Clinical Characteristics and Practice Patterns of Type 2 Diabetes Mellitus (T2D) Patients Treated With Oral Antidiabetic Drugs (OAD) in Japan: Analysis of Medical and Health Care Database of the Medical Data Vision (MDV)
Conditions: Diabetes Mellitus, Type 2
Sponsor: Boehringer Ingelheim

ABCD
001-MCS-90-124_RD-01 (4.0)
TITLE PAGE
Protocol for non-interventional studies based on existing data
TITLE PAGE
Document Number:
c12992044-01
BI Study Number:
1218.178
BI Investigational
Product(s):
Trazenta (Linagliptin)
Title:
Clinical characteristics and practice patterns of type 2 diabetes 
mellitus (T2DM) patients treated with oral antidiabetic drugs 
(OAD) in Japan: analysis of medical and health care database of 
the Medical Data Vision (MDV)
Protocol version 
identifier:
Version 1
Date of last version of 
protocol:
Not Applicable
PASS:
No
EU PAS register 
number:
Not Applicable
Active substance:
Linagliptin
Medicinal product:
Trazenta
Product reference:
Not applicable
Procedure number:
Not applicable
Joint PASS:
No
Research question and 
objectives:
To understand the prescription pattern in T2DM patients of each 
compound and each class for all OADs, available throughout 
study period.
Country(-ies) of study:
Japan
Author:
Marketing authorisation 
holder(s):
Nippon Boehringer Ingelheim Co,, Ltd.
2-1-1, Osaki, Shinagawa-ku, Tokyo 141-6017, Japan

Boehringer Ingelheim
Page 2 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1218.178
c12992044-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
MAH contact person:
Clinical Development and Medical Affairs
Nippon Boehringer Ingelheim Co., Ltd.
2-1-1, Osaki, Shinagawa-ku, Tokyo 141-6017, Japan
In case of PASS, add:
<EU-QPPV:>
Not Applicable
In case of PASS, add:
<Signature of EU-
QPPV:>
Not Applicable
Date:
09 February 2017
Page 1 of 32
Proprietary confidential information
© 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission

Boehringer Ingelheim
Page 3 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1218.178
c12992044-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
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..................................................................... 13
6.
MILESTONES..................................................................................................... 14
7.
RATIONALE AND BACKGROUND................................................................ 15
8.
RESEARCH QUESTION AND OBJECTIVES ................................................. 17
9.
RESEARCH METHODS .................................................................................... 18
9.1
STUDY DESIGN............................................................................................ 18
9.2
SETTING........................................................................................................ 19
9.3
VARIABLES .................................................................................................. 20
9.3.1
Exposures ................................................................................................ 20
9.3.2
Outcomes................................................................................................. 21
9.3.2.1
Primary outcomes..................................................................................21
9.3.2.2
Secondary outcomes..............................................................................21
...................................................................................21
9.3.3
Covariates................................................................................................ 21
9.4
DATA SOURCES........................................................................................... 22
9.5
STUDY SIZE.................................................................................................. 22
9.6
DATA MANAGEMENT................................................................................ 22
9.7
DATA ANALYSIS......................................................................................... 22
9.7.1
Main analysis........................................................................................... 22
....................................................................................... 23
9.8
QUALITY CONTROL................................................................................... 24
9.9
LIMITATIONS OF THE RESEARCH METHODS...................................... 24
9.10
OTHER ASPECTS ......................................................................................... 24
9.11
SUBJECTS...................................................................................................... 24
9.11.1
Cases........................................................................................................ 24
9.11.2
Controls................................................................................................... 24
9.12
BIAS................................................................................................................ 24
10.
PROTECTION OF HUMAN SUBJECTS .......................................................... 26

Boehringer Ingelheim
Page 4 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1218.178
c12992044-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS....................................................................................................... 27
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY 
RESULTS............................................................................................................ 28
13.
REFERENCES .................................................................................................... 29
13.1
PUBLISHED REFERENCES......................................................................... 29
13.2
UNPUBLISHED REFERENCES................................................................... 29
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.............................................. 30
ANNEX 2. ENCEPP CECKLIST FOR STUDY PROTOCOLS ................................. 31
ANNEX 3. ADDITIONAL INFORMATION.............................................................. 32

Boehringer Ingelheim
Page 5 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1218.178
c12992044-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
2.
LIST OF ABBREVIATIONS
AE
Adverse Event
CI
Confidence Interval
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
IEC
Independent Ethics Committee
IRB
Institutional Review Board
i.v.
Intravenous
MedDRA
Medical Dictionary for Drug Regulatory Activities
OAD
Oral Antidiabetic Drugs
OPU
Operative Unit
p.o.
per os (oral)
q.d.
quaque die (once a day)
SAE
Serious Adverse Event
s.c.
Subcutaneous
T2DM
Type 2 Diabetes Mellitus
TCM
Trial Clinical Monitor
t.i.d.
ter in die (3 times a day)
TMM
Team Member Medicine

