Treatment of T2DM Patients in Germany Receiving Empagliflozin: A Retrospective RWE Study Description of Treatment and Population Characteristics of Type 2 Diabetic Patients in Germany Receiving Empagliflozin: A Retrospective Real-World Evidence (RWE) Study Based on German Registries DPV&DIVE
Conditions: Diabetes Mellitus, Type 2
Sponsor: Boehringer Ingelheim

001-MCS-90-124_RD-01 (4.0)
Protocol for non-interventional studies based on existing data
TITLE PAGE
Document Number:
<document number>
BI Study Number:
1245-0198
BI Investigational
Product(s):
NA
Title:
Description of Treatment and Population Characteristics of 
Type 2 Diabetic Patients in Germany receiving Empagliflozin: A 
retrospective Real-World Evidence (RWE) study based on 
German registries DPV & DIVE
Protocol version 
identifier:
1.0
Date of last version of 
protocol:
16 August 2019
PASS:
No
EU PAS register 
number:
NA
Active substance:
Empagliflozin
Medicinal product:
Jardiance®, Synjardy®
Product reference:
NA
Procedure number:
NA
Joint PASS:
–
Research question and 
objectives:
Description of the real-life treatment of adult patients with type-
2 diabetes mellitus (T2DM) receiving Empagliflozin, comparing
the characteristics of patients starting Empagliflozin in three 
time intervals:
- The first analysis will include the patients receiving Empa-
gliflozin before the EMPA-REG-OUTCOME study was 
published (time until mid-Sept. 2015; “Cohort 1”).
- The second analysis will include patients receiving Empa-
gliflozin starting from the EMPA-REG-OUTCOME study 
being published until CV Label Change (time from mid-Sept. 
2015-mid-Jan. 2017; “Cohort 2”). 
-
The third analysis will include all patients receiving 
Empagliflozin starting from mid-Jan. 2017 until last 
available data cut (“Cohort 3").
Country of study:
Germany

Boehringer Ingelheim
Page 2 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1245-0198
<document number>
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
Author:
Marketing authorisation 
holder(s):
MAH contact person:
In case of PASS, add:
<EU-QPPV:>
NA
In case of PASS, add:
<Signature of EU-
QPPV:>
NA
Date:
16 August 2019
Page 1 of 32
Proprietary confidential information
© 2020 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 1245-0198
<document number>
Proprietary confidential information © 2020 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.................................................................................... 7
4.
ABSTRACT........................................................................................................... 8
5.
AMENDMENTS AND UPDATES..................................................................... 13
6.
MILESTONES..................................................................................................... 14
7.
RATIONALE AND BACKGROUND................................................................ 15
8.
RESEARCH QUESTION AND OBJECTIVES ................................................. 16
9.
RESEARCH METHODS .................................................................................... 17
9.1
Study Design................................................................................................... 17
9.2
SETTING and Inclusion/exclusion criteria..................................................... 17
9.3
VARIABLES .................................................................................................. 17
9.3.1
Outcomes................................................................................................. 17
For all three cohorts receiving empagliflozin, the following variables will be assessed:
17
9.3.1.1
Primary outcomes..................................................................................17
9.3.1.2
Secondary outcomes..............................................................................18
9.4
DATA SOURCES........................................................................................... 18
9.5
STUDY SIZE.................................................................................................. 18
9.6
DATA MAIN MANAGEMENT.................................................................... 19
9.7
DATA ANALYSIS......................................................................................... 19
9.7.1
Main analysis........................................................................................... 19
9.7.2
Missing data ............................................................................................ 19
9.8
QUALITY CONTROL................................................................................... 20
9.9
LIMITATIONS OF THE RESEARCH METHODS...................................... 20
9.10
SUBJECTS...................................................................................................... 20
9.11
BIAS................................................................................................................ 20
10.
PROTECTION OF HUMAN SUBJECTS .......................................................... 21
10.1
Principles of good research practice ............................................................... 21
10.2
Patient information and consent...................................................................... 21
10.3
Independent ethics committee (IEC)............................................................... 21

Boehringer Ingelheim
Page 4 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1245-0198
<document number>
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
10.4
Confidentiality ................................................................................................ 21
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS....................................................................................................... 22
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY 
RESULTS............................................................................................................ 23
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.............................................. 25
ANNEX 2. ENCEPP CECKLIST FOR STUDY PROTOCOLS ................................. 26

