
Medical history / Concomitant disease:
Malignant tumor, cardiovascular/cerebrovascular disease, heart failure (severity for 
cardiac failure for patients with cardiac failure (NYHA classification)), urinary tract 
infection, genital infection, hypertension, osteoporosis, dyslipidaemia, intestinal 
obstruction, gout/hyperuricaemia, others, presence or absence of diabetic concomitant 
diagnosis (neuropathy/nephropathy/retinopathy)

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Previous / Concomitant drugs and therapies: 
Antidiabetics (in the 3 months before newly starting TRADIANCE):
Dose, daily frequency, start and end date
Concomitant drugs:
Dose, daily frequency, start and end date, reason for use, route of administration
Exercise and diet therapies:
Start and end date, compliance
Administration of TRADIANCE® Combination Tablets AP or BP: 
Dose, daily frequency, start and end date, primary reason of discontinuation, compliance
Compliance:
All previous antidiabetics drugs compliance, TRADIANCE® Combination Tablets AP or 
BP compliance
Electrocardiogram:
If a resting 12-lead electrocardiogram (ECG) will be performed by investigator’s order 
during the PMS and the investigator should review the ECG data and record the results 
(abnormal Yes or No) in the Electronic Case Report Form (eCRF).
Blood pressure and pulse rate (if applicable):
Systolic / diastolic blood pressure, pulse rate
Physical examination:
Body weight
Laboratory tests (blood biochemistry and urinalysis) (if applicable):
Haematology: 
Erythrocyte count (RBC), haemoglobin (Hb), haematocrit (Hct),
leukocyte counts (WBC) , platelet count
Blood chemistry: HbA1c , fasting plasma glucose, sodium (Na), potassium (K), 
chlorine (Cl), magnesium (Mg), calcium (Ca), phosphorus (P), 
creatinine (CRE), aspartate transaminase (AST, SGOT), alanine 
transaminase (ALT, SGPT), alkaline phosphatase (ALP), gamma-
glutamyl-transferase (-GTP), albumin , lactic dehydrogenase (LDH), 
total bilirubin (T-BIL), blood urea nitrogen (BUN), total cholesterol
(T-CHO), HDL cholesterol (HDL), LDL cholesterol (LDL), 
Triglycerides (TG), Amylase (AMY), Lipase (LIP), uric acid (UA), 
25-OH vitamin D, intact parathyroid hormone (iPTH), ketone, 
creatine kinase (CK)
Urinalysis:
Glucose, protein, urobilinogen, sediment, albumin, ketone, creatinine.
Body Mass Index (BMI):
BMI（kg/m2）=  weight(kg) / height2 (m2)

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Grades for renal dysfunction are as follows.
Normal: 
eGFR ≥90 mL/min/1.73m2
Mild: 
eGFR ≥60 mL/min/1.73m2 and <90 mL/min/1.73m2
Moderate: 
eGFR ≥30 mL/min/1.73m2 and <60 mL/min/1.73m2
Severe: 
eGFR <30 mL/min/1.73m2
Investigator should judge the grade for hepatic dysfunction by using lab data category
as described below and symptoms/concomitant diagnoses.
Normal: 
Normal AST/ALT
Mild: 
AST/ALT >ULN and <3x ULN
Moderate:
AST/ALT≥3xULN and <5x ULN + total Bil<= 2xULN
Severe:
AST/ALT≥5 xULN, or AST/ALT≥3xULN and <5x ULN + total Bil>
2xULN
ULN is taken from the corporate standard reference range (001-MCG-157_RD-01:
Standard Ranges).
Enzymatic method:
eGFR（mL/min/1.73 m2）= 194×Creatinine (mg/dL) - 1.094×Age-0.287
For female, ×0.739
Jaffe rate assay:
eGFR（mL/min/1.73 m2）= 175×Creatinine (mg/dL) －1.154×Age－0.203
For female, ×0.742
See ANNEX 2 for more details.
9.4
DATA SOURCES
Case Report Forms (CRFs) for individual patients will be provided by the sponsor via the
EDC system.
In EDC system, two casebooks will be set:
Book 1 includes baseline, 4 weeks, 12 weeks and 26 weeks. 
Book 2 includes 40 weeks and 52 weeks.
The data are to be transmitted immediately after being entered into EDC at 26 weeks (Book 
1) and 52 weeks (Book 2) after the start of treatment or at discontinuation.
For any adverse events, the data should be immediately entered into EDC and transmitted.
9.5
STUDY SIZE
1000 patients will be included in the study.