Boehringer Ingelheim
Page 6 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1218.178
c12992044-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
3.
RESPONSIBLE PARTIES
• Medical Advisor
Department of Diabetes and Metabolic Diseases
Graduate School of Medicine
The University of Tokyo
Drug Development & Regulatory Science
Faculty of Pharmacy
Keio University
• Person responsible for trial (Alphabetic order in each affiliation)
Clinical Development and Medical Affairs
Nippon Boehringer Ingelheim Co., Ltd.
2-1-1, Osaki, Shinagawa-ku, Tokyo 141-6017, Japan
 (Alliance partner) 
Diabetes products, Medicine Development Unit Japan
Eli Lilly Japan K.K.
4-15-1, Akasaka, Minato-ku, Tokyo 107-0052, Japan
(Statistics/Data analysis)
(Statistics/Data analysis)
Japan Healthcare Practice and Data Analytics
Milliman, Inc.
1-6-2, Kojimachi, Chiyoda-ku, Tokyo 102-0083, Japan

Boehringer Ingelheim
Page 7 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1218.178
c12992044-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
4.
ABSTRACT
Name of company:
Trazenta
Boehringer Ingelheim
Name of finished medicinal 
product:
If applicable, list centrally-authorised 
medicinal product(s) subject to the 
study.
Name of active ingredient:
List pharmacotherapeutic
group(s){ACT codes} and active 
substance(s) subject to the study
A10N,A10H,A10J,A10K,A10L
A10M
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
09 February 2017
1218.178
1.0
Title of study:
Clinical characteristics and practice patterns of type 2 diabetes mellitus 
(T2DM) patients treated with oral antidiabetic drugs (OADs) in Japan: 
analysis of medical and health care database of the Medical Data Vision 
(MDV)
Rationale and 
background:
Renal impairment (RI) is a common complication in patients with type 2 
diabetes. In Japanese patients with T2DM, about 40% of patients have 
microalbuminuria or macroalbuminuria, and other report shows that 55% 
of Japanese patients with T2DM suffer from mild to moderate renal 
dysfunction. 
Many of OADs are contraindicated in severe RI patients or should be 
carefully administered in patients with declined renal function. For 
biguanide, a risk of lactic acidosis increases in RI and biguanide is 
contraindicated in moderate or severe RI. SU and Glinides require caution 
of a risk of hypoglycemia including prolonged hypoglycemia in patients 
with RI. Pioglitazone is used with no contraindication in patients with RI 
in USA, meanwhile in Japan it is contraindicated in severe RI patients and 
it requires careful administration to mild to moderate RI patients. Alpha-
glucosidase inhibitors (α-GIs) also require careful administration in RI 
patients although the levels of severity of RI with caution are different 
from each drug in some measure.
The prescriptions of DPP-4 inhibitors are rapidly increasing in T2DM
patients after its introduction to the Japanese clinical practice in 2009. The 
reason of this trend might result from well-balanced drug characteristics 
with its safety profile, especially low frequency of hypoglycaemia and its 
acceptable efficacy on blood glucose lowering. Therefore many of 
physicians consider DPP-4 inhibitor is widely chosen as a monotherapy 
and one of combination therapy.
As for DPP-4 inhibitors administered on a daily basis, there are seven 
single ingredient drugs in this class and their dose-reduction manners are 
various in RI patients. Linagliptin and teneligliptin are not required dose 
reduction. On the other hand, other five drugs are recommended dose 

Boehringer Ingelheim
Page 8 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1218.178
c12992044-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
Name of company:
Trazenta
Boehringer Ingelheim
Name of finished medicinal 
product:
If applicable, list centrally-authorised 
medicinal product(s) subject to the 
study.
Name of active ingredient:
List pharmacotherapeutic
group(s){ACT codes} and active 
substance(s) subject to the study
A10N,A10H,A10J,A10K,A10L
A10M
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
09 February 2017
1218.178
1.0
reduction or careful administration as excretion might be delayed and 
blood levels also might rise in patients with RI due to the mechanism of 
renal excretion. Furthermore sitagliptin and alogliptin have four and three 
of drug formulations of different contained amount respectively in Japan. 
Japanese physicians are required proper use of complicated regimen in 
accordance with each patient’s renal function.
Thus, appropriate use of OADs including dose-reduction is important for 
patient’s safety in T2DM patients with RI. However, there are insufficient 
data on dose adjustment in accordance with the prescription pattern and 
the risk of RI of OADs, in particular DPP-4 inhibitors, in clinical practice 
in Japan. Therefore, we will investigate OADs usage conditions in T2DM
patients by using Medical Data Vision clinical database in clinical 
practice in Japan.
Research question 
and objectives:
Research question: 
To understand the prescription pattern in T2DM patients of each 
compound and each class for all OADs, available throughout study 
period.
Study objectives:
1.
To analyze the demographic and clinical characteristics of T2DM
patients who have been treated with OADs
 