Boehringer Ingelheim
Page 5 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1245-0198
<document number>
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
2.
LIST OF ABBREVIATIONS
ACE-i
Angiotensin-converting enzyme inhibitor
AD
Anti-diabetic Drug
aDCSI
adapted Diabetes Complications Severity Index
ADR
Adverse Drug Reaction
AE
Adverse Event
AESI
Adverse Event of Special Interest
ARB
Angiotensin receptor blocker
ASA
Acetylsalicylic acid (Aspirin)
ASCVD
Atherosclerotic cardiovascular disease
ATC
Anatomical Therapeutic Chemical / Defined Daily Dose Classification
AWMF
Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e.V.
BÄK
Bundesärztekammer
Ba-Wue.
Baden-Wuerttemberg
BB
Beta blocking agents
BI
Boehringer Ingelheim
CAD
Coronary artery disease
CCB
Calcium-channel blockers
CCI
Charlson Comorbidity Index
CI
Confidence Interval
CRO
Clinical Research Organization
CSME
Clinically significant macular edema/degeneration
CV
Cardiovascular
CVD
Cardiovascular disease
DDD
Defined Daily Dose
DMP
Diseases Management Program
DPP4-i
Dipeptidylpeptidase IV inhibitors
DRG
Diagnosis Related Group
EBM
Einheitlicher Bewertungsmaßstab
EU-QPPV
European Union Qualified Person for Pharmacovigilance
FGS
Fachgruppenschlüssel
GPP
Good Pharmacoepidemiology practices
HMG-CoA
3-hydroxy-3-methyl-glutaryl-coenzyme A
Hosp.
Hospitalization
IC
Informed Consent
ICD
International Statistical Classification of Diseases and Related Health Problems
ICH-GCP
International Council for Harmonization of Technical Requirements for Pharmaceuticals for 
Human Use 
IEC
Independent Ethics Committee
IHD
Ischemic heart disease
IPAM
Institut für Pharmakoökonomie und Arzneimittellogistik
ISPE
International Society for Pharmacoepidemiology
ISPOR
International Society for Pharmacoeconomics and Outcomes Research

Boehringer Ingelheim
Page 6 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1245-0198
<document number>
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
KBV
Kassenärztliche Bundesvereinigung
KM
Kaplan-Meier
LOCF
Last observation carried forward
MAH
Marketing authorization holder
MI
Myocardial infarction
MRA
Mineralocorticoid receptor antagonists / Aldosterone antagonists
NIS
Non-interventional study
NOAC
New Oral Anticoagulant
NYHA
New York Heart Association
OAC
Oral anticoagulation
OPS
"Operationsschlüssel"
PAD
Peripheral artery disease
PAI
Platelet aggregation inhibitor
PASS
post-authorization safety study
PhRMA
Pharmaceutical Research and Manufacturers Association
PVD
Peripheral vascular disease
PY
Patient year
PZN
"Pharmazentralnummer"
RAAS-i
Renin-angiotensin-aldosterone system inibitor
SU
Sulfonylureas
T2DM
Type-2 Diabetes Mellitus
TIA
Transient ischemic attack
VKA
Vitamin K antagonist

Boehringer Ingelheim
Page 7 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1245-0198
<document number>
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
3.
RESPONSIBLE PARTIES
Function
Name
Affiliation
Scientific Lead DPV
 
Scientific Lead DIVE
Project Consultant
Boehringer Ingelheim
Project Manager
Boehringer Ingelheim
Medical Project Member
Boehringer Ingelheim

Boehringer Ingelheim
Page 8 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1245-0198
<document number>
Proprietary confidential information © 2020 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:
Boehringer Ingelheim
Name of finished medicinal 
product:
Jardiance®, Synjardy®
Name of active ingredient:
Empagliflozin
Protocol date:
Study 
number:
Version/Revision:
Version/Revision 
date:
16 August 2019
1245-0198
1.0
Title of study:
Description of Treatment and Population Characteristics of Type 2 
Diabetic Patients in Germany receiving Empagliflozin: A retrospective 
Real-World Evidence (RWE) study based on German registries DPV & 
DIVE