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Hypoglycaemic Adverse Event (AE) is an important factor for evaluating risk-benefit balance 
of diabetes treatment and collected with high sensitivity and specificity in routine care. It is 
used as reference event for the sample size evaluation in PMS studies in Japan.
The proportion of Japanese patients with hypoglycaemic AE was 1.1% in Emapgliflozin + 
Linagliptin group in the 52 weeks data of 1275.19 trial (c14725107). If the true proportion of 
patients with hypoglycaemic AE is assumed to be 2-fold (i.e., 2.2%), the given sample size of 
1000 gives more than 80% power to show that the proportion of patients with hypoglycaemic 
AE is not equal to 1.1% by using one sample chi-square test with a 0.05 two-sided 
significance level. 
9.6
DATA MANAGEMENT
Patients’ data will be gathered by EDC system provided by external vendor below. 
Contract 1
Contract 2
Company Name
Outsourced work
EDC system setting
Patient registration
Clinical Data Management
Document management of 
contract with site.
9.7
DATA ANALYSIS
This is a non-interventional study to collect data on patients under routine medical practice on 
safety, effectiveness and appropriate use of TRADIANCE® Combination Tablets AP and BP 
treatment. Analyses are descriptive in nature, including confidence intervals. Subgroup 
analyses will be performed if sample size allows.
Per local regulation, any patient who meets one of the following criteria is treated as 
ineligible for all analyses:

No safety observation was documented after registration.

No required registration procedure was followed.

No valid site contract was available.
9.7.1
Analyses of Safety
The safety analysis will include all patients who registered in the study and receiving the 
TRADIANCE® Combination Tablets AP or BP treatment at least one time except those who 
are found to have no observation after enrolment, invalid registration, or invalid contract with 
the site (see section 9.7). In general, safety analyses will be descriptive,based on BI 
standards, and focus on AEs related to the TRADIANCE® Combination Tablets AP or BP 
treatment.

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AEs will be coded using the current version of the Medical Dictionary for Drug Regulatory 
Activities (MedDRA) and will be based on the concept of treatment emergent AEs. To this 
end, all AEs occurring between the initiation of TRADIANCE® Combination Tablets AP or 
BP prescribed at baseline visit and 7 days (inclusive) after the last administration will be 
considered ‘treatment emergent’. An AE is considered to be an ADR if either the 
physician/investigator who has reported the AE or the sponsor assesses its causal relationship 
as ‘related’.
The frequency of ADRs will be tabulated by system organ class and preferred term according
to the current MedDRA version. The frequency of SAEs will also be tabulated likewise.
The incidence of ADRs stratified based on patient demographics will also be investigated.
No imputation is planned for missing AE data except for missing onset dates which will be 
handled according to BI standard. 
9.7.3
Interim analyses
Several interim analyses will be performed for the purpose of submission of periodic safety 
reports to PMDA (Pharmaceuticals and Medical Devices Agency) in project (status update of 
using TRADIANCE® Combination Tablets AP and BP not only with this study but all usage, 
every 6 month in two years after approval and every 12 months afterward. The submission 
date is depending on the time from the approval).
Final results will be submitted in the re-examination dossier to PMDA by 25 March 2023.