 
Study design:
Descriptive cohort study
Population:
Medical Data Vision (MDV) clinical database is used.
Inclusion criteria: 
•
Patients with T2DM

Boehringer Ingelheim
Page 9 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1218.178
c12992044-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
Name of company:
Trazenta
Boehringer Ingelheim
Name of finished medicinal 
product:
If applicable, list centrally-authorised 
medicinal product(s) subject to the 
study.
Name of active ingredient:
List pharmacotherapeutic
group(s){ACT codes} and active 
substance(s) subject to the study
A10N,A10H,A10J,A10K,A10L
A10M
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
09 February 2017
1218.178
1.0
•
Patients must have their first prescription for any study drugs 
between 01/01/2014 and 30/09/2016. The index date will be set as 
the first prescription of each drug during the study period.
•
Patients must have at least 6 month enrolment verified by the 
presence of any record except for the study drug prescriptions within 
the database (look back period) prior to the index date for each drug.
Exclusion criteria:
•
Patients who were under 40 y.o. at the time of diagnosis of diabetes.
•
Patients with record of type 1 diabetes mellitus.
•
Patients who prescribed the study drugs during 6 month prior to 
index date for each drug.
•
Patients whose mean visit interval are more than 92 days  
Variables:
Number of patients, age at index date, sex, prior and concomitant use of 
glucose-lowering medications and insulin, comorbidities, serum 
creatinine. eGFR will be calculated using serum creatinine, age, and sex.
Data sources:
Medical Data Vision (MDV) clinical database. The database is health 
insurance claim database. As of end of July 2015, facilities: 200, patients: 
10.95 million, which is covering approximately 12% of acute hospitals in 
Japan. Lab results are also available but number of hospitals providing 
with lab test results are limited.
Study period is from 01/01/2014 to 30/09/2016 in MDV database at the 
time of study protocol approval.
The MDV database is broadly representative of the Japanese population 
with similar distribution comparing with Japanese population; therefore 
we believe our study sample will provide reasonable description of the 
characteristics of patients treated with diagnosis of type 2 diabetes 
mellitus in the general Japanese population. There is research experience 
using the data, 19 publications, 5 conference presentations (as of August 
2015).
Study size:
All available data from 01/01/2014 to 30/09/2016 will be included to 
ensure the maximum number of patient.
All patients with a prescription of OADs and DPP-4 inhibitors from 

Boehringer Ingelheim
Page 10 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1218.178
c12992044-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
Name of company:
Trazenta
Boehringer Ingelheim
Name of finished medicinal 
product:
If applicable, list centrally-authorised 
medicinal product(s) subject to the 
study.
Name of active ingredient:
List pharmacotherapeutic
group(s){ACT codes} and active 
substance(s) subject to the study
A10N,A10H,A10J,A10K,A10L
A10M
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
09 February 2017
1218.178
1.0
01/01/2014 to 31/08/2015 and a diagnosis of T2DM is estimated that 
approximately 9,890 and 7,579 patients respectively have been prescribed 
a study drug in the MDV database to be included in the study.
The power calculation has not been conducted as there will not be any 
hypothesis testing in the analysis. Data of MDV is from all DPC hospitals. 
Data is collected directly from hospitals, so it holds every data of all 
insurances. 
Limitaion: Number of hospitals providing with lab test results are limited.
Data analysis:
•
For the 1st objective, descriptive statistics of each compound and each 
class of OAD will be presented for the baseline demographic and 
clinical characteristics: 
•
Number of patients
•
Age (mean ± SE, mean ± SD)
•
Concomitant medications (drug prescribed at index day) :
•
Use of biguanide (Yes/No)
•
Use of sulfonylurea (Yes/No)
•
Use of thiazolidinediones (Yes/No)
•
Use of glinide (Yes/No)
•
Use of α-GI (Yes/No)
•
Use of GLP-1RA (Yes/No)
•
Use of SGLT2 inhibitors (Yes/No)
•
Use of insulin (Yes/No)
•
Premedications (drug prescribed before index day):
•
Use of biguanide (Yes/No)
•
Use of sulfonylurea (Yes/No)
•
Use of thiazolidinediones (Yes/No)
•
Use of glinide (Yes/No)
•
Use of α-GI (Yes/No)
•
Use of GLP-1RA (Yes/No)
•
Use of SGLT2 inhibitors (Yes/No)