Boehringer Ingelheim
Page 9 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1245-0198
<document number>
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
Rationale 
and 
background:
In the following years, new data for empagliflozin in type 2 diabetes 
(T2D) from clinical studies and PMO data will be limited. To gain a 
comprehensive picture of a drug´s (long-term) effectiveness, the medical 
community, payers and health politicians demand real-world evidence 
(RWE). 
In general, collaboration with a registry allows a continuous scientific 
exchange (e.g. scientific discussions and publications). RWE is also part 
of the basis for generating payer partnerships, e.g. managed-care projects.
Furthermore, the data can be used for value communication for payers and 
medical communities (e.g. via digital channels). In addition, AMNOG 
price negotiations could be supported by such data. 
Therefore, we plan to perform a retrospective, non-interventional study on 
the real-life treatment and treatment-associated outcomes of German T2D 
patients receiving Empagliflozin. We will set up this study based on data 
from the two largest German registries (Diabetes-Patienten-Verlaufs-
dokumentation (DPV) & Diabetes Versorgungs-Evaluation (DIVE)) 
covering currently around 500,000 adult T2D patients in Germany. The 
number of SGLT2i patients in Germany is steadily increasing. 
In this study, only Empagliflozin patients will be analyzed. They will be 
divided in three consecutive cohorts to assess potential differences over 
time.
Research 
question and 
objectives:
Description of the real-life treatment of adult patients with T2DM 
receiving empagliflozin, comparing the characteristics of patients starting 
empagliflozin in three time intervals:
- The first analysis will include the patients receiving Empagliflozin 
before the EMPA-REG-OUTCOME study was published (time until 
mid-Sept. 2015; “Cohort 1”).
- The second analysis will include patients receiving Empagliflozin 
starting from the EMPA-REG-OUTCOME study being published until 
CV Label Change (time from mid-Sept. 2015-mid-Jan. 2017; “Cohort 
2”). 
- The third analysis will include all patients receiving Empagliflozin 
starting from mid-Jan. 2017 until last available data cut (“Cohort 3").
Study design:
Retrospective non-interventional cross-sectional study using real-world 
data from German patient registries. Data will be provided by the largest 
German T2D patient registries DPV& DIVE covering more than 500,000 
patients.
Population:
Inclusion criteria:

Adult patients with at least two outpatient T2DM diagnoses (ICD 
E11.-) in two different quarters and/or at least one inpatient T2DM 
diagnosis (ICD E11.-) – AND –

At least one prescription of an empagliflozin-containing antidiabetic 
drug: 
Jardiance®
(Empagliflozin, 
ATC 
A10BK03, 
former 

Boehringer Ingelheim
Page 10 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1245-0198
<document number>
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
A10BX12) 
or 
Synjardy®
(Empagliflozin/Metformin, 
ATC 
A10BD20)
Exclusion criteria

Any diagnosis of T1DM.

Boehringer Ingelheim
Page 11 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1245-0198
<document number>
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
Variables:
For all three cohorts receiving empagliflozin, the baseline values of the 
following variables will be assessed:

Age (<65; 65 – <75; 75 – 80 , >80)

Gender

Weight [kg]

Height [cm]

HbA1c [% or mmol/ mol], FPG (available in subgroup only)

Previous occurrence of
o
Typical CV comorbidities:

MI

Stroke

CAD

PAD

CHF (form (HFrEF/ HFpEF)
o
Other typical diabetes complications

Neuropathy

Nephropathy / Renal function (eGFR, micro-/
macroalbuminuria)

Diabetic foot syndrome

Retinopathy (background and proliferative)

Antidiabetic and cardiovascular co-medication (lipid-lowering
agents, RAAS blockers, other antihypertensives, beta blockers,
diuretics, antiplatelets and anticoagulants )

Duration of diabetes (time since diagnosis)

Previous glucose-lowering treatment

Dosage of empagliflozin (10mg vs 25mg) (available in subgroup
only)

Participation in Disease Management Programme (DMP) Type 2
Diabetes (from DPV registry)

Hospitalizations (from DPV registry)
Data sources:
Data will be provided by the largest German T2D patient registries DPV& 
DIVE covering more than 500,000 patients. 
The aim of the DPV initiative is to improve treatment outcomes in 
individuals with diabetes through standardized documentation and 
objective comparison of quality indicators as well as through multi-centre 
outcome research. Up to date, there are more than 400 centres 
participating in the initiative predominantly from Germany and from 
Austria.
DIVE is a national initiative for quality management of diabetes care. The 
aim is to transfer the already existing initiatives and software systems 
which collect patient-related data to a national diabetes registry. The DIVE 
registry is one of the biggest, most updated diabetes registries in Germany 
and part of the current development of a national diabetes registry. It is 
part of the first and second registry conference held by German Federal 
Ministry of Health (BMG) and Robert-Koch Institute (RKI).

Boehringer Ingelheim
Page 12 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1245-0198
<document number>
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
Study size:
There will be about 7,900 patients on Empagliflozin included in the 
analysis.
Data 
analysis:
Variables will be assessed in half-yearly periods after index date (date of 
first prescription of empagliflozin), for total study population and 
separated by study cohort.
Anonymized data from the DIVE and the DPV registries will be 
combined; nonparametric descriptive analyses will be used. Group 
comparison will be based on Wilcoxon rank sum test (continuous 
variables) and X²-test for binary/categorial values. Analysis will be 
implemented using SAS 9.4. Complete case analysis will be used.
Analysis will be done by an experienced biostatistician with detailed 
knowledge of the DIVE and the DPV registries. A second independent 
programmer will check the generated SAS code for inconsistencies. The 
medical team (
 
 
 will evaluate the results from a clinical background to ensure 
plausibility.
Quality assurance and control will be the responsibility of the medical 
team (
 
 
Milestones:

Project kick-off: 09 November 2018

Draft of study protocol: 5 July 2019

Final study protocol & approval by: 31 August 2019

Start of data access/data validation: 01 September 2019

End of data analysis by: 31 October 2019

Final report of study results by: 31 December 2019

Finalization of publication draft by: 31 December 2019

Boehringer Ingelheim
Page 13 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1245-0198
<document number>
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
5.
AMENDMENTS AND UPDATES
None.