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9.8
QUALITY CONTROL
All processes are conducted according to GPSP Standard Operating Procedures (SOP) (102-
MLS-90-119). Appropriate records and documents are stored based on the GPSP SOPs and 
these processes are checked by internal self-check.
9.9
LIMITATIONS OF THE RESEARCH METHODS
The general scientific objective of this non-interventional study is to obtain an estimate of the 
occurrence of ADRs in the population under study. Due to the absence of a comparator arm, 
there are issues that may impose limitations in particular on the validity of the assessment 
based on the study data such as selection bias, loss to follow up, channelling bias and 
information and recall bias. Thus, comparisons and causal conclusions cannot be made. To 
provide context to the results of this study, effort will be made to compare data to data from 
similar population available from other studies.
9.10
OTHER ASPECTS
9.10.1
Data quality assurance
This PMS study is to be conducted in accordance with both the in-house SOP and working 
instructions which are in compliance with GPSP.
9.10.2
Study records
CRFs for individual patients will be provided by the sponsor via EDC system.
9.10.2.1
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the study site.
Data entered in the eCRFs that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may need 
to request previous medical records or transfer records, depending on the study; also current 
medical records must be available.
For eCRFs all data must be derived from source documents.
9.10.2.2
Direct access to source data and documents
Direct access to source data and documents for PMS study is not allowed in Japan.

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9.10.3
Completion of study
Completion of the PMS will be notified to PMDA when the re-examination document is 
applied to in accordance with J-PMD Act and GPSP.

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10.
PROTECTION OF HUMAN SUBJECTS
There is no regulation or requirement for ensuring the well-being and rights of participants in 
a non-interventional observational study. 
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the patient’s treating physician.
10.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT
The review by Institutional Review Board is not mandatory for conducting PMS in Japanese 
GPSP. The sponsor will enter into a contract with a representative (e.g., head of hospital) in 
accordance with GPSP. Written informed consent prior to patient participation in the trial is 
not a regulatory or legal requirement in accordance with GPSP. 
10.2
STATEMENT OF CONFIDENTIALITY
Individual patient medical information obtained as a result of this PMS is considered
confidential and disclosure to third parties is prohibited with the exceptions noted below.
Patient confidentiality will be ensured by using patient identification code numbers.
Data generated as a result of the PMS needs to be available for inspection on request by the
regulatory authorities.

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11.
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS
Procedures for the collection, management and reporting of individual cases of adverse
events/adverse reactions (see 001-MCS-05-501-RD-01 for collection requirements) and of
any new information that might influence the evaluation of the benefit-risk balance of the
product while the study is being conducted.
11.1
DEFINITIONS OF ADVERSE EVENTS
Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavourable and unintended 
sign (e.g. an abnormal laboratory finding), symptom, or disease temporally associated with 
the use of a medicinal product, whether or not considered related to the medicinal product.
Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and
unintended. Response in this context means that a causal relationship between a medicinal
product and an AE is at least a reasonable possibility. Adverse reactions may arise from use 
of the product within or outside the terms of the marketing authorisation or from occupational 
exposure. Conditions of use outside the marketing authorization include off label use, 
overdose, misuse, abuse and medication errors.
Serious adverse event
A SAE is defined as any AE which
-
results in death, 
-
is life-threatening, 
-
requires in-patient hospitalization, or
-
prolongation of existing hospitalisation, 
-
results in persistent or significant disability or incapacity, or 
-
is a congenital anomaly/birth defect 
Life-threatening in this context refers to a reaction in which the patient was at risk of death at
the time of the reaction; it does not refer to a reaction that hypothetically might have caused
death if more severe.
Medical and scientific judgement should be exercised in deciding whether other situations
should be considered serious reactions, such as important medical events that might not be
immediately life threatening or result in death or hospitalisation but might jeopardise the
patient or might require intervention to prevent one of the other outcomes listed above.
Examples of such events are intensive treatment in an emergency room or at home for
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or
development of dependency or abuse. Any suspected transmission via a medicinal product of
an infectious agent is also considered a serious adverse reaction.