Boehringer Ingelheim
Page 11 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1218.178
c12992044-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
Name of company:
Trazenta
Boehringer Ingelheim
Name of finished medicinal 
product:
If applicable, list centrally-authorised 
medicinal product(s) subject to the 
study.
Name of active ingredient:
List pharmacotherapeutic
group(s){ACT codes} and active 
substance(s) subject to the study
A10N,A10H,A10J,A10K,A10L
A10M
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
09 February 2017
1218.178
1.0
•
Use of insulin (Yes/No)
•
Comorbidities:
•
Hypertension: Percentage of patients with a diagnosis of 
hypertension
•
Ischemic heart disease (IHD): Percentage of patients with a 
diagnosis of IHD
•
Myocardial Infarction (MI): Percentage of patients with a 
diagnosis of MI
•
Heart Failure (HF): Percentage of patients with a diagnosis 
of HF
•
Stroke: Percentage of patients with a diagnosis of stroke
•
Renal impairment: Percentage of patients with a diagnosis of 
renal impairment
•
Amputation: Percentage of patients with a diagnosis of 
amputation

Boehringer Ingelheim
Page 12 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1218.178
c12992044-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
Name of company:
Trazenta
Boehringer Ingelheim
Name of finished medicinal 
product:
If applicable, list centrally-authorised 
medicinal product(s) subject to the 
study.
Name of active ingredient:
List pharmacotherapeutic
group(s){ACT codes} and active 
substance(s) subject to the study
A10N,A10H,A10J,A10K,A10L
A10M
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
09 February 2017
1218.178
1.0
Milestones:
Submission to IRB (Keio University)                     10th February 2017
IRB (Keio University) meeting
                   17th February 2017
Registration to clinicaltrials.gov and ENCePP         28th February 2017
Start of data analysis                                                1st March 2017
Start of manuscript preparation
                     1st March 2017
End of data analysis
                                             10th March 2017
Draft study report
                                                   31st March 2017
Final report of study results
                                    20th April 2017
Submission of manuscript to Journal                             26th June 2017

Boehringer Ingelheim
Page 13 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1218.178
c12992044-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
5.
AMENDMENTS AND UPDATES
Number
Date
Section of 
study 
protocol
Amendment or 
update
Reason
None

Boehringer Ingelheim
Page 14 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1218.178
c12992044-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
6.
MILESTONES
Milestone
Planned Date
Submission to IRB (Keio University)
10th February 2017
IRB (Keio University) meeting
17th February 2017
Registration to clinicaltrials.gov and ENCePP
28th February 2017
Start of data analysis 
1st March 2017
Start of manuscript preparation
1st March 2017
End of data analysis
10th March 2017
Draft study report
31st March 2017
Final report of study results
20th April 2017
Submission of manuscript to Journal
26th June 2017

Boehringer Ingelheim
Page 15 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1218.178
c12992044-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
7.
RATIONALE AND BACKGROUND
Renal impairment (RI) is a common complication in patients with T2DM. In Japanese 
patients with T2DM, about 40% of patients have microalbuminuria or macroalbuminuria [1], 
and other report shows that 55% of Japanese patients with T2DM suffer from mild to 
moderate renal dysfunction [2]. 
Many of OADs are contraindicated in severe RI patients or should be carefully administered 
in patients with declined renal function. For biguanide, a risk of lactic acidosis increases in RI 
and biguanide is contraindicated in moderate or severe RI. Pioglitazone is used with no 
contraindication in patients with RI in USA, meanwhile in Japan it is contraindicated in 
severe RI patients and it requires careful administration to mild to moderate RI patients. 
Glinides and α-GIs also require careful administration in RI patients although the levels of 
severity of RI with caution are different from each drug in some measure.
The prescriptions of DPP-4 inhibitors are rapidly increasing in T2DM patients after its 
introduction to the Japanese clinical practice [3]. The reason of this trend might result from 
well-balanced drug characteristics with its safety profile, especially low frequency of 
hypoglycaemia and its acceptable efficacy on blood glucose lowering. Therefore many of 
physicians consider DPP-4 inhibitor is widely chosen as a monotherapy and one of 
combination therapy.
As for DPP-4 inhibitors administered on a daily basis, there are seven single ingredient drugs 
in this class and their dose-reduction manners are various in RI patients. Linagliptin and 
teneligliptin are not required dose reduction. On the other hand, other five drugs are 
recommended dose reduction or careful administration. Furthermore sitagliptin and alogliptin 
have four and three of drug formulations of different contained amount respectively in Japan. 
Japanese physicians are required proper use of complicated regimen in accordance with each 
patient’s renal function.
Currently, there is no publication of actual situation on the prescription patterns of OADs and 
dose-reduction especially in DPP-4 inhibitors and other OADs needed to dose-reduction. 
However from viewpoint of appropriate use, relevant dose-reduction can contribute patients 
benefit. This study aims to assess the actual condition of dose selection of OADs among RI 
patients in Japan by using MDV database.
MDV provides commercial claims database for inpatient and outpatient consisting medical 
records from more than 12.94 million patients from 230 large acute care DPC hospitals as of 
Feb 2016.  According to the data released by the company in Sept 2016 [1], in one year 
period between July 2015 and June 2016, cumulative number of patients in the claims 
database was 7,546,862 patients. 82% of patients (6,152,732) were associated with outpatient 
claims only, while 15% of patients (1,131,869) had claims from both in and out-patient care. 
Only 3% of patients (262,261) had exclusively in-patient claims. Laboratory data is available 
for approximately 10% of patients contained in the database. The DPC is a case-mix system, 
similar to Medicare in the US. It comprises of 18 Major Diagnosis Categories, 520 diagnostic 
groups and 2,658 case-mix groups. In the DPC algorithm, the diagnosis, procedure and 
comorbidities/complications are the 3 key variables for classification. The diagnosis and 
comorbidities/complications are coded using the ICD10 scheme, while the procedures are 
coded using the Japanese Procedure Codes. Not only administrative claims data but also 

