CORDIALLY® - CEE: Characteristics of Patients With Type 2 Diabetes Treated With Modern Antidiabetic Drugs. A Real World Data Collection of Patient Baseline Characteristics, Treatment Patterns and Comorbidities in Central Eastern European (CEE) Countries
Conditions: Diabetes Mellitus, Type 2
Sponsor: Boehringer Ingelheim

ABCD 
001-MCS-90-124_RD-01(4.0) 
Protocol for non-interventional studies based on existing data 
TITLE PAGE 
Document Number: 
c24436488-02 
BI Study Number: 
1245-0187 
BI Investigational 
Product(s): 
Jardiance® Synjardy® Trajenta® Jentadueto® 
Title: 
CORDIALLY® - CEE: Characteristics of patients with Type 2 Diabetes 
treated with modern antidiabetic drugs.  
A real-world data collection of patient baseline characteristics, treatment 
patterns and comorbidities in Central Eastern European (CEE) countries  
Protocol version identifier: 
2.0 
Date of last version of 
protocol: 
12 Dec 2018 
PASS: 
No 
EU PAS register number: 
EUPAS28505 
Clinicaltrials.gov number: NCT03807440 
Active substance: 
empagliflozin (ATC: A10BK03) 
linagliptin (ATC: A10BH05)  
Medicinal product: 
Jardiance® 10mg empagliflozin oral tablet 
Jardiance® 25mg empagliflozin oral tablet 
Synjardy® 5 mg empagliflozin 850 mg metformin oral tablets 
Synjardy® 5 mg empagliflozin 1,000 mg metformin oral tablets 
Synjardy® 12.5 mg empagliflozin 850 mg metformin oral tablets 
Synjardy® 12.5 mg empagliflozin 1,000 mg metformin oral tablets 
Trajenta® 5mg linagliptin oral tablet 
Jentadueto® 2,5mg linagliptin / 850 mg metformin oral tablet 
Jentadueto® 2,5mg linagliptin / 1000 mg metformin oral tablet 
Product reference: 
Jardiance EMEA/H/C/2677 
Synjardy EMEA/H/C/3770 
Trajenta EMEA/H/C/707 
Jentadueto EMEA/H/C/2279 
Procedure number: 
n.a. 
Joint PASS: 
No 
Research question and 
objectives: 
1. To describe and compare T2D patients baseline characteristics when 
initiating either empagliflozin- or other SGLT2i, DPP4i or GLP1a on 
top of current antidiabetic treatment by different HCP specialties in 
CEE countries  
2. To describe the burden of comorbidities (prevalence of CVD, CKD) 
and CVD/CKD risk factors in this T2D patient population at index date 
1 
3. To describe and compare the actual treatment at study index date 1 
in patients with and without established CVD 
Established CV disease defined as acute myocardial infarction (AMI), 
cardiology intervention, ischemic heart disease (IHD), congestive heart 
failure (CHF), peripheral arterial disease (PAD), or stroke. 

 
 
 
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4. To describe the association of socioeconomic parameters with 
treatment decisions at index date 1 
5. To assess the discontinuation rate, reasons for discontinuation and 
average duration of treatment for GLP1a, DPP4i and SGLT2i after a 
follow up of approximately one year from the initial time point (= 
index date 2) 
Country(-ies) of study: 
Bulgaria, Czech Republic, Hungary, Poland, Serbia, Slovenia, Russia 
Author:  
 
Marketing authorisation 
holder(s): 
MAH: 
This study is initiated, managed and sponsored by: 
In case of PASS, add: 
<EU-QPPV:> 
n.a. 
In case of PASS, add: 
<Signature of EU-
QPPV:> 
n.a. 
Date: 
11 May  2020 
 
Page 1 of 49 
 
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© 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights 
reserved. 
This document may not – in full or in part – be passed on, reproduced, published or otherwise used 
without prior written permission 
 
 
 

 
 
 
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1. 
TABLE OF CONTENTS 
TITLE PAGE .................................................................................................................. 1 
1. 
TABLE OF CONTENTS ....................................................................................... 3 
2. 
LIST OF ABBREVIATIONS ................................................................................ 5 
3. 
RESPONSIBLE PARTIES .................................................................................... 6 
4. 
ABSTRACT ........................................................................................................... 7 
5. 
AMENDMENTS AND UPDATES ..................................................................... 11 
6. 
MILESTONES ..................................................................................................... 12 
7. 
RATIONALE AND BACKGROUND ................................................................ 13 
8. 
RESEARCH QUESTION AND OBJECTIVES ................................................. 14 
8.1 
RATIONALE FOR PERFORMING THE STUDY ....................................... 14 
8.2 
STUDY OBJECTIVES ................................................................................... 15 
9. 
RESEARCH METHODS .................................................................................... 16 
9.1 
STUDY DESIGN ............................................................................................ 16 
9.2 
SETTING ........................................................................................................ 18 
9.2.1 
Inclusion criteria ...................................................................................... 18 
9.2.2 
Exclusion criteria ..................................................................................... 19 
9.3 
VARIABLES .................................................................................................. 19 
9.3.1 
Exposures ................................................................................................ 19 
9.3.2 
Outcomes ................................................................................................. 20 
9.3.3 
Covariates ................................................................................................ 23 
9.4 
DATA SOURCES ........................................................................................... 23 
9.5 
STUDY SIZE .................................................................................................. 24 
9.6 
DATA MANAGEMENT ................................................................................ 24 
9.7 
DATA ANALYSIS ......................................................................................... 25 
9.7.1 
Planned analyses ..................................................................................... 25 
9.7.2 
Handling of missing data ......................................................................... 26 
9.8 
QUALITY CONTROL ................................................................................... 26 
9.9 
LIMITATIONS OF THE RESEARCH METHODS ...................................... 26 
9.10 
OTHER ASPECTS ......................................................................................... 27 
9.10.1 
Informed Consent, Data Protection, Study Records ............................... 27 
9.10.2 
Study Approval, Patient Information, and Informed Consent ................ 27 
9.10.2.1 
Data Quality Assurance .................................................................. 28 

 
 
 
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9.10.2.2 
Records ........................................................................................... 28 
9.10.2.2.1 Source documents ........................................................................... 28 
9.10.2.2.2 Direct access to source data and documents ................................... 29 
9.10.2.3 
Statement of Confidentiality ........................................................... 29 
9.10.2.4 
Completion of Study ....................................................................... 29 
9.10.2.5 
Protocol Violations ......................................................................... 29 
9.11 
SUBJECTS ...................................................................................................... 30 
9.11.1 
Cases ........................................................................................................ 30 
9.11.2 
Controls ................................................................................................... 30 
9.12 
BIAS  .............................................................................................................. 30 
10. 
PROTECTION OF HUMAN SUBJECTS .......................................................... 32 
11. 
MANAGEMENT AND REPORTING OF ADVERSE EVENTS & ADVERSE 
DRUG REACTIONS .......................................................................................... 33 
11.1 
DEFINITIONS OF ADVERSE EVENTS ...................................................... 33 
11.2 
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION AND 
REPORTING .................................................................................................. 34 
11.3 
REPORTING TO HEALTH AUTHORITIES................................................ 36 
12. 
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
 ............................................................................................................................. 37 
13. 
REFERENCES .................................................................................................... 38 
13.1 
PUBLISHED REFERENCES ......................................................................... 38 
13.2 
UNPUBLISHED REFERENCES ................................................................... 40 
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS .............................................. 41 
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .............................. 42 
ANNEX 3. ADDITIONAL INFORMATION .............................................................. 49 

 
 
 
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2. 
LIST OF ABBREVIATIONS 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AESI 
CEE 
CKD 
Adverse Event of Special Interest 
Central Eastern Europe 
Chronic Kidney Disease 
CML 
Local Clinical Monitor  
CRA 
Clinical Research Associate 
CVD 
CVOT 
Cardiovascular Disease 
Cardiovascular Outcomes Trial 
eCRF 
Electronic Case Report Form 
DMP 
Data Management Plan 
DPP4 
DPP4 i 
Dipeptidyl-peptidase 4 
Dipeptidyl-peptidase 4 inhibitor 
EU 
European Union 
FDC 
Fix Dose Combination 
GCP 
Good Clinical Practice 
GEP 
Good Epidemiological Practice 
GLP1 
GLP1 a 
Glucagon-like peptide 1 
Glucagon-like peptide 1 agonist 
GPP 
HCP 
HDL 
Good Pharmacoepidemiology Practice 
Health Care Provider 
High Density Lipoprotein 
IEC 
Independent Ethics Committee 
ISF 
LDL 
Investigator Site File 
Low Density Lipoprotein 
MedDRA 
Medical Dictionary for Drug Regulatory Activities 
mMRC 
Modified Medical Research Council Scale 
NIS 
Non-Interventional Study 
PGE 
Physician’s Global Evaluation 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
SGLT2i 
Standard deviation 
Sodium Glucose Transporter 2 inhibitor 
SmPC 
Summary of Product Characteristics 
T2D 
UACR 
Type 2 Diabetes 
Urine Albumin Creatinin Ratio 
WHO 
World Health Organisation 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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3. 
RESPONSIBLE PARTIES 
Medical 
 
 of Medical Affairs
Team Member Medical Affairs
(TM MA) 
 