Boehringer Ingelheim
Page 14 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1245-0198
<document number>
Proprietary confidential information © 2020 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

Boehringer Ingelheim
Page 15 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1245-0198
<document number>
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
7.
RATIONALE AND BACKGROUND
In the following years, new data for empagliflozin in type 2 diabetes (T2D) from clinical 
studies and PMO data will be limited. To gain a comprehensive picture of a drug´s (long-
term) effectiveness, the medical community, payers and health politicians demand real-world 
evidence (RWE). 
In general, collaboration with a registry allows a continuous scientific exchange (e.g. 
scientific discussions and publications). RWE is also part of the basis for generating payer 
partnerships, e.g. managed-care projects. Furthermore, the data can be used for value 
communication for payers and medical communities (e.g. via digital channels). In addition, 
AMNOG price negotiations could be supported by such data. 
Therefore, we plan to perform a retrospective, non-interventional study on the real-life 
treatment and treatment-associated outcomes of German T2D patients receiving Empa-
gliflozin. We will set up this study based on data from the two largest German registries (Dia-
betes-Patienten-Verlaufsdokumentation (DPV) & Diabetes Versorgungs-Evaluation (DIVE)) 
covering currently around 500,000 adult T2D patients in Germany. The number of SGLT2i 
patients in Germany is steadily increasing. 
In this study, only Empagliflozin patients will be analyzed. They will be divided in three 
consecutive cohorts to assess potential differences over time.

Boehringer Ingelheim
Page 16 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1245-0198
<document number>
Proprietary confidential information © 2020 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
Description of the real-life treatment of adult patients with T2DM receiving empagliflozin, 
comparing the characteristics of patients starting Empagliflozin in three time intervals:
-
The first analysis will include the patients receiving Empagliflozin before the EMPA-
REG-OUTCOME study was published (time until mid-Sept. 2015; “Cohort 1”).
-
The second analysis will include patients receiving Empagliflozin starting from the 
EMPA-REG-OUTCOME study being published until CV Label Change (time from 
mid-Sept. 2015-mid-Jan. 2017; “Cohort 2”).
-
The third analysis will include all patients receiving Empagliflozin starting from mid-
Jan. 2017 (“Cohort 3") until last available data cut.

Boehringer Ingelheim
Page 17 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1245-0198
<document number>
Proprietary confidential information © 2020 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
Retrospective non-interventional cross-sectional study using real-world data from German 
patient registries. Data will be provided by the largest German T2D patient registries DPV& 
DIVE covering more than 500,000 patients. An anonymized dataset will be delivered by 
DIVE and DPV, respectively. The two datasets will then be combined.
9.2
SETTING AND INCLUSION/EXCLUSION CRITERIA
Description of the real-life treatment of adult patients with T2DM receiving empagliflozin, 
comparing the characteristics of patients starting empagliflozin in three time intervals:

The first analysis will include the patients receiving Empagliflozin before the EMPA-
REG-OUTCOME study was published (time until mid-Sept. 2015; “Cohort 1”).

The second analysis will include patients receiving Empagliflozin starting from the 
EMPA-REG-OUTCOME study being published until CV Label Change (time from 
mid-Sept. 2015-mid-Jan. 2017; “Cohort 2”). 

The third analysis will include all patients receiving Empagliflozin starting from mid-
Jan. 2017 until last available data cut (“Cohort 3").
Inclusion criteria:

At least two outpatient T2DM diagnoses (ICD E11.-) in two different quarters and/or 
at least one inpatient T2DM diagnosis (ICD E11.-)

At least one prescription of an empagliflozin-containing antidiabetic drug: 
Jardiance® (Empagliflozin, ATC A10BK03, former A10BX12) or Synjardy®
(Empagliflozin/ Metformin, ATC A10BD20)
Exclusion criteria

Any diagnosis of T1DM
9.3
VARIABLES
9.3.1
Outcomes
For all three cohorts receiving empagliflozin, the following variables will be assessed:
9.3.1.1
Primary outcomes

Previous occurrence (percentages) of
o
Typical CV comorbidities:

MI

Stroke

CAD

PAD

CHF (form (HFrEF/ HFpEF)

Boehringer Ingelheim
Page 18 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1245-0198
<document number>
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
o
Other typical diabetes complications:

Neuropathy

Nephropathy / Renal function (eGFR, micro-/ macroalbuminuria)

Diabetic foot syndrome

Retinopathy (background and proliferative)

Antidiabetic and cardiovascular co-medication (lipid-lowering agents, RAAS
blockers, other antihypertensives, beta blockers, diuretics, antiplatelets and
anticoagulants )
9.3.1.2
Secondary outcomes

Age (<65; 65 – <75; 75 – 80 , >80)

Gender

Weight [kg]

Height [cm]

HbA1c [% or mmol/ mol], FPG (available in subgroup only)

Duration of diabetes (time since diagnosis)

Previous glucose-lowering treatment

Dosage of empagliflozin (10mg vs 25mg) (available in subgroup only)

Participation in Disease Management Programme (DMP) Type 2 Diabetes (from DPV
registry)

Hospitalizations (from DPV registry)
9.4
DATA SOURCES
Data will be provided by the largest German T2D patient registries DPV& DIVE covering 
more than 500,000 patients. 
The aim of the DPV initiative is to improve treatment outcomes in individuals with diabetes 
through standardized documentation and objective comparison of quality indicators as well as 
through multi-centre outcome research. Up to date, there are more than 400 centres 
participating in the initiative predominantly from Germany and from Austria.
DIVE is a national initiative for quality management of diabetes care. The aim is to transfer 
the already existing initiatives and software systems which collect patient-related data to a 
national diabetes registry. The DIVE registry is one of the biggest, most updated diabetes 
registries in Germany and part of the current development of a national diabetes registry. It is 
part of the first and second registry conference held by German Federal Ministry of 
Health (BMG) and Robert-Koch Institute (RKI).
9.5 
STUDY SIZE
There will be about 7,900 patients on Empagliflozin included in the analysis.

Boehringer Ingelheim
Page 19 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1245-0198
<document number>
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
9.6
DATA MAIN MANAGEMENT
The medical team (
 
 
will be responsible for data management, including quality checking of the data. It is pointed 
out that no individual patient data will be used in this study and that data will only be 
presented in aggregated form.
9.7
DATA ANALYSIS
9.7.1
Main analysis
Variables will be assessed in half-yearly periods after index date (date of first prescription of 
empagliflozin), for total study population and separated by study cohort.
Anonymized data from the DIVE and the DPV registries will be combined; nonparametric 
descriptive analyses will be used. Group comparison will be based on Wilcoxon rank sum 
test (continuous variables) and X²-test for binary/categorial values. Analysis will be 
implemented using SAS 9.4. Complete case analysis will be used.
Analysis will be done by an experienced biostatistician with detailed knowledge of the DIVE 
and the DPV registries. A second independent programmer will check the generated SAS 
code for inconsistencies. The medical team (
 
 
 will evaluate the results from a clinical background to ensure 
plausibility.
Quality assurance and control will be the responsibility of the medical team (
 
9.7.2
Missing data
In general, imputation of missing data will not be applied. In addition to that, no “Last 
observation carried forward” (LOCF) approach will be applied. 
Implausible values will be set to missing values, as no correcting of values is possible due to 
the nature of the dataset. The defined lower and upper bounds for an acceptable range of 
continuous study variables are listed in Table 1; note that these ranges are defined with 
regards to obvious documentation mistakes.
Table 1: Lower and upper bounds for continuous study variables
Variable
Unit
Acceptable range
Age
Years
40 to 110
Prescriptions of CV or AD drugs per patient year
Number
1 to 300
In case of missing data for specific variables, reporting category “not reported/not available” 
will be used.

Boehringer Ingelheim
Page 20 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1245-0198
<document number>
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
9.8
QUALITY CONTROL
Analysis will be done by an experienced biostatistician with detailed knowledge of the DIVE 
and the DPV registries. A second independent programmer will check the generated SAS 
code for inconsistencies. The medical team (
 