Boehringer Ingelheim
Page 16 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1218.178
c12992044-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
detailed patient data are collected for all the inpatients discharged from the participating 
hospitals.

Boehringer Ingelheim
Page 17 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1218.178
c12992044-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
8.
RESEARCH QUESTION AND OBJECTIVES
Research question: 
To understand the prescription pattern in T2DM patients of each compound and each class 
for all OADs, available throughout study period i.e. DPP-4 inhibitors, sulfonylureas, 
biguanides, thiazolidinediones, α-GIs, glinides.
Study objectives:
1.
To analyze the demographic and clinical characteristics of T2DM patients who have 
been treated with OADs

Boehringer Ingelheim
Page 18 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1218.178
c12992044-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
9.
RESEARCH METHODS
9.1
STUDY DESIGN
Study design:
•
Descriptive cohort study
Comparison group
•
OAD group, DPP-4 inhibitors group, SU group, BG group, TZD group, α-GI group, and 
Glinide group. 
Strength of the study design
•
Up-to-date information can be obtained and nationwide actual treatment status can be 
illustrated with using large-scale real-world database.
Analysis
•
First analysis: type and dosage of drug prescribed for T2DM patients.
•
 
 
•
Main measures: number of patients, baseline characteristics at index month (age, sex), 
prior and concomitant use of glucose-lowering medications and insulin (type, dose), 
comorbidities (types and their percentages of patients), stage of RI defined by eGFR or 
serum creatinine value, glucose-lowering medications and their dosages (based on daily 
dose) for patients with RI, 
 
•
Potential limitation
•
The data held in MDV database is collected from DPC hospitals, not GP data. However 
they are including outpatient data because many of Japanese patients prefer to visit a 
hospital even though chronic disease.
•
The rate of laboratory test data held in MDV database is limited. About 350,000 patients 
out of 2,600,000 patients (13.5%, April 2008 ~ April 2016) have laboratory data.
•
The MDV database does not hold the time diagnosis of T2DM if it is out of study period. 
Therefore the onset date of diabetes or the first record of T2DM cannot obtain for all 
patients.
•
The information on medication is based on prescribed record, not include adherence 
result. It means that exact dosage may not reveal actual dispensed prescription and 
dosage perfectly.
•
Laboratory test date is not exactly matched with the index day of the first prescription of 
OAD. The sample size will have some impacts (reduction) to assure simultaneous timing 
of data. The latest lab result 30 days before the index date will be considered the status at 
the time of prescription
•
All information of each patient is from consent given DPC hospitals. If patients have 
visits to other medical institutions, these data are not included in the MDV data.