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An AE which possibly leads to disability will be reported as an SAE. Every new occurrence 
of cancer or an exacerbation of an existing cancer will be reported as a SAE regardless of the 
duration between discontinuation of the drug and the occurrence of the cancer.
No AESIs have been defined for this study.
11.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT REPORTING
The investigator shall maintain and keep detailed records of all AEs in their patient files.
Collection of AEs
The study design is of non-interventional nature and the study is conducted within the
conditions of the approved marketing authorization. Sufficient data from controlled
interventional trials are available to support the evidence on the safety and efficacy of the
studied BI drug. For this reason the following AE collection and reporting requirements have
been defined.
The following must be collected by the investigator in the eCRF. When any adverse events
occur, the data should be immediately entered into eCRF and transmitted. :
-
all ADRs (serious and non-serious),
-
all AEs with fatal outcome,
All ADRs, including those persisting after study completion must be followed up until they
are resolved, have been sufficiently characterized, or no further information can be obtained. 
The investigator carefully assesses whether an AE constitutes an ADR using the information
below.
Causal relationship of adverse event
The definition of an adverse reaction implies at least a reasonable possibility of a causal
relationship between a suspected medicinal product and an AE. An adverse reaction, in 
contrast to an AE, is characterized by the fact that a causal relationship between a medicinal 
product and an occurrence is suspected.
Medical judgment should be used to determine the relationship, considering all relevant
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge,
confounding factors such as concomitant medication, concomitant diseases and relevant
history.
Arguments that may suggest a reasonable causal relationship could be:
•
The event is consistent with the known pharmacology of the drug 
•
The event is known to be caused by or attributed to the drug class.
•
A plausible time to onset of the event relative to the time of drug exposure.
•
Evidence that the event is reproducible when the drug is re-introduced
•
No medically sound alternative etiologies that could explain the event (e.g. 
preexisting or concomitant diseases, or co-medications).

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•
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.
Intensity of adverse event
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) which is/are easily tolerated
Moderate:
Enough discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Pregnancy:
In rare cases, pregnancy might occur in a study. Once a subject has been enrolled into the
study, after having taken TRADIANCE® Combination Tablets AP or BP, the investigator 
must report any drug exposure during pregnancy, which occurred in a female subject or in a 
partner to a male subject to the Sponsor by means of Part A of the Pregnancy Monitoring 
Form. The outcome of the pregnancy associated with the drug exposure during pregnancy 
must be followed up and reported by means of Part B of the Pregnancy Monitoring Form.
In the absence of a reportable AE, only the Pregnancy Monitoring Form must be completed,
otherwise the Non-interventional Study AE form is to be completed and forwarded as well as 
soon as possible.
Priority survey items:
Fluid volume decreased events and Hypoglycaemia (important identified risks), safety of
administration to patients with renal impairment or elderly patients (important missing
information) stated in the Japan Risk Management Plan 
Information required
For each reportable adverse event, the investigator should provide the information requested
on the appropriate (e)CRF pages.

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Reporting of related Adverse Events associated with any other BI drug
The investigator is encouraged to report all AEs related to any BI drug other than
TRADIANCE® Combination Tablets AP and BP, according to the local regulatory 
requirements for spontaneous AE reporting at the investigator’s discretion by using the 
locally established routes and AE report forms. The term AE includes drug exposure during 
pregnancy, and, regardless of whether an AE occurred or not, any abuse, off-label use, 
misuse, medication error, occupational exposure, lack of effect, and unexpected benefit.
11.3
REPORTING TO HEALTH AUTHORITIES
Adverse event reporting to regulatory agencies will be done by the MAH according to the 
local and international regulatory requirements.

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12.
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS
The progress reports and final reports will be submitted to PMDA in Japan Periodic
safety report. And also the final report for this PMS is included in re-examination
documents.
This study is planned for the publication based on the final report.
The rights of the physician and of the sponsor with regard to publication of the results of this 
PMS study are described in the contract. As a general rule, no PMS study results should be 
published prior to finalization of the Study Report.
In addition, further interim analysis might be performed for the scientific presentations and 
publications for the purposes of promoting appropriate use of TRADIANCE® Combination 
Tablets AP and BP.