 will evaluate the results from a clinical background to ensure 
plausibility/validity.
Study design and study conduct will be in line with legal and regulatory requirements, as well 
as with scientific purpose, value and rigor and follow generally accepted research practices 
such as Good Pharmacoepidemiology Practices (GPP) issued by the International Society for 
Pharmacoepidemiology (ISPE), the International Society for Pharmacoeconomics and 
Outcomes Research (ISPOR) guidelines, Pharmaceutical Research and Manufacturers 
Association (PhRMA) guidelines and similar rules.
9.9
LIMITATIONS OF THE RESEARCH METHODS
DPV & DIVE data are observational data; treatment, especially the use of Empagliflozin, is 
not randomized to the patients. This has to be kept in mind for the interpretation of the 
results. Also, a systematic difference (bias) between patients documented in the registry 
versus patients treated at facilities not participating in either of the registries cannot be
entirely excluded.
9.10
SUBJECTS
All patients with T2DM from the DPV & DIVE registries receiving Empagliflozin will be 
included. The patients will be divided in three cohorts based on the time point of 
Empagliflozin treatment start to better identify the differences between these cohorts.
9.11
BIAS
DPV & DIVE data are observational data; treatment, especially the use of Empagliflozin, is 
not randomized to the patients. This has to be kept in mind for the interpretation of the 
results. Also, a systematic difference (bias) between patients documented in the registry 
versus patients treated at facilities not participating in either of the registries cannot be 
entirely excluded.

Boehringer Ingelheim
Page 21 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1245-0198
<document number>
Proprietary confidential information © 2020 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
In this study, only anonymized data will be analyzed.
10.1
PRINCIPLES OF GOOD RESEARCH PRACTICE
The guidelines of Good Clinical Practice developed by the International Council for 
Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH-GCP 
guidelines) will be followed whenever applicable.
10.2
PATIENT INFORMATION AND CONSENT
No informed consent is needed due to the exclusive use of anonymized data.
10.3
INDEPENDENT ETHICS COMMITTEE (IEC)
Not applicable for this analysis. However, the registries have been approved by the respective 
local ethics commission (
 for DIVE and 
 for DPV).
10.4
CONFIDENTIALITY
BI as well as all investigators ensure adherence to applicable data privacy protection 
regulation. Data are transferred in anonymized form only. The entire documentation made 
available to BI does not contain any data which, on its own account or in conjunction with 
other freely available data, can be used to re-identify natural persons. 
Study findings stored on a computer will be stored in accordance with local data protection 
laws.

Boehringer Ingelheim
Page 22 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1245-0198
<document number>
Proprietary confidential information © 2020 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
Not applicable based on secondary use of data without any potential that any employee of BI 
or agent working on behalf of BI will access individually identifiable patient data.

Boehringer Ingelheim
Page 23 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1245-0198
<document number>
Proprietary confidential information © 2020 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 this study shall be published. 
 
 
 Current guidelines and 
recommendation on good publication practice will be followed (e.g. GPP2 Guidelines [1],
STROBE [2]). 

Boehringer Ingelheim
Page 24 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1245-0198
<document number>
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
REFERENCES
1. Graf C, Battisti WP, Bridges D, Bruce-Winkler V, Conaty JM, Ellison JM, Field EA, 
Gurr JA, Marx M-E, Patel M, Sanes-Miller C, Yarker YE: Research Methods & 
Reporting. Good publication practice for communicating company sponsored medical 
research: the GPP2 guidelines. BMJ (Clinical research ed.) 2009;339:b4330.
2. Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP: 
Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) 
statement: guidelines for reporting observational studies. BMJ (Clinical research ed.) 
2007;335:806–808

Boehringer Ingelheim
Page 25 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1245-0198
<document number>
Proprietary confidential information © 2020 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
Documents listed in Annex 1 can be maintained separately from the study protocol. They 
should be clearly identifiable and provided on request. Write “None” if there is no document 
or list documents in a table as indicated below.
None.

Boehringer Ingelheim
Page 26 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1245-0198
<document number>
Proprietary confidential information © 2020 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
Doc.Ref. EMA/540136/2009 
ENCePP Checklist for Study Protocols (Revision 3)
Adopted by the ENCePP Steering Group on 01/07/2016
The European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP)
welcomes innovative designs and new methods of research. This Checklist has been developed by 
ENCePP to stimulate consideration of important principles when designing and writing a 
pharmacoepidemiological or pharmacovigilance study protocol. The Checklist is intended to 
promote the quality of such studies, not their uniformity. The user is also referred to the ENCePP 
Guide on Methodological Standards in Pharmacoepidemiology, which reviews and gives direct 
electronic access to guidance for research in pharmacoepidemiology and pharmacovigilance.
For each question of the Checklist, the investigator should indicate whether or not it has been 
addressed in the study protocol. If the answer is “Yes”, the section number of the protocol where 
this issue has been discussed should be specified. It is possible that some questions do not apply 
to a particular study (for example, in the case of an innovative study design). In this case, the 
answer ‘N/A’ (Not Applicable) can be checked and the “Comments” field included for each section 
should be used to explain why. The “Comments” field can also be used to elaborate on a “No” 
answer. 
This Checklist should be included as an Annex by marketing authorisation holders when submitting 
the protocol of a non-interventional post-authorisation safety study (PASS) to a regulatory 
authority (see the Guidance on the format and content of the protocol of non-interventional post-
authorisation safety studies). The Checklist is a supporting document and does not replace the 
format of the protocol for PASS as recommended in the Guidance and Module VIII of the Good 
pharmacovigilance practices (GVP).
Study title: Description of Treatment and Population Characteristics of Type 2 Diabetic 
Patients in Germany receiving Empagliflozin: A retrospective Real-World Evidence 
(RWE) study based on German registries DPV & DIVE
Study reference number: 1245-0198
European Network of Centres for 
Pharmacoepidemiology and 
Pharmacovigilance