Boehringer Ingelheim
Page 19 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1218.178
c12992044-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
•
MDV database is composed of data from patients who hospitalized in DPC hospital so 
that more severe patient will be included in the database.
9.2
SETTING
Medical Data Vision (MDV) clinical database is used.
Inclusion criteria
•
Patients with T2DM (ICD code: E11 or E14).
•
Patients must have their first prescription (defined as index date*) for any study drugs 
between 01/01/2014 and 30/09/2016.
•
Patients must have at least 6 months enrolment verified by the presence of any record 
except for the study drug prescriptions within the database (look back period) prior to the 
index date for each drug.
Exclusion criteria
•
Patients who were under 40 y.o. at the time of diagnosis of diabetes.
•
Patients with record of type 1 diabetes mellitus (ICD code: E10).
•
Patients who prescribed the study drugs during 6 month prior to index date for each drug.
•
Patients whose mean visit interval are more than 92 days   
*Index date is defined as follows:
•
In case of comparing drugs within class, index date is defined as the date of first 
prescription for any study drugs as general name. Change of dosage is not counted as the 
index.
•
In case of comparing drugs between class, index date is defined as the date of first 
prescription for study drug of class. Change of dosage is not counted as the index.
Sitagliptin†, Linagliptin†
Sitagliptin†
Sitagliptin†
Sitagliptin 25mg†
Linagliptin†
Sitagliptin 50mg
Comparison within class
Case 1
Case 2
Case 3
Case 4
Sulfonylurea†, DPP-4 inhibitor†
Sulfonylurea†
DPP-4 inhibitor†
Sulfonylurea, dosage increase
Comparison between class
Case 5
Case 6
Case 7
Case 8
Sulfonylurea†
Sulfonylurea†
Sulfonylurea + DPP-4 inhibitor†
†: drug prescription that is assigned as index date
Sitagliptin + Linagliptin†
* The hospitalization period is not included in the mean visit interval.
Figure 1
Definition of Index data(date of first prescription for any study drugs)

Boehringer Ingelheim
Page 20 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1218.178
c12992044-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
9.3
VARIABLES
Number of patients, age at index date, sex, prior and concomitant use of glucose-lowering 
medications and insulin, comorbidities and serum creatinine.
Potential confounding for the type and dosage (based on daily dose)of medications and their 
 
age, sex, comorbidities, serum creatinine.
9.3.1
Exposures
Prescriptions for an OAD issued between 01/01/2014 and 30/09/2016 described below:
•
DPP-4 inhibitors therapies:
•
Alogliptin 
•
Alogliptin/Pioglitazone single-pill combination
•
Anagliptin 
•
Linagliptin 
•
Saxagliptin 
•
Sitagliptin 
•
Teneligliptin 
•
Vildagliptin 
•
Sulfonylurea therapies: 
•
Acetohexamide 
•
Glyclopyramide 
•
Glibenclamide 
•
Chlorpropamide 
•
Tolbutamide Tablets
•
Tolbutamide Powders 
•
Gliclazide 
•
Glimepiride
•
Glimepiride Orally-disintegrating tablet
•
Biguanide therapies:
•
Buformine 
•
Metformin 
•
Thiazolidinedione therapies:
•
Pioglitazone 
•
Pioglitazone Orally-disintegrating tablet 
•
Glimepiride/Pioglitazone single-pill combination OD
•
Metformin/Pioglitazone single-pill combination OD
•
α-GI:
•
Acarbose 
•
Acarbose Orally-disintegrating tablet 
•
Voglibose
•
Voglibose Orally-disintegrating tablet 
•
Miglitol 
•
Miglitol Orally-disintegrating tablet
•
Glinide therapies:
•
Nateglinide 

Boehringer Ingelheim
Page 21 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1218.178
c12992044-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
•
Mitiglinide 
•
Repaglinide
•
Mitiglinide/Voglibose single-pill combination 
* Combined in general name if the drug has been sold in several brand name.
9.3.2
Outcomes
9.3.2.1
Primary outcomes
Outcome name: demographic and clinical characteristics of patients who had a prescription of 
OADs.
Time frame: on the index month
Safety issue: N/A
9.3.2.2
Secondary outcomes
Outcome name: drug and dosage (based on daily dose) they are prescribed as there are 
different cut-offs for renal functions.
Time frame: on the index month
Safety issue: N/A
9.3.3
Covariates
Age at index date
Sex
Prior and concomitant use of glucose-lowering medications and insulin (type, dose): drug 
name was defined by ATC code and drug name. 
Comorbidities (types and their percentages of patients): defined by ICD-10 code
Stage of RI: defined by eGFR or serum creatinine value (See Annex 3). 
eGFR is calculated using serum creatinine, age, and sex as follows (formula for Japanese): 
The latest serum creatinine value within 6 months from index date will be used.
*where Cr is serum creatinine (mg/dL), age is the age at index date.
•
eGFR formula*: 
eGFR (mL/min/1.73m2) = 194 × Cr-1.094 × age (year)-0.287  (× 0.739 if female) 
*The formula recommended by the Japanese Society of Nephrology in clinical practice in 
Japan is the above formula calculated from three data of serum creatinine, age and sex.
<References>