Team Member Medicine (TMM) 
 
Trial Clinical Monitor (TCM) 
 
Coordinating Investigator (CI) 
associate 
 
/
 
 
 
 
 
 
 
 

 
 
 
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4. 
ABSTRACT  

 
 
 
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Name of company: 
 
 
Boehringer Ingelheim 
Name of finished medicinal product:  
Jardiance® Synjardy® Trajenta® 
Jentadueto® 
 
Name of active ingredient: 
empagliflozin 
linagliptin 
 
Protocol date: 
 
Study number: 
Version/Revision: 
Version/Revision date: 
12 Dec 2018 
1245.187 
Version 2.0/ Revision 1.0 
11 May 2020 
Title of study: 
CORDIALLY® - CEE: Characteristics of patients with Type 2 Diabetes treated 
with modern antidiabetic drugs.  
A real-world data collection of patient baseline characteristics, treatment 
patterns and comorbidities in Central Eastern European (CEE) countries 
Rationale and 
background: 
Cardiovascular Disease (CVD) is the most common cause of mortality in T2D 
patients. Also, chronic kidney disease (CKD) is associated with increased all-
cause mortality, which is substantially higher in patients with a diagnosis of 
diabetes. Registry outcomes imply that patient characteristics might differ 
between patients initiating empagliflozin or other glucose lowering drugs.  
Research question 
and objectives: 
The objective of CORDIALLY® - CEE is to get insights into T2D patient 
characteristics when initiating different types of T2D treatments, including 
associated comorbidities (CVD, CKD), concomitant medications and the 
association of socioeconomic factors with treatment decisions.  
1. To describe and compare T2D patients’ baseline characteristics when 
initiating either empagliflozin- or other SGLT2i, DPP4i or GLP1a by different 
HCP specialties in CEE countries  
2. To describe the prevalence of comorbidities (prevalence of CVD, CKD) at 
index date 1 in this T2D patient population  
3. To describe the actual treatment used at index date 1 in patients with and 
without established CVD. 
Established CV disease defined as acute myocardial infarction (AMI), 
cardiology intervention, ischemic heart disease (IHD), congestive heart failure 
(CHF), peripheral arterial disease (PAD), or stroke. 
4. To describe the association of socioeconomic parameters with treatment 
decisions at index date 1 
5. To assess the discontinuation rate, reasons for discontinuation and average 
duration of treatment for GLP1a, DPP4i and SGLT2i after a follow up of 
approximately one year from the initial time point (= index date 2) 
Study design: 
This is a non-interventional study using existing data including medical chart 
review.  
Population: 
Adult patients (18 years of age or older) with T2D diagnosis, naïve to treatment 
with empagliflozin or other SGLT2i, DPP4i or GLP1a at index date 1 

 
 
 
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Name of company: 
 
 
Boehringer Ingelheim 
Name of finished medicinal product:  
Jardiance® Synjardy® Trajenta® 
Jentadueto® 
 
Name of active ingredient: 
empagliflozin 
linagliptin 
 
Protocol date: 
 
Study number: 
Version/Revision: 
Version/Revision date: 
12 Dec 2018 
1245.187 
Version 2.0/ Revision 1.0 
11 May 2020 
Variables: 
1. 
Patient demographics (age, gender, height, weight, BMI, ethnicity) 
2. 
Time since diagnosis of Type 2 Diabetes 
3. 
Clinical parameters relevant for T2D, CVD, CKD assessment such as 
HbA1c, blood pressure as valid on index date 1 
4. 
Comorbidities like cardiovascular diseases and related risk factors such 
as smoking, overweight and Comorbidities like chronic kidney disease 
and related risk factors such as smoking, overweight at index date 1 
5. 
T2D medication the treating HCP newly prescribes at study index date 1 
6. 
Concomitant T2D medications at index date 1 
7. 
Concomitant CVD and CKD medications at index date 1 
8. 
Involvement of other HCPs in treatment decisions at study index date 1 
and study index date 2 
9. 
Relevant socioeconomic parameters such as employment status, family 
status, type of health insurance at index date 1 
10. 
Stop date and reason of therapy discontinuation at index date 2 
(approximately one year after index date 1) 
Data sources: 
Existing patient data (Medical chart review) previously collected by Health care 
professionals during routine documentation in patients treated for T2D in an 
endocrinologist, diabetologist or cardiologist office-based setting (nonhospital). 
Study size: 
Approximately 4000 patients from 7 countries (Bulgaria, Czech Republic, 
Hungary, Poland, Serbia, Slovenia, Russia) 

 
 
 
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Protocol for non-interventional studies based on existing data 
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Name of company: 
 
 
Boehringer Ingelheim 
Name of finished medicinal product:  
Jardiance® Synjardy® Trajenta® 
Jentadueto® 
 
Name of active ingredient: 
empagliflozin 
linagliptin 
 
Protocol date: 
 
Study number: 
Version/Revision: 
Version/Revision date: 
12 Dec 2018 
1245.187 
Version 2.0/ Revision 1.0 
11 May 2020 
Data analysis: 
Primary outcomes:  
T2D patients’ baseline characteristics when initiating either empagliflozin - or 
other SGLT2i, DPP4i or GLP1a on top of current antidiabetic treatment by 
different HCP specialties in CEE countries.  
Secondary outcomes:  
• 
Burden of comorbidities (prevalence of CVD, CKD and CVD/CKD 
risk factors) in this T2D patient population at index date 1 
• 
Actual treatment used at index date 1 in patients with and without 
established CVD (defined as acute myocardial infarction (AMI), 
cardiology intervention, ischemic heart disease (IHD), congestive heart 
failure (CHF), peripheral arterial disease (PAD), or stroke) 
• 
Discontinuation rate of actual treatment at index date 2, reasons for 
discontinuation and average duration of treatment for GLP1a, DPP4i 
and SGLT2i 
• 
The association of socioeconomic parameters with treatment decisions 
at index date 1 
All analyses will be descriptive. Baseline patient characteristics will be tabulated 
for different subgroups (i.e. according to medication (empagliflozin or other 
GLP1a or DPP4i or SGLT2i), country and physician speciality). Results will be 
presented as means, standard deviations, medians, minimum and maximum and 
interquartile range (IQR) for continuous variables and as counts and percentages 
for categorical variables. Subgroup analyses will be done using χ2-test or Fisher’s 
exact test for categorical variables and Willcoxon-Mann-Whitney test for 
continuous variables. 
Details regarding the statistical analysis will be specified within the statistical 
analysis plan. 
Milestones: 
Planned start of data collection: Q1 2019 
Planned end of data collection: Q1 2021 
Planned database clean (Hard lock): Q3 2021 
Planned final Report: Q4 2021 
 
 
 

 
 
 
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5. 
AMENDMENTS AND UPDATES 
Protocol v2.0, Amendment 1, 06 May 2020 
Number 
Section of study 
protocol 
Change 
Reason 
1 
Cover page, 
Abstract, Section 
8.2 
Inclusion of new objective 
Therapy duration and reasons for 
therapy discontinuation should be 
addressed by recording of data at a 2nd 
index date. This requires collection of 
new variables 
2 
Abstract, Section 
9.1, Section 9.3, 
Section 9.3.2, 
Section 9.7.1, 
Section 9.10.2.2.1 
- Inclusion of new variables 
- Defining of new secondary 
outcomes 
- Specification of parameters 
and variables to be collected at 
index date 2 
3 
Abstract, Section 6 
Change of milestones 
Time delay due to insertion of 
amendment 1 
4 
Section 8.1 
Inclusion of rationale for new 
objective 
To address rationale for new 
objectives 
5 
Section 9.1, Section 
9.2.1, Section 9.3.1, 
9.11.1, Section 9.12 
Extension of index date 1 from 
1 month to 4 months 
Due to change of milestones, index 
date 1 for eligible patients is extended, 
too. 
6 
Section 9.9 
Adapting to new objective 
Adapting to new study design 
7 
Section 9.10.2 
Adapting to new study design 
with 2 index dates 
8 
Section 11 
Completely revised according to 
usual BI wording 
Because of possible reporting of 
adverse drug reactions as reason for 
treatment discontinuation this section 
is completely adapted. 
 