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13.
REFERENCES
13.1
PUBLISHED REFERENCES
R14-4302
The Japan Diabetes Society. Treatment Guide for Diabetes 
2014-2015. Tokyo: Bunkodo; 2014.
13.2
UNPUBLISHED REFERENCES
001_MCG_157 RD_01 
Standard Ranges, current version, IDEA for CON.
c14725107
 A phase III, randomised, double-
blind, parallel group, 52-week study to evaluate efficacy and 
safety of once daily empagliflozin and linagliptin fixed dose 
combination compared with linagliptin plus placebo in Japanese 
type 2 diabetes mellitus patients with insufficient glycaemic 
control after 16 weeks treatment with once daily linagliptin 5 
mg. BI Trial No. 1275.19. 28 June 2017.
102-MLS-90-119
Standard Operating Procedure for Good Post-marketing Study 
Practice, current version, IDEA for CON.
001-MCS-05-501-RD-01
Individual Case Safety Report (ICSR) collection, processing 
and reporting by Source, current version, IDEA for CON.

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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
Number
Document 
Reference Number
Date
Title
None
None

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ANNEX 2. FLOW CHART OF VARIABLES
Time point
Item
Observation period *1
Before first 
administration of
TRADIANCE®
Combination Tablets
AP or BP
Week 12
Week26
Week 40
Week 52 or at 
discontinuation
Registration
X*2
Demographics
X
Physical examination
(Body weight, height)
X
X*3
X*3
X*3
X*3
HbA1c and fasting plasma 
glucose
X
X
X
X
X
Concomitant disease/
medical history
X
Waist circumference
X
Prior Antidiabetic drugs
X*4
Administration status of
TRADIANCE® Combination 
Tablets AP or BP
X (Record throughout the observation period)
Concomitant drug and
Concomitant therapy
X*
X (Record throughout the observation period)
Blood pressure, pulse rate and 
ECG
(X)
(X)
(X)
(X)
(X)
Pregnancy status*5
X (confirm throughout the observation period)
X (confirm throughout the 
observation period)
Laboratory tests
(X)
(X)
(X)
(X)
(X)
Adverse events
X (Examine throughout the observation period)
*1: Time points during the observation period are approximate. Collected data should be reported as of the 
closest available visit.
*2: Patients administered TRADIANCE® Combination Tablets AP or BP will be registered within 14 days 
from whenever the day of first administration is possible.
*3: Body weight only
*4: From 3 month before first administration of TRADIANCE® Combination Tablets AP or BP
*5: Only for female patients
(X): If applicable
eCRF (electronic case report form): At 26 weeks, 52 weeks, and each time an adverse event has occurred, data 
in corresponding observation period should be entered into the eCRF and transmitted using the EDC system.

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c20025178
2.0
1275-0026-nis-protocol-revision-01
Post Marketing Surveillance in Japan on Long Term Drug Use of TRADIANCE
Combination Tablets AP and BP in Patients with type 2 Diabetes Mellitus
Author-Clinical Trial Leader
23 Nov 2018 08:10 CET
Approval-EU Qualified Person
Pharmacovigilance
23 Nov 2018 08:37 CET
Approval-Team Member Medical
Affairs
23 Nov 2018 09:26 CET
Approval-Therapeutic Area 
23 Nov 2018 09:51 CET
Approval-
 Pharmacovigilance
23 Nov 2018 11:10 CET
Approval-Team Member Drug
Safety
23 Nov 2018 11:15 CET
Author-Trial Statistician
26 Nov 2018 05:47 CET
Approval-Safety
27 Nov 2018 18:16 CET

Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c20025178
2.0
Approval-Clinical 
30 Nov 2018 03:27 CET