Boehringer Ingelheim
Page 27 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1245-0198
<document number>
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
Section 1: Milestones
Yes
No
N/A
Section
Number
1.1
Does the protocol specify timelines for 
1.1.1 Start of data collection1
6
1.1.2 End of data collection2
6
1.1.3 Study progress report(s)
–
1.1.4 Interim progress report(s)
–
1.1.5 Registration in the EU PAS register
–
1.1.6 Final report of study results.
6
Comments:
Section 2: Research question
Yes
No
N/
A
Section
Number
2.1
Does the formulation of the research question 
and objectives clearly explain: 
8
2.1.1 Why the study is conducted? (e.g. to address 
an important public health concern, a risk identified in 
the risk management plan, an emerging safety issue)
7
2.1.2 The objective(s) of the study?
8
2.1.3 The target population? (i.e. population or 
subgroup to whom the study results are intended to be 
generalised)
9.2
2.1.4 Which hypothesis(-es) is (are) to be 
tested?
–
2.1.5 If applicable, that there is no a priori
hypothesis?
7
Comments:
Section 3: Study design
Yes
No
N/
A
Section 
Number
3.1
Is the study design described? (e.g. cohort, case-
control, cross-sectional, new or alternative design) 
9.1
3.2
Does the protocol specify whether the study is 
based on primary, secondary or combined data 
collection?
9.1
3.3
Does the protocol specify measures of 
occurrence? (e.g. incidence rate, absolute risk)
9.7
                                                
1 Date from which information on the first study is first recorded in the study dataset or, in the case of 
secondary use of data, the date from which data extraction starts.
2 Date from which the analytical dataset is completely available.

Boehringer Ingelheim
Page 28 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1245-0198
<document number>
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
Section 3: Study design
Yes
No
N/
A
Section 
Number
3.4
Does the protocol specify measure(s) of 
association? (e.g. relative risk, odds ratio, excess risk, 
incidence rate ratio, hazard ratio, number needed to harm 
(NNH) per year)
9.7
3.5
Does the protocol describe the approach for the 
collection and reporting of adverse 
events/adverse reactions? (e.g. adverse events that 
will not be collected in case of primary data collection)
(11)
Comments:
Section 4: Source and study populations
Yes
No
N/A
Section 
Number
4.1
Is the source population described?
9.4
4.2
Is the planned study population defined in terms 
of:
9.2
4.2.1 Study time period?
9.2
4.2.2 Age and sex?
9.2
4.2.3 Country of origin?
9.2
4.2.4 Disease/indication?
9.2
4.2.5 Duration of follow-up?
9.2
4.3
Does the protocol define how the study 
population will be sampled from the source 
population? (e.g. event or inclusion/exclusion criteria)
9.2
Comments:
Section 5: Exposure definition and measurement
Yes
No
N/
A
Section
Number
5.1
Does the protocol describe how the study 
exposure is defined and measured? 
(e.g. operational details for defining and categorizing 
exposure, measurement of dose and duration of drug 
exposure)
–
5.2
Does the protocol address the validity of the 
exposure measurement? (e.g. precision, accuracy, use 
of validation sub-study)
–
5.3
Is exposure classified according to time 
windows? (e.g. current user, former user, non-use)
–
5.4
Is exposure classified based on biological 
mechanism of action and taking into account the 
pharmacokinetics and pharmacodynamics of the 
drug?
–