Boehringer Ingelheim
Page 22 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1218.178
c12992044-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
・(Japanese) Evidence-based Clinical Practice Guideline for CKD 2013 (the Japanese
Society of Nephrology) 
URL (accessed on 1st Feb, 2017):
http://www.jsn.or.jp/guideline/pdf/CKD_evidence2013/all.pdf 
-
(English) Japanese Society of Nephrology. Clin Exp Nephrol 2014;18: 346.
9.4
DATA SOURCES
Medical Data Vision (MDV) clinical database. The database is health insurance claim 
database. As of end of July 2015, facilities: 200, patients: 10.95 million, which is covering 
approximately 12% of acute hospitals in Japan. Lab results are also available but number of 
hospitals providing with lab test results are limited.
Study period is from 01/01/2014 to 30/09/2016 in MDV database at the time of study 
protocol approval.
The MDV database is broadly representative of the Japanese population with similar 
distribution comparing with Japanese population; therefore we believe our study sample will 
provide reasonable description of the characteristics of patients treated with diagnosis of type 
2 diabetes mellitus in the general Japanese population. There is research experience using the 
data, 19 publications, 5 conference presentations (as of August 2015).
9.5
STUDY SIZE
All available data from 01/01/2014 to 30/09/2016 will be included to ensure the maximum 
number of patient.
All patients with a prescription of OADs and DPP-4 inhibitors from 01/01/2014 to 
31/08/2015 and a diagnosis of T2DM is estimated that approximately 9,890 and 7,579 
patients respectively have been prescribed a study drug in the MDV database to be included 
in the study. 
9.6
DATA MANAGEMENT
Data were provided as electrical data formatted csv by Medical Data Vision Co., Ltd.
SAS and Microsoft Excel were used for statistics.
9.7
DATA ANALYSIS
9.7.1
Main analysis
•
For the primary objective, descriptive statistics of patients prescribed each compound 
and each class of OAD at least once will be presented for the baseline demographic and 
clinical characteristics: 
•
Number of patients (n, % of total patients)
•
Age (mean ± SE, mean ± SD)
•
Sex
•
Concomitant medications (drug prescribed at index day) :
•
Use of biguanide (Yes/No)
•
Use of sulfonylurea (Yes/No)
•
Use of thiazolidinediones (Yes/No)

Boehringer Ingelheim
Page 23 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1218.178
c12992044-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
•
Use of glinide (Yes/No)
•
Use of α-GI (Yes/No)
•
Use of GLP-1RA (Yes/No)
•
Use of SGLT2 inhibitors (Yes/No)
•
Use of insulin (Yes/No)
•
Premedications (drug prescribed before index day):
•
Use of biguanide (Yes/No)
•
Use of sulfonylurea (Yes/No)
•
Use of thiazolidinediones (Yes/No)
•
Use of glinide (Yes/No)
•
Use of α-GI (Yes/No)
•
Use of GLP-1RA (Yes/No)
•
Use of SGLT2 inhibitors (Yes/No)
•
Use of insulin (Yes/No)
•
Comorbidities:
•
Hypertension: Percentage of patients with a diagnosis of hypertension
•
Ischemic heart disease (IHD): Percentage of patients with a diagnosis of IHD
•
Myocardial Infarction (MI): Percentage of patients with a diagnosis of MI
•
Heart Failure (HF): Percentage of patients with a diagnosis of HF
•
Stroke: Percentage of patients with a diagnosis of stroke
•
Renal impairment: Percentage of patients with a diagnosis of renal impairment
•
Amputation: Percentage of patients with a diagnosis of amputation

Boehringer Ingelheim
Page 24 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1218.178
c12992044-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
9.8
QUALITY CONTROL
Milliman, Inc. will conduct a quality check as below:
Calculation check: both of program codes for calculation and the data codes used the 
calculation will be checked by different person from that who calculated. 
Pre-release peer review: comprehensive check on methodology, calculation process, and 
consistency of results will be performed by qualified peer-reviewer.
Post-release peer review: comprehensive check on the project will be conducted by 
qualified peer-reviewer belonging to another office.
9.9
LIMITATIONS OF THE RESEARCH METHODS
•
The data held in MDV database is collected from DPC hospitals, not GP data. However 
they are including outpatient data because many of Japanese patients prefer to visit a 
hospital even though chronic disease.
•
The rate of laboratory test data held in MDV database is limited. About 350,000 patients 
out of 2,600,000 patients (13.5%, April 2008 ~ April 2016) have laboratory data.
•
The MDV database does not hold the time diagnosis of T2DM if it is out of study period. 
Therefore the onset date of diabetes or the first record of T2DM cannot obtain for all 
patients.
•
The information on medication is based on prescribed record, not include adherence 
result. It means that exact dosage may not reveal actual dispensed prescription and 
dosage perfectly.
•
Laboratory test date is not exactly matched with the index day of the first prescription of 
OAD. The sample size will have some impacts (reduction) to assure simultaneous timing 
of data. The latest lab result 30 days before the index date will be considered the status at 
the time of prescription
•
All information of each patient is from consent given DPC hospitals. If patients have 
visits to other medical institutions, these data are not included in the MDV data.
•
MDV database is composed of data from patients who hospitalized in DPC hospital so 
that more severe patient will be included in the database.
9.10
OTHER ASPECTS
9.11
SUBJECTS
9.11.1
Cases
Not Applicable
9.11.2
Controls
Not Applicable
9.12
BIAS
•
All information of each patient is from consent given DPC hospitals. If patients have 
visits to other medical institutions, these data are not included in the MDV data.

Boehringer Ingelheim
Page 25 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1218.178
c12992044-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
•
MDV database is composed of data from patients who hospitalized in DPC hospital so 
that more severe patient will be included in the database.

Boehringer Ingelheim
Page 26 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1218.178
c12992044-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
10.
PROTECTION OF HUMAN SUBJECTS
As this is a study based on databases using anonymous and personally unidentifiable data; 
therefore protection of human subjects is not applicable for this study.
Ethical considerations: 
•
Ethical guidelines to be followed

This study is to be carried out according to “Ethical Guidelines for Medical and 
Health Research Involving Human Subjects” (April 1, 2015).
URL: 

(Japanese) http://www.mhlw.go.jp/file/06-Seisakujouhou-10600000-
Daijinkanboukouseikagakuka/0000069410.pdf

(Provisional Translation, as of March 2015) http://www.mhlw.go.jp/file/06-
Seisakujouhou-10600000-Daijinkanboukouseikagakuka/0000080278.pdf
•
Protection of personal information and consent  

This survey is a study using existing record/information. These materials to be used 
are anonymized with permission of secondary use from the providing medical 
institution. Therefore, in accordance with “Ethical Guidelines for Medical and 
Health Research Involving Human Subjects” (April 1, 2015), consent from patients 
to be investigated subject is not required.
We will apply the study for Institutional Review Board in Keio University. We will start 
the analysis after the IRB approval. 

Boehringer Ingelheim
Page 27 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1218.178
c12992044-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
11.
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS
The outcomes of the study are the baseline characteristics (pre-treatment) and medication 
prescriptions. We will not be looking at outcomes during the treatment period; therefore 
safety reporting is not applicable for this study.

Boehringer Ingelheim
Page 28 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1218.178
c12992044-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
12.
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS
The results of the study will be written as a conference abstract as well as a manuscript to be 
submitted to a peer-reviewed journal.
Target of journal submission: End of June 2017.

Boehringer Ingelheim
Page 29 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1218.178
c12992044-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
13.
REFERENCES
13.1
PUBLISHED REFERENCES
[1] Yokoyama H, et al; Diabetes Care. 2007; 30: 989-992.
[2] Kanatsuka A, et al; J. Japan Diab. Soc. 2012; 55: 671-680.
[3] Kohro T, et al; Int Heart J. 2013; 54(2): 93-97.
13.2
UNPUBLISHED REFERENCES
N/A

Boehringer Ingelheim
Page 30 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1218.178
c12992044-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
Number
Document 
Reference Number
Date
Title
None

Boehringer Ingelheim
Page 31 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1218.178
c12992044-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
ANNEX 2. ENCEPP CECKLIST FOR STUDY PROTOCOLS
N/A

Boehringer Ingelheim
Page 32 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1218.178
c12992044-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
ANNEX 3. ADDITIONAL INFORMATION
1. Stage of renal function by eGFR
eGFR 
(ml/min/1.73m2)
G1
Normal or high
≥90
G2
Normal or mildly decreased
60-89
G3a
Mildly to moderately decreased
45-59
G3b
Moderately to severely decreased
30-44
G4
Severely decreased
15-29
G5
ESKD
<15
ESKD: End Stage Kidney Disease
2. Stage of renal function by serum creatinine value
Serum Creatinine (Cr)
(mg/dL)
Normal
Male：0.6＜Cr ≤1.2
Female：0.4＜Cr ≤ 0.9
Mild
Male：1.2＜Cr ≤ 1.4
Femal：0.9＜Cr ≤ 1.2
Moderate
Male：1.4＜Cr ≤ 2.4
Female：1.2＜Cr ≤ 2.0
Severe/
ESKD
Male：Cr＞2.4
Female：Cr＞2.0

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c12992044
1.0
nis_protocol_based_on_existing data_1218_0178
Clinical characteristics and practice patterns of Type 2 Diabetes Mellitus (T2D)
patients treated with oral antidiabetic drugs (OAD) in Japan: analysis of medical and
health care database of the Medical Data Vision (MDV)
Approval-Clinical Program
10 Feb 2017 01:46 CET
Approval-Medical
10 Feb 2017 03:37 CET
Approval
Medical Affairs
10 Feb 2017 04:10 CET

Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c12992044
1.0