All Sections 
Former ‘index date’ is changed 
to index date 1 
Introduction of a 2nd index date 
requires to specify former index date. 
 
 
 

 
 
 
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6. 
MILESTONES 
Milestone 
Planned Date 
Start of data collection 
Q3 2019 
End of data collection 
Q1 2021 
Final report of study results: 
Q4 2021 
 
 
 

 
 
 
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7. 
RATIONALE AND BACKGROUND 
Prevalence of diabetes is high with about 425 million of patients worldwide and it is expected 
that this number will increase to more than 630 million in 2040 (1). Diabetes related 
complications including micro- and macrovascular complications, which have huge impact on 
patients’ quality of life, as well as healthcare budgets.  
The most common cause of mortality in patients with type 2 diabetes (T2D) is cardiovascular 
disease (CVD), accounting for more than 50 % of deaths and causing an average reduction of 
life years in a 60 years old male of about 12 years when compared with the general population 
(1-4). T2D patients have a wide range of cardiovascular (CV) risk factors which not only 
increase CV mortality but also CV morbidity rates (5-13). Even if diabetes related CV 
complications have declined with improved standard of care, a substantial burden remains (14) 
and all-cause mortality is still high in this vulnerable population, significantly reducing life 
expectancy (3). Also, chronic kidney disease (CKD) is associated with increased all-cause 
mortality which is substantially higher in patients with a diabetes diagnosis. (15).  
 
While Cardiovascular outcomes Trials (CVOT) on DPP4 inhibitors just confirmed 
cardiovascular safety but did not provide significant CV benefits over placebo when added to 
standard of care, data from recent CVOTs with SGLT2 inhibitors and GLP1receptor agonists 
provided significant cardiovascular benefits (19). Empagliflozin in the EMPA-REG 
OUTCOME trial and liraglutide in the LEADER trial resulted in lower risk for CV and all-
cause mortality when compared with placebo added to standard of care in patients with T2D 
and established CV disease and/or CV risk factors (17, 18). The number of patients needed to 
treat to prevent one premature death was 98 patients for 3 years with liraglutide (18) and 39 
patients treated for 3 years with empagliflozin (17). Empagliflozin also reduced the risk of 
hospitalization for heart failure by 35% and was associated with slower progression of kidney 
disease and renal event rates (17). 
 
In international and numerous national guidelines for T2D treatment it is currently stated, that 
in patients with T2D and CVD, cardioprotective drug(s) should be included early in the 
treatment pattern (20). Also in the European Cardiology (ESC) guidelines it was stated that 
empagliflozin should be considered early in T2D patients in order to prevent or delay 
hospitalization for heart failure and prolong life (20, 21). 
  
 
 

 
 
 
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8. 
RESEARCH QUESTION AND OBJECTIVES 
8.1 
RATIONALE FOR PERFORMING THE STUDY  
Cardiovascular disease (CVD) is the most common cause of mortality in patients with type 2 
diabetes (T2D), accounting for more than 50 % of deaths and significantly reducing patients’ 
life expectancy. (1-4). Recent Diabetes and Cardiology guidelines have pointed out that 
modern antidiabetic drugs like empagliflozin and liraglutide should be used early in the 
treatment of T2D patients to reduce major adverse CV events and CV mortality (20, 21, 22).  
 
Recent data from Sweden demonstrate a prevalence of CVD in T2D patients as high as 34% 
(16), while comparable data from CEE countries which would allow raising the awareness on 
this health topic do not exist. An extrapolation from other European countries to this region, 
mainly dominated by low income countries with limited healthcare spending will not allow 
useful conclusions on drug utilization with innovative medications. 
 
In spite of these clear treatment recommendations (20, 21, 22), a recently published US real 
world study points out that a significant number of patients who would have met the criteria 
for treatment with drugs like empagliflozin or liraglutide, are not treated according to eligibility 
criteria (25). The real world use of these drugs based on the Diabetes Collaborative Registry 
(DCR) was low and these drugs were used mainly in the low-risk diabetes population in which 
the benefit of CV risk reduction is less likely to happen or was not studied (25). 
 
Knowing the characteristics of T2D patients initiating different treatment for their diabetes can 
lead to a better understanding for the prescription patterns with modern antidiabetic drugs.  
 
Due to the fact that Diabetes registries or other valid sources, which would allow monitoring 
of the quality of care in terms of risk factors and the potential complications of diabetes are not 
available in Central Eastern Europe, there is also a lack of information on patient profiles, 
receiving prescriptions for modern antidiabetic medications like sodium glucose transporter 2 
inhibitor (SGLT2i), dipeptidyl peptidase 4 inhibitor (DPP4i), glucagon like peptide 1 agonist 
(GLP1a).  
 
Knowledge on patient characteristics when treated with these drugs, their comorbidities, drug 
utilization in different HCP specialty groups as well as socioeconomic factors which could 
limit the use of these modern T2D medications have also not yet been evaluated in CEE. In 
addition, to learn more about the application of these medications in the real-world settings, 
status of their use over time, especially reasons for treatment discontinuation (if applicable), 
are of interest.  
 
To address these questions, medical charts of T2D patients from health care professionals 
(HCPs) of different specialties who can initiate innovative antidiabetic treatment in the office-
based setting (Endocrinologist, Diabetologist, Cardiologist) will be collected.  
 

 
 
 
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8.2 
STUDY OBJECTIVES 
The objective of the study is 
 
1. To describe and compare T2D patients’ baseline characteristics when initiating either 
empagliflozin - or other SGLT2i, DPP4i or GLP1a on top of current antidiabetic treatment 
by different HCP specialties in CEE countries  
2. To describe the prevalence of comorbidities (prevalence of CVD, CKD) in this T2D 
patient population at index date 1 
3. To describe and compare the actual treatment uses at index date 1 in patients with and 
without established CVD  
Established CV disease defined as acute myocardial infarction (AMI), cardiology 
intervention, ischemic heart disease (IHD), congestive heart failure (CHF), peripheral 
arterial disease (PAD), or stroke. 
4. To describe the association of socioeconomic parameters with treatment decisions at index 
date 1 
5. To assess the discontinuation rate, reasons for discontinuation and average duration of 
treatment for GLP1a, DPP4i and SGLT2i after a follow up of approximately one year from 
the initial timepoint (= index date 2) 
 
 

 
 
 
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9. 
RESEARCH METHODS 
9.1 
STUDY DESIGN 
This is a non-interventional study using existing data including medical chart review. The study 
will include all patients fulfilling the inclusion and not fulfilling the exclusion criteria in the 
period of 4 months (September – December 2018) (= index date 1). 
 
Parameter 
Assessed at 
study index 
date 1 
Written Informed Consent* 
X 
Inclusion / Exclusion Criteria 
X 
Patient demographics (age, gender, height, weight, BMI, ethnicity) 
X 
Time since diagnosis of Type 2 Diabetes 
X 
Clinical parameters relevant for T2D, CVD, CKD assessment  
x 
Comorbidities like cardiovascular diseases and related risk factors 
X 
Comorbidities like chronic kidney disease and related risk factors  
X 
T2D medication the treating physician newly prescribes at study index date 
X 
Concomitant T2D medications at study index date  
X 
Concomitant CVD and CKD medications at index date 
X 
Other HCPs involved in treatment decisions at study index date  
X 
Relevant socioeconomic parameters  
X 
* Patients who were enrolled before amendment 1 and who have consented to data collection at index date 1 have to consent 
to data collection at index date 2 separately. Newly enrolled patients have to give their consent for data collection at index 
date 1 and 2 before data transfer into eCRF. 
 
Approximately 1 year (± 2 months) after index date 1, parameters regarding status of newly 
initiated T2D treatment will be collected. 
 
Parameter 
Assessed at 
study index 
date 2 
Continuation / Discontinuation of T2D therapy initiated at index date 1 
X 
In case of discontinuation: stop date  
X 
In case of discontinuation: reason for discontinuation 
X 
In case of discontinuation: other HCPs involved in treatment decision 
X 
 

 
 
 
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An overview of study design is given in Figure 1. 
 
 
Figure 1: Overview of study design 

 
 
 
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9.2 
SETTING 
Data collection from approximately 4000 patients from up to 8 countries is planned. Site 
selection will be performed to reflect routine T2D care in the participating countries in order 
to secure representativeness of the T2D population. The following countries will participate in 
this non-interventional study: Bulgaria, Czech Republic, Hungary, Poland, Russia, Serbia, 
Slovenia. 
A log of all patients included into the study (i.e. having given informed consent) will be 
maintained in the Investigator Site File (ISF). 
Boehringer Ingelheim reserves the right to discontinue the study or to remove a patient at a 
particular study site for the following reasons: 
1. Failure to meet expected enrollment goals overall or at a particular study site.  
2. Emergence of any efficacy/safety information that could significantly affect continuation 
of the study, or any other administrative reasons, i.e. lack of recruitment.  
3. Violation of the protocol, the contract, or applicable laws and regulations for non-
interventional studies, which could disturb the appropriate conduct of the NIS. 
 
Site selection:  
 
Office based HCP of different medical specialties (endocrinologist, diabetologist or 
cardiologist) will be requested in order to check for feasibility prior to site selection. Amongst 
other criteria, sites will be eligible if HCPs have access and can prescribe at least 2 of the T2D 
drug classes of interest (SGLT2i, DPP4i and/or GLP1a). Sites will also be asked for the number 
of expected patients meeting inclusion/exclusion criteria in a given time window (1 month 
September 2018) by means of being newly initiated with empagliflozin or other SGLT2i, 
DPP4i or GLP1a in September 2018. In case that more than a representative number of sites 
which will be assessed during the feasibility, are signaling their willingness to participate in 
the study, the sites will be randomly selected. 
To get basic information into demographics for site distribution, data on physicians’ age, 
gender, office postal code will be collected. 
 
9.2.1 
Inclusion criteria 
Patients can be included if all of the following criteria are met: 
1. Written informed consent prior to participation 
2. Female and male patients age ≥ 18 years 
3. Patients with T2D diagnosis 
4. Patients who have been newly initiated (first ever use) with empagliflozin or other 
SGLT2i, DPP4i or GLP1a between September 2018 and December 2018 (study index 
date 1)  
5. Patients have been naïve to treatment with empagliflozin or other SGLT2i, DPP4i or 
GLP1a at study index date 1 
 

 
 
 
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9.2.2 
Exclusion criteria 
1. Patients age < 18 years 
2. Patients with diagnosis of other types of diabetes than T2D 
3. Patients who do not provide written consent to the terms of the study 
 
9.3 
VARIABLES 
The following parameters will be collected and assessed at study index date 1:  
 
1. Patient demographics (age, gender, height, weight, BMI, ethnicity)  
2. Time since diagnosis of Type 2 Diabetes 
3. Clinical parameters relevant for T2D, CVD, CKD assessment (see below) as valid on 
study index date 1 
4. Comorbidities like cardiovascular disease and related risk factors (see below) and 
Comorbidities like chronic kidney disease and related risk factors (see below) at study 
index date 1 
5. T2D medication the treating physician newly prescribes at study index date 1 
6. Concomitant T2D medications at study index date 1 
7. Concomitant CVD and CKD medications at index date 1 
8. Involvement of other HCPs in treatment decisions at study index date 1 
9. Relevant socioeconomic parameters (see below) at index date 1 
 
The following parameters will be collected and assessed at study index date 2 (= approximately 
one year ± 2 months after index date 1): 
 
1. Status of T2D medication (continuation / discontinuation) 
2. If discontinuation: 
a. stop date of initial(index date 1) T2D medication (if available) 
b. Reason for therapy discontinuation (see below) 
c. Involvement of other HCPs in decision for therapy discontinuation 
 
9.3.1 
Exposures 
Exposure to each treatment of interest is defined as having received a first prescription of the 
treatment of interest between September and December 2018.  
 
 

 
 
 
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9.3.2 
Outcomes 
1. Patient demographics:  
• age 
• gender 
• height  
• weight 
• BMI 
• Ethnicity* 
*assessment of ethnicity (black or non-black) necessary for calculation of  eGFR 
 
2. Time since diagnosis of Type 2 Diabetes (years) 
 
3. Clinical parameters relevant for T2D, CVD, CKD assessment (last available and 
date when it was collected) as valid on study index date 1 
• T2D 
o HbA1c (numeric value) 
 
• CVD 
o Blood pressure (numeric value for systolic and diastolic blood 
pressure) 
o LVEF (numeric value and info on whether an Echo was performed) 
o Blood lipids (numeric values for total cholesterol, LDL, HDL, and 
triglycerides) 
 
• CKD 
o Serum creatinine (numeric value) 
o eGFR (calculated for analysis according to the CKD-EPI formula 
considering serum creatinine level, gender, age, and ethnicity) 
o UACR (numeric value) 
 
4. Prevalence of comorbidities and related risk factors for CVD, CKD at index date 
1 
 
• Comorbidities 
o History of acute myocardial infarction (yes/no) 
o History of cardiology intervention (such as Percutaneous Coronary 
Intervention (PCI), Coronary Artery Bypass Grafting (CABG)) 
(yes/no)  
o Ischemic heart disease (defined as coronary artery disease, angina) 
(yes/no) 
o Heart failure (yes/no)  
▪ Confirmed by echocardiography (yes/no) 
o History of stroke (yes/no) 

 
 
 
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o Peripheral arterial disease (including limb angioplasty, stenting, 
bypass surgery, amputation, significant peripheral artery stenosis,) 
(yes/no) 
 
• Risk factors 
o Being overweight (BMI ≥25 to <30) (yes/no) or obese (BMI ≥30) 
(yes/no) according to the WHO criteria (26) 
o Hypertension (defined as systolic blood pressure ≥140 mmHg and / 
or diastolic blood pressure ≥90 mmHg) (y/n) 
o 10-year Risk for fatal CVD according to the applying SCORE Risk 
Chart (European Society of Cardiology) taking into account 
patient´s age, gender, systolic blood pressure, smoking status, and 
total cholesterol value at index date. 
o Tobacco smoking (current smoker/ ex-smoker/ never smoker) 
o Being physically inactive (defined as less than 2.5 hours of 
moderate-intensity aerobic exercise or less than 75 minutes of 
vigorous aerobic exercise per week) (yes/no) 
o Having a family history of early heart disease (yes/no) 
o Having a family history of early kidney disease (yes/no) 
 
5. T2D medication the treating physician newly prescribes at study index date 1 
and reason for the choice 
 
• SGLT2i 
o canagliflozin 
o dapagliflozin 
o empagliflozin 
o ertugliflozin 
 
• DPP4i 
o alogliptin 
o linagliptin 
o sitagliptin 
o saxagliptin 
o vildagliptin 
 
• GLP1a 
o dulaglutide 
o exenatide 
o liraglutide 
o semaglutide 
o lixisenatide 
 
• Reasons for choosing the treatment rated as not relevant at all/ 
moderately relevant/ highly relevant  
o HbA1c lowering 
o Weight loss 

 
 
 
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o Cardiovascular risk reduction 
o Favorable side effect profile 
o Simple dosing / administration 
o Guideline recommendation  
 
6. Concomitant T2D medications (given as monotherapy or as fix combination with 
main T2D medication) at study index date 1  
• Metformin 
• Sulfonylurea 
• Acarbose 
• Pioglitazone 
• Insulin 
• others 
 
7. Concomitant CVD and CKD medications at index date 1 (on class level only) 
• Antihypertensives ACEi or ARBs 
• Statins 
• Low dose aspirin 
• Beta blockers 
• Diuretics 
 
8. Involvement of other HCPs in treatment decisions with regard to SGLT2i, DPP4i 
or GLP1a prescription at study index date 1 and with regard to discontinuation 
at index date 2 (yes/no; if yes, the medical specialty of the involved physician(s) 
should be specified) 
 
9. Association of socioeconomic parameters with treatment decisions (such as 
employment status, family status, type of health insurance) at study index date 1 
 
10. Status of T2D therapy approximately one year (± 2 months) after start 
• Stop date, if available 
• Reasons for discontinuation 
o Investigator’s decision 
o Patient’s request (difficulties in medication handling) 
o Patient’s request (financial burden regarding co-payment) 
o Patient’s request (other) 
o Lost to follow-up 
o Adverse event (in case of adverse reaction to empagliflozin or 
linagliptin or fatal adverse event, see Section 11) 
o Death 
o Unknown 
o Other 
 
 
 

 
 
 
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Primary outcomes 
• 
T2D patients’ baseline characteristics when initiating either empagliflozin - or other 
SGLT2i, DPP4i or GLP1a on top of current antidiabetic treatment by different HCP 
specialties in CEE countries.  
 
Secondary outcomes 
• 
Burden of comorbidities (prevalence of CVD, CKD and CVD/CKD risk factors) in 
this T2D patient population at study index date 1 
• 
Actual treatment use at study index date 1 in patients with and without established 
CVD (Established CV disease defined as acute myocardial infarction (AMI), 
cardiology intervention, ischemic heart disease (IHD), congestive heart failure 
(CHF), peripheral arterial disease (PAD), or stroke) 
• 
To describe the association of socioeconomic parameters with treatment decisions at 
study index date 1 
• 
To assess the discontinuation rate, reasons for discontinuation and average duration 
of treatment for GLP1a, DPP4i and SGLT2i after a follow up of approximately one 
year from the initial time point (= index date 2) 
 
9.3.3 
Covariates 
Not applicable 
 
9.4 
DATA SOURCES 
Data will be collected retrospectively from existing patient data (Medical chart review) 
previously documented by Health care professionals during routine practice in patients treated 
for T2D in an endocrinologist, diabetologist or cardiologist office-based setting (nonhospital). 
Medical records of patients meeting inclusion/exclusion criteria and having provided written 
informed consent will be used to collect all study data. The delegated site personnel of the 
participating sites will enter the relevant parameters into the electronic Case Report Forms 
(eCRF) in a timely manner. This method has been chosen as method of data collection as 
systematic diabetes registries do not exist in CEE countries. 
 
Patients who are potentially eligible for study participation will be contacted by the delegated 
site personnel by phone or by sending a letter, inviting the patient to the next routine visit. In 
addition, patients will be informed about the study project and his/her potential eligibility for 
participating into the study.  

 
 
 
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9.5 
 STUDY SIZE 
No formal sample size calculation is provided for this study. This NIS has been designed to 
describe, in a real-world setting, usage patterns and outcomes associated with empagliflozin or 
other SGLT2i or DPP4i or GLP1a in the clinical routine practice. The sample size of 
approximately 4000 patients is driven by the need to enroll an adequate number of patients to 
address the mentioned objectives, also across various subgroups, such as physician or country 
specific analyses. It is aspired to document at least 500 patients in the GLP1a and at least 1000 
patients each in the SGLT2i and DPP4i subgroups. However, no formal limitations will be 
applied for recruitment of patients to subgroups with regard to medication of interest.   
 
9.6 
DATA MANAGEMENT 
A data validation plan (DVP) and a data management plan (DMP) will be created to describe 
all functions, processes, and specifications for data collection via the electronic Case Report 
Forms (eCRFs). The eCRF will include programmable edits to obtain immediate feedback if 
data are missing (also negative answers, unknown), out of range, illogical or potentially 
erroneous. These rules may encompass simple checks such as range validation or 
presence/absence of data. Concurrent manual data review including query processes may be 
performed as defined in the data management plan (DMP). This involves ad hoc queries within 
the eCRF which will be followed up for resolution. The database will be hosted in a physically 
and logically secure computer system maintained in accordance with a written security policy. 
The system will meet the standards of the International Committee on Harmonization guideline 
E6R1 regarding electronic study data handling. Data confidentiality will be strictly maintained. 
 
 

 
 
 
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9.7 
DATA ANALYSIS 
Details will be described in the statistical epidemiological analysis plan (SEAP) 
9.7.1 
Planned analyses  
All patients who have received a first prescription of respective study medication will be 
included in the analysis; this is the prescribed patient set. All analyses will be performed on the 
prescribed patient set. If patients have missing values for an outcome, those patients will be 
excluded for that outcome’s analysis. 
The assessment will be carried out using SAS® software. The statistical characteristics 
presented in the end-of-text tables will be N / mean / SD / min / median / max for continuous 
variables. Tabulations of relative and absolute frequencies will be presented for categorical 
variables. Incidence rates and 95% CI will be given when appropriate. Subgroup analyses e.g. 
according to medication (i.e. empagliflozin or SGTL2i or DPP4i or GLP1a), country and 
physician specialty are planned, as well as per history of CV disease. Descriptive analyses will 
be supplemented using χ2-test or Fisher’s exact test for categorical variables and Wilcoxon-
Mann-Whitney test for continuous variables. The analyses are purely explorative, hence no 
correction for multiple testing is needed. 
 
The analyses will relate to the following data as recorded in the eCRF: 
 
1. Patient demographics (age, gender, height, weight, BMI, ethnicity) 
2. Time since diagnosis of Type 2 Diabetes 
3. Clinical parameters relevant for T2D, CVD, CKD assessment as valid on index date 1 
4. Comorbidities like cardiovascular disease and related risk factors at index date 1 
5. Comorbidities like chronic kidney disease and related risk factors at index date 1 
6. T2D medication the treating physician newly prescribes at study index date 1 
7. Reason(s) for treatment decision at index date 1 
8. Concomitant T2D medications at study index date 1 
9. Concomitant CVD and CKD medications at index date 1 
10. Other HCPs involved in treatment decisions at study index date 1 and at index date 2 
11. Relevant socioeconomic parameters 
12. Discontinuation rate, reason for discontinuation, duration of T2D therapy after one year 
(± 2 months) 
 
All adverse events and adverse drug reactions collected per study protocol will be included and 
summarized in the final study report. Refer to the corresponding Section 11. 
  
Main analysis  
For the main analysis data from research question 1 to 5 will be evaluated in a descriptive 
manner for the total number of prescribed patients enrolled in the study. 
 
 

 
 
 
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9.7.2 
Handling of missing data  
By using a simple and non-complex eCRF in which the amount of data to be assessed is limited, 
the amount of missing data is expected to be low. Every effort will be made to collect complete 
data by using validation checks within the eCRF and possibly involving manual query 
processes (see Section 9.8).  Please refer to the analysis plan for details. 
 
9.8 
QUALITY CONTROL 
The study sites will be trained on the study procedures and on handling of the eCRF before 
documentation of the first patient at the respective study site. 
To ensure data quality, automatic data checks upon data entry (eChecks) will be programmed 
within the eCRF. Therefore, plausible ranges of values for numeric data entries as well as 
logical data entries and listings will be provided for the respective entry field. Based on this, 
checks on completeness and plausibility will be performed upon data entry in the eCRF. 
Validity of data entry thus is ensured by integrated validation checks performed by the system, 
indicating missing or implausible entries to the document list or investigator. All corrections 
will be visible from the systems audit trail. Data management activities by means of manual 
query processes might be implemented as defined in the DMP to increase data integrity. 
No regular source data verification is planned in this study. However, in case of decreasing 
data quality (i.e. of missing data, data discrepancies, protocol violations, etc.) a for-cause audit 
or risk-based monitoring visit will be performed. 
 
9.9 
LIMITATIONS OF THE RESEARCH METHODS 
The intention of this NIS is to analyze existing data of T2D patients when initiating on different 
types of T2D drugs, their comorbidities, their co-medications and socioeconomic factors with 
possible influence on treatment decisions and treatment duration.  
A NIS is the most suitable instrument for obtaining information about the use of medicines in 
everyday clinical practice.  
A possible limitation of the retrospective study design of this NIS is that the time windows of 
4 months (index date 1) and of 12 (± 2) months (index date 2) will give limited information in 
the population at a specific point in time. Medication availability might differ between 
countries due to different reasons (commercial availability, reimbursement status) which will 
be collected in research question 4 for further data interpretation.  
 
 

 
 
 
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9.10 
OTHER ASPECTS 
9.10.1 
Informed Consent, Data Protection, Study Records 
The study will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, and as close as possible to the standards of the International 
Conference of Harmonisation (ICH) Tripartite Guideline for Good Clinical Practice (GCP), 
Guidelines 
for 
Good 
Epidemiological 
Practice 
(GEP) 
[R10-4560], 
Good 
Pharmacoepidemiology Practice (GPP) [R09-0182] and relevant BI Standard Operating 
Procedures (SOPs). 
The rights of the investigator and of the sponsor with regard to publication of the results of this 
study are described in the investigator contract. As a general rule, no study results should be 
published prior to finalization of the Study Report. 
 
 
9.10.2 
Study Approval, Patient Information, and Informed Consent 
This study will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Independent Ethics Committee (IEC) and competent authority 
(CA), if needed according to national and international regulations. The same applies for the 
implementation of changes introduced by amendments. 
Patients potentially eligible for study participation will be contacted by the delegated site 
personnel by phone or by sending a letter, reminding the patient of the next routine visit. In 
addition, patients will be informed about the study project and his/her potential eligibility for 
participating in the study. 
Prior to patient participation in the study, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative). Each signature must be personally 
dated by each signatory and the informed consent and any additional patient-information form 
retained by the investigator as part of the study records. A signed copy of the informed consent 
and any additional patient information must be given to each patient or the patient’s legally 
accepted representative. 
The patient must be informed that his/her personal study-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of disclosure 
must also be explained to the patient. 
The patient must be informed that his / her medical records may be examined by authorized 
monitors (CML/CRA) or Clinical Quality Assurance auditors appointed by Boehringer 
Ingelheim, by appropriate IEC members, and by inspectors from regulatory authorities. 
After having provided written informed consent, the patients will be registered within the 
study’s EDC system to document all relevant variables.  
Patients already registered before protocol amendment 1 will have to consent to additional data 
collection at index date 2. 
 

 
 
 
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9.10.2.1 
Data Quality Assurance 
A quality assurance audit/inspection of this study may be conducted by the sponsor or 
sponsor’s designees or by IECs or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s study-related files and correspondence, 
and the informed consent documentation of this study. 
 
9.10.2.2 
Records 
All of the clinical data and site/investigator characteristics will be captured via a web-based 
Electronic Data Capturing system. The delegated site staff will enter and edit the data via a 
secure network, with secure access features (username, password and secure identification – 
an electronic password system). A complete electronic audit trail will be maintained. 
Patients must not be identified on the eCRF by name. Appropriately coded identification (i.e. 
Patient numbers) must be used. 
 
9.10.2.2.1 Source documents 
The relevant study data will be derived from the patient´s medical record, which is maintained 
either paper-based or electronically depending on the routine at the respective study site. Data 
relevant for this study will be reviewed and entered into the study´s eCRF by delegated site 
staff. Data entered in the eCRFs that are transcribed from source documents must be consistent 
with the source documents.  
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected.  
For the eCRF, the following data must be derived from source documents: 
1. Patient demographics (age, gender, height, weight, BMI, ethnicity) 
2. Time since diagnosis of Type 2 Diabetes 
3. Clinical parameters relevant for T2D, CVD, CKD assessment as valid on index date 1 
4. Comorbidities like cardiovascular disease and related risk factors at index date 1 
5. Comorbidities like chronic kidney disease and related risk factors at index date 1 
6. T2D medication the treating physician newly prescribes at study index date 1 
7. Reason(s) for treatment decision at index date 1 
8. Concomitant T2D medications at study index date 1 
9. Concomitant CVD and CKD medications at index date 1 
10. Other HCPs involved in treatment decisions at study index date 1 and at index date 2 
11. Relevant socioeconomic parameters 
12. Status of T2D treatment (stop date and reason for discontinuation, if available) at index 
date 2 
 

 
 
 
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9.10.2.2.2 Direct access to source data and documents 
The investigator / institution will permit study-related monitoring, audits, IEC review and 
regulatory inspection, providing direct access to all related source data / documents. eCRFs 
and all source documents, including progress notes and copies of laboratory and medical test 
results must be available at all times for review by the sponsor’s clinical study monitor, auditor 
and inspection by health authorities. The Clinical Research Associate (CRA) / on site monitor 
and auditor may review all eCRFs and written informed consents. The accuracy of the data will 
be verified by reviewing the documents described in Section 9.10.2. 
9.10.2.3 
Statement of Confidentiality  
Individual patient medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited. Patient confidentiality will be ensured 
by using patient identification code numbers. 
Data generated as a result of the study need to be available for inspection on request by the 
participating physicians, the sponsor’s representatives, by the IEC and the regulatory 
authorities, i.e. the competent authority (CA). 
9.10.2.4 
Completion of Study 
The EC/competent authority in each participating EU member state needs to be notified about 
the end of the study (last patient out) or early termination of the study. 
9.10.2.5 
Protocol Violations 
There are no protocol waivers. All protocol violations must be reported to the sponsor 
immediately. 
 
 
 

 
 
 
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9.11 
SUBJECTS 
9.11.1 
Cases 
The study will include all patients fulfilling inclusion/exclusion criteria and receiving a first 
filled prescription for medication of interest in the period of 4 months (September – December 
2018)  
 
Inclusion criteria 
 
Written informed consent prior to participation 
Female and male patients age ≥ 18 years 
Patients with T2D diagnosis 
Patients who have been newly initiated with empagliflozin or other SGLT2i, DPP4i or 
GLP1a between September 2018 and December 2018 (study index date 1) 
Patients have been naïve to treatment with empagliflozin or other SGLT2i, DPP4i or 
GLP1a at study index date 1 
 
Exclusion criteria 
 
Patients age < 18 years 
Patients with diagnosis of other types of diabetes than T2D 
Patients who do not provide written consent to the terms of the study 
 
9.11.2 
Controls 
Not applicable 
 
9.12 
BIAS 
Selection bias could occur at the site level and the patient level.  
 
To minimize the site level selection bias, sites will be eligible if HCPs initiate second line 
medications in their T2D patients. In addition to that, the number of proposed sites will be 
150% of sites to be finally included which will allow random selection of site.  
 
In order to limit the variability of outcomes, sites will be eligible if they have access and can 
prescribe at least 2 of the T2D drug classes of interest (SGLT2i, DPP4i, GLP1a) for the targeted 
T2D.  
 
To minimize selection bias at the patient level, physicians are requested to include all patients 
meeting inclusion and exclusion criteria in the study period of 4 months (September – 
December 2018) into the study. However, there may be a bias regarding patient groups at index 
date 1 and 2, since not all patients who have consented to documentation at index date 1 may 
or can give their consent (e.g. due to death or loss to follow-up) to further documentation at 
index date 2. 

 
 
 
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Information bias will be minimized by the use of standard eCRF and physicians’ training on 
the study protocol and handling of the eCRF. 
 
 

 
 
 
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10. 
PROTECTION OF HUMAN SUBJECTS 
Please refer to Section 9.10.1 
 
 

 
 
 
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11. 
MANAGEMENT AND REPORTING OF ADVERSE EVENTS & 
ADVERSE DRUG REACTIONS 
Screening for potential treatment naïve study subjects occurs outside of the study. Therefore, 
patients included into the study will have no previous exposure to any BI product for the disease 
in scope of the study (DM type 2) or any other SGLT-2i, DPP4-i or GLP-1a prior to index date. 
No prospective data collection will occur as part of the study after having received prescription 
at index date 1.  
However, due to the possibility that adverse drug reactions are reported as reason for T2D 
treatment discontinuation at index date 2, definitions and reporting are stated below.  
 
11.1 
DEFINITIONS OF ADVERSE EVENTS 
Adverse event 
An adverse event (AE) is defined as any untoward medical occurrence in a patient or 
clinical investigation subject administered a medicinal product and which does not 
necessarily have a causal relationship with this treatment. An adverse event can therefore 
be any unfavorable and unintended sign (e.g. an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product. 
 
Adverse drug reaction 
An adverse drug reaction (ADR) is defined as a response to a medicinal product which is 
noxious and unintended. Response in this context means that a causal relationship 
between a medicinal product and an adverse event is at least a reasonable possibility. 
Adverse reactions may arise from use of the product within or outside the terms of the 
marketing authorization or from occupational exposure. Conditions of use outside the 
marketing authorization include off-label use, overdose, misuse, abuse and medication 
errors. 
 
Serious adverse event 
A serious adverse event is defined as any AE which 
- results in death, 
- is life-threatening, 
- requires in-patient hospitalization, or 
- prolongation of existing hospitalization, 
- results in persistent or significant disability or incapacity, or 
- is a congenital anomaly/birth defect 
 
Life-threatening in this context refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might 
have caused death if more severe. 
 
Medical and scientific judgement should be exercised in deciding whether other 

 
 
 
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situations should be considered serious reactions, such as important medical events 
that might not be immediately life threatening or result in death or hospitalization but 
might jeopardize the patient or might require intervention to prevent one of the other 
outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization or development of dependency or abuse. Any suspected transmission via 
a medicinal product of an infectious agent is also considered a serious adverse reaction. 
 
Adverse Event of Special Interest (AESI) 
The term Adverse Event of Special Interest (AESI) relates to any specific AE that has 
been identified at the project level as being of particular concern for prospective safety 
monitoring and safety assessment within this study, e.g. the potential for AEs based on 
knowledge from other compounds in the same class. 
 
No AESIs have been defined for this study. 
 
11.2 
ADVERSE EVENT AND SERIOUS ADVERSE EVENT 
COLLECTION AND REPORTING 
The investigator shall maintain and keep detailed records of all AEs in their patient files.  
 
Collection of AEs 
The investigator carefully assesses whether an AE constitutes an ADR using the information 
below. 
 
Causal relationship of adverse event 
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an adverse event. An adverse 
reaction, in contrast to an adverse event, is characterized by the fact that a causal 
relationship between a medicinal product and an occurrence is suspected. 
Medical judgment should be used to determine the relationship, considering all 
relevant factors, including pattern of reaction, temporal relationship, de-challenge or 
re-challenge, confounding factors such as concomitant medication, concomitant 
diseases and relevant history. 
 
Arguments that may suggest a reasonable causal relationship could be: 
• 
The event is consistent with the known pharmacology of the drug 
• 
The event is known to be caused by or attributed to the drug class 
• 
A plausible time to onset of the event relative to the time of drug exposure 
• 
Evidence that the event is reproducible when the drug is re-introduced 
• 
No medically sound alternative etiologies that could explain the event 
(e.g. preexisting or concomitant diseases, or co-medications). 
• 
The event is typically drug-related and infrequent in the general population 
not exposed to drugs (e.g. Stevens-Johnson syndrome). 

 
 
 
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• 
An indication of dose-response (i.e. greater effect size if the dose is increased, 
smaller effect size if dose is diminished). 
 
Arguments that may suggest that there is no reasonable possibility of a causal 
relationship could be: 
• 
No plausible time to onset of the event relative to the time of drug exposure is 
evident (e.g. pre-treatment cases, diagnosis of cancer or chronic disease within 
days/weeks of drug administration; an allergic reaction weeks after 
discontinuation of the drug concerned) 
• 
Continuation of the event despite the withdrawal of the medication, taking 
into account the pharmacological properties of the compound (e.g. after 5 
half-lives). 
Of note, this criterion may not be applicable to events whose time course is 
prolonged despite removing the original trigger. 
• 
Additional arguments amongst those stated before, like alternative explanation 
(e.g. situations where other drugs or underlying diseases appear to provide a 
more likely explanation for the observed event than the drug concerned). 
• 
Disappearance of the event even though the study drug treatment continues or 
remains unchanged. 
 
Intensity of adverse event 
The intensity of the AE should be judged based on the following: 
Mild: Awareness of sign(s) or symptom(s) which is/are easily tolerated 
Moderate: Enough discomfort to cause interference with usual activity 
Severe: Incapacitating or causing inability to work or to perform usual activities 
 
Pregnancy: 
In rare cases, pregnancy might occur in a NIS. Once a patient has been enrolled in the 
study and has taken study medication, the investigator must report any drug exposure 
during pregnancy in a study participant within 7 days after becoming aware by means 
of Part A of the Pregnancy Monitoring Form to the sponsor’s unique entry point. 
The outcome of the pregnancy associated with the drug exposure during pregnancy must 
be followed up and reported to the sponsor’s unique entry point on the Pregnancy 
Monitoring Form (Part B). 
 
 
The following must be reported to the Sponsor on the NIS AE Form and/or Pregnancy 
Monitoring Form for Studies in case such AE/drug exposure during pregnancy information 
is identified in the course of the review of the individual records: 
 
        

 
 
 
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All serious ADRs associated with Jardiance®, 
Synjardy®, Trajenta®, Jentadueto® 
immediately within 24 hours after becoming 
aware 
All AEs with fatal outcome in patients exposed to 
Jardiance®, Synjardy®, Trajenta®, Jentadueto® 
immediately within 24 hours after becoming 
aware 
All non-serious ADRs associated with Jardiance® 
Synjardy® Trajenta® Jentadueto®  
7 calendar days after becoming aware 
Drug exposure during pregnancy 
7 calendar days after becoming aware 
 
The same timelines apply if follow-up information becomes available for the respective events.  
 
11.3 
REPORTING TO HEALTH AUTHORITIES 
Adverse event reporting to regulatory agencies will be done by the Marketing Authorization 
Holder according to local and international regulatory requirements. 
 
 
 

 
 
 
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12. 
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS 
Results of this non-interventional study will be disclosed on encepp.eu and clinicaltrials.gov. 
A study specific publication plan will be developed. 
 
 
 
 

 
 
 
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13. 
REFERENCES 
13.1 
PUBLISHED REFERENCES  
 
1. R16-4703  
International Diabetes Federation [webpage on the Internet]. IDF 
Diabetes Atlas. 7th ed. Brussels: The Federation; 2015. Available from: 
http://www.Diabetesatlas.org/Resources/2015-Atlas.html. (accessed February 5, 2018)  
 
2. R12-1453 Morrish et al Mortality and causes of death in the WHO multinational study 
of vascular disease in diabetes. Diabetologia (2001) 44 supplement 2: 24-21.  
 
3. R18-3104 Emerging Risk Factors Collaboration, Di Angelantonio E, Kaptoge S, et al. 
Association of cardiometabolic multimorbidity with mortality. JAMA. 2015; 
314(1):52–60.  
 
4. R18-3103 
Heart 
UK 
-Risk 
factors 
for 
CVD: 
https://heartuk.org.uk/files/uploads/documents/huk_fs_mfsI_riskfactorsforchd_v2.pdf
_(accessed February 5, 2018)  
 
5. R15-5186 Nwanari C et al., Mortality in type 2 diabetes mellitus: magnitude of the 
evidence from a systematic review and meta-analysis. British Journal of 
Diabetes&Vascular Disease 2013;13  
 
6. R18-3102 Svensson MK et al Albuminuria and renal function as predictors of 
cardiovascular events and mortality in a general population of patients with type 2 
diabetes: A nationwide observational study from the Swedish National diabetes 
register. Diab Vasc Dis Res 2013;10;520-9.  
 
7. R15-1368  
Das SR et al. Increased cardiovascular risk associated with diabetes in 
Dallas county. Am Heart J 2006;151:1087-93.  
 
8. R12-2030  
Sarwar N et al., Diabetes mellitus, fasting blood glucose concentration 
and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. 
Lancet 2010;375;2215  
 
9. R11-5199 Seshasai SRK et al. Diabetes mellitus, fasting glucose and risk of cause-
specific death, NEJM 2011;364:829-41.  
 
10. R04-4255 Lewington S et al. Age specific relevance of usual blood pressure to vascular 
mortality: a meta-analysis of individual data for one million adults in 61 prospective 
studies. Lancet 2002, 1903-13.  
 
 
 

 
 
 
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11. P04-11488 Grundy SM, Cleeman JI, Bairey Merz CN, Brewer HB, Clark 
LT,Hunninghake DB, Pasternak RC, Smith SC, Stone NJ. Implications of recent 
clinical trials for the national cholesterol education program adult treatment panel III 
guidelines. Circulation 2004;110(2):227-239 
 
12. R18-3101 Taylor AJ, Evidence to support aggressive management of HDL-cholesterol: 
implications of recent trials. Eur Heart J Suppl 2006;8  
 
13. R13-0026  
Balkau B et al., International Day for the evaluation of Abdominal 
Obesity (IDEA) a Study of Waist Circumference, Cardiovascular Disease and Diabetes 
Mellitus in 168000 Primary Care Patients in 63 Countries. Circulation 2007, 116;1942-
51.  
 
14. R14-3924 Gregg et al. Changes in diabetes-related complications in the United States 
990-2010, N Engl J Med 2014;370: 1514–1523.  
 
15. R18-3100 Tonelli M et al., Risk of coronary events in people with chronic kidney 
disease compared with those with diabetes: a population-level cohort study. The Lancet, 
2012; 380, 807.  
 
16. R18-2261 Norhammar et al. Incidence, prevalence and mortality of type 2 diabetes 
requiring glucose-lowering treatment, and associated risks of cardiovascular 
complications: a nationwide study in Sweden, 2006–2013. Diabetologia (2016) 
59:1692–1701  
 
17. P15-09840 Zinman B et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in 
Type 2 Diabetes. N Engl J Med. 2015 Nov 26;373(22):2117-28. doi: 
10.1056/NEJMoa1504720. Epub 2015 Sep 17. 
 
18. R17-1732 Marso SP et al. Liraglutide and Cardiovascular Outcomes in Type 2 
Diabetes. N Engl J Med. 2016 Jul 28;375(4):311-22. doi: 10.1056/NEJMoa1603827. 
Epub 2016 Jun 13. 
 
19. P17-13883 Cefalu W et al., Cardiovascular Outcomes Trials in Type 2 Diabetes: Where 
Do We Go From Here? Reflections From a Diabetes Care Editors Expert Forum. 
Diabetes Care 2018: 41:14-31 
 
20. R18-1776 ADA guidelines: Standards of Medical Care in Diabetes 2018, Diabetes Care 
2018;41(Suppl. 1):S1–S2 
 
 
 
 
 
 

 
 
 
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21. P16-06194 Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano AL, et 
al. 2016 European guidelines on cardiovascular disease prevention in clinical practice: 
the Sixth Joint Task Force of the European Societyof Cardiology and Other Societies 
on Cardiovascular Disease Prevention in Clinical Practice (constituted by 
representatives of 10 societies and by invited experts), developed with the 
specialcontribution of the European Association for Cardiovascular Prevention & 
Rehabilitation (EACPR). European Heart Journal, Advance Access published May 23, 
2016, doi: 10.1093/eurheartj/ehw106; 2016. 
 
22. P16-05920 Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, 
al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart 
failure: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart 
Failure of the European Society of Cardiology (ESC), developed with the special 
contribution of the Heart Failure Association (HFA) of the ESC. European Heart 
Journal, Advance Access published May 20, 2016, doi: 10.1093/eurheartj/ehw128; 
2016. 
 