Boehringer Ingelheim
Page 29 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1245-0198
<document number>
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
Comments:
As this is a cross-sectional study, there will be no follow-up period and thus no exposure
measurement. A patient will be included after the first available record of drug use.
Section 6: Outcome definition and measurement
Yes
No
N/
A
Section 
Number
6.1
Does the protocol specify the primary and 
secondary (if applicable) outcome(s) to be 
investigated?
9.3
6.2
Does the protocol describe how the outcomes
are defined and measured? 
9.3
6.3
Does the protocol address the validity of 
outcome measurement? (e.g. precision, accuracy, 
sensitivity, specificity, positive predictive value, prospective 
or retrospective ascertainment, use of validation sub-study)
9.8
6.4
Does the protocol describe specific endpoints 
relevant for Health Technology Assessment? 
(e.g. HrQoL, QALYs, DALYS, health care services utilization, 
burden of disease, disease management)
9.3
Comments:
Section 7: Bias
Yes
No
N/
A
Section
Number
7.1
Does the protocol describe how confounding will 
be addressed in the study?
7.1.1. Does the protocol address confounding by 
indication if applicable?
–
7.2
Does the protocol address:
7.2.1. Selection biases (e.g. healthy user bias)
7.2.2. Information biases (e.g. misclassification of 
exposure and endpoints, time-related bias)
7.3
Does the protocol address the validity of the 
study covariates?
Comments:
Section 8: Effect modification
Yes
No
N/
A
Section
Number
8.1
Does the protocol address effect modifiers?
(e.g. collection of data on known effect modifiers, sub-group 
analyses, anticipated direction of effect) 
Comments:

Boehringer Ingelheim
Page 30 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1245-0198
<document number>
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
Section 9: Data sources
Yes
No
N/A
Section 
Number
9.1
Does the protocol describe the data source(s) 
used in the study for the ascertainment of:
9.1.1 Exposure? (e.g. pharmacy dispensing, general 
practice prescribing, claims data, self-report, face-to-face 
interview)
9.1.2 Outcomes? (e.g. clinical records, laboratory 
markers or values, claims data, self-report, patient 
interview including scales and questionnaires, vital 
statistics)
9.1.3 Covariates?
9.2
Does the protocol describe the information 
available from the data source(s) on:
9.2.1 Exposure? (e.g. date of dispensing, drug quantity, 
dose, number of days of supply prescription, daily 
dosage, prescriber)
9.2.2 Outcomes? (e.g. date of occurrence, multiple 
event, severity measures related to event)
9.2.3 Covariates? (e.g. age, sex, clinical and drug use 
history, co-morbidity, co-medications, lifestyle)
9.3
Is a coding system described for: 
9.3.1 Exposure? (e.g. WHO Drug Dictionary, Anatomical 
Therapeutic Chemical (ATC) Classification System)
9.3.2 Outcomes? (e.g. International Classification of 
Diseases (ICD)-10, Medical Dictionary for Regulatory 
Activities (MedDRA))
9.3.3 Covariates?
9.4
Is a linkage method between data sources
described? (e.g. based on a unique identifier or other)
–
Comments:
Section 10: Analysis plan
Yes
No
N/
A
Section
Number
10.1 Is the choice of statistical techniques described? 
9.7
10.2 Are descriptive analyses included?
9.7.1
10.3 Are stratified analyses included?
9.7.1
10.4 Does the plan describe methods for adjusting for 
confounding?
9.8
10.5 Does the plan describe methods for handling 
missing data?
9.7.2
10.6 Is sample size and/or statistical power 
estimated?
Comments:

Boehringer Ingelheim
Page 31 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1245-0198
<document number>
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
Section 11: Data management and quality 
control
Yes
No
N/
A
Section
Number
11.1 Does the protocol provide information on data 
storage? (e.g. software and IT environment, database 
maintenance and anti-fraud protection, archiving)
9.6
11.2 Are methods of quality assurance described?
9.8
11.3 Is there a system in place for independent 
review of study results? 
9.8
Comments:
Section 12: Limitations
Yes
No
N/
A
Section 
Number
12.1 Does the protocol discuss the impact on the 
study results of:
12.1.1 Selection bias?
9.11
12.1.2 Information bias?
9.9
12.1.3 Residual/unmeasured confounding?
(e.g. anticipated direction and magnitude of such biases, 
validation sub-study, use of validation and external data, 
analytical methods)
12.2 Does the protocol discuss study feasibility?
(e.g. study size, anticipated exposure, duration of follow-up 
in a cohort study, patient recruitment)
9.5
Comments:
Section 13: Ethical issues
Yes
No
N/
A
Section 
Number
13.1 Have requirements of Ethics Committee/ 
Institutional Review Board been described?
10.3
13.2 Has any outcome of an ethical review procedure 
been addressed?
–
13.3 Have data protection requirements been
described?
10
Comments:
Section 14: Amendments and deviations
Yes
No
N/
A
Section
Number
14.1 Does the protocol include a section to document 
amendments and deviations? 
–
Comments:

Boehringer Ingelheim
Page 32 of 32
Protocol for non-interventional studies based on existing data
BI Study Number 1245-0198
<document number>
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
Section 15: Plans for communication of study 
results
Yes
No
N/
A
Section
Number
15.1 Are plans described for communicating study 
results (e.g. to regulatory authorities)?
12
15.2 Are plans described for disseminating study 
results externally, including publication?
12
Comments:
Name of the main author of the 
protocol:
Date: 8/12/2020
Signature: