Empagliflozin Functional Capacity - Non-Interventional Study
Conditions: Heart Failure
Sponsor: Boehringer Ingelheim

ABCD
Non-Interventional Study (NIS) Protocol
TITLE PAGE
Document Number:
c37191900-03
BI Study Number:
1245-0259
BI Investigational 
product:
Jardiance®
Title:
Empagliflozin functional capacity - Non-Interventional Study
Brief lay title:
Emp-Activity
Protocol version 
identifier:
Final 3.0
Date of last version of 
protocol:
14 Jun 2022
PASS
No
EU PAS register 
number:
Not applicable
Active substance:
Empagliflozin (ATC: A10BK03)
Medicinal Product:
Jardiance® film-coated tablet containing 10 mg empagliflozin
Product reference:
Jardiance EMEA/H/C/2677
Procedure number:
n.a.
Marketing 
authorisation holder(s):
MAH:
This study is initiated, managed and sponsored by:

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Joint PASS:
No
Research question and 
objectives:
Primary objective:
To describe the change of the Kansas City Cardiomyopathy 
Questionnaire (KCCQ) scores [clinical summary score (CSS), 
total symptom score (TSS), overall summary score (OSS)] from 
baseline to 24 weeks in patients newly treated with empagliflozin 
according to routine practice.
Secondary objectives:
•
To describe the change of the New York Heart Association 
(NYHA) Class from baseline to 24 weeks in patients newly 
treated with empagliflozin.
•
To capture real-world patterns of patient characteristics and 
clinical disease presentation according to therapeutic regimen 
chosen in participants with chronic HF
Country(-ies) of study:
Poland, Romania, Hungary, Switzerland, Czech Republic, Bulgaria,
Slovenia, Serbia
Author:
In case of PASS, add:
MAH contact person:
Not applicable
In case of PASS, add:
EU-QPPV
Not applicable
In case of PASS, add:
Signature of EU-
QPPV
Not applicable
Date
30 Sep 2022
Page 1 of 40
Proprietary confidential information
© 2022 Boehringer Ingelheim Group of 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 .................................................................................................... 12
6.
MILESTONES.................................................................................................................................... 13
7.
RATIONALE AND BACKGROUND................................................................................................ 14
8.
RESEARCH QUESTION AND OBJECTIVES.................................................................................. 17
9.
RESEARCH METHODS ................................................................................................................... 18
9.1
STUDY DESIGN........................................................................................................................... 18
9.2
SETTING....................................................................................................................................... 18
9.2.1
Study sites ............................................................................................................................... 19
9.2.2
Study population...................................................................................................................... 19
9.2.3
Study visits.............................................................................................................................. 20
9.2.4
Study discontinuation.............................................................................................................. 21
9.3
VARIABLES ................................................................................................................................. 22
9.3.1
Exposures ................................................................................................................................ 24
9.3.2
Outcomes................................................................................................................................. 24
9.3.2.1
Primary outcomes............................................................................................................. 25
9.3.2.2
Secondary outcomes......................................................................................................... 25
9.3.3
Covariates................................................................................................................................ 25
9.4
DATA SOURCES.......................................................................................................................... 25
9.5
STUDY SIZE.................................................................................................................................. 25
9.6
DATA MANAGEMENT............................................................................................................... 26
9.7
DATA ANALYSIS......................................................................................................................... 26
9.7.1
Main analysis........................................................................................................................... 27
9.7.3
Safety analysis......................................................................................................................... 27
9.8
QUALITY CONTROL.................................................................................................................. 28
9.9
LIMITATIONS OF THERESEARCH METHODS...................................................................... 28
9.10
OTHER ASPECTS....................................................................................................................... 29

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9.10.1
Data quality assurance...........................................................................................................29
9.10.2
Study records.........................................................................................................................29
9.10.3
Source documents..................................................................................................................29
9.10.4
Direct access to data and documents .....................................................................................29
9.10.5
Completion of study..............................................................................................................30
10.
PROTECTION OF HUMAN SUBJECTS......................................................................................31
10.1
STUDY APPROVAL, PATIENT INFORMATION AND INFORMED CONSENT.................31
10.2
STATEMENT OF CONFIDENTIALITY....................................................................................31
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE REACTIONS .......32
11.1
DEFINITIONS OFADVERSE EVENTS....................................................................................32
11.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION AND 
REPORTING .........................................................................................................................................33
11.3
REPORTING TO HEALTH AUTHORITIES .............................................................................35
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS......................36
13.
REFERENCES................................................................................................................................37
13.1
PUBLISHED REFERENCES......................................................................................................37
13.2
UNPUBLISHED REFERENCES................................................................................................38
14.
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS............................................................39
15.
ANNEX 2 ADDITIONAL INFORMATION..................................................................................40

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2.
LIST OF ABBREVIATIONS
ADR
Adverse Drug Reaction
AE
Adverse Event
AESI
Adverse Event of Special interest
CA
Competent Authority
CEE
Central Eastern Europe
CRA
Clinical Research Associate
CRF
Case Report Form
CRO
Contract Research Organization
CSS
Clinical summary score
DMP
Data Management Plan
DMRP
Data Management and Review Plan
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EF
Ejection Fraction
ENCePP
European network of Centers for Pharmacoepidemiology 
and Pharmacovigilance
FAS
Full Analysis Set
FDA
Food and Drug Administration
GPP
Good Pharmacoepidemiology Practice
HCP
Health Care Practitioner
HDL
High-density Lipoprotein
HF
Heart Failure
HFmrEF
Heart Failure with mildly reduced Ejection Fraction
HFpEF
Heart Failure with preserved Ejection Fraction
HFrEF
Heart Failure with reduced Ejection Fraction
ICD
International Statistical Classification of Diseases and 
Related Health Problems
IEC
Independent Ethics Committee
IRB
Institutional Review Board
KCCQ
Kansas City Cardiomyopathy Questionnaire
LDL
Low-density Lipoprotein
LV
Left ventricular/ventricle
LVEF
Left ventricular ejection fraction
MAH
Marketing Authorization Holder
MedDRA
Medical Dictionary for Regulatory Activities
NIS
Non-interventional Study
NYHA
New York Heart Association
OSS
Overall Summary Score
PASS
Post-authorization safety study
PRO
Patient-reported Outcome
QoL
Quality of Life
SAP
Statistical Analysis Plan
SGLT2
Sodium-Glucose Co-Transporter 2
TSS
Total Symptom Score

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3.
RESPONSIBLE PARTIES
BI NIS
, Regional Medical 
Affairs Manager
Trial Clinical Monitor (TCM)
Coordinating Investigator
Contract Research Organization 
(CRO)

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4.
ABSTRACT
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Jardiance®
Name of active ingredient:
empagliflozin
Protocol date:
24.Jan.2022
Study number:
1245-0259
Version/Revision:
3.0
Version/Revision date:
30 September 2022
Title of study:
Empagliflozin functional capacity – Non-Interventional Study
Rationale and 
background:
The Emp-Activity study is a multinational, multi-center, non-interventional 
study conducted in CEE countries and based on newly collected data with the 
aim to close the gap between clinical trial data and available data regarding 
changes in patient-reporting outcomes after empagliflozin initiation in routine 
practice. QoL will be assessed by means of the complete version of KCCQ in 
real-world HF-patients treated with empagliflozin according to approval.
Until now, limited data are available regarding PRO changes after 
empagliflozin initiation in routine practice. Since participants of clinical trials 
commonly differ from the broader population for whom a therapy may be 
used in clinical practice, there is a need to better characterize symptom 
changes and health related QoL more broadly following empagliflozin 
initiation in routine clinical practice.
On the other hand, HF-patients treated initially with empagliflozin or with a 
different drug class (not including SGLT2i) will be included. Patients’ 
characteristics, patient reported QoL, HF drugs used as well as physician’s 
reason for not choosing empagliflozin for treatment will be collected at study 
index date 1 of these two cohorts. Hence, this NIS will additionally provide 
data regarding adoption of guidelines directed medical therapy in the real 
world.
Research 
question and 
objectives:
This non-interventional study (NIS) will look at contemporary, real-
world patterns of patient characteristics, clinical disease presentation, 
and therapeutic regimen chosen in participants with chronic heart 
failure ( HF). Disease parameters recorded by the physician according 
to clinical routine as well as changes in patient-reported outcomes
(PROs) will be evaluated through 24 weeks in HF patients treated with 
empagliflozin following the outpatient initiation of treatment.

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Study number: 1245-0259
Document number: c37191900-03
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Jardiance®
Name of active ingredient:
empagliflozin
Protocol date:
24.Jan.2022
Study number:
1245-0259
Version/Revision:
3.0
Version/Revision date:
30 September 2022

To capture patient characteristics, patient reported QoL, clinical 
disease presentation at the initiation of the given therapeutic regimen 
chosen in patients with HF

To describe the change in quality of life from visit 1 (=initiation of 
empagliflozin) to visit 2 (= 24 weeks after visit 1) by use of the 
disease-specific Kansas City Cardiomyopathy Questionnaire (KCCQ) 
scores in HF patients newly treated with empagliflozin according to 
routine practice: clinical summary score (CSS), total symptom score 
(TSS), overall summary score (OSS)

To describe the change from visit 1 to visit 2 (= 24 weeks after visit 
1) in the New York Heart Association NYHA Class in HF patients
newly treated with empagliflozin in real world conditions as 
evaluated by the treating health care practitioner (HCP)
Study design:
This is a multinational non-interventional study based on newly 
collected data to assess demographics, disease, and treatment pattern of 
patients with HF in a two-cohort design: one cohort will receive first 
prescription of empagliflozin as routine therapy for HF, the other 
cohort will receive HF therapy with drugs with another mechanism of 
action. Treatment of HF according to routine practice is determined
by the physician independent of the participation of the patient in this 
non-interventional study.
Within the study there are 2 study-related visits: a visit 1 (= index date 
1) and, for patients treated with empagliflozin, a second visit after 
approximately 24 weeks (visit 2 = index date 2). Thus, only patients 
receiving empagliflozin will be available for analysis regarding change 
in disease parameters and quality of life from index date 1 to index date
2. Patients treated with other drugs will not be followed up. These 
patients only have to fill in the KCCQ at index date 1.

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Study number: 1245-0259
Document number: c37191900-03
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Jardiance®
Name of active ingredient:
empagliflozin
Protocol date:
24.Jan.2022
Study number:
1245-0259
Version/Revision:
3.0
Version/Revision date:
30 September 2022
On overview of the study is given in the following figure:
Population:
Indication
Patients to be recruited within this study must have a physician 
diagnosed symptomatic chronic HF for which empagliflozin is an 
indicated treatment. Diabetic patients as well as non-diabetic patients
can be enrolled.
Inclusion criteria
Patients can be included if all of the following criteria are met:

Written informed consent prior to study participation

Male and female patients ≥18 years at visit 1

Patients must be contractually capable and mentally able to understand 
and follow the instructions of the study personnel

Patients with diagnosis of chronic heart failure NYHA Class 2-4 

Treatment-naïve for SGLT2i at visit 1

Women of childbearing potential must take appropriate precautions 
against getting pregnant according to approval of chosen HF drug(s)

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Study number: 1245-0259
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Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Jardiance®
Name of active ingredient:
empagliflozin
Protocol date:
24.Jan.2022
Study number:
1245-0259
Version/Revision:
3.0
Version/Revision date:
30 September 2022
Exclusion criteria

Missing physician’s diagnosis of chronic heart failure

Patients hospitalized at visit 1

Life expectancy ≤12 months according to physician’s assessment

Lack of informed consent

Pregnant or lactating females

Participation in a parallel interventional clinical trial

Chosen treatment with another SGLT2i drug than empagliflozin

Having been enrolled into the non-empagliflozin-arm of this non-
interventional study

Current or prior treatment with SGLT2i at visit 1

Patients with dependency or relationship to the treating physician
Variables:
Patient demographics (Year of birth, gender, height, weight) 
Date of first diagnosis of HF , etiology of HF
Clinical parameters relevant for HF [LVEF, current NYHA Class according 
to treating physician, electrocardiogram (ECG), heart rate, blood pressure
(systolic, diastolic), laboratory diagnostic according to clinical routine (last
available value and date when it was collected), 6-min-walking test according 
to clinical routine
Alcohol consumption and smoking status (non-smoker, previous smoker, 
current smoker)
Concomitant diseases / Comorbidities
Previous HF hospitalizations within the last 6 months 
HF related medication used in the last 6 months
Current HF related and other relevant concomitant medication
Newly prescribed treatment regime [Date of prescription, medication 
(empagliflozin and / or other drug), reason, if no prescription of 
empagliflozin]
Patient reported outcomes (KCCQ 23 items)
Date of discontinuation of empagliflozin treatment, reason (if applicable)

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Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Jardiance®
Name of active ingredient:
empagliflozin
Protocol date:
24.Jan.2022
Study number:
1245-0259
Version/Revision:
3.0
Version/Revision date:
30 September 2022
Variables for safety evaluation: ADRs (serious and non-serious), fatal adverse 
events (AEs), pregnancies, HF related hospitalizations
Data sources:
Medical records collected through routine clinical care will be used for 
patient demographic, disease relevant data and medication data.
Patient reported outcome:
All enrolled patients have to complete the KCCQ at index date 1, whereas 
only patients treated with empagliflozin were asked to fill in the KCCQ at 
index date 2.
Study size:
It is planned that data of approximately 7000 HF patients in 8 countries will be 
collected (Poland, Romania, Hungary, Switzerland, Czech Republic, Bulgaria, 
Slovenia, Serbia).
Data analysis:
Primary outcome
-
Change of each of the Kansas City Cardiomyopathy Questionnaire 
(KCCQ) scores [clinical summary score (CSS), total symptom score 
(TSS), overall summary score (OSS)] from index date 1 to 24 weeks 
after index date 1 in patients newly treated with empagliflozin
according to routine practice.
Subgroup analyses based on age at baseline, gender, country, baseline LVEF
(reduced EF vs. preserved EF vs. mildly reduced EF), and status of diabetes
mellitus at baseline. All recorded data for efficacy up to week 24 after index 
date 1 will be included.
Secondary outcome:
-
Change of the New York Heart Association (NYHA) Class from index 
date 1 to 24 weeks after index date 1 in patients newly treated with 
empagliflozin
-
Real-world patterns at study index date 1 of patient characteristics, 
clinical disease presentation and therapeutic regimen chosen in 
participants with chronic HF
Milestones:
Planned start of data collection: December 2022
Planned end of data collection: December 2023
Planned final study report: June 2024

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5.
AMENDMENTS AND UPDATES
V 1.0 dated 24 Jan 2022
V 2.0 dated 14 Jun 2022

Changes of participating countries
V 3.0 dated 30 Sep 2022

Changes in timelines, number of patients and number of participating countries

Change of responsible Trial Clinical Monitor

Due to approval extension for empagliflozin adaptation of wording, patients with HF irrespective 
of EF will be included, update of inclusion and exclusion criteria and update of section 7.

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6.
MILESTONES
Milestone
Planned Date
IRB/IEC approval
Q3 2022
Start of data collection
Q4 2022
End of data collection
Q4 2023
Study progress report 1
Q2 2023
Study progress report 2
Q2 2024
Final report of study results
Q2 2024

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7.
RATIONALE AND BACKGROUND
Heart failure (HF) is a chronic disease which is characterized by reduced pumping capacity of the heart 
and / or elevated intracardial pressure. Clinical symptoms are often not present in the early stages of 
this disease. Underlying cardiac reasons are myocardial abnormalities resulting in systolic and/or 
ventricular dysfunction, and or abnormalities of the valves, pericardium, endocardium, heart rhythm 
and conduction [1].
HF is a major cause of hospitalizations, impaired health status, and deaths. Among the risks for 
developing HF are hypertension, obesity, and diabetics. Worldwide, prevalence increases due the 
ageing population and improvements in medical treatment [2].
Based on left ventricular ejection fraction (LVEF), HF can be classified into 3 subtypes with different 
underlying aetiologies, demographics, co-morbidities and response to therapies: 1) HF with reduced 
ejection fraction (LVEF ≤40%), 2) HF with preserved ejection fraction (LVEF ≥50%) and 3) HF with 
mildly reduced LV systolic function (LVEF = 41-49%). Until 2022, only in HF patients with reduced 
ejection fraction (HFrEF therapies have been approved to reduce both morbidity and mortality[1]. 
Nevertheless, there is no cure of HF; therefore, there is further need for improvement of therapies
leading to higher quality of life in patients with HF.
Recently, a new drug class, which originally was developed to treat diabetes was approved for treatment 
of HFrEF. The new agent, available as film-coated tablets, promote glucose excretion in urine by 
inhibiting a transport protein, the sodium-glucose cotransporter 2 (SGLT2), thereby reducing renal 
glucose reabsorption.
The agent empagliflozin is a reversible, highly, and selective competitive inhibitor of SGLT2. Due to 
results of clinical trials that demonstrated its potential of lowering blood glucose levels in diabetic 
patients, empagliflozin was approved in Europe in June 2014 for the treatment of patients with type 2 
diabetic as an adjunct to diet and exercise as monotherapy when metformin is considered inappropriate 
due to intolerance or in addition to other medicinal products for the treatment of diabetes [1],[4],[5]. 
An unexpected finding of the clinical trials with diabetes patients was that empagliflozin additionally 
reduces hospitalizations due to HF and cardiac death. The EMPA-REG OUTCOME study which 
randomly assigned type 2 diabetes patients to receive 10 mg or 25 mg of empagliflozin or placebo once 
daily focused on cardiovascular outcomes. Results showed that patients with type 2 diabetes at high 
risk for cardiovascular events who received empagliflozin, as compared with placebo, had a lower rate 
of the cardiovascular outcomes and of death from any cause when the study drug was added to standard 
care [6], [7].
Thus, the EMPEROR-Reduced randomized clinical trial tested 10 mg empagliflozin or placebo in 
diabetic and non-diabetic patients additionally to appropriate treatment with e.g. diuretics, inhibitors of 
the renin-angiotensin system, beta-blockers. It was designed to evaluate the effect of empagliflozin on 
the risk of cardiovascular death or hospitalization for heart failure in patients with established symptoms 
of HF accompanied by evidence of systolic dysfunction [8]. Empagliflozin reduced the risk of 
hospitalization for HF in patients regardless of the presence or absence of diabetes [9]. Given the 
positive results of this trial, the therapeutic indication for use of empagliflozin (Jardiance®) has been
extended by the European Medicine Agency (EMA) in July 2021. In addition to treatment of type 2 
diabetes mellitus, empagliflozin is also indicated in adults for the treatment of symptomatic chronic 
heart failure with reduced ejection fraction. The recommended dose for this new indication is 10 mg 
once daily [10]. Since August 2021, empagliflozin is also approved in the USA in adults with HFrEF. 

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In 2022, EMA and FDA both expanded the approval of empagliflozin for use in adults with HF,
regardless of ejection fraction, to reduce the risk of cardiovascular death and HF hospitalization.
Approval was based on results of the EMPEROR-Preserved study, a randomized, double-blind, 
international trial. 5988 patients with class II-IV heart failure and an ejection fraction of more than 40% 
were randomized to receive empagliflozin (10 mg once daily) or placebo, in addition to usual therapy. 
The primary outcome was a composite of cardiovascular death or hospitalization for heart failure.
Results showed that Empagliflozin reduced the combined risk of cardiovascular death or hospitalization 
for HF in patients with heart failure and a preserved ejection fraction [11]. 
However, the mechanism of action on HF is still not fully understood. More evidence is needed 
regarding the effects of SGLT2 inhibitors in patients across the broad spectrum of HF.
Besides improvements in clinical endpoints such as survival or risk of hospitalization, improvements
in quality of life (QoL) as recorded by the patients in form of symptoms or physical function have 
become an independent factor which is also underlined by the guidance statements from regulatory 
agencies and the recognition of Kansas City Cardiomyopathy Questionnaire (KCCQ) and the 
Minnesota Living with Heart Failure Questionnaire by the Food and Drug Administration as a clinical 
trial endpoint, or component of a combined endpoint to evaluate devices or drugs for heart failure 
[12][13].
The KCCQ is a 23-item (15 question) self-administered questionnaire designed to quantify physical 
limitations, symptoms (frequency, severity and recent change over time), social limitations, self-
efficacy, and quality of life. To facilitate interpretability, two summary scores were developed. 
Combining the physical limitation and symptom domains (excluding symptom stability) forms a 
functional status score. A clinical summary core can be calculated by combining the functional status 
with the QoL and social limitation domains [14].
QoL data during empagliflozin therapy have been examined in a double-blind, placebo- controlled trial 
with nondiabetic HFrEF patients who received either 10 mg empagliflozin daily or placebo [15]. Within
this clinical trial the short form of KCCQ (KCCQ-12) was used. Results showed a significant
improvement in QoL in empagliflozin-treated patients compared to placebo-treated ones. In the 
EMPEROR-Preserved trial the KCCQ-23 was used to assess QoL. Results revealed meaningful 
improvement of patients who received empagliflozin compared to placebo [16].
However, since patients in clinical trials are selected by several inclusion and exclusion criteria with 
regard to organ function or comorbidities, and receive medication as stated in the protocol, these 
patients are not necessarily representative of patients in routine practice. 
As shown in a contemporary US outpatient HFrEF registry, most patients did not receive target doses 
of medical therapy at any point during longitudinal follow-up and few patients had doses increased over 
time. Patients did not receive optimum doses of medication for many reasons, including medication 
intolerance, patient preference, clinician preference, healthcare systems-based reasons, and clinical 
inertia [17].

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Study number: 1245-0259
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Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
The Emp-Activity study is a multinational, multi-center, non-interventional study conducted in CEE 
countries and based on newly collected data with the aim to close the gap between clinical trial data 
and available data regarding changes in patient-reporting outcomes after empagliflozin initiation in 
routine practice. QoL will be assessed by means of the complete version of KCCQ in real-world HF-
patients treated with empagliflozin according to approval. Until now, limited data are available 
regarding PRO changes after empagliflozin initiation in routine practice. As mentioned before, 
participants of clinical trials commonly differ from the broader population for whom a therapy may be 
used in clinical practice. Thus, there is a need to better characterize symptom changes and health related 
QoL more broadly following empagliflozin initiation in routine clinical practice.
On the other hand, HF-patients treated initially with or without empagliflozin will be included. Patients’ 
characteristics, HF drugs used as well as physician’s reason for not choosing empagliflozin for 
treatment will be collected at baseline of these two cohorts. Hence, this NIS will additionally provide 
data regarding adoption of guidelines directed medical therapy in the real world.

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.
8.
RESEARCH QUESTION AND OBJECTIVES
Primary objective:
To describe the change of the Kansas City Cardiomyopathy Questionnaire (KCCQ) scores [clinical 
summary score (CSS), total symptom score (TSS), overall summary score (OSS)] from baseline to 24 
weeks in patients newly treated with empagliflozin according to routine practice.
Secondary objectives:

To describe the change of the New York Heart Association (NYHA) Class from baseline to 
24 weeks in patients newly treated with empagliflozin.

To capture real-world patterns of patient characteristics and clinical disease presentation 
according to therapeutic regimen chosen in participants with chronic HF

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9.
RESEARCH METHODS
9.1
STUDY DESIGN
This is a multinational non-interventional study based on newly collected data to assess demographics 
and treatment pattern of patients with HF in a two-cohort design: One cohort will receive first 
prescription of emagliflozin as routine therapy for HF, the other cohort not. Treatment of HF 
according to routine practice is determined by the physician independent of the participation of the 
patient in this non-interventional study.
During visit 1 (= index date 1), a routine visit in the clinical practice, patients will be recruited. All 
patients fulfilling the inclusion/exclusion criteria can be enrolled, irrespective of the HF-treatment they 
will receive. Patients will be enrolled consecutively by the participating physicians until the sample
size requirement is met. The treating physician will make the decision on the medications which will be
prescribed to their patients, either Empagliflozin or a drug with different mechanism of action. For all 
enrolled patients, demographic data, disease data, and treatment data will be collected at baseline.
All patients irrespective of treatment in addition of standard of care shall fill in the KCCQ at visit 1. 
Additionally, only for patients receiving empagliflozin a second time point of data collection is planned 
24 weeks after visit 1 (= visit 2). At this time point, HF disease parameters will be collected as specified 
in table 1, and patients have to fill in the KCCQ for the second time.
  
A study overview is given Figure 1.
Figure 1: Overview study design
9.2
SETTING
In this NIS, data in a total of about 4600 HF patients will be collected during routine clinical practice by 
private practice and clinics in 8 countries.
There will be no procedure outside routine clinical practice except for handing out the KCCQs to the 
enrolled patients by the study stuff. The physician’s decision to initiate treatment with empagliflozin or

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HF drug(s) with another mechanism of action is independent of the registration of the patient in this 
study. Empagliflozin and all other HF drugs will be prescribed according to approval.
This study is planned to observe patients treated with empagliflozin for approximately 24 weeks, 
whereas data of patients without empagliflozin prescription are collected at visit 1 exclusively.
In addition to data collected by the physician, all patients should fill in the KCCQ-questionnaire at visit 
1, whereas only patients receiving empagliflozin must fill in the questionnaire after approximately 24 
weeks to address the change in disease specific symptoms and items regarding physical functioning 
and self-care during empagliflozin therapy in a real-world patient population.
Since this is a real-world study, there are no specifical eligibility criteria other than life expectancy ≤ 
12 months and hospitalization at visit 1; patients having been enrolled into the non-empagliflozin arm 
must not be enrolled into the empagliflozin-arm afterwards. The contraindications and 
recommendations as stated in the SmPCs of empagliflozin and the other HF drugs have to be adhered 
to. For ethical and / or medical reasons, pregnant or lactating women, patients not willing to consent 
and patients with dependency relationship to the treating physician will be excluded.
9.2.1
Study sites
It is planned to collect data of approximately 4600 patients by approximately 1000 sites in 8 countries 
located in central east Europe (CEE): Switzerland, Poland, Romania, Hungary, Czech Republic,
Bulgaria, Slovenia and Serbia). It is strived to include a minimum of about 3300 patients starting with 
empagliflozin treatment.
It is expected that each participating site will enroll 5 patients to ensure country-specific 
representativeness of collected data, so that a minimum target number of 100 patients per country will 
be reached.
9.2.2
Study population
Indication
Patients to be recruited within this study must have a physician diagnosed symptomatic chronic HF 
for which empagliflozin is an indicated treatment. Diabetic patients as well as non-diabetic patients 
can be enrolled.
Patients fulfilling the following eligibility criteria will be enrolled consecutively into the empagliflozin 
or the non-empagliflozin arm according to the physician’s choice of HF treatment.
Inclusion criteria
Patients can be included if all of the following criteria are met:

Written informed consent prior to study participation

Male and female patients ≥18 years at Visit 1

Patients must be contractually capable and mentally able to understand and follow the 
instructions of the study personnel

Patients with diagnosis of chronic heart failure NYHA Class 2-4

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
Treatment-naïve for SGLT2i at visit 1

Women of childbearing potential must take appropriate precautions against getting pregnant 
according to approval of chosen HF drug(s)
Exclusion criteria
Patients cannot be included if any of the following criteria is met:

Missing physician’s diagnosis of chronic heart failure

Patients hospitalized at visit 1

Life expectancy ≤12 months according to physician’s assessment

Lack of informed consent

Pregnant or lactating females

Participation in a parallel interventional clinical trial

Chosen treatment with another SGLT2i drug than empagliflozin

Having been enrolled into the non-empagliflozin-arm of this non-interventional study

Current or prior treatment with SGLT2i at visit 1

Patients with contraindications according to current SmPC

Patients with dependency or relationship to the treating physician
9.2.3
Study visits
Table 1 presents all data collected and assessments performed at each visit.
Table 1: Planned visits and data collected
Parameter
Visit 1
Visit 2
Day 0 = index date 1 = Day of 
newly prescribed HF drug
24 weeks (±2 weeks) after index date 1
= End of observation [index date 2]
All patients
Only patients treated with 
empagliflozin
Informed Consent
X
Inclusion / Exclusion Criteria
X
Patient demographics (age, 
gender, height, and weight)
X
X (weight only)
Medical history
X
Alcohol consumption / 
Smoking status
X
LVEF
X
X
Current NYHA Class
X
X

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Table 1: Planned visits and data collected (cont.)
Parameter
Visit 1
Visit 2
Day 0 = index date 1 = Day of 
newly prescribed HF drug
24 weeks (±2 weeks) after index date 1
= End of observation [index date 2]
All patients
Only patients treated with 
empagliflozin
HF related examinations 
according to clinical routine*
X
X
HF related Hospitalizations in 
the last 6 months
X
HF medication used in the last 
6 months
X
Current HF related or other 
relevant concomitant 
medication
X
X
Prescribed HF drug at Day 0
Patient questionnaire: 23 
items-KCCQ
Safety: Adverse Drug 
Reactions (serious and non-
serious), fatal AEs, pregnancy, 
HF-related hospitalizations
X
X
X
X
X
Discontinuation of treatment 
with empagliflozin during 
study treatment (yes/no)
X
Intention to continue or 
discontinue treatment with 
empagliflozin after study 
period (yes/no)
X
Rationale for treatment 
discontinuation, if applicable
X
* Last available value and date when it was collected
9.2.4
Study discontinuation
Boehringer Ingelheim reserves the right to discontinue the study overall or at a particular study site at 
any time for the following reasons:
1.
Failure to meet expected enrolment goals overall or at a particular study site
2.
Emergence of any effectiveness/safety information that could significantly affect continuation of 
the study

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3.
Violation of Good Pharmacoepidemiology Practice (GPP), the study protocol, or the contract by a 
study site, investigator or research collaborator, disturbing the appropriate conduct of the study
The investigator/the study site/research collaborator will be reimbursed for reasonable expenses 
incurred in case of study/site termination (except in case of the third reason).
The patients have the right to stop study participation at any time and for any reason, without affecting 
their further treatment. Study participation may be stopped for a given patient in case of individual 
safety issues.
9.3
VARIABLES
The following parameters will be collected at visit 1 (= index date 1) of all registered patients:
1.
Patient demographics:

Year of birth

Gender

Height, weight, BMI (will be calculated from height and weight)
2.
Date of first diagnosis of HF
3.
Etiology of heart failure

Coronary artery disease

Hypertension

Valve disease

Cardiomyopathy

Congenital heart disease

Drug induced

Infective

Storage disorders

Diabetes

Obesity

Other
4.
Clinical parameters relevant for HF (last available value and date when it was collected) as 
valid at baseline and performed during clinical routine:

LVEF

Current NYHA Class according to treating physician

Electrocardiogram (ECG)

Heart rate

Blood pressure (systolic, diastolic)

Laboratory diagnostic according to clinical routine (last available value and date when it was 
collected):
o
BNP (B-type natriuretic peptide) and/or pro-BNP (N-terminal pro–B-type 
natriuretic peptide)
o
Lipids (cholesterol, HDL, LDL)
o
Blood urea nitrogen (BUN)
o
Serum creatinine

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o
Sodium, potassium
o
Complete blood count

6-min-walking test according to clinical routine
5.
Alcohol consumption and smoking status (non-smoker, previous smoker, current smoker)
6.
Concomitant diseases / Comorbidities

Disease according to ICD-10 (diabetes, hypertension, coronary artery disease, infarction, 
chronic kidney disease, atrial fibrillation, cancer, other)

Date of first diagnosis
7.
Previous HF hospitalizations within the last 6 months
8.
HF related medication used in the last 6 months

Medication

Indication

Application

Dose

Start date, end date, continuing
9.
Current HF related and other relevant concomitant medication

Medication

Indication

Application

Dose

Start date, end date, continuing
10. Newly prescribed treatment regime:

Date of prescription

Medication (empagliflozin and / or other drug)

Reason, if no prescription of empagliflozin
11. Patient reported outcomes:

KCCQ (23 items) completed by patients during the visit
The following parameters will be collected at routine visit 2 [= index date 2: 24 weeks (±2 weeks) 
after index date 1] only of registered patients treated with empagliflozin:
1.
Weight, BMI (will be calculated from height and weight)
2.
Clinical parameters relevant for HF performed during clinical routine (last available value and 
date when it was collected):

LVEF

Current NYHA Class according to treating physician

Electrocardiogram (ECG)

Heart rate

Blood pressure (systolic, diastolic)

Laboratory diagnostic according to clinical routine (last available value and date when it was 
collected):
o
BNP (B-type natriuretic peptide) and/or pro-BNP (N-terminal pro–B-type 
natriuretic peptide)

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o
Lipids (cholesterol, HDL, LDL)
o
Blood urea nitrogen (BUN)
o
Serum creatinine
o
Sodium, potassium
o
Complete blood count

6-min-walking test according to clinical routine
3.
Current HF related or other relevant concomitant medication
4.
HF drug(s) prescribed at visit 2
5.
Patient reported outcomes:

KCCQ (23 items) completed by patients during the visit
6.
Safety: ADRs (serious and non-serious), fatal adverse events (AEs), pregnancies, HF related 
hospitalizations
7.
Discontinuation of treatment with empagliflozin during study period (yes/no)

If yes: date of discontinuation, reason (if applicable)
8.
Continuation or discontinuation of treatment with empagliflozin after study period (yes/no)

In case of discontinuation: date of discontinuation, reason (if applicable)
9.3.1
Exposures
The drug of interest is Jardiance® with the active ingredient empagliflozin. Within this study, there are 
two HF patient cohorts: patients receiving first prescription of empagliflozin and those who have been 
prescribed  a drug with a different mechanism of action for the treatment of HF.
During this study, it is planned to observe for each patient who receives a first prescription of 
empagliflozin a treatment period of approximately 24 weeks. Patients not treated with empagliflozin 
will not be observed further after visit 1.
The recommended daily dose of empagliflozin for treatment of heart failure is 10 mg once daily.
9.3.2
Outcomes
This NIS will describe contemporary, real-world patterns of patient characteristics, clinical disease 
presentation, and therapeutic regimen chosen in participants with chronic HF in CEE countries. 
Additionally, PRO is assessed by use of the disease specific KCCQ. These data will be collected at visit 
1 of all registered patients.
The primary objective is to document and analyze QoL data from patients with HF receiving first 
treatment with empagliflozin in daily routine care. For this approach, the disease specific KCCQ is used 
to examine changes from index date 1 to index date 2 (= 24 weeks after study index date 1) in these 
patients. The primary outcome will be evaluated on patients receiving initial prescription of 
empagliflozin at visit 1 and who have filled in the KCCQ at visit 1 and visit 2.
The primary and secondary outcomes do not touch any safety questions.

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9.3.2.1
Primary outcomes
Change of each of the Kansas City Cardiomyopathy Questionnaire (KCCQ) scores [clinical summary 
score (CSS), total symptom score (TSS), overall summary score (OSS)] from index date 1 to index 
date 2 (= 24 weeks after index date 1) in patients newly treated with empagliflozin according to 
routine practice
9.3.2.2
Secondary outcomes

Change of the New York Heart Association (NYHA) Class from index date 1 to index date 2 (= 
24 weeks after index date 1) in patients newly treated with empagliflozin

Capture of real-world patterns of patient characteristics, clinical disease presentation and 
therapeutic regimen chosen in participants with chronic HF as well as of patient reported 
outcome at visit 1.
9.3.3
Covariates
Covariates for adjustment will include patient demographics and disease characteristics. These will be 
discussed in the Statistical Analysis Plan (SAP).
9.4
DATA SOURCES
Medical records collected through routine clinical care will be used to assess the inclusion/exclusion 
criteria of patients as well as for patient demographics, collection of current 
HF medication, 
concomitant diseases, and concomitant medication, as well as for the health data of the patient at visit 
2.
The KCCQ will be provided as paper version by the treating physician or trained site stuff to the patient 
to be filled out in writing at visit 1 (all patients) and visit 2 (patients with initial empagliflozin treatment 
only).
9.5
STUDY SIZE
With no formal a-priori hypotheses, this observational study uses a hypothesis-free approach 
focused on descriptive analyses. Thus, no formal sample size calculation is provided. The study is 
designed to describe the use of empagliflozin and PRO in clinical routine. In the 8 participating 
countries sites in urban as well as rural areas will be included. The nationwide distribution of the 
participating sites and the number of 4600 patients enrolled are intended to ensure that the data

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collected are representative. Based on random identification, it is expected that about 3300 patients 
will receive empagliflozin. The large sample size overall was chosen to support a large range of 
analyses from general scientific questions to specific regional or subgroup questions with 
sufficient precision. A minimum target number of 100 patients per country is chosen to provide 
reasonable sample size for scientific questions applicable across countries and subgroups of 
interest. The sample size will ensure that the descriptive data are sufficiently precise and 
meaningful at a country or subgroup level.
9.6
DATA MANAGEMENT
The data management plan (DMP) is summarized below. Full details of the data management plan are 
documented in a separate NIS-Data Management and Review Plan (NIS-DMRP).
The NIS-DMRP will describe all functions, processes, and specifications for data collection, cleaning 
and validation. The contract research organization (CRO) 
) is 
assigned for electronic data capture (EDC) system development. The electronic Case Report Forms 
(eCRF) are part of the EDC system which allows documentation of the relevant study variables by all 
participating sites in a standardized manner. 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 by personnel of data management of the CRO
may be performed based on parameters dictated by the DMP. Ad hoc queries to the sites may be 
generated and followed up for resolution.
The database will be housed 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 and the safety 
requirements of the FDA (US Food & Drug Administration) concerning systems for the data acquisition 
of clinical studies in accordance with "Title 21 Code of Federal Regulations (21 CFR Part 11): 
Electronic Records; Electronic Signatures. Patient confidentiality will be strictly maintained.
9.7
DATA ANALYSIS
Statistical analysis will be performed by 
).
The statistical analysis plan (SAP) for the study is summarized below. Full details of the statistical 
analysis will be documented in the SAP, which will be finalized before the end of data collection.
In general, all analyses will be carried out by using descriptive and exploratory statistical methods 
including exploratory confidence intervals and p-values. For the analyses SAS® software version 9.4 or 
higher will be used.
All data captured at visit 1 will be analyzed on all registered patients [Full analysis set (FAS)]. All 
patients who have received at least one dose of empagliflozin for HF and have filled in KCCQ at time 
points ‘index date 1’ and ‘index date 2 (= week 24 after index date 1)’ will be included in the ‘primary 
endpoint set’ which will be used for primary endpoint analysis.
Safety set: All patients who received empagliflozin at least once will be used for safety and further 
analyses.

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9.7.1
Main analysis
Analysis of the primary outcome
-
Change of each of the Kansas City Cardiomyopathy Questionnaire (KCCQ) scores [clinical 
summary score (CSS), total symptom score (TSS), overall summary score (OSS)] from index 
date 1 to index date 2 (= 24 weeks after index date 1) in patients newly treated with 
empagliflozin according to routine practice
will be performed according to the analysis manual for the KCCQ. Changes in the KCCQ scores will 
be calculated for each patient. Results will be presented as N, mean, standard deviation, median, 
minimum and maximum values as well as number of missings as extra column. A change of 5 points 
of OSS will be considered as clinically meaningful.
Change from index date 1 in clinical summary score for HF symptoms and physical limitations domains 
of the KCCQ at week 24 will be evaluated further by subgroup analyses based on age at index date 1, 
gender, country, baseline LVEF (rEF, mpEF pEF), and status of diabetes mellitus at visit 1. All recorded
data for efficacy up to week 24 will be included.
Analysis of the secondary outcome
-
Change of the New York Heart Association (NYHA) Class from index date 1 to index date 2 
(= 24 weeks after index date 1) in patients newly treated with empagliflozin
tabulation of relative and absolute frequencies will be presented.
For the analysis of the secondary outcome
-
Capture of real-world patterns of patient characteristics, clinical disease presentation and 
therapeutic regimen chosen in participants with chronic HF as well as of patient reported
outcome at visit 1
tabulations of relative and absolute frequencies will be presented. Comparison of data at visit 1 
between patients receiving empagliflozin or not for treatment of HF will be performed by Chi-
quadrat-test or Mann-Whitney-U-test.
9.7.3
Safety analysis
All adverse drug reactions (ADRs) (serious and non-serious), all AEs with fatal outcome, 
hospitalizations due to HF as collected per study protocol will be included and summarized in the final 
study report.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
coding dictionary. Standard BI summary tables and listings will be produced. All patients treated with 
empagliflozin for HF will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature.

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Statistical analysis and reporting of adverse events will concentrate on treatment-emergent adverse events.
All adverse events occurring on empagliflozin treatment plus 7 days will be considered ‘treatment-
emergent’. Deterioration of pre-existing conditions will also be considered ‘treatment- emergent’.
Frequency, severity, and causal relationship of adverse events will be tabulated by system organ class 
and preferred term after coding according to the current version of MedDRA.
9.8
QUALITY CONTROL
The quality control, review, and monitoring plan are summarized below. Greater details are 
documented in the NIS-DMRP.
All participating sites will receive a comprehensive study site file with all information on the NIS. Site 
staff will be trained on the study procedures and on handling of the eCRF before documentation of the 
first patient by a mandatory webinar or on-site, whatever will be more feasible (e.g. influenced by 
pandemic situation). Training will be documented in the study site file.
To improve and secure data quality, automatic data checks (eChecks) upon data entry will be done 
within the eCRF. In the eCRF, plausible ranges of values for numeric data entries as well as logical 
data entries and listings will be provided for each 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.
To provide further quality assurance of the documented patient observations, routine monitoring will 
take place at the site with the highest number of patients currently enrolled two months after the First 
Patient In (FPI) in the respective country. If on-site visits are not possible due to pandemic situation, 
remote quality review may be performed. Risk-based monitoring or for-cause audit will be performed 
based on the key risk indicators in case of decreasing data quality (i.e. of missing data, data 
discrepancies, protocol violations, etc.). Details will be specified in the study monitoring plan.
9.9
LIMITATIONS OF THERESEARCH METHODS
This is a single arm non-interventional study based on newly collected data with the aim to gather data 
of HF treatment as well as PRO in clinical routine. Generally, a NIS is the most suitable instrument for 
obtaining information about the use of medicines in everyday clinical practice. The eligibility criteria 
are non-restrictive which will permit the enrolment of a broad patient population. Thus, patients are 
more different in baseline characteristics and disease data than patients enrolled into a clinical trial. The 
choice of treatment and performance of examinations is at the discretion of the investigator. Therefore, 
results of disease specific examinations recorded may comprise various time periods. There may also 
be more missing values as in clinical trials, since the non-interventional nature means that no 
specification is provided on examinations to be carried out.
Selection bias could occur at the site level and the patient level. The site of the patient selection may 
affect the outcomes given patient differences across practice sites. To minimize the site level selection

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bias, the goal is to have a great number of participating centers. To minimize selection bias at the patient 
level, consecutive enrolment is performed. Additionally, a non-empagliflozin treated cohort is added in 
order to get an overview of the HF patients at the respective sites.
Information bias will be minimized by the use of standard eCRF and validated patient questionnaire as 
well as by physicians’ training on the study protocol.
9.10
OTHER ASPECTS
9.10.1
Data quality assurance
A quality assurance audit/inspection of this study may be conducted by the sponsor or sponsor’s 
designees or by Institutional Review Boards (IRBs) / Independent Ethics Committees (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
Study records
Electronic Case Report Forms (eCRFs) for individual patients will be provided by the sponsor, via 
remote data capture.
All study relevant data 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 (i.e. 
electronic password system with username and password and secure identification). A complete 
electronic audit trail will be maintained.
9.10.3
Source documents
Source documents provide evidence for the existence of the patient and substantiate the integrity of the 
data collected. Source documents are filed at the investigator’s site.
Data entered in the eCRFs that are transcribed from source documents must be consistent with the 
source documents or the discrepancies must be explained. The investigator may need to request 
previous medical records or transfer records, depending on the study; also current medical records must 
be available.
For eCRFs, all data must be derived from source documents.
9.10.4
Direct access to data and documents
The investigator/institution will permit study-related monitoring, audits, IRB/IEC review and 
regulatory inspection, providing direct access to all related source data/documents. CRFs/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 (e.g. US Food and Drug Administration (FDA)). BI study staff and auditor may

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review all CRFs/eCRFs, and written informed consents. The accuracy of the data will be verified by 
reviewing the documents described in Section 9.10.1.
9.10.5
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/patient out, unless specified differently in Section 9.2 or early 
termination of the study.
After completion of the study, the CRO will transfer all study documents to BI for archiving.

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10.
PROTECTION OF HUMAN SUBJECTS
The study will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, Guidelines for Good Pharmacoepidemiology Practice (GPP), and the relevant 
BI Standard Operating Procedures (SOPs). Standard medical care (prophylactic, diagnostic and 
therapeutic procedures) remains the responsibility of the treating physician of the patient.
The investigator should inform the sponsor immediately of any urgent safety measures taken to protect 
the study subjects against any immediate hazard, and also of any serious breaches of the protocol.
10.1
STUDY APPROVAL, PATIENT INFORMATION AND INFORMED 
CONSENT
This NIS will be initiated only after all required legal documentation has been reviewed and approved 
by the respective Institutional Review Board (IRB)/Independent Ethics Committee (IEC) and 
Competent Authority (CA) according to national and international regulations. The same applies for 
the implementation of changes introduced by amendments.
Prior to patient participation in the study, written informed consent must be obtained from each patient 
(or the patient’s legally accepted representative) per GPP and according to the regulatory and legal 
requirements of the participating country.
The patient must be informed orally and in writing that his/her personal study-related data will be 
recorded pseudonymized and used by Boehringer Ingelheim in accordance with the local data 
protection law. The level of disclosure must also be explained to the patient.
The patients’ study participation is voluntary and the patients have the right to stop study participation 
any time and for any reason, without any disadvantage on their further treatment.
10.2
STATEMENT OF CONFIDENTIALITY
Individual patient medical information obtained as a result of this study is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted below. Patient confidentiality will be 
ensured by using patient identification code numbers. The identification key is kept confidentially by 
the physician at the study site.
Treatment data may be given to the patient’s personal physician or to other appropriate medical 
personnel responsible for the patient’s welfare. 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 
IRB/IEC and the regulatory authorities, i.e. the competent authority. The medical and personal patient 
data may be inspected by dedicated study site staff and by dedicated monitors (CRAs) for quality 
assurance reasons. All these personnel are obligated to confidentiality. For those quality checks and 
authority inspection the patient releases the treating physician from the medical confidentiality.
During the study, medical results and reports and personal information from the patients will be 
collected in patient files at the study sites. Those data important for the study will be collected 
pseudonymized via an eCRF.
Before analysis, the data will be anonymized and the reports from this analysis will be provided to the 
sponsor of the study, Boehringer Ingelheim. After analysis and finalization of the study report, the 
anonymized data will be transferred to Boehringer Ingelheim.
Study data will be kept according to local requirements and then be destroyed.

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11.
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS
11.1
DEFINITIONS OFADVERSE 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 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.

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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).
•
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:

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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 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 ISF will contain the Pregnancy Monitoring Form (Part A and B). As pregnancy itself is not to be 
reported as an AE, in the absence of an accompanying serious ADR and/or AESI, only the Pregnancy 
Monitoring Form and not the NIS AE form is to be completed. If there is a serious ADR and/or AESI 
associated with the pregnancy a NIS AE form must be completed in addition.
The study design is of non-interventional nature and the study is conducted within the conditions of the 
approved marketing authorization. Sufficient data from controlled interventional trials are available to 
support the evidence on the safety and efficacy of the studied BI drug, For this reason the following AE 
collection and reporting requirements have been defined.
The following must be collected by the investigator in the (e)CRF from signing the informed consent 
onwards until the end of the study:
-
all adverse drug reactions (ADRs) (serious and non-serious),
-
all AEs with fatal outcome,
-
HF-related hospitalizations.
All ADRs, including those persisting after study completion must be followed up until they are 
resolved, have been sufficiently characterized, or no further information can be obtained.
Expedited Reporting of AEs and Drug Exposure during Pregnancy to BI Pharmacovigilance
The following must be reported by the investigator on the NIS AE form and/or Pregnancy Monitoring 
Form from signing the informed consent onwards until the end of the study and provide to BI unique 
entry point:
All serious ADRs associated with the
studied medical product empagliflozin
Immediately within 24 hours
All AEs with fatal outcome in patients
exposed to studied medical product 
empagliflozin
Immediately within 24 hours
All non-serious ADRs associated with the
studied medical product empagliflozin
7 calendar days
Drug exposure during pregnancy
7 calendar days
The same timelines apply if follow-up information becomes available for the respective events. In 
specific occasions the Investigator could inform the Sponsor upfront via telephone. This does not 
replace the requirement to complete and fax the NIS AE form.

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Information required
For each reportable adverse event, the investigator should provide the information requested on the
appropriate (e)CRF page and the NIS AE form.
11.3
REPORTING TO HEALTH AUTHORITIES
Adverse event reporting to regulatory agencies will be done by the Marketing Authorization 
Holder (MAH) 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 and a 
study specific publication plan will be developed to describe planned publications.
The rights of the investigator and of the sponsor with regard to publication of the results of this study 
are described in the investigator contract. As a general rule, no study results should be published prior 
to finalization of the Study Report.

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13.
REFERENCES
13.1
PUBLISHED REFERENCES
[1]
McDonagh TA , Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, Burri H, et al; 
ESC Scientific Document Group. 2021 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. Eur Heart J. 2021 
2021 Sep 21;42(36):3599-3726. doi: 10.1093/eurheartj/ehab368
[2]
Savarese G, Lund LH. Global Public Health Burden of Heart Failure. Card Fail Rev. 2017 
Apr;3(1):7-11. doi: 10.15420/cfr.2016:25:2
[3]
Roden M, Weng J, Eilbracht J, Delafont B, Kim G, Woerle HJ, Broedl UC; EMPA-REG 
MONO trial investigators. Empagliflozin monotherapy with sitagliptin as an active 
comparator in patients with type 2 diabetes: a randomised, double-blind, placebo-controlled, 
phase 3 trial. Lancet Diabetes Endocrinol. 2013 Nov;1(3):208-19. doi: 10.1016/S2213-
8587(13)70084-6
[4]
Kovacs CS, Seshiah V, Swallow R, Jones R, Rattunde H, Woerle HJ, Broedl UC; EMPA-
REG PIO™ trial investigators. Empagliflozin improves glycaemic and weight control as add-
on therapy to pioglitazone or pioglitazone plus metformin in patients with type 2 diabetes: a 
24-week, randomized, placebo-controlled trial. Diabetes Obes Metab. 2014 Feb;16(2):147-58. 
doi: 10.1111/dom.12188
[5]
Ferrannini E, Berk A, Hantel S, Pinnetti S, Hach T, Woerle HJ, Broedl UC. Long-term safety 
and efficacy of empagliflozin, sitagliptin, and metformin: an active-controlled, parallel-group, 
randomized, 78-week open-label extension study in patients with type 2 diabetes. Diabetes 
Care. 2013 Dec;36(12):4015-21. doi: 10.2337/dc13-0663
[6]
Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, et al; 
EMPA-REG OUTCOME Investigators. Empagliflozin, Cardiovascular Outcomes, and 
Mortality in Type 2 Diabetes. N Engl J Med. 2015 Nov 26;373(22):2117-28. doi: 
10.1056/NEJMoa1504720
[7]
Fitchett D, Inzucchi SE, Cannon CP, McGuire DK, Scirica BM, Johansen OE, Sambevski S, 
et al. Empagliflozin Reduced Mortality and Hospitalization for Heart Failure Across the 
Spectrum of Cardiovascular Risk in the EMPA-REG OUTCOME Trial. Circulation. 2019 
Mar 12;139(11):1384-1395. doi: 10.1161/CIRCULATIONAHA.118.037778
[8]
Packer M, Butler J, Filippatos GS, Jamal W, Salsali A, Schnee J, Kimura K, et al; 
EMPEROR-Reduced Trial Committees and Investigators. Evaluation of the effect of sodium-
glucose co-transporter 2 inhibition with empagliflozin on morbidity and mortality of patients 
with chronic heart failure and a reduced ejection fraction: rationale for and design of the 
EMPEROR-Reduced trial. Eur J Heart Fail. 2019 Oct;21(10):1270-1278. doi: 
10.1002/ejhf.1536
[9]
Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, Januzzi J, et al; 
EMPEROR-Reduced Trial Investigators. Cardiovascular and Renal Outcomes with 
Empagliflozin in Heart Failure. N Engl J Med. 2020 Oct 8;383(15):1413-1424. doi: 
10.1056/NEJMoa2022190
[10]
Jardiance® SmPC website.ema.europa.eu/en/medicines/human/EPAR/jardiance#product-
information-section; last accessed on 15.09.2022)

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[11]
Anker SD, Butler J, Filippatos G, Ferreira JP, Bocchi E, Böhm M, Brunner-La Rocca HP, et 
al. EMPEROR-Preserved Trial Investigators. Empagliflozin in Heart Failure with a 
Preserved Ejection Fraction. N Engl J Med. 2021 Oct 14;385(16):1451-1461. doi: 
10.1056/NEJMoa2107038
[12]
Clinical Outcome Assessments (COA) - Qualification Submissions Office of Cardiology 
Hematology, Endocrinology, and Nephrology (OCEHM) Division of Cardiovascular and 
Nephrology (DCN). DDT COA #000084: Kansas City Cardiomyopathy Questionnaire 
(KCCQ). website.fda.gov/drugs/clinical-outcome-assessment-coa-qualification-program/ddt-
coa-000084-kansas-city-cardiomyopathy-questionnaire-kccq (last assessed on 02.08.2021)
[13]
US-FDA. Treatment for Heart Failure: Endpoints for Drug Development Guidance for
Industry. website.fda.gov/regulatory-information/search-fda-guidance-documents/treatment-
heart-failure-endpoints-drug-development-guidance-industry (last assessed on 02.08.2021)
[14]
Green CP, Porter CB, Bresnahan DR, Spertus JA. Development and evaluation of the Kansas 
City Cardiomyopathy Questionnaire: a new health status measure for heart failure. J Am Coll 
Cardiol. 2000 Apr;35(5):1245-55. doi: 10.1016/s0735-1097(00)00531-3
[15]
Santos-Gallego CG, Vargas-Delgado AP, Requena-Ibanez JA, Garcia-Ropero A, Mancini D,
Pinney S, Macaluso F, et al; EMPA-TROPISM (ATRU-4) Investigators. Randomized Trial of 
Empagliflozin in Nondiabetic Patients With Heart Failure and Reduced Ejection Fraction. J 
Am Coll Cardiol. 2021 Jan 26;77(3):243-255. doi: 10.1016/j.jacc.2020.11.008
[16]
Butler J, Filippatos G, Jamal Siddiqi T, Brueckmann M, Böhm M, Chopra VK, Pedro Ferreira 
J, et al. Empagliflozin, Health Status, and Quality of Life in Patients With Heart Failure and 
Preserved Ejection Fraction: The EMPEROR-Preserved Trial. Circulation. 2022 Jan 
18;145(3):184-193. doi: 10.1161/CIRCULATIONAHA.121.057812
[17]
Greene SJ, Fonarow GC, DeVore AD, Sharma PP, Vaduganathan M, Albert NM, Duffy CI, et 
al. Titration of Medical Therapy for Heart Failure With Reduced Ejection Fraction. J Am Coll 
Cardiol. 2019 May 21;73(19):2365-2383. doi: 10.1016/j.jacc.2019.02.015
13.2
UNPUBLISHED REFERENCES
Not applicable.

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14.
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
Not applicable

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15.
ANNEX 2 ADDITIONAL INFORMATION
None.