23. R10-4560 Good Epidemiological Practice (GEP). IEA Guidelines for Proper Conduct 
of Epidemiological Reseach (2007). 
 
24. R09-0182 
Guidelines 
for 
Good 
Pharmacoepidemiology 
Practices 
(GPP). 
Pharmacoepidemiology and Drug Safety 17, 200 - 208 (2008). 
 
25. P17-10086 Arnold S, Inzucchi et al., Real-world use and modeled impact of glucose-
lowering therapies evaluated in recent cardiovascular outcomes trials: An NCDR® 
Research to Practice Project. European Journal of Preventive Cardiology 2017, Vol 
24(15) 1637-45. 
 
26. R05-0351World Health Organization, Obesity: preventing and managing the global 
epidemic. Report of WHO consultation. World Health Organ Rep Ser 894, 1-253 
(2000) 
 
13.2 
UNPUBLISHED REFERENCES 
n.a. 

 
 
 
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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS 
 
Number 
Document 
Reference 
Number 
Date 
Title 
1 
eCRF 
formfakes 
21 November 2018 
cordially_formfakes_2018-11-21.pdf 
 
 
 
 
 
 
 
 
 

 
 
 
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ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS 
Doc.Ref. EMA/540136/2009  
 
 
ENCePP Checklist for Study Protocols (Revision 4) 
Adopted by the ENCePP Steering Group on 15/10/2018 
The 
European 
Network 
of 
Centres 
for 
Pharmacoepidemiology 
and 
Pharmacovigilance 
(ENCePP)(website.encepp.eu) 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 
(website.encepp.eu/standards_and_guidances/index.html), 
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. 
(website.ema.europa.eu/docs/en_GB/document_library/Other/2012/10/WC500133174.pdf). 
The 
Checklist is a supporting document and does not replace the format of the protocol for PASS 
presented in the Guidance and Module VIII of the Good pharmacovigilance practices (GVP). 
 
Study title: 
CORDIALLY® - CEE: Characteristics of patients with Type 2 Diabetes patients 
treated with modern antidiabetic drugs.  
A real-world data collection of patient baseline characteristics, treatment 
patterns and comorbidities in Central Eastern European (CEE) countries 
 
 
EU PAS Register® number: EUPAS28505 
Study reference number (if applicable): 1245-0187 
 
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 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. 

 
 
 
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Section 1: Milestones 
Yes 
No 
N/A 
Section 
Number 
1.1.3 Progress report(s) 
 
 
 
 
1.1.4 Interim 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) 
 
 
 
8.1 
2.1.2 The objective(s) of the study? 
 
 
 
8.2 
2.1.3 The target population? (i.e. population or 
subgroup to whom the study results are intended to be 
generalised) 
 
 
 
9.11, 
9.7.1 
2.1.4 Which hypothesis(-es) is (are) to be 
tested? 
 
 
 
 
2.1.5 If applicable, that there is no a priori 
hypothesis? 
 
 
 
 
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, other 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., rate, risk, prevalence) 
 
 
 
 
3.4 
Does the protocol specify measure(s) of 
association? (e.g. risk, odds ratio, excess risk, rate 
ratio, hazard ratio, risk/rate difference, number needed to 
harm (NNH)) 
 
 
 
 
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) 
 
 
 
 

 
 
 
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Comments: 
 
 
Section 4: Source and study populations 
Yes 
No 
N/
A 
Section 
Number 
4.1 
Is the source population described? 
 
 
 
9.2, 
9.2.1, 
9.2.2, 
9.11 
4.2 
Is the planned study population defined in 
terms of: 
 
 
 
 
4.2.1 Study time period 
 
 
 
9.1 
4.2.2 Age and sex 
 
 
 
9.2.1 
4.2.3 Country of origin 
 
 
 
9.2 
4.2.4 Disease/indication 
 
 
 
9.2.1 
4.2.5 Duration of follow-up 
 
 
 
 
4.3 
Does the protocol define how the study 
population will be sampled from the source 
population? (e.g. event or inclusion/exclusion criteria) 
 
 
 
9.2.1 
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 categorising 
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 categorised according to time 
windows?  
 
 
 
 
5.4 
Is intensity of exposure addressed?  
(e.g. dose, duration) 
 
 
 
 
5.5 
Is exposure categorised based on biological 
mechanism of action and taking into account 
the pharmacokinetics and pharmacodynamics 
of the drug? 
 
 
 
 
5.6 
Is (are) (an) appropriate comparator(s) 
identified? 
 
 
 
 
Comments: 
Data of patients who are newly initiated with SGLT2i, DPP4i, or GLP1a for Type 2 
Diabetes between September 2018 and December 2018 are retrospectively collected. 
Since this study doesn’t address safety outcomes, exposure is only collected 

 
 
 
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qualitatively by means of being newly prescribed with the medication of interest at 
index date 1 (September 2018 – December 2018).  
 
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? 
 
 
 
9.3.2 
6.2 
Does the protocol describe how the outcomes 
are defined and measured?  
 
 
 
9.3.2, 
9.7.1 
6.3 
Does the protocol address the validity of 
outcome measurement? (e.g. precision, accuracy, 
sensitivity, specificity, positive predictive value, use of 
validation sub-study) 
 
 
 
 
6.4 
Does the protocol describe specific outcomes 
relevant for Health Technology Assessment? 
(e.g. HRQoL, QALYs, DALYS, health care services 
utilisation, burden of disease or treatment, compliance, 
disease management) 
 
 
 
 
Comments: 
To question 6.3: The study outcomes will be analyzed in a purely descriptive manner, 
no sensitivity analyses will be performed. 
 
Section 7: Bias 
Yes 
No 
N/
A 
Section 
Number 
7.1 
Does the protocol address ways to measure 
confounding? (e.g. confounding by indication) 
 
 
 
9.12 
7.2 
Does the protocol address selection bias? (e.g. 
healthy user/adherer bias) 
 
 
 
9.12 
7.3 
Does the protocol address information bias? 
(e.g. misclassification of exposure and outcomes, time-
related bias) 
 
 
 
9.12 
Comments: 
 
 
Section 8: Effect measure 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: 
 
 
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: 
 
 
 
 

 
 
 
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Section 9: Data sources 
Yes 
No 
N/
A 
Section 
Number 
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 and other characteristics? 
 
 
 
 
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 and other characteristics? 
(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), Medical Dictionary for Regulatory 
Activities (MedDRA)) 
 
 
 
 
9.3.3 Covariates and other characteristics? 
 
 
 
 
9.4 
Is a linkage method between data sources 
described? (e.g. based on a unique identifier or other)  
 
 
 
 
Comments: 
To question 9.2.2, no safety outcomes will be analyzed as research question. Adverse 
events reported in this study are solely listed in the CSR, no analysis will be made in 
this regard. 
 
Section 10: Analysis plan 
Yes 
No 
N/
A 
Section 
Number 
10.1 Are the statistical methods and the reason for 
their choice described?  
 
 
 
9.7.1 
10.2 Is study size and/or statistical precision 
estimated? 
 
 
 
 
10.3 Are descriptive analyses included? 
 
 
 
 
10.4 Are stratified analyses included? 
 
 
 
9.7.1 
10.5 Does the plan describe methods for analytic 
control of confounding? 
 
 
 
 
10.6 Does the plan describe methods for analytic 
control of outcome misclassification? 
 
 
 
 

 
 
 
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Section 10: Analysis plan 
Yes 
No 
N/
A 
Section 
Number 
10.7 Does the plan describe methods for handling 
missing data? 
 
 
 
9.7.1 
10.8 Are relevant sensitivity analyses described? 
 
 
 
 
Comments: 
 
 
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?  
 
 
 
 
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? 
 
 
 
9.12 
12.1.2 Information bias? 
 
 
 
9.12 
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 uptake, duration of 
follow-up in a cohort study, patient recruitment, precision 
of the estimates) 
 
 
 
9.2 
Comments: 
 
 
Section 13: Ethical/data protection issues 
Yes 
No 
N/
A 
Section  
Number 
13.1 Have requirements of Ethics Committee/ 
Institutional Review Board been described? 
 
 
 
9.10.2 
13.2 Has any outcome of an ethical review 
procedure been addressed? 
 
 
 
 
13.3 Have data protection requirements been 
described? 
 
 
 
9.10.2 

 
 
 
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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?  
 
 
 
5 
Comments: 
 
 
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: dd/Month/year 
 
Signature:   
 
 
 
 

 
 
 
Boehringer Ingelheim 
Page 49 of 49
Protocol for non-interventional studies based on existing data 
BI Study Number 1245-0187 
c24436488-02
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
ANNEX 3. ADDITIONAL INFORMATION 
none