Conditions: Heart Failure
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 530
Healthy volunteers: no

Brief summary:
This is a study in adults who are in hospital for acute heart failure. The purpose of this study is to find out whether starting to take a medicine called empagliflozin soon after first being treated in hospital helps people with acute heart failure.

Participants are in the study for about 3 months. At the beginning, participants are still in hospital. Later, they visit the hospital about 3 times and get 1 phone call. Participants are put into 2 groups by chance. One group takes 1 empagliflozin tablet a day. The other group takes

1 placebo tablet a day. Placebo tablets look like empagliflozin tablets but do not contain any medicine. Empagliflozin belongs to a class of medicines known as SGLT-2 inhibitors. It is used to treat type 2 diabetes.

During the study, the doctors check whether participants have additional heart failure events like needing to go to the hospital again because of heart failure. The participants answer questions about how their heart failure affects their life. We then compare the results between the empagliflozin and placebo groups. The doctors also regularly check the general health of the participants.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Empagliflozin intervention 2: Placebo to Empagliflozin
Intervention descriptions: intervention 1: Film-coated tablet intervention 2: Film-coated tablet

Protocol document:
Prot_000.pdf: 
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Clinical Trial Protocol
TITLE PAGE
Document Number:
c28603082-02
EudraCT No.
2019-002946-19
BI Trial No.
1245-0204
BI Investigational
Medicinal Product(s)
Jardiance®, empagliflozin
Title
A multicentre, randomised, double-blind, 90-day superiority trial 
to evaluate the effect on clinical benefit, safety and tolerability of 
once daily oral EMPagliflozin 10 mg compared to placebo, 
initiated in patients hospitalised for acUte heart faiLure (de novo 
or decompensated chronic HF) who have been StabilisEd 
(EMPULSE)
Lay Title
A study to test the effect of empagliflozin in patients who are in 
hospital for acute heart failure.
Clinical Phase
III
Clinical Trial Leader
Phone: 
Fax: 
Coordinating 
Investigators
Phone: 
/ Fax: 
Phone: 
/ Fax: 
Status
Final Protocol (Revised Protocol (based on global amendment 1))
Version and Date
Version: 2.0
Date: 04 Jun 2020
Page 1 of 87
Proprietary confidential information.
2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Protocol date
09 Oct 2019
Revision date
04 Jun 2020
BI trial number
1245-0204
Title of trial
A multicentre, randomised, double-blind, 90-day superiority trial to 
evaluate the effect on clinical benefit, safety and tolerability of once 
daily oral EMPagliflozin 10 mg compared to placebo, initiated in 
patients hospitalised for acUte heart faiLure (de novo or 
decompensated chronic HF) who have been StabilisEd (EMPULSE)
Coordinating 
Investigators
Phone: 
/ Fax: 
Phone: 
/ Fax: 
Trial site(s)
Multi-centre trial
Clinical phase
III
Trial rationale
Other trials with empagliflozin are performed to assess mortality and 
morbidity, functional capacity and safety of empagliflozin in patients 
with chronic heart failure under stable conditions (i.e. after hospital 
discharge).
Due to its mode of action (MOA), empagliflozin is expected to 
potentially alleviate congestive symptoms seen in patients shortly 
after initial stabilisation of acute cardiac decompensation helping to 
improve heart failure (HF)-related outcomes within several weeks 
after discharge from hospital. 
In-hospital initiation of different therapies is one of the best predictors 
of long-term adherence to medications and long-term improved 
prognosis.
Trial objective(s)
The main objective of this study is to assess whether in-hospital 
administration of empagliflozin results in improvement in HF-related 
outcomes (clinical benefit including death, heart failure events (HFE) 
and the burden of symptoms as assessed by the Kansas City 
Cardiomyopathy Questionnaire (KCCQ) total symptom score) in 
patients hospitalised for acute heart failure (de novo or decompensated 


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chronic HF) and after initial stabilisation.
Secondary objectives are to further assess whether it is safe to start 
empagliflozin in patients admitted to hospital in this setting.
Trial endpoints
Primary Endpoint:

Clinical benefit, a composite of death, number of heart failure 
events (HFEs) (including hospitalisations for heart failure 
(HHFs), urgent heart failure visits and unplanned outpatient 
visits), time to first HFE and change from baseline in Kansas City 
Cardiomyopathy Questionnaire - Total Symptom Score (KCCQ-
TSS) after 90 days of treatment assessed by the win ratio.
Secondary Endpoints:

Improvement in KCCQ-TSS of ≥ 10 points after 90 days of 
treatment

Change from baseline in KCCQ-TSS after 90 days of treatment

Change from baseline in log-transformed N-Terminal Pro-Brain 
Natriuretic Peptide (NT-proBNP) level over 30 days of treatment 
(area under the curve (AUC)).

Days alive and out of hospital from study drug initiation until 30 
days after initial hospital discharge

Days alive and out of hospital from study drug initiation until 90 
days after randomisation

Time to first occurrence of cardiovascular (CV) death or HFE 
until end of trial visit

Occurrence of HHF until 30 days after initial hospital discharge

Occurrence of chronic dialysis or renal transplant or sustained 
reduction of ≥40% estimated glomerular filtration rate (eGFR)
Chronic Kidney Disease Epidemiology Collaboration Equation 
((CKD-EPI)cr), or
o
sustained eGFR (CKD-EPI)cr <15 mL/min/1.73 m2 for 
patients with baseline eGFR ≥30 mL/min/1.73 m2
o
sustained eGFR (CKD-EPI)cr <10 mL/min/1.73 m2 for 
patients with baseline eGFR <30 mL/min/1.73 m2

Diuretic effect as assessed by weight loss per mean daily loop 
diuretic dose after 15 days of treatment 

Diuretic effect as assessed by weight loss per mean daily loop 
diuretic dose after 30 days of treatment
Trial design
Randomised, double-blind, parallel-group, placebo controlled, 
multinational and multicentre study
Total number of patients 
randomised 
Approximately 500
Number of patients on 
each treatment
Approximately 250
Diagnosis
Patients admitted to hospital for treatment of acute HF (de novo or 
decompensated chronic HF). Patients should be randomised after at 
least 24 hours and no later than 5 days after hospital admission. 
Randomisation should occur as soon as the patient is stabilised (see 
inclusion criterion 7).


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Main in- and exclusion 
criteria
Main Inclusion Criteria:

Currently hospitalised for the primary diagnosis of acute heart 
failure (de novo or decompensated chronic HF), regardless of 
ejection fraction (EF). Patients with a diagnosis of hospitalised 
heart failure must have HF symptoms at the time of hospital 
admission

Evidence of left ventricular ejection fraction (LVEF, either 
reduced or preserved EF) as per local reading preferably measured 
during current hospitalisation or in the 12 months prior to 
randomisation

Patients must be randomised after at least 24 hours and no later 
than 5 days after admission, as early as possible after stabilisation
and while still in hospital

Patients must fulfil the following stabilisation criteria (while in 
the hospital):
-
SBP ≥100mm Hg and no symptoms of hypotension in the 
preceding 6 hours, 
-
no increase in i.v. diuretic dose for 6 hours prior to 
randomisation,
-
no i.v. vasodilators including nitrates within the last 6 hours 
prior to randomisation
-
no i.v. inotropic drugs for 24 hours prior to randomisation.

Elevated NT-proBNP ≥ 1600pg/mL or BNP ≥400 pg/mL 
according to the local lab, for patients without atrial fibrillation 
(AF); or elevated NT-proBNP ≥ 2400pg/mL or BNP ≥600 pg/mL 
for patients with AF, measured during the current hospitalisation 
or in the 72 hours prior to hospital admission,. For patients treated 
with an angiotensin receptor neprilysin inhibitor (ARNI) in the 
previous 4 weeks prior to randomisation, only NT-proBNP values 
should be used

HF episode leading to hospitalisation must have been treated with 
a minimum dose of 40 mg of i.v. furosemide (or equivalent i.v. 
loop diuretic defined as 20 mg of torasemide or 1 mg of 
bumetanide)
Main Exclusion Criteria:

Cardiogenic shock

Current hospitalisation for acute heart failure primarily triggered 
by pulmonary embolism, cerebrovascular accident, or acute 
myocardial infarction (AMI)

Current hospitalisation for acute heart failure not caused primarily 
by intravascular volume overload;

Below interventions in the past 30 days prior to randomisation or 
planned during the study:
-
Major cardiac surgery, or TAVI (Transcatheter Aortic Valve 
Implantation), or PCI, or Mitraclip
-
All other surgeries that are considered major according to 


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investigator judgement
-
Implantation of cardiac resynchronisation therapy (CRT)
device 
-
cardiac mechanical support implantation
-
Carotid artery disease revascularisation (stent or surgery)

Acute coronary syndrome / myocardial infarction, stroke or 
transient ischemic attack (TIA) in the past 90 days prior to 
randomisation

Heart transplant recipient, or listed for heart transplant with 
expectation to receive a transplant during the course of this trial 
(according to investigator judgement), or planned for palliative 
care for HF, or currently using left ventricular assist device 
(LVAD) or intra-aortic balloon pump (IABP) or any other type of 
mechanical circulatory support, or patients on mechanical 
ventilation, or patients with planned inotropic support in an out-
patient setting

Haemodynamically significant (severe) uncorrected primary 
cardiac valvular disease planned for surgery or intervention 
during the course of the study (note: secondary mitral 
regurgitation or tricuspid regurgitation due to dilated
cardiomyopathy is not excluded unless planned for surgery or 
intervention during the course of the study)

Impaired renal function, defined as eGFR < 20 mL/min/1.73 m2
as measured during hospitalisation (latest local lab measurement 
before randomisation) or requiring dialysis

Type 1 Diabetes Mellitus (T1DM)

History of ketoacidosis, including diabetic ketoacidosis (DKA)
Test product(s)
Empagliflozin
dose
10 mg q.d.
mode of 
administration
Oral (p.o.)
Comparator product(s)
Placebo
dose
Not applicable
mode of
administration
Oral (p.o.)
Duration of treatment
90 days
Statistical methods
The primary endpoint is clinical benefit (as defined in Section 7.2.2) 
assessed by the win ratio. The statistical model will be a non-
parametric generalised pairwise comparison within HF status strata. 
The variance of the win ratio will be calculated using the asymptotic 
normal U statistics approach.


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FLOW CHART
Trial Periods
Screen
Randomised Treatment
Follow-up
Visit
1
2 (in hospital)
3
4
5 
(EoT)
Early 
Discon-
tinuation 
Visit3
6 (FUP)
(Phone Call) 
a
b2
c2
Days 
-4 to 1
11
3
5
15
30
90
EoT + 7 days
Time window for visits 
(days)
None
±1
±1
±3
±3
±7
+ 7
Informed consent4
X
Demographics
X
Medical history
X
Physical examination
X
X
X
Review of in-/exclusion 
criteria8
X
X
Randomisation (IRT)
X
Weight
X
X
X
X
X
Height
X
Vital signs5
X
X
X
X
X
X
X
Safety lab: blood tests6
X
X
X
X
X
X
X
Safety lab: urinalysis 
including ketones6
X
X
X
X
X
Urine Pregnancy test7
X
X12
X
HbA1c6
X
X
X
eGFR (CKD-EPI)cr 
formula6
X
X
X
X
X
X
X
NT-proBNP (central 
lab)6,8
X
X
X
X
X
X
X
12 lead-ECG9
X
X12
X
KCCQ
X 
X
X
X
X
Patient Global 
Impression of Severity 
of HF Symptoms
X
X
X
X
X
Clinical Congestion 
Score
X
X
X
X
X
X
NYHA Classification
X
X
X
X
X
HCRU
X
X
X
X
X
All AEs/SAEs/AESIs10
X
X
X
X
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
Dispense trial 
medication
X
X
Compliance check
X
X
X
X
Return medication
X
X
X
Completion of patient 
participation (End of 
Study (EOS))
(X)11
X
1
Day of Randomisation / Day of first intake of randomised medication. All Visit 2a assessments must be performed 
before the first dose is taken in hospital. Assessments from Visit 2a will be used as baseline values.
2
Visit 2b and 2c will only be performed, if the patient is still in hospital.


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3
Patients who discontinue trial treatment prematurely should undergo the Early Discontinuation Visit as soon as 
possible and the Follow-up (FUP) Visit 7 days thereafter. Patients should be followed up until Visit 5 (day 90) 
according to their planned visit schedule.
4
Written informed consent must be obtained before any other assessment is performed.
5
Blood pressure and heart rate will be measured with the patient seated and rested for at least 5 minutes. Vital signs at 
Visit 2a need to be checked before first trial medication intake.
6
Samples for central lab (including NT-proBNP) at Visit 2a need to be taken before first trial medication intake.
7
Women of childbearing potential only.
8
For patient’s eligibility, local lab should be used, including a locally performed BNP or NTproBNP result taken during 
the current hospitalisation or in the 72 hours prior hospital admission. At the time the local BNP or NT-proBNP 
sample is collected, the baseline rhythm (e.g. sinus rhythm, AF) of the patient must be clarified using ECG or other 
measures (for example continuous heart monitoring) and documented.
9
In addition to the scheduled ECGs, ECGs should be done and documented at any time of clinical event (e.g. acute 
event of arrhythmia, tachy- or bradycardia, angina, or MI).
10
After the individual patient’s end of the trial the investigator should only report any occurrence of cancer, related 
SAEs and related AESIs of which the investigator may become aware of and only via the SAE form, please see
Section 5.2.7.2.1.
11
Patients who prematurely discontinue medication are followed up according to protocol, and their visit schedule will 
end at their scheduled Visit 5.
12
Urinary pregnancy test and ECG do not need to be repeated if patient prematurely discontinued trial medication and 
these assessments were done at the Early Discontinuation Visit.
For potential modifications of trial conduct in case of restrictions due to COVID-19, please 
refer to Sections 4.1.4, 6.1, 8.1 and 10.5.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................6
TABLE OF CONTENTS ........................................................................................................8
ABBREVIATIONS................................................................................................................12
1.
INTRODUCTION...............................................................................................16
1.1
MEDICAL BACKGROUND.............................................................................16
1.2
DRUG PROFILE................................................................................................17
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................18
1.4
BENEFIT - RISK ASSESSMENT.....................................................................20
1.4.1
Benefits.................................................................................................................20
1.4.2
Risks .....................................................................................................................21
1.4.3
Discussion.............................................................................................................25
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................26
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........26
2.1.1
Main objectives....................................................................................................26
2.1.2
Primary endpoint(s)............................................................................................26
2.1.3
Secondary endpoint(s) ........................................................................................26
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................29
3.1
OVERALL TRIAL DESIGN.............................................................................29
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................30
3.3
SELECTION OF TRIAL POPULATION .......................................................31
3.3.1
Main diagnosis for trial entry ............................................................................32
3.3.2
Inclusion criteria .................................................................................................32
3.3.3
Exclusion criteria ................................................................................................34
3.3.4
Withdrawal of patients from treatment or assessments..................................36
3.3.4.1
Discontinuation of trial treatment .........................................................................37
3.3.4.2
Withdrawal of consent to trial participation .........................................................37
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................38
4.
TREATMENTS...................................................................................................39
4.1
INVESTIGATIONAL TREATMENTS ...........................................................39
4.1.1
Identity of the Investigational Medicinal Products..........................................39
4.1.2
Selection of doses in the trial and dose modifications......................................40
4.1.3
Method of assigning patients to treatment groups...........................................40
4.1.4
Drug assignment and administration of doses for each patient......................41
4.1.5
Blinding and procedures for unblinding...........................................................41


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4.1.5.1
Blinding.................................................................................................................41
4.1.5.2
Unblinding and breaking the code ........................................................................41
4.1.6
Packaging, labelling, and re-supply...................................................................42
4.1.7
Storage conditions...............................................................................................42
4.1.8
Drug accountability.............................................................................................42
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................43
4.2.1
Other treatments and emergency procedures..................................................43
4.2.2
Restrictions ..........................................................................................................44
4.2.2.1
Restrictions regarding concomitant treatment ......................................................44
4.2.2.2
Restrictions on diet and life style..........................................................................45
4.2.2.3
Contraception requirements..................................................................................45
4.3
TREATMENT COMPLIANCE........................................................................45
5.
ASSESSMENTS..................................................................................................46
5.1
ASSESSMENT OF EFFICACY........................................................................46
5.1.1
Clinical Benefit....................................................................................................46
5.1.2
NT-proBNP and BNP .........................................................................................46
5.1.3
Clinical Congestion Score...................................................................................46
5.1.4
New York Heart Association classification.......................................................47
5.1.5
Patient Global Impression of Severity of Heart Failure Symptoms...............48
5.2
ASSESSMENT OF SAFETY.............................................................................48
5.2.1
Physical examination ..........................................................................................48
5.2.2
Vital signs.............................................................................................................48
5.2.3
Body weight and height ......................................................................................49
5.2.4
Safety laboratory parameters ............................................................................49
5.2.4.1
Renal Function......................................................................................................50
5.2.4.2
Pregnancy Testing.................................................................................................51
5.2.4.3
Criteria for hypoglycaemic events........................................................................51
5.2.4.4
Urinary tract infection and genital infections .......................................................51
5.2.5
Electrocardiogram ..............................................................................................51
5.2.6
Other safety parameters.....................................................................................51
5.2.7
Assessment of adverse events.............................................................................52
5.2.7.1
Definitions of AEs ................................................................................................52
5.2.7.1.1
Adverse event........................................................................................................52
5.2.7.1.2
Serious adverse event............................................................................................52
5.2.7.1.3
AEs considered “Always Serious”........................................................................52
5.2.7.1.4
Adverse events of special interest.........................................................................53
5.2.7.1.5
Intensity (severity) of AEs....................................................................................54
5.2.7.1.6
Causal relationship of AEs....................................................................................54
5.2.7.2
Adverse event collection and reporting ................................................................55
5.2.7.2.1
AE Collection........................................................................................................55
5.2.7.2.2
AE reporting to the sponsor and timelines............................................................55
5.2.7.2.3
Pregnancy..............................................................................................................56
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................56
5.4
ASSESSMENT OF BIOMARKER(S) ..............................................................56


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5.5
BIOBANKING ....................................................................................................56
5.6
OTHER ASSESSMENTS...................................................................................57
5.6.1
Health Care Resource Utilisation (HCRU).......................................................57
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................57
6.
INVESTIGATIONAL PLAN.............................................................................58
6.1
VISIT SCHEDULE.............................................................................................58
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................58
6.2.1
Screening and run-in period(s)..........................................................................58
6.2.2
Treatment period(s)............................................................................................59
6.2.3
Follow-up period and trial completion..............................................................60
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................61
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................61
7.2
PLANNED ANALYSES.....................................................................................61
7.2.1
General considerations .......................................................................................61
7.2.2
Primary endpoint analyses.................................................................................62
7.2.3
Secondary endpoint analyses .............................................................................63
7.2.5
Safety analyses.....................................................................................................64
7.2.6
Interim Analyses .................................................................................................65
7.3
HANDLING OF MISSING DATA ...................................................................65
7.4
RANDOMISATION ...........................................................................................65
7.5
DETERMINATION OF SAMPLE SIZE .........................................................65
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........67
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................67
8.2
DATA QUALITY ASSURANCE ......................................................................68
8.3
RECORDS...........................................................................................................68
8.3.1
Source documents ...............................................................................................68
8.3.2
Direct access to source data and documents.....................................................69
8.3.3
Storage period of records ...................................................................................69
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................70
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........70
8.6
TRIAL MILESTONES.......................................................................................70
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................71
9.
REFERENCES....................................................................................................73
9.1
PUBLISHED REFERENCES............................................................................73
9.2
UNPUBLISHED REFERENCES......................................................................76
10.
APPENDICES.....................................................................................................77
10.1
KCCQ (KANSAS CITY CARDIOMYOPATHY QUESTIONNAIRE)........77
10.2
INCLUSION OF ILLITERATE PATIENTS - KCCQ ...................................79


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10.3
PATIENT GLOBAL IMPRESSION OF SEVERITY OF HEART 
FAILURE SYMPTOMS: SHORTNESS OF BREATH, FATIGUE AND 
SWELLING.........................................................................................................79
10.4
ACCEPTED FORMS OF CONTRACEPTION FOR PATIENTS IN
ITALY..................................................................................................................79
10.5
POTENTIAL MODIFICATION OF TRIAL CONDUCT IN CASE OF 
RESTRICTIONS DUE TO COVID-19.............................................................79
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................82
11.1
GLOBAL AMENDMENT 1 ..............................................................................82


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ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Event of Special Interest
AF
Atrial Fibrillation
ALCOA
Attributable, Legible, Contemporaneous, Original, Accurate 
ALT
Alanine Aminotransferase
AMI
Acute myocardial infarction
ANCOVA
Analysis of Covariance
ARNI
Angiotensin Receptor Neprilysin Inhibitor
AST
Aspartate Aminotransferase
AUC
Area under the Curve
BI
Boehringer Ingelheim
BNP
Brain Natriuretic Peptide
BUN
Blood Urea Nitrogen
CA
Competent Authority
CEC
Clinical Event Committee
CHF
Chronic Heart Failure
CK
Creatine Kinase
CKD-EPlcr
Chronic Kidney Disease Epidemiology Collaboration Equation
COPD
Chronic Obstructive Pulmonary Disease
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
CRO
Contract Research Organisation
CRT
Cardiac resynchronisation therapy
CT
Computed Tomography
CT Leader
Clinical Trial Leader
CT Manager
Clinical Trial Manager
CTP
Clinical Trial Protocol
CV
Cardiovascular
DILI
Drug Induced Liver Injury
DKA
Diabetic Ketoacidosis
DM
Diabetes Mellitus


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DMC
Data Monitoring Committee
DBP
Diastolic Blood Pressure
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
eDC
Electronic Data Capture
EF
Ejection Fraction
EOS
End of Study
eGFR
Estimated Glomerular Filtration Rate
EMPA-REG
Empagliflozin – Reducing Excess Glucose
EoT
End of Treatment
EU
European Union
EudraCT
European Clinical Trials Database
ExCom
Executive Committee
FDA
Food and Drug Administration
FUP
Follow-up
γ-GT
Gamma-Glutamyl Transferase
GCP
Good Clinical Practice
GI
Gastrointestinal
GMP
Good Manufacturing Practice
HA
Health Authority
Hb
Haemoglobin
HbA1c
Glycosylated haemoglobin
HCRU
Health Care Resource Utilisation
HDL
High Density Lipoprotein
HF
Heart Failure
HFE
Heart Failure Event
HFmrEF
Heart Failure with mid-range Ejection Fraction
HFpEF
Heart Failure with Preserved Ejection Fraction
HFrEF
Heart Failure with Reduced Ejection Fraction
HHF
Hospitalisation for Heart Failure
HR
Hazard Ratio
i.v.
intravenous


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IABP
Intra-Aortic Balloon Pump
IB
Investigator’s Brochure
ICD
Implantable Cardioverter Defibrillator
ICF
Informed Consent Form
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
ITT
Intention To Treat
JVP
Jugular Venous Pressure
KCCQ
Kansas City Cardiomyopathy Questionnaire
KCCQ-CSS
Kansas City Cardiomyopathy Questionnaire - Clinical Summary Score
KCCQ-TSS
Kansas City Cardiomyopathy Questionnaire - Total Symptom Score
LDL
Low-Density Lipoprotein
LPLT
Last Patient Last Treatment
LVAD
Left Ventricular Assist Device
LVEF
Left Ventricular Ejection Fraction
MACE
Major Adverse Cardiovascular Events
MedDRA
Medical Dictionary for Drug Regulatory Activities
MMRM
Mixed Model Repeated Measure
MOA
Mode of Action
MRI
Magnetic Resonance Imaging
NCC
National Coordinator Committee
NT-proBNP
N-Terminal Pro-Brain Natriuretic Peptide
NYHA
New York Heart Association
OPU
Operative Unit
PCI
Percutaneous coronary intervention
PGI-S
Patient Global Impression of Severity of Heart Failure Symptoms
PPS
Per Protocol Set
PRO
Patient Reported Outcome
PV
Pharmacovigilance


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q.d.
quaque die (once a day)
RA
Regulatory Authority
RBC
Red Blood Cells / Erythrocytes
REP
Residual Effect Period
RS
Randomised Set
SAE
Serious Adverse Event
SBP
Systolic Blood Pressure
SGLT-1
Sodium Glucose Co-Transporter 1
SGLT-2
Sodium Glucose Co-Transporter 2
SMQ
Standardised MedDRA Query
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reactions
T1DM
Type 1 Diabetes Mellitus
T2DM
Type 2 Diabetes Mellitus
TAVI
Transcatheter Aortic Valve Implantation
TIA
Transient Ischemic Attack
TMF
Trial Master File
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
TSS
Total Symptom Score
ULN
Upper Level of Normal
UTI
Urinary Tract Infections
VT
Ventricular Tachycardia
WBC
White Blood Cells / Leukocytes
WHO
World Health Organisation
WOCBP
Woman of childbearing potential


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Heart failure (HF) is one of the most prevalent chronic diseases associated with high 
mortality and morbidity. Over 22 million people around the world suffer from chronic heart 
failure (CHF), of which more than 5.5 million live in the US. Patients with HF are at high 
risk of mortality and morbidity, 50% die within 5 years of their diagnosis of HF and a large 
number are re-hospitalised for exacerbation of HF symptoms [P16-03952, P16-05920]. Heart 
failure is the most frequent cause of hospital admission among patients 65 years or older 
[P16-03952], and there are over 1 million hospitalised patients each year with HF as a 
primary diagnosis [R19-2918].
The cost burden of treating patients with HF is estimated to be $32 billion a year, and 
expected to rise to $70 billion a year by 2030. Approximately 80% of the cost is related to 
hospital admission [R19-2917].
Two main types of HF have been defined mainly based on the left ventricular ejection 
fraction (LVEF) and also other structural changes in the heart. They consist of heart failure 
with reduced EF (HFrEF) ≤40% and heart failure with preserved EF (HFpEF) >40%. 
Relative prevalence of HFrEF among HF patients is approximately 50% [R16-1528]. 
European Society of Cardiology in their 2016 guideline introduced a third type of heart 
failure with LVEF ranging between 40-49% named heart failure with mid-range ejection 
fraction (HFmrEF). The exact characteristics of these patients, response to therapy or 
prognosis is yet to be determined. In this trial, HF patients with full spectrum of EF are 
allowed to participate.
Outcomes for patients after a hospitalisation for HF (HHF) remain poor. Among patients with 
HF, 40-50% demonstrate worsening of HF symptoms, and 30-40% are re-hospitalised within 
6 months after discharge from hospital [R19-2916, R19-2915]. After HHF, the one-year 
mortality rate is high and essentially not different between patients with preserved or reduced 
LVEF [R16-2217], underscoring a high unmet medical need in this population.
Most hospital admissions for acute decompensation of HF are due to volume overload, 
evident by weight gain or information gathered from haemodynamic monitors or insertable 
devices [R19-2914]. In addition, despite apparent symptom control at the time of discharge 
from hospital, up to 40% of patients still have residual congestion [R19-2913].
The current treatment strategy for patients hospitalised for acute cardiac decompensation is 
mainly focused around maintaining previously established guideline directed medical 
therapy, blood pressure stabilisation, optimising volume status, in HFrEF pts initiating life-
saving therapies, and initiating beta-blockers if indicated [P13-06404]. Based on available 
data, in well-selected patients who are haemodynamically stable during hospitalisation for 
HF, guideline-recommended HF-related medications can be safely initiated [R19-2924], 
including a recent trial of sacubitril/valsartan, which demonstrated safe and efficacious use in 
stabilised patients with acute decompensated heart failure with low EF before discharge 
[R19-2932].


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In-hospital initiation of different therapies is one of the best predictors of long-term 
adherence to medications [R19-2911, R19-2919, R19-2921] and long-term improvement in 
prognosis [R19-2924].
Empagliflozin is an orally available inhibitor of the renal dependent sodium glucose 
cotransporter 2 (SGLT-2), promoting urinary glucose excretion. Empagliflozin is indicated 
for reduction of blood glucose in patients with Type 2 Diabetes Mellitus (T2DM), and for 
cardiovascular (CV) death risk reduction in patients with T2DM and established CV disease. 
Empagliflozin also reduces blood pressure, arterial stiffness and measures of myocardial 
workload, likely through various mechanisms, as well as improving other CV risk factors 
(e.g. uric acid, visceral fat mass, albuminuria; [P15-00589, P15-09541].
In 2010, BI initiated the EMPA-REG (Empagliflozin – Reducing Excess Glucose) 
OUTCOME trial to explore the CV benefit of the drug as well as to establish the CV safety of 
empagliflozin [P15-09840]. This trial was completed in 2015 and showed that empagliflozin, 
when given in addition to standard of care treatment in high CV risk patients with T2DM, 
reduces the risk of 3-point major adverse cardiovascular events (MACE) by 14%, which was 
mostly driven by a 38% reduction in CV death. Furthermore, this trial demonstrated a relative
reduction in the prespecified and adjudicated composite outcome of CV death or HHF by 
34% and HHF by 35%.
Consistent with the main results of the EMPA-REG OUTCOME trial, in approximately 10% 
of the trial population who had investigator-reported heart failure at baseline (with subtype of 
heart failure not characterized), empagliflozin showed reduction in CV death, HHF, and the 
composite of HHF or CV death [P16-01253].
In the EMPA-REG OUTCOME trial, empagliflozin was associated with a lower risk of post-
acute heart failure rehospitalisation and mortality [P19-01985]. These results indicate that 
treatment with empagliflozin may play a role in reducing the risk in the post-acute HF period, 
with a significant early impact on HF hospital readmissions and mortality.
Currently, two large clinical outcome trials are ongoing in patients with chronic HFpEF 
(EMPEROR-preserved) or HFrEF (EMPEROR-reduced) to evaluate the effect of 
empagliflozin for the reduction of cardiovascular death and heart failure hospitalisation.
In addition, two clinical trials in patients with chronic HFpEF (EMPERIAL-preserved
[c26554599-01]) or HFrEF (EMPERIAL-reduced [c26554767-01]) to evaluate the effect of 
empagliflozin on exercise ability using the 6 minute walk test are completed.
It should be noted, that with the exception of smaller investigator-initiated case studies, no 
prior clinical trial has assessed the effect of empagliflozin in patients hospitalized with HF.
1.2
DRUG PROFILE
Empagliflozin is an orally available, potent, and selective inhibitor of the renal SGLT-2. Its 
selective inhibition reduces renal reabsorption of sodium and glucose. This leads to both 
increased urinary sodium and glucose excretion. While urinary sodium excretion returns to 


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near normal within a few days of empagliflozin administration, the effect on urinary glucose 
continues for as long as the medication is used.
Empagliflozin has been developed for the treatment of T2DM, and has received marketing 
approval in various regions including for example the European Union, Latin American 
countries, USA and Japan where it is marketed under the brand name Jardiance®.
For a more detailed description of the drug profile please refer to the current Investigator’s 
Brochure (IB) [c01678844] and local prescribing information for empagliflozin.
The Residual Effect Period (REP) of empagliflozin is 7 days. This is the period after the last 
dose with measurable drug levels and/or pharmacodynamic effects still likely to be present.
1.3
RATIONALE FOR PERFORMING THE TRIAL
Outcomes for patients after a HHF remain poor but in-hospital initiation of different therapies 
is one of the best predictors of long-term adherence to medications [R19-2911, R19-2919, 
R19-2920] and long-term improved prognosis [R19-2924], see Section 1.1 for further details.
For empagliflozin, the mode of action (MOA) suggests a potential for improving patients` 
fluid retention and congestion in the context of cardiac decompensation, which is the rational 
for performing this study:

The glucosuria mediated osmotic diuresis, as well as natriuresis, is thought to result in 
long-lasting haemodynamic changes, less extracellular volume, increase of 
haemoglobin, shift in fuel supply from glucose to fat oxidation and towards more 
energy-efficient ketones, possible reduction of vascular wall stress, decrease of 
ventricular load and improving cardiac function [P15-00589, P15-09541]. While 
empagliflozin lowers blood pressure, this change is not associated with an increase in 
heart rate unlike what has been observed for vasodilators [P14-01668].

The described effects start as early as with the first dose of empagliflozin taken or 
within the first few weeks of its administration [P16-01830], which would be in line 
with the observed early effects on reduction in HHF as shown in the EMPA-REG 
OUTCOME trial. See Figure 1.3: 1.


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Figure 1.3: 1 Kaplan-Meier estimates of time to first heart failure requiring hospitalisation in 
patients with baseline cardiac failure [narrow standardized MedDRA query (SMQ)], pooled 
empagliflozin doses versus placebo-treated set. X-axis: study day [c02695839-01]. 

Patients with HFpEF are thought to benefit from combined beneficial effects of 
empagliflozin (see above). This benefit is expected based on the increased prevalence 
of obesity, hypertension, and anaemia in patients with HFpEF [R17-1562], as these 
concomitant conditions may affect heart failure (obesity: increased peripheral 
resistance; hypertension: increased cardiac workload and oxygen consumption; 
anaemia: reduced cardiac oxygen supply).

Although HFpEF and HFrEF are considered as different disease entities, patients with 
HFrEF are thought to profit from the same combined effects of empagliflozin, with 
potentially different weighting of the individual beneficial effects.

Presently, there are two large clinical outcome trials ongoing with empagliflozin, the 
EMPEROR-reduced (NCT03057977, EudraCT 2017-004073-14) and EMPEROR-
preserved trials (NCT03057951, EudraCT 2017-004072-59), investigating the long-
term CV mortality and morbidity benefits in patients with chronic HFrEF and HFpEF. 
Even if these trials are proven positive for long-term clinical morbidity and mortality, 
it will not be known if in-hospital use of empagliflozin is safe in patients hospitalised 
for acute heart failure, since hospitalised patients were excluded from the EMPEROR 
trials. Due to its fast MOA, empagliflozin is expected to potentially alleviate 
congestive symptoms and residual fluid retention seen in patients with acute heart 
failure helping to stabilise HF-related symptoms within the first few days and weeks
after discharge from hospital.


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As early treatment initiation is important but not covered by the ongoing clinical outcome 
trials in chronic HF, this trial is performed to assess HF-related outcomes (effect on heart 
failure events (HFEs), death and Kansas City Cardiomyopathy Questionnaire – Total 
Symptom Score (KCCQ-TSS)), and safety and tolerability of early initiation of treatment 
with empagliflozin in patients hospitalised for acute HF after stabilisation but still in hospital.
1.4
BENEFIT - RISK ASSESSMENT
Empagliflozin is currently indicated for reduction of blood glucose in patients with T2DM, 
and for CV death risk reduction in patients with T2DM and established CV disease. 
The safety profile of empagliflozin has been well established in over 15000 patients with 
T2DM treated in clinical studies (of which more than 10000 were treated with empagliflozin) 
with maximum treatment duration of 4 years. Empagliflozin was tested in over 4600 patients 
with T2DM and high CV risk for median treatment duration of 2.6 years [P15-09840]. In 
addition, approximately 550 healthy volunteers were exposed to empagliflozin (up to 800 mg 
single dose and up to 50 mg multiple dosing). Based on the mode of action of empagliflozin, 
which is independent of insulin and potential concomitant T2DM, it is not expected that the 
safety profile in patients without T2DM would be different to that in patients with T2DM 
[P17-04479].
Because of the mode of action, blockade of the SGLT2 transporter by empagliflozin leads to 
glucosuria in patients with and without diabetes, although with less average daily glucose 
excretion in non-diabetic patients. Therefore, it is considered likely that the tolerability of 
empagliflozin in non-diabetic patients will be as favourable as in those with T2DM.
Available data from completed and ongoing trials do not indicate safety concerns for non-
diabetic CHF patients, other than those already described for patients with T2DM.
1.4.1
Benefits
A detailed rationale for the use of empagliflozin in HF can be found in Section 1.1 and 1.3.
Patients with HF are thought to benefit from combined effects of empagliflozin such as 
persistent osmodiuresis, reduction in blood pressure, weight loss, increase in haematocrit, and 
changes in cardiometabolic parameters as early as the first few weeks of empagliflozin 
administrations. Due to the combination of positive effects, empagliflozin is expected to 
address the unmet medical need of reducing congestion in this patient population. 
It has been shown in healthy volunteers that dosing with empagliflozin results in glycosuria 
approximating 2/3 the average glucosuria in patients with T2DM. This is similar to the 
amount of glucose lost in T2DM subjects with moderate renal impairment [P13-04190]. 
Because no difference in CV benefit was detected for patients with renal impairment vs. the 
overall population in the EMPA-REG OUTCOME study, it is hypothesised that the amount 
of glucosuria is not the main factor for obtaining CV effects with empagliflozin. In the same 
study, empagliflozin improved the main outcome of CV death and HHF with a similar 
magnitude in patients with low or high levels of glycosylated haemoglobin (HbA1c) at 
baseline, and independent of the amount of HbA1c change throughout the trial. In addition, a 


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mechanistic study in non-diabetic subjects [P16-01830] provide supporting evidence that the 
benefit of empagliflozin in treating HF patients should also be expected in patients without 
diabetes. Taking all the data into consideration, the risk reduction for HF outcome appears to 
be independent of the glycaemic status at baseline or the degree of glycaemic control 
throughout the trial or the amount of glucosuria, which suggests the benefits could be 
achieved in both diabetic and non-diabetic populations. [P15-09840, P18-10152]
1.4.2
Risks
Table 1.4.2: 1:
Known and potential risks of clinical relevance for the study 
population
Known or potential 
risks of clinical 
relevance for this trial
Summary of data, rationale for the 
risk
Mitigation strategy
Investigational Medicinal Product: Empagliflozin
Hypoglycaemia
The risk of hypoglycaemia was 
increased only when empagliflozin 
was used concomitantly with insulin 
and/or sulfonylurea. The risk of 
hypoglycaemia of patients without 
diabetes mellitus (DM) is considered 
very low. In a mechanistic study 
[c11963611-01] subjects without DM 
had an increase of endogenous 
glucose production in response to 
glycosuria due to empagliflozin.
Patients with type 1 diabetes 
mellitus (T1DM) are excluded 
from the study.
Guidance for the investigator 
provided in the IB.
Volume depletion
Empagliflozin may selectively 
reduce interstitial volume with 
minimal change in intravascular 
volume.
Polyuria and consequent dehydration 
and hypotension were identified as 
risks in patients treated with 
empagliflozin, especially patients 
with known CV disease, history of 
hypotension, taking diuretics, other 
antihypertensive drugs, or elderly 
patients aged 75 years and older.
[P19-02151]
Hospitalised patients will be 
randomised after diuretics 
stabilisation.
Guidance for the investigator 
provided in the IB. 
Information and 
recommendations for the 
patients provided in the 
Informed Consent Form (ICF).


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Table 1.4.2: 1:
Known and potential risks of clinical relevance for the study 
population (cont.)
Known or potential 
risks of clinical 
relevance for this trial
Summary of data, rationale for the 
risk
Mitigation strategy
Investigational Medicinal Product: Empagliflozin
Diabetic ketoacidosis 
(DKA)
Rare cases of DKA, including fatal 
cases, were reported in patients 
treated with SGLT2-inhibitors. In 
patients treated with SGLT2-
inhibitors DKA may occur with 
lower than usual glucose values. The 
risk of DKA is increased in patients 
with lower than needed insulin 
intake, T1DM, low carbohydrate 
intake, acute illness, major trauma, 
operation, severe dehydration or 
alcohol use.
Patients with T1DM are 
excluded from the study.
Guidance for the investigator 
provided in the IB. Training 
will be provided. Information 
and recommendations for the 
patients provided in the ICF.
DKA is an adverse even of 
special interest (AESI). Cases 
reported as DKA or metabolic 
acidosis are adjudicated. (see 
Sections 4.2.1 and 8.7; details 
are also described in the 
adjudication charter) 
Complicated urinary 
tract infections (UTI)
Cases of complicated UTI, including 
pyelonephritis and urosepsis were 
reported in patients treated with 
empagliflozin.
Guidance for the investigator 
provided in the IB. 
Information and 
recommendations for the 
patients provided in the ICF.
Necrotizing fasciitis of 
perineum (Fournier’s 
gangrene)
Rare cases of Fournier’s gangrene, 
including fatal cases, were reported 
in patients treated with SGLT2-
inhibitors.
Guidance for the investigator 
provided in the IB. 
Information and 
recommendations for the 
patients provided in the ICF.
Hypersensitivity
The risks of allergic skin reactions 
(e.g. rash, urticaria) and angioedema 
were identified for empagliflozin 
based on post-marketing experience.
As with all drugs, the risk of severe 
and unexpected allergic reactions 
cannot be excluded.
Patients with hypersensitivity 
to empagliflozin are excluded 
from trial participation.


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Table 1.4.2: 1:
Known and potential risks of clinical relevance for the study 
population (cont.)
Known or potential 
risks of clinical 
relevance for this trial
Summary of data, rationale for the 
risk
Mitigation strategy
Investigational Medicinal Product: Empagliflozin
Drug-induced liver 
injury (DILI)
No risk of DILI was identified for 
empagliflozin. However, DILI 
generally can be severe and lead to 
fatal outcome or need of liver 
transplant. Therefore, careful 
monitoring and assessment of 
patients for potential DILI is needed.
Parameters for potential liver 
injury are included in the 
safety laboratory.
Cases of liver impairment are 
defined as an AESI. Severe 
cases of liver impairment are 
adjudicated. (see Sections 
5.2.4, 5.2.7 and 8.7; details are 
also described in the 
adjudication charter)
Renal safety
In clinical trials in patients with DM, 
the incidence of renal impairment 
was similar to placebo. An initial 
decrease of estimated glomerular 
filtration rate (eGFR) was seen in 
patients treated with empagliflozin, 
which improved during continuous 
treatment or discontinuation of 
empagliflozin.
Cases of renal impairment, including 
requiring dialysis, were reported in 
patients using SGLT2-inhibitors. Due 
to the renal mode of action and risk 
of volume depletion, the renal safety 
should be monitored.
Parameters for potential renal 
impairment are included in the 
safety laboratory.
Cases of renal impairment are 
defined as an AESI (see 
Sections 5.2.4 and 5.2.7.1.4).
Women of childbearing 
potential (WOCBP)
The safety of empagliflozin in 
pregnant women was not established.
In accordance with 
international regulatory 
guidelines, WOCBP are 
excluded from trial 
participation unless they agree 
to use highly effective 
contraceptive method.
All WOCBP undergo
pregnancy testing before being 
randomised.


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Known and potential risks in healthy volunteers and patients with T2DM:
For the main risks, please refer to Table 1.4.2: 1
In clinical studies, empagliflozin was well tolerated in both healthy volunteers and patients 
with T2DM including patients with high CV risk. The frequency of overall adverse events 
(AEs), AEs leading to discontinuation and serious adverse events (SAEs) were comparable to 
placebo [c01678844].
In general there was a small increase in frequency of urinary tract infection (UTI) compared 
to placebo. There was an increase in frequency of genital infections with the use of 
empagliflozin. There was a small increase in total cholesterol, low-density lipoprotein (LDL) 
cholesterol and high-density lipoprotein (HDL) cholesterol and no significant changes in 
triglycerides. No clinically relevant changes in electrolytes were observed with empagliflozin 
[c01678844].
Known and potential risks in patients with CHF and without T2DM:
In the empagliflozin HF program including two ongoing large EMPEROR outcome trials, 
and two EMPERIAL exercise capacity trials (with more than 7500 patients being followed-
up as of May 2019), the frequencies of overall adverse events (AE), severe AE, serious AE, 
and AE leading to treatment discontinuation reported in patients without DM were similar or 
lower than the ones reported in patients with DM and consistent with the known safety 
reporting described in the Investigator Brochure. The frequency of AE of hypoglycaemia in 
patients without DM was lower than in patients with DM.
As of July 2019 based on blinded data review there has been no severe hypoglycaemia (i.e. 
requiring assistance) or serious hypoglycaemic events and no case of ketoacidosis reported in 
patients without DM and no other safety concerns were raised in this population.
Adverse events related to volume depletion, hypotension, urinary tract infections and genital 
infections in patients without DM were reported with similar frequency as in patients with 
DM.
Many patients with HF have renal impairment, and to ensure that the trial results reflect this 
population, patients with estimated glomerular filtration rate (eGFR) ≥ 20 ml/min/1.73m2 can 
be included. In the EMPA-REG Outcome trial, the cardiovascular benefits for empagliflozin 
were not driven by its pharmacological effect of lowering blood glucose and were 
consistently noted in patients with different degrees of renal impairment, including 540 
patients with eGFR between > 30 and < 45 ml/min/1.73m2. In previous trials in patients with 
T2DM, the safety profile in moderate and severe renal impairment was comparable to the 
overall trial population [P17-10453].
In the ongoing EMPEROR trials there have been more than 1300 patients with eGFR 
between ≥ 30 and < 45 ml/min/1.73m2 with no safety issue identified to date. As part of the 
periodic Data Monitoring Committee (DMC) review, the safety in more than 400 patients 
with eGFR less than 30 ml/min/1.73m2 has also been specifically evaluated and as of July 
2019 there have been no safety issues. 


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In addition, a dapagliflozin outcome trial in over 4700 patients with HFrEF showed a 
significant risk reduction in the composite primary outcome of CV death and HHF with a 
similar safety profile compared to placebo. In this trial, patients without DM (nearly 60%) 
also showed a positive trend towards improvement of CV death and HHF and a safety profile 
similar to patients with DM. There was no increased risk of hypoglycaemia or ketoacidosis in 
patients without DM [R19-3125].
Renal safety will be closely monitored throughout the trial (see Section 5.2.4; Flow Chart).
In addition an independent Data Monitoring Committee (DMC) is implemented who is 
following up on patients` safety in an unblinded manner. Please refer to Section 8.7 for 
details.
Risk evaluation in relation with COVID-19
Patients with chronic heart diseases are at higher risk for severe illness from COVID-19. 
Therefore, in case of local high risk of COVID-19 infection, physical visits to the sites should 
be avoided as much as possible. In the event of restriction to visit the investigator site, certain 
procedures can be done remotely, and local labs can be used instead of central lab. These 
changes are meant to keep the integrity of the trial and they will not affect the benefit-risk of
empagliflozin.
There is no indication that empagliflozin may increase the risk of COVID-19 infection. As 
with any acute illness, empagliflozin during COVID-19 infection has the potential to increase 
the risk of ketoacidosis. The risk of ketoacidosis in case of acute illness is adequately 
addressed in the IB. The study drug should be discontinued in case of severe COVID-19 
disease.
1.4.3
Discussion
The overall tolerability and safety profile, as outlined in this Section 1.4 and the evidence as 
summarized in the current Investigator’s Brochure (IB), supports chronic safe administration 
of empagliflozin 10 mg in human studies, specifically in the heart failure population intended
for inclusion into this trial.
Patients will be treated according to standard of care and trial medication will be given in 
addition to standard therapy. It should also be noted that empagliflozin has not been approved 
for the treatment of HF. Given the short duration of the trial, the lack of an indication of 
empagliflozin for the treatment of heart failure and the gap in knowledge in heart failure 
patients in the acute setting, it is justified to include patients with type 2 diabetes mellitus in 
this trial, who may receive other antidiabetic therapies for controlling their glucose levels. 
Therefore, the placebo controlled trial design does not constitute a risk for the population in 
this study.
Due to the combination of positive effects, empagliflozin is expected to address the unmet 
medical need of reducing congestion in the patient population under investigation in this trial.
Overall the potential benefits, coupled with an acceptable safety profile support the initiation 
of the trial.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main objective of this study is to assess whether in-hospital administration of 
empagliflozin results in improvements in HF-related clinical events and patient-reported 
outcomes (death, HFE and KCCQ-TSS as a measure of health status (symptoms)) in patients 
hospitalised for acute heart failure (de novo or decompensated chronic HF) and after initial 
stabilisation.
Secondary objectives are to further assess whether it is safe to start empagliflozin in patients 
admitted to hospital in this setting. See Section 2.1.3.
This trial is part of an investigational clinical trial program of empagliflozin in patients with
HF.
2.1.2
Primary endpoint(s)
The primary endpoint is clinical benefit, a composite of death, number of heart failure events 
(HFE) (including hospitalisations for heart failure (HHFs), urgent heart failure visits and 
unplanned outpatient visits), time to first HFE and change from baseline in KCCQ-TSS after 
90 days of treatment assessed by the win ratio.
2.1.3
Secondary endpoint(s)
Secondary endpoints to assess safety and efficacy in this setting are:

Improvement in KCCQ-TSS of ≥ 10 points after 90 days of treatment.

Change from baseline in KCCQ-TSS after 90 days of treatment.

Change from baseline in log-transformed N-Terminal Pro-Brain Natriuretic Peptide (NT-
proBNP) level over 30 days of treatment (area under the curve (AUC)).

Days alive and out of hospital from study drug initiation until 30 days after initial hospital 
discharge.

Days alive and out of hospital from study drug initiation until 90 days after
randomisation.

Time to first occurrence of CV death or HFE until end of trial visit.

Occurrence of HHF until 30 days after initial hospital discharge.


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
Occurrence of chronic dialysis or renal transplant or sustained1 reduction of ≥40% eGFR 
Chronic Kidney Disease Epidemiology Collaboration Equation ((CKD-EPI)cr), or
o sustained eGFR (CKD-EPI)cr <15 mL/min/1.73 m2 for patients with baseline 
eGFR ≥30 mL/min/1.73 m2
o sustained eGFR (CKD-EPI)cr <10 mL/min/1.73 m2 for patients with baseline 
eGFR <30 mL/min/1.73 m2

Diuretic effect as assessed by weight loss per mean daily loop diuretic dose after 15 days 
of treatment.

Diuretic effect as assessed by weight loss per mean daily loop diuretic dose after 30 days 
of treatment.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN
This is a randomised, double-blind, parallel-group, placebo controlled, multinational and 
multicentre study.
A total of approximately 500 male and female patients admitted to the hospital for acute HF 
will (de novo or decompensated chronic HF) be randomised (1:1) in the study in about 13 
countries. 
The pre-screening period will start when patients are admitted. Screening (Visit 1) and 
randomisation (Visit 2a) can happen on the same day. Randomisation should occur after at 
least 24 hours and no later than 5 days after admission and before discharge when patients 
fulfil criteria to indicate clinical stability including a stable dose of diuretics. Visit 2 consists 
of two further visits (Visit 2b and 2c) that will be performed only if the patient is still in 
hospital. All patients will be treated on top of standard of care. Patients will receive the study 
drug for 90 days. A follow-up phone call will be performed 7 days after the End of Treatment 
Visit.
Figure 3.1: 1 Trial design
Placebo
Empagliflozin 10 mg
Follow
-up
Visit 5
Day 90
Visit 6**
Day 97
(phone 
visit)
End of Treatment
Pre-
Screening
Visit 2a
Day 1
Visit 3
Day 15
Randomisation
Hospitalisation
(in-hospital)*
Visit 2b: Day 3
Visit 2c: Day 5 
Visit 4
Day 30
Visit 1
Day-4 to 1
*Visit 2b and 2c are optional and will only be performed if the patient is still in hospital
** Visit 6 will be performed as a phone visit
Screening


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The primary endpoint will be assessed at Visit 5.
Patients who prematurely stop medication should have an End of Treatment Visit but be 
followed up until their planned Visit 5 (Day 90) according to the visit schedule. 
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
Hospitalisation for HF identifies patients at increased risk of death and re-hospitalisation 
following discharge. In the EMPEROR trials (see Section 1.1) patients hospitalised for HF 
were excluded. 
Since the long-term mortality and morbidity of empagliflozin in patient with chronic HF will 
be assessed in EMPEROR trials, the main objective of this study is to assess whether in-
hospital administration of empagliflozin leads to an improvement in clinical benefit (a 
composite of death, number of HFEs, time to first HFE and change from baseline in KCCQ-
TSS) in patients hospitalised for acute heart failure (de novo or decompensated chronic) and 
after initial stabilisation assessed by the win ratio. Secondary objectives are to further assess 
whether it is safe to start empagliflozin in patients already admitted to hospital in this setting.
Choice of endpoint:
Patient-reported outcomes (PRO) can provide information on a range of patients’ health 
status. Improving patient’s symptoms, physical limitations and quality of life is one of the 
key goals of managing HF, and is endorsed by practice guidelines and the regulators. Health 
authorities, including US FDA, and major payers such as the Center for Medicare and 
Medicaid are increasingly interested in PROs [R19-3040, R19-3126]. To better evaluate the 
effect of empagliflozin on improving health status (symptoms, and physical limitations), the 
Kansas City Cardiomyopathy Questionnaire (KCCQ) will be used in this trial. The KCCQ is 
one of the most validated, clinically responsive and widely used HF PRO instruments [R17-
2687].
In addition, in DAPA-HF, an outcome trial in over 4700 patients with HFrEF, dapagliflozin 
showed significant improvement in change in Kansas City Cardiomyopathy Questionnaire -
Total Symptom Score (KCCQ-TSS) from baseline at 8 months. A similar improvement in 
KCCQ overall summary score and KCCQ-TSS was also detected in DEFINE-HF, a study of 
approximately 260 patients evaluating the effect of dapagliflozin compared to placebo on 
biomarkers, symptoms, and functional status in patients with HFrEF (both with and without 
DM) [R19-3125, R19-3124]. KCCQ is a self-administered questionnaire designed and 
validated to evaluate physical limitations, symptoms (frequency, severity, and changes over 
time), social limitations, self-efficacy, and quality of life in patients with HF (refer to 
Appendix 10.1).
In this trial, the KCCQ-TSS will be assessed by the win ratio as part of a composite clinical
benefit endpoint including mortality and HF events (see Section 7.2.2).
General safety including parameters relevant to the empagliflozin MOA i.e. hypotension and 
renal function will be the focus of the safety assessment in this trial. Although it is likely that 
clinical events like death and hospitalisations will occur in this trial, this study is limited in its 


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statistical power to conclusively assess the effect on morbidity and mortality outcomes with 
the planned sample size.
Control group:
Due to its mode of action, empagliflozin has the potential to be efficacious in treating 
patients’ congestion with HF. However, the effect of empagliflozin in patients with acute 
heart failure (de novo or decompensated chronic) after stabilisation in hospital has not yet 
been systematically assessed in a randomised clinical trial. Currently, two large clinical 
outcome trials are ongoing in patients with HFpEF (EMPEROR-preserved) or HFrEF 
(EMPEROR-reduced) to evaluate empagliflozin for the reduction of cardiovascular death and 
heart failure hospitalisation in patients outside the hospital setting.
The placebo-controlled design is considered ethically acceptable on the basis of appropriate 
criteria for patient selection and discontinuation, the ability to change background therapy to 
maintain, or obtain sufficient levels of haemodynamic and glycaemic control (in patients with 
T2DM) as defined in relevant local and regional guidelines for optimised standard of care.
Patients should be receiving appropriate care as defined by their physician or practitioner for 
all cardiovascular conditions according to the prevailing guidelines. In HFrEF patients, this 
includes, but is not limited to (if indicated and not contraindicated) acetylsalicylic acid, 
statins, a diuretic, an inhibitor of the renin-angiotensin system with or without neprilysin 
inhibitor, a beta-blocker and a mineralocorticoid receptor antagonist, each to be given at 
clinically appropriate doses, and the use of implantable devices like pacemakers or 
implantable cardioverter defibrillators (ICDs, or cardiac resynchronisation therapies (CRTs)). 
This therapy should be selected in the context of local or regional guidelines for primary or 
secondary CV disease prevention.
Duration:
Due to the potential early effect of empagliflozin (see Section 1.1 for mode of action and 
EMPA-REG-OUTCOME results) empagliflozin is expected to exert its effect within a few 
days to weeks of administration.
The primary endpoint is clinical benefit, a composite of death, number of HFEs, time to first 
HFE and change from baseline in KCCQ-TSS at Day 90 assessed by the win ratio.
Thus, a 90 day time point is considered suitable for the assessment of the primary endpoint
and evaluation of empagliflozin safety.
3.3
SELECTION OF TRIAL POPULATION
A total number of approximately 500 patients are planned to be randomised in about 13 
countries and approximately 125 sites.


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The study is planned to be conducted in the US/North America and in Europe and may be 
expanded to additional countries (e.g. in Asia, South America or Eastern Europe) and more 
sites based on patient availability.
Screening of patients for this trial is competitive, i.e. screening for the trial will stop at all 
sites at the same time once a sufficient number of patients has been screened. Investigators 
will be notified about screening completion and will then not be allowed to screen additional 
patients for this trial.
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the Investigator Site File (ISF) irrespective of whether they have been treated 
with investigational drug or not.
If a patient is enrolled in error (does not meet all inclusion criteria or meets one or more 
exclusion criteria on the day of enrolment), the sponsor should be contacted immediately.
3.3.1
Main diagnosis for trial entry
Patients admitted to the hospital for treatment of acute HF (de novo or decompensated 
chronic HF). Patients should be randomised after at least 24 hours and no later than 5 days 
after hospital admission. Randomisation should occur as soon as the patient is stabilised (see 
inclusion criterion 7).
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
1.
Of full age of consent (according to local legislation, at least ≥ 18 years) at screening.
2.
Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial.
3.
Male or female patients. Women of childbearing potential (WOCBP)3 must be ready and 
able to use highly effective methods of birth control per ICH M3 (R2) that result in a low 
failure rate of less than 1% per year when used consistently and correctly. A list of 
contraception methods meeting these criteria is provided in the patient information.
4.
Currently hospitalised for the primary diagnosis of acute heart failure (de novo or 
decompensated chronic HF), regardless of EF. Patients with a diagnosis of hospitalised 
heart failure must have the following HF signs and symptoms at the time of hospital 
admission:
                                                
3 A woman is considered of childbearing potential, i.e. fertile, following menarche and until becoming post-menopausal 
unless permanently sterile.
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
Tubal ligation is NOT a method of permanent sterilisation. A woman who underwent tubal ligation is still considered as 
WOCBP. However tubal ligation is considered as a method of highly effective birth control.
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.


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a.
Persistent dyspnoea at rest or with minimal exertion, and,
b. Signs of fluid overload, at least two of the following must apply:
i. Congestion on chest X-ray,
ii. Rales on chest auscultation,
iii. Clinical relevant oedema (e.g. ≥1+ on a 0 to 3+ scale), indicating 
indentation of skin with mild digital pressure that requires 10 or more 
seconds to resolve in any dependent area including extremities or sacral 
region,
iv. Elevated jugular venous pressure (JVP).
5.
Evidence of LVEF (either reduced or preserved EF, preferably quantitative) as per local 
reading (by e.g. echocardiography, radionuclide ventriculography, invasive angiography, 
MRI or CT) preferably measured during current hospitalisation. A historical LVEF 
assessment may be used if there is no in-hospital measurement and if it was measured 
within 12 months prior to randomisation provided there was no major intervening disease 
affecting EF like MI. The LVEF should preferably be documented in a local report prior 
to randomisation. If no such report is available, LVEF, valve status and relevant 
pathologic cardiac findings from echocardiography or other local readings should be 
mentioned in the source documents.
6.
Patients must be randomised after at least 24 hours and no later than 5 days after
admission, as early as possible after stabilisation and while they are still hospitalised.
7.
Patients must fulfil the following stabilisation criteria (while in the hospital):
-
Systolic BP ≥100mm Hg and no symptoms of hypotension in the preceding 6 hours, 
-
no increase in i.v. diuretic dose for 6 hours prior to randomisation, 
-
no i.v. vasodilators including nitrates within the last 6 hours prior to randomisation
-
no i.v. inotropic drugs for 24 hours prior to randomisation.
8.
Elevated NT-proBNP ≥ 1600 pg/mL or BNP ≥400 pg/mL according to the local lab for 
patients without atrial fibrillation (AF); or elevated NT-proBNP ≥ 2400 pg/mL or BNP 
≥600 pg/mL for patients with AF, measured during the current hospitalisation or in the 
72 hours prior to hospital admission. For patients treated with an angiotensin receptor 
neprilysin inhibitor (ARNI) in the previous 4 weeks prior to randomisation, only NT-
proBNP values should be used.
9.
HF episode leading to hospitalisation must have been treated with a minimum single 
dose of 40 mg of i.v. furosemide (or equivalent i.v. loop diuretic defined as 20 mg of 
torasemide or 1 mg of bumetanide).


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3.3.3
Exclusion criteria
1.
Cardiogenic shock.
2.
Current hospitalisation for acute heart failure primarily triggered by pulmonary 
embolism, cerebrovascular accident, or acute myocardial infarction (AMI)4 diagnosed 
using electrocardiogram (ECG), and/or cardiac imaging and/or coronary angiography.
3.
Current hospitalisation for acute heart failure not caused primarily by intravascular 
volume overload; for example triggered by significant arrhythmia (e.g., sustained 
ventricular tachycardia, or atrial fibrillation/flutter with sustained ventricular response 
>130 beats per minute, or bradycardia with sustained ventricular arrhythmia <45 beats 
per minute), infection/sepsis, severe anaemia, or acute exacerbation of chronic 
obstructive pulmonary disease (COPD).
4.
Below interventions in the past 30 days prior to randomisation or planned during the 
study:
-
Major cardiac surgery (for example coronary artery bypass graft or valve 
replacement), or Transcatheter Aortic Valve Implantation (TAVI), or percutaneous 
coronary intervention (PCI), or Mitraclip
-
All other surgeries that are considered major according to investigator judgement, 
-
Implantation of a cardiac resynchronisation therapy device (CRT) (pacemakers or 
implantable cardioverter defibrillators (ICD) without resynchonization function are 
allowed),
-
cardiac mechanical support implantation
-
Carotid artery disease revascularisation (stent or surgery)
5.
Acute coronary syndromes / myocardial infarction (increase in cardiac enzymes in 
combination with symptoms of ischaemia or newly developed ischaemic ECG changes), 
stroke or TIA in the past 90 days prior to randomisation.
6.
Symptomatic ventricular tachycardia (VT) with syncope in patients without an ICD in 
the past 90 days prior to randomisation.
7.
Current use or prior use of a SGLT-2 inhibitor or combined SGLT-1 and 2 inhibitor in 
the past 90 days prior to randomisation. Discontinuation of a SGLT-2 inhibitor or 
combined SGLT-1 and 2 inhibitor for the purposes of study enrolment is not permitted.
8.
Heart transplant recipient, or listed for heart transplant with expectation to receive a 
transplant during the course of this trial (according to investigator judgement), or 
planned for palliative care for HF, or currently using or plan for left ventricular assist 
device (LVAD) or intra-aortic balloon pump (IABP) or any other type of mechanical 
                                                
4 Please note: Troponin elevations are frequently seen in patients with acute heart failure and therefore are not 
sufficient for a diagnosis of AMI. In order to exclude an AMI, concomitant objective evidence of AMI based on 
typical symptoms, ECG, and/or cardiac imaging and/or coronary angiography should be available.


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circulatory support, or patients on mechanical ventilation, or patients with planned 
inotropic support in an out-patient setting.
9.
Haemodynamically significant (severe) uncorrected primary cardiac valvular disease 
planned for surgery or intervention during the course of the study (note: secondary mitral 
regurgitation or tricuspid regurgitation due to dilated cardiomyopathy is not excluded 
unless planned for surgery or intervention during the course of the study).
10. Cardiomyopathy due to infiltrative diseases (e.g. amyloidosis), accumulation diseases 
(e.g. haemochromatosis, Fabry disease), muscular dystrophies, cardiomyopathy with 
reversible causes (e.g. stress cardiomyopathy), hypertrophic obstructive cardiomyopathy, 
complex (according to investigator`s judgement) congenital heart disease, or known 
pericardial constriction.
11. Heart failure caused by peripartum cardiomyopathy or Tako-Tsubo cardiomyopathy 
diagnosed within the past 6 months, or active myocarditis, or uncorrected thyroid disease, 
or other acute structural heart disease as cause for acute cardiac decompensation (e.g. 
acute mitral cord rupture as cause for hospital admission for heart failure).
12. Symptomatic bradycardia or third degree heart block without a pacemaker.
13. SBP ≥ 180 mmHg at randomisation (confirmed with second measurement after 5 
minutes).
14. Atrial fibrillation or atrial flutter with a documented resting heart rate > 110 bpm in ECG 
performed before randomisation (Visit 2a).
15. Impaired renal function, defined as eGFR < 20 mL/min/1.73 m2 as measured during 
hospitalisation (latest local lab measurement before randomisation) or requiring dialysis.
16. Type 1 Diabetes Mellitus (T1DM).
17. Indication of liver disease, defined by serum levels of either alanine aminotransferase
(ALT) (SGPT), aspartate aminotransferase (AST) (SGOT), or alkaline phosphatase 
above 3 x upper limit of normal (ULN) as measured during hospitalisation (latest local 
lab measurement before randomisation) or history of cirrhosis with evidence of portal 
hypertension such as varices.
18. Haemoglobin < 9 g/dl as measured during hospitalisation (latest local lab measurement 
before randomisation).
19. History of ketoacidosis, including DKA.
20. Gastrointestinal (GI) surgery or GI disorder that could interfere with trial medication 
absorption in the investigator’s opinion.
21. Any documented active or suspected malignancy or history of malignancy within 2 years 
prior to screening, except appropriately treated basal cell carcinoma of the skin or in situ 


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carcinoma of uterine cervix or low risk prostate cancer (biopsy Gleason score of ≤ 6 and 
clinical stage T1c or T2a).
22. Presence of any disease other than heart failure with life expectancy less than 1 year.
23. Decision for palliative care in HF (informed patient decision to adhere to limited heart 
failure treatments only).
24. Patients who must or wish to continue the intake of restricted medications (see Section 
4.2.2) or any drug considered likely to interfere with the safe conduct of the trial
25. Current or previous randomisation in another empagliflozin heart failure trial (i.e. studies 
1245.110, 1245.121, 1245-0167, 1245-0168) or currently enrolled in another 
investigational device or drug trial, or less than 30 days since ending another 
investigational device or drug trial(s), or receiving other investigational treatment(s). 
Patients participating in a purely observational trial will not be excluded.
26. Known allergy or hypersensitivity to empagliflozin or any excipient of the 
Investigational Medicinal Product (IMP), or other SGLT-2 inhibitors.
27. Chronic alcohol or drug abuse or any condition that, in the investigator’s opinion, makes 
them an unreliable trial patient or unlikely to complete the trial.
28. Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
29. Any other clinical condition that would jeopardise patients safety while participating in 
this trial, or may prevent the patient from adhering to the trial protocol.
3.3.4
Withdrawal of patients from treatment or assessments
Patients may discontinue trial treatment or withdraw consent to trial participation as a whole
(“withdrawal of consent”) with very different implications; please see Sections 3.3.4.1 and 
3.3.4.2 below.
An excessive withdrawal rate can have a severe negative impact on the scientific value of the 
trial. The “Intention To Treat (ITT)” analysis requires that all randomised patients be 
followed until trial end even if the trial medication was temporarily interrupted, discontinued 
or never started.
Every effort should be made to keep the patients in the trial: if possible on treatment, or at 
least to collect important trial data.
Measures to control the withdrawal rate include careful patient selection, appropriate 
explanation of the trial requirements and procedures prior to trial enrolment, as well as the
explanation of the consequences of withdrawal. 
The decision to discontinue trial treatment or withdraw consent to trial participation and the 
reason must be documented in the patient files and Case Report Form (CRF). If applicable, 


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consider the requirements for Adverse Event collection reporting (please see Sections 
5.2.7.2.1 and 5.2.7.2).
3.3.4.1
Discontinuation of trial treatment
An individual patient will discontinue trial treatment if:

The patient wants to discontinue trial treatment, without the need to justify the decision.

The patient has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing or 
able to adhere to the trial requirements in the future. 

The patient needs to take concomitant medication that interferes with the investigational 
medicinal product (see Section 4.2.2.1) for restricted medication

The patient can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events, other diseases, or pregnancy).In case of a temporary reason for treatment 
discontinuation, trial treatment should be restarted if medically justified, please see Section
4.1.4.
Given the patient’s agreement, the patient will undergo the procedures for the Early 
Discontinuation Visit as soon as possible after treatment discontinuation and the Follow-up 
Visit as outlined in the Flow Chart and Section 6.2.3.
In addition, if the patient discontinues early, every effort should be made for the patient to 
attend the regularly scheduled study visits and have all study procedures performed except 
those pertaining to drug intake. However if this is not possible, then the remaining visits
should be conducted by phone. In the rare case that even this is not possible, at least vital 
status and information about HFEs should be retrieved and documented at the day of the 
scheduled Visit 5 (Day 90).
If a patient becomes pregnant during the trial, the trial medication will be stopped, the patient 
will be followed up during the trial and until birth or termination of the pregnancy (see 
further details in Section 5.2.7.2).
If new efficacy/safety information becomes available, Boehringer Ingelheim will review the 
benefit-risk-assessment and, if needed, pause or discontinue the trial treatment for all patients 
or take any other appropriate action to guarantee the safety of the trial patients.
3.3.4.2
Withdrawal of consent to trial participation
Patients may withdraw their consent to trial participation at any time without the need to 
justify the decision.
This will however mean that no further information may be collected for the purpose of the 
trial and negative implications for the scientific value may be the consequence. Furthermore 
it may mean that further patient follow up on safety cannot occur.
If a patient wants to withdraw consent, the investigator must be involved in the discussion 
with the patient and explain the difference between trial treatment discontinuation and 
withdrawal of consent to trial participation, as well as explain the options for continued 
follow-up after trial treatment discontinuation, please see Section 3.3.4.1 above.


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3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site.
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial.
3. Deviations from GCP, the trial protocol, or the contract impairing the appropriate conduct 
of the trial.
Further follow up of patients affected will occur as described in Section 3.3.4.1.
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
The trial medication will be provided by Boehringer Ingelheim Pharma GmbH & Co.KG.
4.1.1
Identity of the Investigational Medicinal Products
The characteristics of test products are below:
Table 4.1.1: 1
Test product 1
Substance:
Empagliflozin
Pharmaceutical formulation:
Film-coated tablet
Source:
Boehringer Ingelheim GmbH & Co.KG
Unit strength:
10 mg
Posology
1 tablet once daily
Route of administration:
Oral
Table 4.1.1: 2
Test product 2
Substance:
Placebo to Empagliflozin 10 mg
Pharmaceutical formulation:
Film-coated tablet
Source:
Boehringer Ingelheim GmbH & Co.KG
Unit strength:
-
Posology
1 tablet once daily
Route of administration:
Oral


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4.1.2
Selection of doses in the trial and dose modifications
Empagliflozin 10 mg and 25 mg are approved for the treatment of T2DM.
Empagliflozin exerts its effect by promoting glucosuria and consequent haemodynamic
changes associated with diuresis, improvement in arterial stiffness, blood pressure lowering 
effect with no increase in heart rate and reduction in heart rate multiplied by pressure 
product, an index of myocardial oxygen consumption. These modes of actions support the 
scientific rationale of testing empagliflozin in patients with HF.
In the EMPA-REG-OUTCOME trial both doses were administered to patients with T2DM
and showed to be equally effective in reducing CV death, HHF, and composite of HHF or CV
death in patients with HF at baseline.
In a subgroup analysis, empagliflozin improved the main outcome of CV death and HHF with
a similar magnitude in patients with low or high levels of HbA1c at baseline and irrespective 
of the dose of empagliflozin [P18-10152]. This indicates the risk reduction for this outcome
is independent of the degree of glycaemic control at baseline, suggesting that these benefits 
can be achieved with the 10 mg dose similar to the 25 mg dose in the non-diabetic population. 
The mechanism of action is supported by studies in healthy volunteers where both doses 
were associated with a glucosuria of about 50g per day.
Given the lower exposure with empagliflozin 10 mg and similar general safety, and similar 
observed CV effects for both doses, empagliflozin 10 mg once daily has been selected as the 
dose in this trial.
For further details see current version of the IB [c01678844].
4.1.3
Method of assigning patients to treatment groups
After the assessment of all inclusion and exclusion criteria, each eligible patient will be 
randomised to receive empagliflozin 10 mg, or matching placebo according to a 
randomisation plan in a 1:1 ratio, stratified according to HF status (de novo or 
decompensated chronic) at Visit 2a via Interactive Response Technology (IRT). Note that the 
medication number is different from the patient number (the latter is generated during 
screening via the IRT System).
To facilitate the use of the IRT, the Investigator or delegate will receive a manual including 
all necessary instructions for using the system. A copy of the manual will be available in the 
ISF.
Patient assignment to a treatment group will be determined by a computer generated random 
sequence. Access to the randomisation code will be controlled and documented - for further 
details please refer to Section 4.1.5.1. and 4.1.5.2.
Using this procedure, relevant parties will be blinded to the treatment group assignment.


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4.1.4
Drug assignment and administration of doses for each patient
Patients who qualify will be randomised to one of the treatment groups described in Section 
4.1.1. Trial medication will be dispensed by the pharmacist or the investigator in a double-
blind manner.
IRT will be used to allocate trial medication to patients. At Visit 2a patients will be assigned 
one medication kit for a 30 days treatment period and 5 days of reserve. At Visit 4 patients 
will be assigned two medication kits for 30 days treatment period and 5 days of reserve each.
During the COVID-19 pandemic, there might be situations that would not allow a patient to 
come to the site for the study visit. If the investigator judges it as favourable and safe to 
continue trial medication, trial medication might be shipped from the site to the patient (for 
more details see Sections 6.1, 8.1 and 10.5).
Treatment starts on the day of Visit 2a and ends on the day of Visit 5 (or early 
discontinuation visit). For further details regarding packaging please refer to Section 4.1.6.
From the start of the treatment period patients will be instructed to take the trial medication 
once daily with a glass of water. Empagliflozin can be taken with or without food.
To ensure a dose interval of about 24 hours, the medication should be taken in the morning at 
approximately the same time every day including the days of study visits. If a dose is missed 
by more than 12 hours, that dose should be skipped and the next dose should be taken as 
scheduled. No double doses should be taken.
In case trial medication was discontinued for a temporary reason or by the patient without a 
medical indication, trial treatment can be resumed at any time until Visit 5 (EoT). Trial 
medication should be restarted if and as soon as medically justified (see also Section 3.3.4.1
and 4.2.1).
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
Patients, investigators, central reviewers, and everyone involved in trial conduct or analysis
or with any other interest in this double-blind trial will remain blinded with regard to the 
randomised treatment assignments until after database lock.
The access to the randomisation code will be restricted until its release for analysis.
The DMC will be provided with unblinded data in order to allow them to review efficacy and 
safety and to fulfil their tasks as outlined in the data monitoring committee charter. An 
independent team, not otherwise involved in the conduct of the trial, will provide the 
unblinded results to the DMC.
4.1.5.2
Unblinding and breaking the code
Emergency unblinding will be available to the investigator via IRT. It must only be used in
an emergency situation when the identity of the trial drug must be known to the investigator


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in order to provide appropriate medical treatment or otherwise assure safety of trial
participants. The reason for unblinding must be documented in the source documents and/or 
appropriate CRF page.
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions 
(SUSARs), it may be necessary for a representative from BI’s Pharmacovigilance group to 
access the randomisation code for individual patients during trial conduct. The access to the 
code will only be given to authorised Pharmacovigilance (PV) representatives for processing 
in the PV database system and not be shared further. 
4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI or a designated Contract 
Research Organisation (CRO). They will be packaged and labelled in accordance with the 
principles of Good Manufacturing Practice (GMP). Re-supply to the sites will be managed 
via an IRT system, which will also monitor expiry dates of supplies available at the sites.
For details of packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A
temperature log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the Clinical Research 
Associate (CRA) or the Clinical Trial Manager (CT Manager), as provided in the list of 
contacts, must be contacted immediately.
If the storage conditions are found to be outside the specified range, the process outlined in 
the ISF should be followed.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered by the sponsor 
when the following requirements are fulfilled:

Approval of the clinical trial protocol by the Institutional Review Board (IRB) / ethics 
committee (EC),

Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site,

Approval/notification of the regulatory authority, e.g. competent authority,

Availability of the curriculum vitae of the Principal Investigator,

Availability of a signed and dated clinical trial protocol,

Availability of the proof of a medical license for the Principal Investigator (if applicable), 

Availability of FDA Form 1572 (if applicable).


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Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. Patients should be instructed to return 
unused investigational drug.
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each patient, and the return to the sponsor or warehouse / 
drug distribution centre or alternative disposal of unused products. If applicable, the sponsor 
or warehouse / drug distribution centre will maintain records of the disposal. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational medicinal product and trial
patients. The investigator or designee will maintain records that document adequately that the 
patients were provided the doses specified by the Clinical Trial Protocol (CTP) and reconcile 
all investigational medicinal products received from the sponsor. At the time of return to the 
sponsor <and/or> appointed CRO, the investigator or designee must verify that all unused or 
partially used drug supplies have been returned by the clinical trial patient and that no 
remaining supplies are in the investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
The use of medication for the treatment of HF will be at the discretion of the Investigator and 
should be in accordance with local/international guidelines. 
All concomitant (additional) medications and other therapies should be recorded on the 
appropriate pages of the electronic Case Report Form (eCRF).
Concomitant antidiabetic medications should be adjusted individually as clinically indicated 
by the patient’s usual diabetes care provider. Additional guidance is provided in the IB. 
Restrictions of antidiabetic background therapy are described in Section 4.2.2.
Patients without a diagnosis of DM experiencing repeated or severe symptoms such as 
nervousness, sweating, intense hunger, trembling, weakness and palpitations should contact 
the Investigator or other healthcare professional, as these symptoms might be suggestive of 
hypoglycaemia. In the case of hypoglycaemia, in patients with or without DM, that may put 
the patient at risk (e.g. repeated symptomatic hypoglycaemia or severe hypoglycaemia), 
appropriate care should be provided at the discretion of the Investigator.
Special attention must be paid to the prevention of ketoacidosis. All patients must be made 
aware of this risk and need to be instructed to contact the Investigator or other healthcare 
professional in case of symptoms of metabolic acidosis, ketoacidosis and DKA. 
Cases of DKA have been reported in patients treated with empagliflozin, including fatal cases. 
In a number of reported cases, the presentation of the condition was atypical with only 
moderately increased blood glucose values; below 14 mmol/l (250 mg/dl).


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The risk of DKA must be considered in the event of non-specific symptoms such as nausea, 
vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing, confusion, unusual 
fatigue or sleepiness.
Patients should be assessed and treated for ketoacidosis immediately according to local 
guidelines if these symptoms occur, regardless of blood glucose level. If ketoacidosis is 
suspected, the trial medication should be discontinued, the patient should be evaluated, and 
prompt treatment should be initiated.
Patients who may be at higher risk of ketoacidosis while taking empagliflozin include 
patients on a very low carbohydrate diet (as the combination may further increase ketone 
body production), patients with an acute illness, pancreatic disorders suggesting insulin 
deficiency (e.g. Type 1 diabetes mellitus (T1DM), history of pancreatitis or pancreatic 
surgery), insulin dose reduction (including insulin pump failure), alcohol abuse, severe 
dehydration, and patients with a history of ketoacidosis Empagliflozin should be used with 
caution in these patients. In patients requiring insulin, caution should be taken when the dose 
of insulin is reduced.
In clinical situations known to predispose to ketoacidosis (e.g. prolonged fasting due to acute 
illness or surgery), the Investigator should consider monitoring for ketoacidosis and 
temporarily discontinue the trial medication.
There are no trial specific emergency procedures to be followed.
In patients with heart failure who receive empagliflozin, elderly patients with heart failure 
and in case of conditions that may lead to fluid loss (e.g. gastrointestinal illness), careful 
monitoring of volume status (e.g. physical examination, laboratory tests including 
haematocrit), blood pressure measurement and electrolytes is recommended since 
empagliflozin may potentially lead to hypotension. Temporary interruption of the study drug 
should be considered until the fluid loss is corrected.
Temporary interruption of empagliflozin should be considered in patients with complicated 
urinary tract infections.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
The use of any SGLT-2 inhibitors or combined SGLT-1 and 2 inhibitors except the blinded 
trial medication is prohibited during the course of the trial. This also includes the 7 days 
period between the End of Treatment (EoT) and the Follow-up Visit.
If any restricted treatment is given during the conduct of the trial, the trial medication can be 
discontinued temporarily, or if needed permanently.
If the patient is in need of any additional treatment during this period, this may be given at 
the discretion of the Investigator. The patient can still remain on trial medication.


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4.2.2.2
Restrictions on diet and life style
None.
4.2.2.3
Contraception requirements
Women of childbearing potential must use highly effective methods of birth control per ICH 
M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and 
correctly. A list of contraception methods meeting these criteria is provided in the patient 
information.
4.3
TREATMENT COMPLIANCE
Patients are requested to bring all remaining trial medication including empty package 
material with them when attending visits 3, 4 and 5 (EoT).
Based on tablet counts, treatment compliance will be calculated as shown in the formula 
below. Compliance will be verified by the CRA authorised by the sponsor.
Treatment compliance (%) =
Number of tablets actually taken 100
Number of tablets which should have been taken as 
directed by the investigator
If the number of doses taken is not between 80-120%, site staff will explain to the patient the 
importance of treatment compliance. However, randomised patients will not be discontinued 
for poor compliance without prior discussion with the monitor or designee.
Patients who are not compliant with their medication should again be carefully interviewed 
and again re-informed about the purpose and the conduct of the trial.


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
5.1.1
Clinical Benefit
Clinical benefit is a composite of death, HFEs (including HHFs, urgent heart failure visits
and unplanned outpatient visits) and KCCQ-TSS.
Investigators will evaluate patients at each study visit and assess for any interim 
hospitalisation, urgent heart failure visit or unplanned outpatient visit and record the patient 
response on the dedicated CRFs. Death and HFEs will be categorised by the investigator 
according to pre-specified criteria [R19-3245] (more details can be found in the ISF). 
Attempts should be made to obtain supporting medical records for these healthcare 
interactions.
KCCQ is a commonly used 23 item self-administered questionnaire designed to evaluate
physical limitations, symptoms (frequency, severity, and changes over time), social
limitations, self-efficacy, and quality of life in patients with HF (refer to Appendix 10.1).
The questionnaire takes less than 15 minutes to complete and will be assessed according to the
Flow Chart. Please refer to Section 6.2.2 for order of completion of patient reported outcome 
measures.
The Investigator (or designated site-personnel) should ensure that the patient has access to a
quiet area at the site where he/she can be left alone to record her/his response in the
questionnaire. In instances where a patient cannot give or decide upon a response, no response
should be recorded. The Investigator (or designated site-personnel) should check that all items
have been completed by the patient, but the response to each item should not be scrutinised.
Instructions to patients are included in the questionnaire. The respective procedure for
illiterate patients (if included) is described in the Appendix 10.2.
5.1.2
NT-proBNP and BNP 
NT-proBNP or BNP measurements available from standard of care (local laboratory) will be 
used in all patients to determine eligibility.
NT-proBNP will be obtained at all visits from Visit 2 until Visit 5 (see Flow Chart) using 
central laboratory to investigate a potential effect of the trial medication. 
5.1.3
Clinical Congestion Score
Patient’s congestion will be assessed using a clinician-based outcome assessment of 6 
different signs and symptoms: dyspnoea, orthopnoea, fatigue, jugular venous pressure (JVP) 
(as assessed by the investigator), rales, and oedema. Each category will be assessed through a 
four-measure questionnaire which will be further converted to a standardized 4-point scale 
ranging from 0 to 3 as shown in Table 5.1.3: 1.


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Table 5.1.3: 1
Clinical congestion score
Signs/Symptoms
0
1
2
3
Dyspnoea
None
Seldom
Frequent
Continuous
Orthopnoea
None
Seldom
Frequent
Continuous
Fatigue
None
Seldom
Frequent
Continuous
JVP (cm H2O)
(Jugular Venous 
Pressure5)
≤6
6< JVP < 10
10≤JVP <15
≥15
Rales
None
Bases
From base to 
<50%
From base to  
>50%
Oedema
Absent/ trace
Slight
Moderate
Marked
The Clinical Congestion Score will be completed according to the Flow Chart. Please refer to 
Section 6.2.2 for preferred order of completion of assessments.
5.1.4
New York Heart Association classification
The NYHA functional classification will be used to classify the severity of the patients’ heart
failure. The investigator should place the patients in one of the four categories based on how
limited their physical activity are.
Table 5.1.4: 1
New York Heart Association classification
Class
Patient symptoms
I
No limitation of physical activity. Ordinary physical activity does not cause undue
fatigue, palpitation, dyspnoea (shortness of breath)
II
Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity
results in fatigue, palpitation, dyspnoea (shortness of breath)
III
Marked limitation of physical activity. Comfortable at rest. Less than ordinary
activity causes fatigue, palpitation, or dyspnoea
IV
Unable to carry on any physical activity without discomfort. Symptoms of heart
failure at rest. If any physical activity is undertaken, discomfort increases
The classification of patient’s physical activity according to NYHA will be performed at Visits 
2a, 3, 4, 5 and at early discontinuation. 
                                                
5 Jugular venous pressure should be estimated by adding 5 cm H2O to the vertical 
distance of the peak jugular venous pulsation from the sternal angle


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5.1.5
Patient Global Impression of Severity of Heart Failure Symptoms
Patient Global Impression of Severity of Heart Failure Symptoms (PGI-S) is a 1-item 
questionnaire to assess patient’s impression of symptoms severity, specifically: shortness of 
breath, fatigue and swelling.
The PGI-S asks the patient to choose one response that best describes how his/her Heart 
Failure Symptoms, specifically: shortness of breath, fatigue and swelling are now on a 5-
point scale:

Not at all (1)

Mild (2)

Moderate (3)

Severe (4)

Very severe (5)
Please refer to Section 6.2.2 for order of completion of patient reported outcome measure and 
Appendix 10.3.
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
A complete physical examination will be performed at the time points specified in the Flow 
Chart. Complete physical examination will include general appearance as well as evaluation 
of organ systems including an assessment of the cardiovascular system.
The results must be included in the source documents available at the site.
5.2.2
Vital signs
Vital signs will be evaluated at the time points specified in the Flow Chart, prior to blood 
sampling. This includes systolic and diastolic blood pressure and pulse rate (electronically or 
by palpation count for 1 minute) in a seated position after 5 minutes of rest. 
The preferred method for blood pressure measurement is by a standard mercury 
sphygmomanometer. If a standard mercury sphygmomanometer is not available, alternative 
devices recommended by website www.dableducational.org may be used or devices approved 
for use by the appropriate national agency/ies.
At visit 2a, after the patient has rested quietly in the seated position for five minutes, blood 
pressure should be taken in both arms. If the pressures differ by more than 10 mmHg (as for 
example in the presence of a subclavian steal syndrome), the pressure from the arm with the 
higher pressure (systolic or diastolic) should be entered in the eCRF and this arm should be 
used for subsequent measurements. The same method and, if possible, the same device 
should be used throughout the trial for a patient.


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Blood pressure measurements should be recorded to the nearest 2 mmHg only when 
measured with a manual sphygmomanometer; when digital devices are used the value from 
the device should be rounded to the nearest 1 mmHg.
For eCRF entry, decimal places should be rounded to integers (e.g. a DBP of 94.5 would be 
rounded to 95 mmHg and a SBP of 109.4 would be rounded to 109 mmHg).
The results must be included in the source documents available at the site.
5.2.3
Body weight and height
Measurements of body weight and height will be performed at the time points specified in the 
Flow Chart.
Body weight should be measured as follows:

after the urine sampling (weight after bladder voiding),

shoes and coat/jackets should be taken off, and

pockets should be emptied of heavy objects (i.e. keys, coins etc.).
5.2.4
Safety laboratory parameters
Safety laboratory parameters needed for assessing patients eligibility including NT-
proBNP/BNP will be assessed based on local lab.
Safety laboratory parameters to be assessed during the trial are listed in Table 5.2.4: 1. For 
the sampling time points please see the Flow Chart.
All analyses will be performed by a central laboratory, the respective reference ranges will be 
provided in the ISF. Patients do not have to be fasted for the blood sampling for the safety 
laboratory. 
Instructions regarding sample collection, sample handling/ processing and sample shipping 
are provided in the Laboratory Manual in the ISF. 
The central laboratory will send reports to the investigator. It is the responsibility of the 
investigator to evaluate the laboratory reports. Clinically relevant abnormal findings as 
judged by the investigator will be reported as adverse events (please refer to Section 5.2.7).
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.2.7.1 and the DILI Checklist provided in the ISF and 
electronic data capture (eDC) system. The amount of blood taken from the patient concerned 
will be increased due to this additional sampling.
The central laboratory will transfer the results of the analysis to the sponsor.


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Table 5.2.4: 1 Safety laboratory tests
Haematology
Hematocrit
Haemoglobin (Hb)
Reticulocyte Count (reflex test if Hb outside normal range)
Red Blood Cells (RBC) / Erythrocytes
WBC / Leukocytes
Platelet Count / Thrombocytes
Clinical chemistry
Albumin
Alkaline phosphatase
γ-GT (gamma-glutamyl transferase) reflex test triggered by elevated alkaline phosphatase 
on two sequential measures
ALT (alanine transaminase, SGPT)
AST (aspartate transaminase, SGOT)
Bicarbonate
Bilirubin total, fractionated if increased
Chloride
Creatinine
Creatine kinase (CK)
High sensitivity Troponin I (reflex tests, if CK is elevated)
Glucose
Potassium
Protein total
Sodium
Urea (blood urea nitrogen (BUN)
Uric acid
Urine
Urinalysis: test including for example (but not limited to) ketones semi-quantitative 
measurement, white blood cells, blood
(glucose measurement in urine will not be performed)
5.2.4.1
Renal Function
The estimated glomerular filtration rate (eGFR) will be derived from serum creatinine values,
age, sex and race based on the CKD-EPIcr equation [R12-1392].


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5.2.4.2
Pregnancy Testing
Pregnancy testing (urine) will be performed in female patients of child bearing potential 
according to the time points indicated in the Flow Chart. Pregnancy kits will be provided by 
the Central Laboratory. For reporting of pregnancy event refer to Section 5.2.7.2.
5.2.4.3
Criteria for hypoglycaemic events
All symptomatic hypoglycaemia events, or severe hypoglycaemias (e.g. if the patient 
required assistance of another person), or any hypoglycaemia episode with glucose values < 
54 mg/dl (< 3.0 mmol/l), or if the investigator considered the event to be an AE should be 
documented as an AE "hypoglycaemic event". In non-diabetic or pre-diabetic patients, the 
investigator should consider and rule out other alternative causes for such symptoms and can 
perform blood glucose levels to confirm the diagnosis of hypoglycaemia.
5.2.4.4
Urinary tract infection and genital infections
Patients having a history of chronic/recurrent urinary tract infections (UTI) or genital 
infections, or an acute episode of UTI or genital infection at screening will be identified and 
this condition has to be documented as medical history or baseline condition in the eCRF, 
respectively.
For documentation of symptomatic acute UTI during trial conduct, a urine culture sample has 
to be taken and sent to central lab for confirmation of the diagnosis.
5.2.5
Electrocardiogram
12-lead ECGs will be performed at Visits 2a and 5 (EoT) as indicated in the Flow Chart. The 
investigator or a designee will evaluate whether the ECG is normal or abnormal and assess 
clinical relevance. ECGs may be repeated for quality reasons and a repeated recording used 
for analysis.
Additional ECGs may be recorded for safety reasons. Dated and signed printouts of ECG 
with findings should be documented in patient’s medical record.
Clinically relevant abnormal findings will be reported either as baseline condition (if 
identified at the screening visit) or otherwise as AEs and will be followed up and/or treated as 
medically appropriate.
5.2.6
Other safety parameters
There are no additional safety parameters in the trial.


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5.2.7
Assessment of adverse events
5.2.7.1
Definitions of AEs
5.2.7.1.1
Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including 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.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):
Worsening of the underlying disease or of other pre-existing conditions.
Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the investigator.
If such abnormalities already exist prior to trial inclusion, they will be considered as baseline 
conditions and should be collected in the eCRF only.
5.2.7.1.2
Serious adverse event
A serious adverse event (SAE) is defined as any AE, which fulfils at least one of the 
following criteria:
-
results in death,
-
is life-threatening, which refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe,
-
requires inpatient hospitalisation or prolongation of existing hospitalisation,
-
results in persistent or significant disability or incapacity,
-
is a congenital anomaly / birth defect,
-
is deemed serious for any other reason if it is an important medical event when based 
on appropriate medical judgement which may jeopardise the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions. Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalisation or development of dependency or abuse.
5.2.7.1.3
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as 
defined above.


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The latest list of “Always Serious AEs” can be found in the eDC system. A copy of the latest 
list of “Always Serious AEs” will be provided upon request. These events should always be 
reported as SAEs as described in Section 5.2.7.2.
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the drug and must be reported as 
described in 5.2.7.2, subsections “AE Collection” and “AE reporting to sponsor and 
timelines”.
5.2.7.1.4
Adverse events of special interest
The term adverse events 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 trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.7.2.2.
The following are considered as AESIs:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 

an elevation of AST (Aspartate Aminotransferase) and/or ALT (Alanine 
Aminotransferase) ≥3 fold ULN combined with an elevation of total bilirubin ≥2 fold 
ULN measured in the same blood draw sample, or

Aminotransferase (ALT, and/or AST) elevations ≥5 fold ULN.
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the eDC system.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
Decreased renal function
Decreased renal function is defined by a creatinine value showing a ≥ 2 fold increase from 
baseline and is above the Upper Limit of Normal (ULN).
For the AESI “decreased renal function” patients need to be followed up appropriately based 
on local clinical guidance.


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Ketoacidosis
If metabolic acidosis, ketoacidosis and DKA is suspected further investigations should be 
done according to the medical judgment and the clinical course until a diagnosis is made 
and/or the patient is recovered.
Due to its mechanism of action, empagliflozin may potentially modify the clinical 
presentation of ketoacidosis which may occur at lower plasma glucose levels in patients with 
DM and potentially also in non-diabetic patient population. The diagnosis of ketoacidosis in 
these patients can be based on arterial pH ≤7.30, serum bicarbonate levels <15 mmol/L and 
measurement of serum beta-hydroxybutrate levels. Other diagnostic criteria which can 
support the diagnosis of ketoacidosis are urine ketones and anion gap >10 mmol/L.
Investigators should note that not all criteria mentioned above need to apply for the diagnosis 
of ketoacidosis, and clinical judgment should also be taken into consideration.
5.2.7.1.5
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated.
Moderate:
Sufficient discomfort to cause interference with usual activity.
Severe:
Incapacitating or causing inability to work or to perform usual activities.
5.2.7.1.6
Causal relationship of AEs
Medical judgement should be used to determine whether there is a reasonable possibility of a 
causal relationship between the adverse event and the given study treatment, 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 that there is a reasonable possibility of a 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 aetiologies that could explain the event (e.g. pre-
existing 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 reduced).


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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 trial drug treatment continues or remains 
unchanged.
5.2.7.2
Adverse event collection and reporting
5.2.7.2.1
AE Collection
The investigator shall maintain and keep detailed records of all AEs in the patient files.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards until the individual patient’s end of trial
participation (End of Study (EOS)): 
all AEs (serious and non-serious) and all AESIs.

After the individual patient’s end of trial: 
the investigator does not need to actively monitor the patient for new AEs but should only 
report any occurrence of cancer and trial treatment related SAEs and trial treatment 
related AESIs of which the investigator may become aware of by any means of 
communication, e.g. phone call. Those AEs should be reported on the BI SAE form (see 
Section 5.2.7.2.2), but not on the CRF.
For some types of AEs additional information will be collected in the eCRF due to the nature 
of the event and mechanisms of action of the trial medication. These listed AEs are distinct 
from AESI. The list of types of AEs for which additional information will be collected may 
change during the trial based on potential new knowledge about the safety profile of 
empagliflozin:

Hypoglycaemic event

Bone fracture

Hypotension
5.2.7.2.2
AE reporting to the sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form immediately (within 24 hours ) to the sponsor’s 


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unique entry point (country specific contact details will be provided in the ISF). The same 
timeline applies if follow-up information becomes available. In specific occasions, the 
investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and send the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information. All (S)AEs, including those persisting after individual patient’s end of trial must 
be followed up until they have resolved, have been assessed as “chronic” or “stable” , or no 
further information can be obtained.
5.2.7.2.3
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in the 
clinical trial and has taken trial medication, the investigator must report any drug exposure 
during pregnancy in a trial participant immediately (within 24 hours) 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 for Clinical Studies (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Studies (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Studies and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
This study will not analyse pharmacokinetic or pharmacodynamics parameters.
5.4
ASSESSMENT OF BIOMARKER(S)
Established biomarkers of efficacy and safety are described and discussed in Section 5.1 and 
5.2.
This study will not analyse exploratory biomarkers.
5.5
BIOBANKING
Not applicable.


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5.6
OTHER ASSESSMENTS
5.6.1
Health Care Resource Utilisation (HCRU)
HCRU will be captured via interview with the patient and verified against medical records 
where available and entered in the eCRF at the visits specified in the Flowchart. Information 
on utilization of following resources will be collected:

All-cause hospital admissions (first and recurrent).

Hospital admission due to worsening of heart failure (first and recurrent).

All-cause emergency room visits (first and recurrent).

Emergency room visits due to worsening of heart failure (requiring i.v. diuretic 
therapy) (first and recurrent).

Any unscheduled outpatient visits (first and recurrent).

Unscheduled outpatient visits related to heart failure (first and recurrent).

Length of hospital stay(s) (initial and recurrent).

Length of ICU stay during hospital stay (initial and recurrent).

Intensification of diuretic therapy (adding a new diuretic, increase of dose).
5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor safety aspects, and to determine empagliflozin efficacy and 
safety in an appropriate way.
For more details on NT-proBNP, please refer to Section 3.2.
The scheduled measurements are appropriate to see drug induced changes in vital signs, 
standard laboratory values, the biomarker NT-proBNP, and in ECG. The primary and 
secondary endpoints are accepted for evaluation of efficacy, safety and tolerability of an oral 
HF drug and they are widely used in respective pivotal phase III HF studies.
Health related quality of life questionnaires (specifically the KCCQ) are a necessary part for 
this phase III trial in order to collect data on patient related outcomes (as part of the primary 
endpoint).
Therefore, the appropriateness of all measurements applied in this trial is given.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
All patients are to adhere to the visit schedule as specified in the Flow Chart. If any visit has to
be rescheduled, subsequent visits should follow the original visit date schedule. The trial
medication packs contain sufficient medication to allow for the allowed time windows.
All trial visits should take place at approximately the same time of day and preferably before
noon.
During the COVID-19 pandemic, there might be situations when patients might not be able to 
come to the site for the scheduled visit. This might be e.g. due to restrictions set by 
authorities or by the investigator site/institution, because the patient is quarantined, or 
because of any patient specific situation that the investitator judges as being not safe for the 
patient to come to the site. 
For details on potential modifications of the trial conduct related to the COVID-19 pandemic, 
please refer to Section 10.5.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
Please refer to the Flow Chart and Section 5 for details of the procedures performed at each 
visit.
6.2.1
Screening and run-in period(s)
Due to the short time window when patients can be randomised (between 24 hours after 
hospitalisation and no later than 5 days), potential study patients should be identified as soon 
as possible and their improvement followed up accordingly (pre-screening). Potential study 
patients should be approached to assess their interest in volunteering as a participant in this 
trial as soon as possible.
Screening Period
The investigations for the main diagnosis for inclusion are to be completed and documented 
per standard of care as a prerequisite to consideration for study participation. Patients will be 
included in the study based on local BNP or NT-proBNP and other available laboratory 
measurements.
Following informed consent, the patient will undergo Visit 1/screening assessments as 
indicated in the Flow Chart. The assessments must all fall within the acceptable screening 
visit window but do not need to be performed on the same day. The patient should be 
registered in IRT as a screened patient.
Re-screening within the same hospitalisation and current episode of acute decompensation is 
not allowed. Nevertheless, if a patient who failed screening before has another episode of 


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acute decompensation that leads to a new hospitalisation, patient can be screened again and 
considered for the study.
Medical History:
Medical History will be documented using pre-specified categories as given in the eDC 
system. For detailed requirements please see Section 8.3.1.
Baseline Conditions
Ongoing conditions/diagnosis from the Medical History questionnaire will be documented as 
Baseline Conditions.
If the patient meets the entry criteria, Visit 2a should occur as soon as possible once it has 
been confirmed that the patient is eligible to continue. If the patient does not meet the entry 
criteria, (i.e. fail to meet one or more of the inclusion criteria, and/or meet one or more of the 
exclusion criteria) following Visit 1 procedures, they should be registered as a screen failure 
in IRT.
6.2.2
Treatment period(s)
After a final check of all in- and exclusion criteria, patients eligible will be randomised at
Visit 2a using IRT. Randomisation can occur at the same day as the screening visit. All Visit 
2a assessments must be performed before the first dose is taken in hospital. Assessments from 
Visit 2a will be used as baseline values.
Patients will undergo visit assessments as indicated in the Flow Chart.
Patients will have further visits with a reduced number of assessments two and four days 
thereafter if they are still hospitalised (Visits 2b and 2c at Day 3 and 5).
The patients will return to the clinic for regularly scheduled Visits 3, 4 and 5 (EoT) on days
15, 30 and 90 respectively after randomisation as specified in the Flow Chart. These on-site 
visits will assess the occurrence of safety and efficacy endpoints, trial medication compliance 
(Visit 3, 4 and 5), concomitant therapy or intervention. The assessments at these visits can be 
performed post-dose. Patients should be instructed to take their medication on the morning of
their visits at home like all days. Visits should be routinely scheduled at approximately the
same time of day for each visit.
All other medications the patient is receiving should be taken as instructed by the physician.
At any time during the treatment period, the HF background therapy is allowed to be adjusted 
and optimised according to local and international guidelines.
If any additional therapy is considered necessary for the patient’s welfare during the 
treatment period it may be given at the discretion of the Investigator (see also restrictions in 
Section 4.2.2).
Patient reported outcome measures (first KCCQ, then PGI – Severity – Heart Failure 
Symptoms questionnaire) should be done first and laboratory samples should be taken at the 
end of each visit. All other measures should be performed after PGI-S and before laboratory 
sampling.


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Allocation of medication kit number(s) will be managed through the IRT. Patients will be 
assigned medication at Visit 2a, starting treatment in hospital and will receive their trial 
mediation kit at discharge to take home. This kit contains sufficient medication until Visit 4. 
At this visit patients should return the medication and compliance check will be done. At 
Visit 4 new medication kits will be dispensed. Visit 5 (EoT) is the last day of treatment and 
the patient should return all remaining medication during this visit.
Early permanent trial medication discontinuation is only justified when any contraindications 
arise, or when the patient requests to stop trial medication. See Section 3.3.4.1 for details on 
how to handle trial medication discontinuations. An Early Discontinuation Visit should be 
performed with the procedures indicated in the Flow Chart.
6.2.3
Follow-up period and trial completion
A Follow-up Visit will be performed 7 days (+7 day window) after the last dose of trial 
medication. The assessments to be performed at the Follow-up Visit are indicated in the Flow 
Chart. The Follow-up Visit marks the completion of the study for the individual patient who 
completed the study on trial medication.
As a standard, Follow-up Visit should be performed as phone call. If considered necessary 
e.g. for safety reasons requiring personal follow-up, the visit can be done as a site visit.
See Section 3.3.4.1 for procedures to be followed in case a patient prematurely discontinues 
trial treatment.
For patients who early discontinued trial medication but followed up according to the visit 
schedule, Visit 5 (EoT) marks the completion of the study for the individual patient.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
The eligible patients for this trial will be randomised to one of two treatment groups 
(empagliflozin or placebo) in a 1:1 ratio, stratified according to HF status (de novo or 
decompensated chronic HF).
The primary endpoint is clinical benefit defined in Section 7.2.2 [R16-4813 and R19-3448]. 
The statistical model will be a non-parametric generalised pairwise comparison within HF 
status strata. The variance of the win ratio will be calculated using the asymptotic normal U 
statistics approach [R19-3448].
The primary model will be conducted on all randomised patients.
7.1
NULL AND ALTERNATIVE HYPOTHESES
For the primary endpoint, superiority of empagliflozin vs. placebo will be evaluated with 
one-sided tests, at a significance level of 0.025, in the following structure:
Null hypothesis – There is no difference between the effect of placebo and the effect of 
empagliflozin or the effect of placebo is greater.
Alternative hypothesis – The effect of empagliflozin is greater than the effect of placebo.
Secondary and further endpoints will be evaluated in an exploratory manner.
7.2
PLANNED ANALYSES
7.2.1
General considerations
The efficacy analysis will be based on the randomised set (RS), including all randomised 
patients. Analyses will be performed according to the intention-to-treat principle, with the use 
of all available data (on and off-treatment) through the trial period. This equates to a 
treatment-policy style estimand. 
 
If a Per Protocol Set (PPS) is required, this will also be specified in the TSAP. Important 
protocol deviations will be described in the TSAP.
The safety analysis will be based on the treated set (TS), which consists of all patients treated
with at least one dose of trial medication.
For both efficacy and safety analyses, treatment will be evaluated as randomised.
For all endpoints, baseline will be defined as the last available measurement before start of 
trial medication.


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7.2.2
Primary endpoint analyses
The primary endpoint is clinical benefit, a composite of death, number of HFEs, time to first 
HFE and change from baseline in KCCQ-TSS after 90 days of treatment. This will be 
assessed using a win ratio approach.
All patients randomised to empagliflozin are compared to all patients randomised to placebo
within their stratum. 
For any two patients, a patient will win, i.e. achieve a better clinical outcome, as determined 
by assessing the following criteria sequentially, stopping when an advantage for either patient 
is shown:
1. Death within common follow-up time

death is worse than no death

earlier death is worse

tied, if not possible to determine
2. Number of HFEs within common follow-up time

more HFEs is worse

tied, if same number of HFEs
3. Time to first HFE within common follow-up time

earlier HFE is worse

tied, if not possible to determine
4. KCCQ-TSS change from baseline at Day 90

more positive change from baseline is better

the threshold for the difference is >= 5 for a win

tied, if difference < 5
Note, priority is therefore given to death over HFE, and both of these over changes in KCCQ-
TSS. Below are some examples:
1.
Death, e.g.:

Patient A dies 30 days after randomisation (loses)

Patient B dies 40 days after randomisation (wins)
2. If no winner based on death, number of HFEs within common follow-up time, 
e.g.:

Patient A had two HFEs (loses)

Patient B had one HFE (wins)
3. If no winner based on number of HFEs, time to first HFE, e.g.:

Patient A had an HFE 30 days after randomisation (loses)

Patient B had an HFE 50 days after randomisation (wins)


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4. If no winner based on time to first HFE, KCCQ-TSS change from baseline at Day 
90, e.g.:

Patient A: KCCQ-TSS change from baseline at Day 90 is 5 (loses)

Patient B: KCCQ-TSS change from baseline at Day 90 is 11 (wins)
The implemented generalised pairwise comparisons approach compares all patients in one 
treatment group to all other patients within their strata in the other treatment group. The win 
ratio is then calculated as the total number of wins in the empagliflozin group (NW) across all 
strata divided by the total number of losses (NL). So the win ratio is = NW / NL.
The variance is calculated by the asymptotic normal U statistic approach [R19-3448]
Separate summaries for each component of this endpoint will also be presented.
The method of handling missing KCCQ-TSS values for this analysis is described in Section 
7.3.
7.2.3
Secondary endpoint analyses
Secondary endpoints will not be tested in a hierarchical sequence, and no adjustment for 
multiple comparisons is planned.
Change from baseline in continuous endpoints, such as KCCQ-TSS, will be analysed using 
restricted maximum likelihood estimation based on a mixed-effect model for repeated 
measures (MMRM) analysis to obtain adjusted means for the treatment effects. This model 
will include discrete fixed effects for treatment group (empagliflozin or placebo) and HF 
status (de novo or decompensated chronic HF) at each visit and continuous fixed effects for 
baseline value at each visit. Missing data caused by patient withdrawal or other reasons will 
be handled implicitly by the MMRM approach.
Area under the curve (AUC) of change from baseline in log-transformed NT-proBNP level 
over 30 days of treatment will be analysed by an analysis of covariance (ANCOVA). Based 
on literature reviews, NT-proBNP level is regarded as log-normally distributed, therefore 
values will be log-transformed prior to analysis [R19-3044]. The linear trapezoidal rule will 
be used to calculate the AUC after the log-transformation has been applied to each value. 
Analysis of covariance (ANCOVA) with a discrete fixed effect for HF status (de novo or 
decompensated chronic HF) and a continuous fixed effect for baseline NT-proBNP level 
(log-transformed) will be used to compare treatment groups. The method of handling missing 
NT-proBNP levels for this analysis is described in Section 7.3.
Comparisons between treatment groups regarding the binary endpoint variable (improvement 
in KCCQ-TSS of ≥ 10 points after 90 days of treatment) will be performed using a logistic 
regression model adjusting for the binary covariate HF status (de novo or decompensated 
chronic HF). The likelihood-ratio test will be used to test for a difference between treatments. 
Adjusted odds ratios together with 1-sided 97.5% confidence limits will be used to quantify 
the effect of treatment, comparing empagliflozin to placebo as the reference.


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Time to event endpoints will be analysed using the Cox proportional hazards model [R07-
4680] with HF status (de novo or decompensated chronic HF) as a covariate. Hazard ratios 
(HRs) and their associated one-sided 97.5% confidence limits will be estimated for 
evaluating the superiority of empagliflozin to placebo. 
Other secondary endpoints will be summarised descriptively (including days alive and out of 
hospital).
Analysis of recurrent events will be described in the TSAP.
7.2.5
Safety analyses
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities
(MedDRA). Standard BI summary tables and listings will be produced. All adverse events 
with an onset between start of treatment and end of the residual effect period (REP), a period
of 7 days after the last dose of trial medication, will be assigned to the on-treatment period for
evaluation.
All treated patients will be included in the safety analysis. In general, safety analyses will be
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent
adverse events, i.e. all adverse events occurring between start of treatment and end of the
residual effect period. Adverse events that start before first drug intake and deteriorate under
treatment will also be considered as ‘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 the Medical
Dictionary for Drug Regulatory Activities (MedDRA) at the database lock.
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will
be done via comparison of laboratory data to their reference ranges. Values outside the
reference range as well as values defined as clinically relevant will be summarised. Treatment
groups will be compared descriptively with regard to distribution parameters as well as with
regard to frequency and percentage of patients with abnormal values or clinically relevant
abnormal values.


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Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with
regard to possible changes compared to findings before start of treatment.
Reasons for discontinuation and use of post-baseline concomitant medications will be
tabulated.
The details of the analysis will be specified in the TSAP.
7.2.6
Interim Analyses
No interim analysis is planned but a Data Monitoring Committee (DMC) will be in place 
with tasks as described in Section 8.7.
7.3
HANDLING OF MISSING DATA
Missing data for KCCQ-TSS and NT-proBNP will be estimated using multiple imputation, 
according to whether patients are on-treatment or off-treatment.
Further details on multiple imputation and rules for handling missing data for other secondary 
and further endpoints will be specified in the TSAP.
7.4
RANDOMISATION
The trial will be performed as a double-blind design with respect to placebo and
empagliflozin. Patients will be randomised to the trial treatments in a 1:1 ratio. Patients will 
be stratified by HF status (de novo or decompensated chronic HF).
Patients will be randomised in blocks to double-blind treatment via an IRT system.
Approximately equal numbers of patients will be randomised to each treatment group.
BI will arrange for the randomisation and the packaging and labelling of trial medication. The
randomisation list will be generated using a validated system, which involves a pseudo-
random number generator so that the resulting treatment will be both reproducible and non-
predictable.  The block size will be documented in the Clinical Trial Report. Access to the
codes will be controlled and documented.
7.5
DETERMINATION OF SAMPLE SIZE
Powers for superiority in were estimated by simulation using a shared frailty approach. 
Initially a frailty value was simulated for each patient using a gamma distribution. Deaths 
were assumed to have constant hazard for any given patient dependent upon the frailty term, 
leading to a marginal Lomax distribution. HFEs were assumed to have a Poisson distribution 
within patients, again depending on the frailty parameter, leading to a marginal negative 
binomial distribution. The number of HFEs per patient was nominally capped at 7 per patient 
over the 90 day period. For KCCQ-TSS, the frailty terms were directly transformed into a 
capped normal distribution (values below 0 or above 100 set to 0 and 100 respectively). High 
frailties corresponded to low KCCQ-TSS scores and vice versa.  The use of a shared frailty 


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parameter ensures correlation between components of the primary endpoint so that patients 
with poor outcomes in one component are also more likely to have a poor outcome in the 
others. Ten thousand simulations were used for each scenario. Calculations of the win ratio
were performed using the generalised pairwise comparisons method from Section 7.2.2. 
Simulations and calculations were performed using R statistical software Version 3.5.1.
A sample size of 500 randomised patients in total (250 per treatment group) would provide 
87.4% power to detect a difference between the empagliflozin treatment group and placebo 
treatment group, in the win ratio, at a one-sided significance level of 0.025, assuming the 
following:
Proportion of patients who die within 90 days = 5% [R19-2932]
Hazard ratio for death component = 0.8 [P15-09840]
Proportion of patients with at least one HFE within 90 days = 15% [R19-2932]
Hazard ratio for HFE component = 0.7 [P15-09840]
KCCQ-TSS placebo mean = 55 [R17-3082]
KCCQ-TSS baseline adjusted standard deviation = 20 [R17-3097]
KCCQ-TSS treatment effect = 6 [R19-3124]
KCCQ-TSS win threshold = 5 [R17-2687]
Table 7.5: 1
Power estimates for various combinations of KCCQ-TSS treatment 
effects and death/HFE hazard ratios with 500 patients in total
HR for 
death
HR for HFE
KCCQ-TSS treatment effect
4
5
6
7
0.7
0.7
66.9%
80.1%
89.4%
94.7%
0.8
0.7
63.6%
77.2%
87.4%
93.4%
0.8
0.8
54.6%
68.8%
81.3%
89.7%


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU directive 
2001/20/EC / EU regulation 536/2014 and other relevant regulations. Investigators and site 
staff must adhere to these principles. Deviation from the protocol, the principles of ICH GCP 
or applicable regulations as will be treated as “protocol deviation”.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial patients against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor
with regard to publication of the results of this trial are described in the investigator contract. 
As a rule, no trial results should be published prior to finalisation of the Clinical Trial Report.
The certificate of insurance cover is made available to the investigator and the patients, and is
stored in the ISF.
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
This trial 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 trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH-GCP and to the 
regulatory and legal requirements of the participating country. 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 trial 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 given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the patient’s own free will with the 
informed consent form after confirming that the patient understands the contents. The 
investigator or his delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.


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Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
If study conduct may need to be adjusted (see Sections 6.1 and 10.5) during the COVID-19 
pandemic, the patient must be made aware of any modifications and agreement needs to be 
obtained prior to them being implemented.
The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan documents the rationale and strategies for risk management during trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk.
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches.
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual patients will be provided by the sponsor. See Section 4.1.5.2 for rules 
about emergency code breaks. For drug accountability, refer to Section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial patient. Source data as well as reported 
data should follow the “Attributable, Legible, Contemporaneous, Original, Accurate 
(ALCOA) principles” and be attributable, legible, contemporaneous, original and accurate. 
Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case, the investigator must make at least one documented attempt to 
retrieve previous medical records. If this fails, a verbal history from the patient, documented 
in their medical records, would be acceptable.


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If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
For the CRF, data must be derived from source documents, for example:
•
Patient identification: gender, year of birth (in accordance with local laws and 
regulations).
•
Patient participation in the trial (substance, trial number, patient number, date patient was 
informed).
•
Dates of patient’s visits, including dispensing of trial medication.
•
Medical history (including trial indication and concomitant diseases, if applicable).
•
Medication history.
•
Adverse events and outcome events (onset date (mandatory), and end date (if available)).
•
Serious adverse events (onset date (mandatory), and end date (if available)).
•
Concomitant therapy (start date, changes).
•
Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available).
•
Supporting documents and medical records for assessment of death and HFEs.
•
Completion of patient’s participation in the trial” (end date; in case of premature 
discontinuation document the reason for it).
•
Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the patient or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not make 
the patient eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). They may review all CRFs and informed consents. The accuracy of the data will 
be verified by direct comparison with the source documents described in Section 8.3.1. The 
sponsor will also monitor compliance with the protocol and GCP.
8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.


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8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with
regulatory requirements. 
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 7 and 12 of the World Health 
Organisation (WHO) GCP handbook.
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the following exceptions:
Personalised 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 at the site
as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities.
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first patient in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial
(“Last Patient Completed”). The “Last Patient Last Treatment” (LPLT) date is defined as 
the date on which the last patient in the whole trial is administered the last dose of trial 
treatment (as scheduled per protocol or prematurely). Individual investigators will be notified 
of SUSARs occurring with the trial medication until 30 days after LPLT at their site.
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the respective laws.
A final report of the clinical trial data will be written only after all patients have completed 
the trial in all countries (EU or non-EU) to incorporate and consider all data in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient
(EU or non-EU).


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8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
Two Coordinating Investigators are responsible to coordinate investigators at the different 
sites participating in this trial. Tasks and responsibilities are defined in a contract.
An Executive Committee (ExCom) consisting of independent experts (including the 
Coordinating Investigators of this trial) and sponsor representatives will be established to 
support the sponsor in designing the trials and successful execution. The composition of the 
ExCom will be documented in the Trial Master File (TMF). The tasks and responsibilities 
will be agreed in contracts between the ExCom members and the Sponsor and also 
summarised in an ExCom charter. The Executive Committee will assess the baseline 
characteristics of the patients in an ongoing blinded manner and if needed, may take 
appropriate steps, which may include restrictions to enrolment for certain subpopulations.
A National Coordinator Committee (NCC) will be established and will consist of the leading 
expert(s) in each of the participating countries. The NCs will support the Sponsor in the 
successful execution of the trial. The NCC will have an advisory function in the trial. The 
tasks and responsibilities will be agreed in contracts between the NCC member and the 
Sponsor.
A Data Monitoring Committee (DMC) will be established. Members of the DMC are 
independent of BI, they are physicians experienced in the treatment of the disease under 
investigation and a statistician. The DMC will evaluate safety data. While DMC members 
may be unblinded, measures are in place to ensure the blinding for everyone else involved in 
the trial. Regular DMC meetings will be held at specified intervals. The DMC will 
recommend continuation, modification or termination of the trial as detailed in the DMC 
charter. DMC recommendations as well as the final BI decision will be reported to the 
appropriate Regulatory Authorities (RAs)/ Health Authority (Has), IRBs/ECs, and to 
investigators as requested by local law. The tasks and responsibilities of the DMC are 
specified in a charter.
An independent external committee (Clinical Event Committee (CEC)) will be established to 
adjudicate certain hepatic events and ketoacidosis.
Hepatic External adjudication for hepatic events
Certain hepatic events will be adjudicated by external independent experts for severity and 
causal relationship with the trial medication; both in a blinded fashion. Events to be reviewed 
will be defined in a charter.
Events may either be defined by abnormal laboratory values and/or relevant adverse events or 
both.
For qualifying events, relevant source documents generated from any medical evaluations of 
these events will be requested including for example laboratory values, histological analysis, 
reports from ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), 


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scintigraphy, hospital discharge letters, and medical reports from other physicians. All 
evaluations will be performed in a blinded fashion. The assessments will be analysed based 
on empagliflozin data combined from multiple trials (i.e. on project level).
Adjudication of ketoacidosis
Events suspected to be metabolic acidosis, ketoacidosis and DKA will be adjudicated by 
independent external experts in a blinded fashion. Events to be reviewed will be defined in a 
charter.
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the ISF. The investigators will have access to the BI clinical trial portal 
(Clinergize) to facilitate document exchange.
BI has appointed a Clinical Trial Leader (CT Leader), responsible for coordinating all 
required activities, in order to
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of CT Managers, CRAs, and 
investigators of participating countries.
The organisation of the trial in the participating countries will be performed by the respective 
local or regional BI-organisation (Operating Unit, OPU) in accordance with applicable 
regulations and BI SOPs, or by a Contract Research Organisation (CRO) with which the 
responsibilities and tasks will have been agreed and a written contract filed before initiation 
of the clinical trial.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
A central laboratory service and an IRT vendor will be used in this trial. Details will be 
provided in the IRT Manual and Central Laboratory Manual, available in the ISF.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
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Empagliflozin (BI 10773), a potent and selective SGLT2 inhibitor, induces 
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P13-06404
Yancy CW, et.al. 2013 ACCF/AHA Guideline for the Management of 
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Cherney DZI, Perkins BA, Soleymanlou N, Har R, Fagan N, Johansen OE, 
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Inzucchi SE, Zinman B, Wanner C, Ferrari R, Fitchett D, Hantel S, et.al. 
SGLT-2 inhibitors and cardiovascular risk: proposed pathways and review 
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Chilton R, Tikkanen I, Cannon CP, Crowe S, Woerle HJ, Broedl UC, et.al. 
Effects of empagliflozin on blood pressure and markers of arterial stiffness 
and vascular resistance in patients with type 2 diabetes. Diabetes Obes 
Metab. 2015. 17(12): 1180-1193.
P15-09840
Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et.al. 
Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. 
New Engl J Med. 2015. 373(22): 2117-2128.
P16-01253
Fitchett D, Zinman B, Wanner C, Lachin JM, Hantel S, Salsali A, et.al. 
Heart failure outcomes with empagliflozin in patients with type 2 diabetes 
at high cardiovascular risk: results of the EMPA-REG OUTCOME trial. 
Eur Heart J. 2016. 37(19): 1526-1534.
P16-01830
Ferrannini E, Baldi S, Frascerra S, Astiarraga B, Heise T, Bizzotto R, et.al. 
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Al-Jobori H, Daniele G, Cersosimo E, Triplitt C, Mehta R, Norton L, et.al. 
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Wanner C, Lachin JM, Inzucchi SE, Fitchett D, Mattheus M, George J, 
et.al. Empagliflozin and clinical outcomes in patients with type 2 diabetes 
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Inzucchi SE, Kosiborod M, Fitchett D, Wanner C, Hehnke U, Kaspers S, 
et.al. Improvement in cardiovascular outcomes with empagliflozin is 
independent of glycemic control. Circulation. 2018. 138(17): 1904-1907.
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Savarese G, Sattar N, Januzzi J, Verma S, Lund LH, Fitchett D, et.al. 
Empagliflozin is associated with a lower risk of post-acute heart failure 
rehospitalization and mortality. Insights from the EMPA-REG OUTCOME 
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Verma S, McMurray J.J.V. SGLT2 inhibitors and mechanisms of 
cardiovascular benefit: a state-of-the-art review. Diabetologia. 2018. 61: 
2108-2117.
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Levey AS, Stevens LA, Schmid CH, Zhang Y, Castro AF, Feldman HI, 
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in Cardiovascular Diseases. 2005. 47(5): 320-332.
R16-2217
Cheng RK, Cox M, Neely ML, Heidenreich PA, Bhatt DL, Eapen ZJ, et.al. 
Outcomes in patients with heart failure with preserved, borderline, and 
reduced ejection fraction in the Medicare population. Am Heart J. 2014. 
168(5): 721 - 730.e3.
R16-4813
Pocock SJ, Ariti CA, Collier TJ, Wang D. The win ratio: a new approach to 
the analysis of composite endpoints in clinical trials based on clinical
priorities. Eur Heart J. 2012. 33: 176-182.
R17-1562
Bishu K, Redfield MM. Acute heart failure with preserved ejection fraction: 
unique patient characteristics and targets for therapy. Curr Heart Fail Rep. 
2013. 10(3): 190-197.
R17-2687
Spertus J, Peterson E, Conard MW, Heidenreich PA, Krumholz HM, Jones 
P, et.al. Cardiovascular Outcomes Research Consortium Monitoring clinical 
changes in patients with heart failure: a comparison of methods. American 
Heart Journal. 2005. 150(4): 707-715.
R17-3082
Sauser K, Spertus JA, Pierchala L, Davis E, Pang PS. Quality of life 
assessment for acute heart failure patients from emergency department 
presentation through 30 days after discharge: a pilot study with the Kansas 
City Cardiomyopathy Questionnaire. J Card Fail. 2014. 20(1): 18-22. 
R17-3097
Comin-Colet J, Lainscak M, Dickstein K, Filippatos GS, Johnson P, 
Luescher TF, et.al. The effect of intravenous ferric carboxymaltose on 
health-related quality of life in patients with chronic heart failure and iron 
deficiency: a subanalysis of the FAIR-HF study. Eur Heart J. 2013. 34: 30-
38.


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R19-2911
Gattis WA, O’Connor CM, Gallup DS, Hasselblad V, Gheorghiade M., 
et.al. Predischarge initiation of carvedilol in patients hospitalised for 
decompensated heart failure: results of the Initiation Management 
Predischarge: Process for Assessment of Carvedilol Therapy in Heart 
Failure (IMPACT-HF) trial. J Am Coll Cardiol. 2004. 43(9): 1534–41.
R19-2913
Logeart D, Thabut G, Jourdain P, Chavelas C, et al. Predischarge B-type 
natriuretic peptide assay for identifying patients at high risk of re-admission 
after decompensated heart failure. J Am Coll Cardiol. 2004. 43(4): 635-641.
R19-2914
Zile MR, Bennett TB, et.al. Transition from Chronic Compensated to Acute 
Decompensated Heart Failure: Pathophysiological insight from continuous 
monitoring of intracardiac Pressures. Circulation. 2008. 118. 1433-1441.
R19-2915
Gheorghiade M, Vaduganathan M, et al. Rehospitalisation for heart failure: 
problems and perspectives. J Am Coll Cardiol. 2013. 61(4): 391-403.
R19-2916
Torre-Amione G, Milo-Cotter O, Kaluski E, Perchenet L, Kobrin I, Frey A, 
et.al. Early worsening heart failure in patients admitted for acute heart 
failure: time course, hemodynamic predictors, and outcome. J Card Fail. 
2009. 15(8): 639–644.
R19-2917
Heidenreich PA, et al. Forecasting the Impact of Heart Failure in the United 
States: A Policy Statement From the American Heart Association. Circ 
Heart Fail. 2013. 6: 606-619.
R19-2918
Blecker S, Paul M, Taksler G, Ogedegbe G, Katz S. Heart failure associated 
hospitalisations in the United States. J Am Coll Cardiol. 2013. 61(12): 
1259-1267.
R19-2919
Butler J, Arbogast PG, Daugherty J, Jain MK, Ray WA, Griffin MR. 
Outpatient utilization of angiotensin-converting enzyme inhibitors among 
heart failure patients after hospital discharge. J Am Coll Cardiol. 2004. 
43(11): 2036-2043.
R19-2920
Fonarow GC, Gawlinski A, Moughrabi S, Tillisch JH. Improved treatment 
of coronary heart disease by implementation of a Cardiac Hospitalisation 
Atherosclerosis Management Program (CHAMP). Am J Cardiol. 2001. 
87(7): 819-822.
R19-2921
Grodin JL, Liebo MJ, et.al. Prognostic Implications of Changes in Amino-
Terminal Pro-B-Type Natriuretic Peptide in Acute Decompensated Heart 
Failure: Insights from ASCEND-HF. Journal of Cardiac Failure. 2019.
00(00): 1-9.
R19-2924
Aditi A, Bhagat, et.al. Initiation, Continuation, Switching, and Withdrawal 
of Heart Failure Medical Therapies During Hospitalisation. JACC:HF. 
2019. 7(1): 1-12.
R19-2932
Velazquez EJ, Morrow DA, DeVore AD, Duffy CI, Ambrosy AP, 
McCague K, et.al. PIONEER-HF Investigators. Angiotensin-neprilysin 
inhibition in acute decompensated heart failure. N Engl J Med. 2019. 
380(6): 539-548.
R19-3040
Heidenreich PA. Patient-Reported Outcomes: The Future of Heart Failure 
Care. JACC HF. 2019. 7: 1-3.
R19-3044
Schou M, Gustafsson F, Kjaer A, Hildebrandt PM. Long-term clinical 
variation of NT-proBNP in stable chronic heart failure patients. European 
Heart Journal. 2007. 28(2): 177-182.


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R19-3124
Nassif ME, Windsor S, Tang F, Khariton Y, Husain M, Inzucchi S, et.al. 
Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in 
Patients With Heart Failure With Reduced Ejection Fraction: The DEFINE-
HF Trial. Circulation. 2019. 40(140): 1-14.
R19-3125
McMurray JJV, Solomon SD, Inzucchi L, et.al. Dapagliflozin with Patients 
in Heart Failure and Reduced Ejection Fraction. New England Journal of 
Medicine. 2019. 1-13.
R19-3126
U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research, Center for 
Biologics Evaluation and Research. Treatment for Heart Failure: Endpoints 
for Drug Development Guidance for Industry. June 2019.
R19-3245
Hicks KA, Mahaffey KW, Mehran R, Nissen SE, Wiviott SD, et.al. 2017 
Cardiovascular and Stroke Endpoint Definitions for Clinical Trials. Journal 
of the American College of Cardiology. 2018. 71(9): 1021-34.
R19-3448
Dong G, Li D, Ballerstedt S, Vandemeulebroecke M. A generalized 
analytic solution to the win ratio to analyze a composite endpoint 
considering the clinical importance order among components. Pharm Stat. 
2016. 15: 430-437.
9.2
UNPUBLISHED REFERENCES
c02695839-01
. 
Clinical Trial Report: Empagliflozin (BI 10773). The EMPA-REG 
OUTCOME® Trial 1245.25.
c01678844
Investigators Brochure. Empagliflozin. Current Version.
c11963611-01
 Clinical Trial Report: 
Jardiance® (empagliflozin). An open-label, mechanistic study to examine 
the effect of oral empagliflozin (25 mg q.d.) on kinetics of renal glucose 
reabsorption in patients with type 2 diabetes mellitus and healthy controls. 
Trial 1245.66.
c26554599-01
Clinical Trial Report: A phase III randomised, 
double-blind trial to evaluate the effect of 12 weeks treatment of once daily 
EMPagliflozin 10 mg compared with placebo on ExeRcise ability and heart 
failure symptoms, In patients with chronic HeArt FaiLure with preserved 
Ejection Fraction (HFpEF) (EMPERIAL – preserved). Trial 1245-0167
c26554767-01
 Clinical Trial Report: A phase III 
randomised, double-blind trial to evaluate the effect of 12 weeks treatment 
of once daily EMPagliflozin 10 mg compared with placebo on ExeRcise 
ability and heart failure symptoms, In patients with chronic HeArt FaiLure 
with reduced Ejection Fraction (HFrEF) (EMPERIAL – reduced). Trial 
1245-0168


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10.
APPENDICES
10.1
KCCQ (KANSAS CITY CARDIOMYOPATHY QUESTIONNAIRE)


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10.2
INCLUSION OF ILLITERATE PATIENTS - KCCQ
In the event of recruiting an illiterate patient, the following process should be followed with
respect to completion of the self-reported PRO:

At each visit where the administration of the Patient Reported Outcome form is
required, the trial coordinator or designated site personnel will read each of the
items on the questionnaire to the patient, word for word, and without any
accompanying explanation.

The questionnaires will be provided to patients in the language or local dialect that is
understood by the patient using the different language versions of the questionnaire
that are part of the eCRF for the trial.

The patient will choose the most appropriate response to the question, and indicate
the response on the questionnaire by him/herself. If this is not possible, the trial
coordinator or designated site personnel or patient’s caregiver will indicate the
response on the questionnaire based on the patient’s feedback.
In the same way as for all other patients, the completion of the questionnaires should be
performed in a quiet area where the patient can consider his/her responses.
10.3
PATIENT GLOBAL IMPRESSION OF SEVERITY OF HEART FAILURE 
SYMPTOMS: SHORTNESS OF BREATH, FATIGUE AND SWELLING
Please choose one response below that best describes your most recent experience of Heart 
Failure Symptoms: shortness of breath, fatigue and swelling:

Not at all

Mild

Moderate

Severe

Very severe
10.4
ACCEPTED FORMS OF CONTRACEPTION FOR PATIENTS IN ITALY
Acceptable methods include consistent and correct use of hormone containing implants and 
injection contraceptives, combined oral contraceptives, transdermal patches, hormone containing 
intrauterine devices or systems, bilateral tubal occlusion, complete sexual abstinence, and 
vasectomy. No other methods will be accepted.
10.5
POTENTIAL MODIFICATION OF TRIAL CONDUCT IN CASE OF 
RESTRICTIONS DUE TO COVID-19
As mentioned in Section 6.1, in case of any restrictions during the COVID-19 pandemic,
study conduct may need to be adjusted. The following contingency measures have been 
introduced to ensure patient safety and appropriate trial continuation based on a thorough


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benefit risk assessment (see Section 1.4.2).
In exceptional cases, when it is impossible to conduct the visits at the trial site, visits may be 
performed at the patient’s home or remotely (via telephone and/or internet based means of 
communication). The visits may also be performed as a combination of home and remote 
visits. Based on a thorough benefit-risk assessment (see Section 1.4.2), the visit procedures 
may be adjusted for the purpose of particular visits, whereby critical safety measures will 
remain in place. All home/remote visits need to be discussed with and approved by the 
sponsor`s trial team. 
Local regulatory and legal requirements of the participating country need to be respected for 
all modifications.
Under these circumstances, the below modifications can be considered. Patients need to be 
informed about the modifications and agree to them before implementation (see Section 8.1):
Remote visit
If a patient is not able to come to the site for an outpatient visit, a remote visit (by phone) 
should be performed instead and all assessments that can be done by phone performed.
Assessments that can be performed during a remote visit are:
NYHA Classification, HCRU, parts of the congestion score (Dyspnoea, Orthopnoea, 
Fatigue), Adverse Events, concomitant therapy, Patient Global Impression of Severity of 
Heart Failure Symptoms (PGI-S).
KCCQ is a questionnaire that should be answered by the patient alone. Patients can be 
supplied with the questionnaire to be filled out at home. The questionnaire should be 
answered on the day of the remote visit and sent back to the site. The paitent needs to be 
instructed to go alone to a quiet area where she/he can record her/his response in the
questionnaire without interaction with others. In instances where a patient cannot give or
decide upon a response, no response should be recorded. For illiterate patients the the process 
described in Section 10.2 should be followed during the phone visit.
Safety lab, other laboratory tests
If taking blood samples for central lab is not possible, blood analysis for safety lab can be 
done in a local lab. The results of the lab tests are to be reported and transferred to the 
investigator, who has to ensure medical review and proper documentation.
Minimum required safety lab parameters are eGFR and liver enzymes which will be captured 
in the eCRF. An urine analysis should not be performed locally.
Dispensation of Trial medication (IMP)
If a patient is not able to come to visit 4 as planned but the investigator considers it favorable 
and save for patient to continue with IMP, IMP can be shipped from site directly to the 
patient (if legally acceptable according to local regulations).


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If home visits by trial staff members or e.g. “Home Healthcare Nurse” are possible, further 
assessments can be done like e.g. vital sings, blood draw for safety lab and biomarkers as 
well as collection of urine samples to be sent to central lab, or compliance check.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
04 Jun 2020
EudraCT number
EU number
2019-002946-19
BI Trial number
1245-0204
BI Investigational Product(s)
Jardiance®, empagliflozin
Title of protocol
A multicentre, randomised, double-blind, 90-day 
superiority trial to evaluate the effect on clinical 
benefit, safety and tolerability of once daily oral 
EMPagliflozin 10 mg compared to placebo, 
initiated in patients hospitalised for acUte heart 
faiLure (de novo or decompensated chronic HF) 
who have been StabilisEd (EMPULSE)
Global Amendment due to urgent safety reasons
Global Amendment
X
Section to be changed
Title page
Description of change
In the title “decompensatied” was changed to 
“decompensated”
Rationale for change
Correct typo
Section to be changed
Title page and CTP Synopsis
Description of change
Changed to
Rationale for change
Address corrected
Section to be changed
CTP Synopsis (Trial objective(s) and Trial 
endpoints),
Section 2.1 (Main Objectives, Primary and 
Secondary Endpoints) and 
Description of change
Exchange KCCQ-CSS by KCCQ-TSS in trial 
objective(s) and all respective endpoints (primary, 
secondary and further endpoints)


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Rationale for change
Section to be changed
CTP Synopsis (Primary Endpoint and Statistical 
methods), Section 2.1.2.
Description of change
Change in statistical methodology for primary 
endpoint: change from “net benefit” to “win ratio”.
Clarification of how the variance will be calculated 
by providing a more specific description.
Rationale for change
Based on recent publications and public scientific 
discussions involving representatives from FDA 
and other regulatory authorities, the win ratio has 
gained attention in the scientific community. 
Compared to the “net benefit” approach, the result 
arising from the “win ratio” will likely be better 
understood by regulatory authorities and by the 
scientific community.
The overall statistical power for the primary 
endpoint will remain very similar with the win 
ratio.
Section to be changed
Flow Chart, 
 Section 5.1.5 and 
Section 10.3
Description of change
Patient global impression of severity (PGI-S) of 
heart failure symptoms is added as an patient 
reported outcome measure. Time points of 
evaluation are the same than for KCCQ.


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Rationale for change
 
Section to be changed
Flow Chart
Description of change
Reference to footnote 8 added to “Review of in-
/exclusion criteria”
Rationale for change
Clarification: local lab is used for evaluation of all 
in-/exclusion criteria related to lab results
Section to be changed
Section 1.1
Description of change
Wording with regard to EMPERIAL trials updated:
In addition, two clinical trials in patients with 
chronic HFpEF (EMPERIAL-preserved) or HFrEF 
(EMPERIAL-reduced) to evaluate the effect of 
empagliflozin on exercise ability using the 6 
minute walk test are completed.
Rationale for change
To reflect current status of these trials.
Section to be changed
Description of change
 
Rationale for change
Section to be changed
Section 3.3.2
Description of change
Inclusion criterion 9 was changed to
HF episode leading to hospitalisation must have 
been treated with a minimum single dose of 40 mg 
of i.v. furosemide (or equivalent i.v. loop diuretic 
defined as 20 mg of torasemide or 1 mg of 
bumetanide).
Rationale for change
To clarify that the dose refers to a single dose given 
for the treatment of the HF episode.


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Section to be changed
Section 3.3.3
Description of change
Exclusion criterion 14:
Reference to “Visit 1” is replaced by “in ECG 
before randomisation (Visit 2a)”
Rationale for change
To reflect the availability of respective trial related 
assessments. 
Section to be changed
Section 3.3.3
Description of change
Exclusion criteria 17 and 18:
Reference to “Visit 1” is replaced by “as measured 
during hospitalisation (latest local lab measurement 
before randomisation)”.
Rationale for change
To clarify which local available lab assessment 
should be used for assessing the exclusion criteria. 
Section to be changed
Section 5.1.1
Description of change
Assessment of efficacy “Net Clinical Benefit” was 
changed to “Clinical Benefit”.
Rationale for change
To reflect the changes in the statistical analysis in 
the naming of the assessment.
Section to be changed
Section 5.2.4
Description of change
Table 5.2.4:1 Safety laboratory tests:
Urinalysis: “dipstick” deleted.
Rationale for change
To clarify and reflect the current process.
Urinalysis will be done at central lab not using 
dipstick tests
Section to be changed
Section 5.2.7.2.2
Description of change
The mode of sending SAE forms (“by fax”) is 
deleted. 
The wording is changed to:
The investigator must report SAEs, AESIs, and 
non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form 
immediately (within 24 hours) to the sponsor’s 
unique entry point (country specific reporting 
process will be provided in the ISF). The same 
timeline applies if follow-up information becomes 
available.
In specific occasions, the investigator could inform 
the sponsor upfront via telephone. This does not 
replace the requirement to complete and send the 
BI SAE form.
Rationale for change
To reflect future changes in the SAE reporting 
when alternative methods of SAE report 


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transmission to fax will be introduced for all trials.
Section to be changed
Section 7.5
Description of change
Changed description of primary endpoint and 
added the win ratio. Changed KCCQ-CSS to 
KCCQ-TSS. Added relevant source references for 
assumptions made. Added further assumptions for 
KCCQ-TSS placebo mean and win threshold. 
Updated power estimates to be based on the win 
ratio.
Rationale for change
See rationale described above for Sections 2.1, 
2.1.2 and 7.2.2. Source references omitted in 
previous version.
Section to be changed
Section 9
Description of change
The following references are deleted:
R19-3016, R19-3043, R19-3046, R98-1473
The following references are added:
R16-4813, R17-3082, R17-3097, R19-3448, 
c26554599-01, c26554767-01
Rationale for change
Updated to reflect the changes in the statistical 
analysis.
Section to be changed
Section 10.4
Description of change
An appendix with accepted forms of contraception 
for patients in Italy was added
Rationale for change
To comply with the request form AIFA (Italian 
Regulatory Authority).
Section to be changed
Section 1.4.2
Description of change
Risk evaluation in relation with COVID-19 added:
Patients with chronic heart diseases are at higher 
risk for severe illness from COVID-19. Therefore, 
in case of local high risk of COVID-19 infection,


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physical visits to the sites should be avoided as 
much as possible. In the event of restriction to visit 
the investigator site, certain procedures can be done 
remotely, and local labs can be used instead of 
central lab. These changes are meant to keep the 
integrity of the trial and they will not affect the 
benefit-risk of empagliflozin.
There is no indication that empagliflozin may 
increase the risk of COVID-19 infection. As with 
any acute illness, empagliflozin during COVID-19 
infection has the potential to increase the risk of 
ketoacidosis. The risk of ketoacidosis in case of 
acute illness is adequately addressed in the IB. The 
study drug should be discontinued in case of severe 
COVID-19 disease.
Rationale for change
COVID-19 pandemic
Section to be changed
Section 4.1.4, 6.1, 8.1 and 10.5; Flow Chart
Description of change
Contingency measures have been introduced to 
ensure patient safety and appropriate trial 
continuation based on a thorough benefit risk 
assessment (see Section 1.4.2) and above.
Introduce flexibility for trial visits: to allow in 
exemptional cases visits to be done as home/remote 
visists; to allow for IMP shipment from site to 
patient in this cases. Patients need to agree to 
changes prior to them being implemented.
Comment added below the Flow Chart to refer to 
the contingency measures if they are needed.
Rationale for change
COVID-19 pandemic


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c28603082
2.0
clinical-trial-protocol-version-02
A multicentre, randomised, double-blind, 90-day superiority trial to evaluate the
effect on clinical benefit, safety and tolerability of once daily oral EMPagliflozin 10
mg compared to placebo, initiated in patients hospitalised for acUte heart faiLure (de
novo or decompensated chronic HF) who have been StabilisEd (EMPULSE).
Author-Clinical Trial Leader
04 Jun 2020 16:02 CEST
Approval-Therapeutic Area 
04 Jun 2020 21:50 CEST
Author-Trial Statistician
05 Jun 2020 11:25 CEST
Approval-Team Member Medicine
05 Jun 2020 16:43 CEST
Verification-Paper Signature
Completion
08 Jun 2020 09:21 CEST


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Document Number: 
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(Continued) Signatures (obtained electronically) 
 
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Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2.0

SAP_001.pdf: 
001-MCS-50-415_RD-01 (2.0) / Saved on: 06 Dec 2019
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c32295612-01
BI Trial No.:
1245-0204
Title:
A multicentre, randomised, double-blind, 90-day superiority trial 
to evaluate the effect on clinical benefit, safety and tolerability of 
once daily oral EMPagliflozin 10 mg compared to placebo, 
initiated in patients hospitalised for acUte heart faiLure (de novo 
or decompensated chronic HF) who have been StabilisEd 
(EMPULSE)
Including Protocol Amendment 1 1245-0204-protocol-
amendment-1 [c28603082-02]
Investigational
Product(s):
Jardiance®, empagliflozin
Responsible trial 
statistician(s):
Phone: 
Fax: N/A
Date of statistical 
analysis plan:
11-MAR-2021 SIGNED
Version:
FINAL
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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......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................8
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................9
5.
ENDPOINTS .........................................................................................................9
5.1
PRIMARY ENDPOINT .......................................................................................9
5.2
SECONDARY ENDPOINTS.............................................................................10
5.2.1
Key secondary endpoint .....................................................................................10
5.2.2
Secondary endpoints...........................................................................................10
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................12
6.1
TREATMENTS...................................................................................................12
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................13
6.3
SUBJECT SETS ANALYSED...........................................................................15
6.5
POOLING OF CENTRES .................................................................................17
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................18
6.6.1
Imputation methods............................................................................................18
6.6.2
Missing data.........................................................................................................19
6.6.3
Longitudinal Analyses ........................................................................................21
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................21
6.8 
CALCULATION OF TIME TO EVENT.........................................................23
6.8.1
Start date..............................................................................................................23
6.8.2
Date of event ........................................................................................................23
6.8.3
Censoring.............................................................................................................24
7.
PLANNED ANALYSIS......................................................................................26
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........26
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................27
7.3
TREATMENT COMPLIANCE........................................................................27
7.4
PRIMARY ENDPOINT .....................................................................................27
7.4.1
Primary analysis of the primary endpoint........................................................28
7.5
SECONDARY ENDPOINTS.............................................................................30
7.5.1
Key secondary endpoint .....................................................................................30


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7.5.2
Secondary endpoints...........................................................................................30
7.7
EXTENT OF EXPOSURE.................................................................................32
7.8
SAFETY ANALYSIS..........................................................................................32
7.8.1
Adverse Events ....................................................................................................32
7.8.2
Laboratory data ..................................................................................................39
7.8.3
Vital signs.............................................................................................................41
7.8.4
ECG......................................................................................................................42
7.8.5
Others...................................................................................................................42
8.
REFERENCES....................................................................................................43
9.
ADDITIONAL SECTIONS ...............................................................................44
9.1
DERIVATION OF KCCQ DOMAINS.............................................................44
9.1.1
Kansas City Cardiomyopathy Questionnaire (KCCQ)...................................44
9.2
ALGORITHM FOR IMPUTATION ACCORDING TO JUMP-TO-
PLACEBO METHOD........................................................................................49
10.
HISTORY TABLE..............................................................................................53


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LIST OF TABLES
Table 6.1: 1
Treatment regimens / study intervals................................................................12
Table 6.1: 2
Endpoint specific assignment to the on-treatment phase..................................13
Table 6.2: 1
Important protocol deviations...........................................................................13
Table 6.6.1: 1 Adjusted multiple imputation “jump-to-placebo” approach – the missing 
data imputation method ....................................................................................18
Table 6.7: 1
Time windows ..................................................................................................22
Table 7.8.2: 1 CKD staging .....................................................................................................41
Table 10: 1
History table .....................................................................................................53


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ACE 
Angiotensin Converting Enzyme
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine transaminase
ANCOVA
Analysis of covariance
ARB 
Angiotensin Receptor Blocker
ARNI 
Angiotensin Receptor blocker-Neprilysin Inhibitor
ASA
Acetylsalicylic acid
AST
Aspartate transaminase
ATC
Anatomical-Therapeutic-Chemical
AUC
Area under the curve
BI
Boehringer Ingelheim
BIcMQ
Boehringer Ingelheim customized MedDRA Query
BMI
Body mass index
BP
Blood pressure
bpm
beats per minute
CEC
Clinical Event Committee
CIF
Cumulative Incidence Function
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CRT 
Cardiac resynchronisation therapy
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Cardiovascular
DAOH
Days alive and out of hospital
DBL
Data base lock
DBP
Diastolic Blood Pressure
DKA
Diabetic ketoacidosis
DM 
Diabetes mellitus
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EF
Ejection Fraction


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Term
Definition / description
eGFR
Estimated glomerular filtration rate
EMA
European Medicines Agency 
EoT
End-Of-Text
EOT
End of treatment
EudraCT
European Clinical Trials Database
GI
Gastrointestinal
HbA1c
Glycosylated haemoglobin
HF
Heart failure
HFE
Heart failure event
HLT
High level term
HR
Hazard ratio
IC
Informed consent
ICD 
Implantable Cardioverter Defibrillator
ICH
International Conference on Harmonisation
iPD
Important protocol deviation
IRT
Interactive Response Technology
ITT
Intention-to-treat
KCCQ
Kansas City Cardiomyopathy Questionnaire
KCCQ-TSS
Kansas City Cardiomyopathy Questionnaire Total Symptom Score
kg
kilogram
LLT
Low level term
LVEF
Left ventricular ejection fraction
MAR
Missing at random
Max
Maximum
MCMC
Markov Chain Monte Carlo
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram
mg/dL
Milligram per decilitre
MI
Myocardial infarction
Min
Minimum
MMRM
Mixed models repeated measures
MNAR
Missing not at random


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Term
Definition / description
MRA 
Mineralocorticoid Receptor Antagonist
NT-proBNP
N-terminal pro B-type natriuretic peptide
NYHA
New York Heart Association Classification
OC-AD
Observed Case including data After Discontinuation
OC-OT
Observed Case On Treatment
PPS
Per Protocol Set
PT
Preferred term
Q1
Lower quartile
Q3
Upper quartile
RS
Randomised set
SAE
Serious adverse event
SAS
Statistical Analysis System
SBP
Systolic blood pressure
SCR
Screened set
SD
Standard deviation
SE
Standard error
SGLT-1
Sodium-glucose co-transporter 1
SGLT-2
Sodium-glucose co-transporter 2
SI
Système international d'unités
SLR
Sequential linear regression
SMQ
Standardized MedDRA query
SOC
System organ class
TBILI
Total bilirubin
TS
Treated set
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
UTI
Urinary tract infection


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3.
INTRODUCTION
As per the International Conference on Harmonisation (ICH) E9 guidance (1), the purpose of 
this document is to provide a more technical and detailed elaboration of the principal features 
of the analysis described in the protocol, and to include detailed procedures for executing the 
statistical analysis of the primary and secondary variables and other data.
This Trial Statistical Analysis Plan (TSAP) assumes familiarity with the Clinical Trial 
Protocol (CTP), including Protocol Amendments. In particular, the TSAP is based on the 
planned analysis specification as written in CTP Section 7 “Statistical Methods and 
Determination of Sample Size”. Therefore, TSAP readers may consult the CTP for more 
background information on the study, e.g., on study objectives, study design and population, 
treatments, definition of measurements and variables, planning of sample size, randomisation.
SAS® Version 9.4 or later will be used for all analyses.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
In the CTP, a stratified win ratio is described, but the weighting method for each stratum is 
not mentioned. Therefore, the weighting method to be used has been described here in 
Section 7.4.1.
In the logistic regression models used for the binary endpoint variables (e.g. improvement in 
KCCQ-TSS of ≥ 10 points after 90 days of treatment), an additional continuous covariate 
(baseline KCCQ-TSS score) is included (see Section 7.5.2).
5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
The primary endpoint is specified in the CTP Section 2.1.2.
An HFE is:
-
A hospitalization/ER visit OR
-
An urgent care visit OR
-
An Outpatient visit
With all of the following:
-
The question “Was visit related to the primary diagnosis or worsening of heart failure 
in the opinion of the treating physician?” is answered yes
-
At least one symptom of 
o
dyspnea, 
o
decreased exercise tolerance, 
o
fatigue, 
o
edema
o
other symptoms of worsened end-organ perfusion or volume overload
-
At least two physical examination findings OR (one physical examination finding and 
at least one laboratory criterion). 
o
Physical examination are 

peripheral edema, 

increased abdominal distention or ascites, 

pulmonary rates/crackles/crepitations, 

Increased jugular venous pressure and/or hepatojugular reflux, 

S3 gallop, 

Clinically significant or rapid weight gain thought to be related to fluid 
distention, 

other
o
Laboratory criteria are:

Increased BNP or NT-proBNP, 

radiological or ultrasonographic evidence of pulmonary congestions, 


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
non-invasive diagnostic evidence of clinically significant elevated 
ventr. filling pressure or low cardiac output 

invasive diagnostic evidence with right heart catheterization showing a 
pulmonary capillary wedge pressure >=18 mmHG, central venous
pressure >=12 mmHg or cardiac index <2.2 L/min/m² 

Other
-
Intensification of therapy (significant augmentation of oral diuretics, IV diuretics´, 
vasoactive agent, or mechanical or surgical intervention)
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoint
Not applicable.
5.2.2
Secondary endpoints
Secondary endpoints are specified in the CTP Section 2.1.3.  Regarding the CV death 
endpoint, adverse events on the eCRF death event form where the primary cause of death is 
CV death or unknown cause of death, will be classed as CV death.
Regarding the secondary endpoint “occurrence of HHF until 30 days after initial hospital 
discharge”, HHFs are defined as the subset of HFEs where the investigator has checked the 
hospitalisation tick box.
Regarding the secondary endpoint “occurrence of chronic dialysis or renal transplant or 
sustained reduction of ≥40% eGFR Chronic Kidney Disease Epidemiology Collaboration 
Equation ((CKD-EPI)cr), or
o sustained eGFR (CKD-EPI)cr <15 mL/min/1.73 m2 for patients with baseline 
eGFR ≥30 mL/min/1.73 m2
o sustained eGFR (CKD-EPI)cr <10 mL/min/1.73 m2 for patients with baseline 
eGFR <30 mL/min/1.73 m2”,
the following applies: an eGFR (CKD-EPI)cr reduction is considered sustained, if it is 
determined by two or more consecutive post-baseline central laboratory measurements 
separated by at least 30 days (first to last of the consecutive eGFR values). Chronic dialysis is 
regarded as chronic if the frequency of dialysis is twice or more per week for at least 90 days.  
Chronic dialysis and renal transplant will be confirmed by medical review of data from the 
concomitant non-drug therapy eCRF page.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
There will be three basic treatment phases in this trial: screening, study treatment phase (with 
either empagliflozin 10mg or matching placebo) and post-treatment.  However, during the 
study treatment phase, patients are allowed to go off-treatment and subsequently re-start 
treatment.  This may happen not at all or repeatedly for a given patient.
The purpose of the definitions below is to describe all the different study/treatment intervals, 
in which a patient can participate in during the course of the trial. Note that the term 
"treatment regimen" also covers the “off-treatment” time periods.
Table 6.1: 1
Treatment regimens / study intervals
Label
Interval
Start date 
Screening
Screening
Date of informed consent
Placebo/
Empagliflozin 10mg
Treatment
Date of first administration of study 
medication
Off-treatment (if applicable)
During treatment 
interval, but not on
treatment
Date of last administration of study 
medication before temporary 
discontinuation + 1 day
Placebo/
Empagliflozin 10mg 
(if applicable)
During treatment 
interval, after 
restart of study 
medication
Date study medication re-started
Post-treatment
Post-treatment
Date of last administration of study 
medication + 1 day
Details on the definition of the on-treatment period for different endpoints are listed in 
Table 6.1:2. The efficacy analyses will follow the intention-to-treat (ITT) principle in 
assigning patients to treatment groups, i.e. patients will be analysed as randomised. 
Safety analyses will also assign patients to the treatment group as randomised.
If a patient erroneously receives the wrong trial drug, all subsequent medication packs 
dispensed to the patient will still be for the treatment group to which the patient was 
randomised. Therefore, the adverse events will be analysed as per randomised treatment, 
which is expected to reflect the prevailing treatment. 
In the exceptional case that a patient took the wrong treatment, adverse events may occur 
while being on the wrong treatment. Analyses of this data are described in Section 7.8.1.6. 


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Table 6.1: 2
Endpoint specific assignment to the on-treatment phase
Endpoint
Last day of assignment to the on-
treatment phase
(days after last intake of study 
medication)
Adverse events
7
   Safety laboratory measurements
3
Heart rate
1
Glycosylated haemoglobin (HbA1c)
7
Glucose
1
Body weight
1
Creatinine and estimated glomerular filtration 
rate (eGFR)
1
N-terminal pro B-type natriuretic peptide (NT-
proBNP)
1
Blood pressure (BP)
1
Patient reported outcome
7
6.2
IMPORTANT PROTOCOL DEVIATIONS
A protocol deviation is important, if it affects the rights or safety of the patients or if it can 
potentially influence the primary outcome measure for the respective patients in a way that is 
neither negligible nor in accordance with the study objectives.
The important protocol deviations (iPDs) will be described in the clinical trial report (CTR). 
A listing of patients with medication code broken at the trial sites will be provided.
Table 6.2: 1
Important protocol deviations
Category / 
Code
Description
Requirements
Excluded 
from
A
Entrance criteria not met
A1
Target indication not met
A1.07
Conditions on ejection fraction (EF) not 
met
Inclusion criterion #5 not met
None
A1.08
Conditions on NT-proBNP not met
Inclusion criterion #8 not met 
None
A2
/3
Eligibility criteria not met


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Table 6.2: 1
Important protocol deviations (cont.)
Category / 
Code
Description
Requirements
Excluded 
from
A2.04
eGFR out of range
Exclusion criterion #15 met
None
A3.51
Type 1 diabetes
Exclusion criterion #16 met
None
A3.55
Not currently hospitalised for the 
primary diagnosis of acute heart 
failure (de novo or decompensated 
chronic HF), regardless of EF
Inclusion criterion #4 not met
None
A3.56
Randomisation outside of window
Inclusion criterion #6 not met
None
A3.57
Patient not hemodynamically 
stabilised
Inclusion criterion #7 not met
None
A3.58
HF episode leading to hospitalisation 
not sufficiently treated
Inclusion criterion #9 not met
None
A3.60
Cardiogenic shock
Exclusion criterion #1 met
None
A3.61
Primary diagnosis is not acute heart 
failure
Exclusion criterion #2 met
None
A3.62
Primary diagnosis is acute heart 
failure not triggered by volume 
overload
Exclusion criterion #3 met
None
B
Informed consent
B1
Informed consent not available
Informed consent date missing
All
B2
Informed consent too late
Informed consent date was after Visit 1
None
C
Trial medication and 
randomisation
C1.02
Incorrect trial medication taken
Wrong medication taken for more than 
20% of the overall treatment duration 
Can only be finally judged after data base 
lock (DBL), since unblinding information 
is required.
None
C3.01
Non-compliance with study drug 
intake
Compliance <80% or >120%
None
C4.011
Medication code broken 
inappropriately
Medication code was broken for no 
valid reason.
Final decision at the DBL meeting 
based on medical judgement. 
None
D
Concomitant medication
D2.02
Use of prohibited medication 
Review of eCRF for prohibited 
medication.
Final decision at the DBL meeting 
based on medical judgement.
None
G
Study-specific analysis
G3.501
Assessment order not followed that 
could influence PRO at baseline or 
Day 90
PRO measurements not before any other 
assessment at baseline or Day 90
None
I
Other safety-related deviations
I2.01
Pregnancy
None
1 needs to be checked at site by Local Clinical Monitors (CMLs) / Clinical Research Associates (CRAs) as these cannot be 
checked programmatically


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6.3
SUBJECT SETS ANALYSED
The following patient sets are defined:

Screened Set (SCR)
Consists of all patients screened for the trial, with informed consent given and who 
completed at least one screening procedure at Visit 1.

Randomised set (RS)
This patient set includes all randomised patients, whether treated or not.

Treated set (TS)
This patient set includes all patients who were dispensed study medication and were 
documented to have taken at least one dose of investigational treatment.
A Per Protocol Set (PPS) will not be specified for this trial.


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6.5
POOLING OF CENTRES
This section is not applicable because centre/country is not included in the statistical model.


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6.6
HANDLING OF MISSING DATA AND OUTLIERS
6.6.1
Imputation methods
There will be no imputation of data for safety analyses. 
For patients who discontinue the trial treatment prematurely, all efforts will be made to follow 
patients for survival and for any other endpoints including the primary and secondary 
endpoints until the end of the trial. 
Multiple imputations:
Missing data for the Kansas City Cardiomyopathy Questionnaire Total Symptom Score 
(KCCQ-TSS), as part of the stratified win ratio and NT-proBNP (log-transformed values) will 
be estimated using multiple imputation, according to whether patients are on-treatment or off-
treatment.  
Values measured after premature discontinuation of study drug will be included in the 
analyses. All available on- and off-treatment data up to the planned measurement at Day 90
will be included.
There will be different types of missing data to be considered for the imputation.
Table 6.6.1: 1 Adjusted multiple imputation “jump-to-placebo” approach – the missing data 
imputation method 
Missing data imputation
(Assumption of missingness)
Non-monotone
Monotone
On-treatment data
MCMC-MI1
(MAR3)
SLR-MI2
(MAR)
Off-treatment4 data 
Jump-to-Placebo
(MNAR5)
Jump-to-Placebo
(MNAR)
1 Markov Chain Monte Carlo – Multiple imputation (MCMC-MI)
2 Sequential linear regression – Multiple imputation (SLR-MI)
3 Missing at random (MAR)
4 Any instance of a patient discontinuing treatment will lead to all future measurements being considered as off-treatment.
5 Missing not at random (MNAR)
As the first step, the non-monotone on-treatment missing data will be imputed using Markov 
Chain Monte Carlo (MCMC) simulation and standard techniques; MI will be performed 
separately by treatment with baseline value as a continuous variable and HF status as a binary
variable (de novo or decompensated chronic HF). One hundred imputations will be performed 
to ensure adequate efficiency and stability of the estimation for missing data.  This step will 
be referred to as ‘MCMC-MI’.
For the monotone missing on-treatment data, a sequential linear regression MI approach will 
be used and referred to as ‘SLR-MI’. The MI will be performed on a data set only including 
on treatment data and once per imputation from the previous step. This procedure will impute 
values for all missing time points both on- and off-treatment, so imputations for off-treatment 
values will then be deleted. The regression models will be fitted separately by treatment and 


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include the baseline value as a continuous covariate, HF status as a class covariate and the 
values at previous time points as separate continuous covariates.
To impute the missing off-treatment data, a residual-based approach will be used to enact the 
‘jump-to-placebo’. Throughout this imputation, all observed off-treatment data will be 
temporarily removed and added back at the end. A covariate-adjusted difference between the 
relevant treatment arm and placebo (i.e. 0 for those in the placebo arm) will be calculated at 
each visit using ANCOVA (with HF status and treatment as categorical covariates and 
baseline value as a continuous covariate). Next, the relevant estimated treatment difference 
will be deducted from all observed data in the active treatment groups. Note that the 
adjustments are for the duration of the imputation only and the original values for the 
observed data will be in the final imputed data set.
SLR-MI will then be performed once per imputation upon this modified data but only 
including patients either with missing values and/or those in the placebo arm, ensuring 
imputations are performed using the placebo distribution. The models will include baseline 
value as a continuous covariate, HF status as a class covariate and the values at previous time 
points as separate continuous covariates. All missing data will therefore follow the 
distribution of the placebo arm, jumping from one arm’s distribution to the placebo’s at the 
point of missingness, while still accounting for past within-treatment performance (the 
residuals). After this imputation, all the original observed values (i.e. off-treatment values) 
will be restored.
For NT-proBNP, the AUC of change from baseline in log-transformed NT-proBNP level will 
be calculated using these imputed data sets (imputation performed on the log-transformed
data first before AUC values are calculated).  Then an ANCOVA model will be applied (see 
Section 7.5.2). Rubin’s rules (13) will be used to combine treatment estimates across the 100 
imputations.  Missing values at Visits 2b and 2c will not be imputed, but observed values at 
these visits will be used.
For KCCQ-TSS, the stratified win ratio will be calculated using these imputed data sets, by 
combining with the non-imputed death and HFE data.  Because the stratified win ratio is log-
normally distributed (10), Rubin’s rules (13) can be used on the log-transformed win ratios to 
combine treatment estimates across the 100 imputations.
The implicit assumption underlying the imputations and analyses is that unobserved off 
treatment patient measurements will lose any treatment effect immediately post-treatment 
discontinuation.
A more technical description of the method can be found in Appendix 9.2.
6.6.2
Missing data
Adverse event data 
Missing or partial date information for AEs will be replaced according to general Boehringer 
Ingelheim (BI) rules described in the BI guidance for handling of missing and incomplete AE 
dates (2).


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Death date
For patients with a record of death captured on the electronic case report form (eCRF) with 
missing or only partial death date from all available sources, the death date will be derived.   
The latest date of any of the following dates will be used: event onset and end dates from 
either the AE page, or CEC adjudicated onset dates, by using also imputed AE dates, last day 
known to be alive + 1 day, range of possible days based on partial death date and date of trial 
completion. 
Missing information on the date of first administration of trial drug
If the date of first drug administration is missing but the patient was randomised, the date of 
the first drug administration will be set to the date of randomisation. If the date of first 
administration is partially missing with the month and year present, the day will be set to the 
date of randomisation, if randomisation was in the same month. If randomisation was in the 
month prior to the first drug administration, the missing day will be imputed as the first day of 
the month. 
Missing information on the date of trial medication stop
If the date is partially or completely missing, use the minimum of the following dates:

end of treatment visit date, if available

date of death

trial completion (last contact date)

longest extrapolated treatment duration (assuming 1 tablet/day)
In case of a partially missing date, if the imputed date is before the first day of the month/year 
given as the partial date, the first day of the month/year will be used. 
All other cases need to be assessed by the trial team on an individual patient basis, using the 
points above as guidance.  
Missing information on concomitant therapy or non-medication therapy dates
For incomplete date information, generally the midpoint of the possible interval will be used. 
If only the year is present, the day and month will be imputed as 01 July, if year and month is 
present the day will be imputed as 15. If the year is missing, the date will be considered 
missing. 
If this leads to contradictions for the start or end date of a concomitant therapy (e.g. imputed 
end date before documented start date), a partial end date will be imputed as the end of the 
interval or a partial start date will be imputed as the start of the interval in the database to 
resolve this contradiction. 
If it is unclear from the partial date, whether a therapy was before or after date of baseline, 
then it will be assumed, that the therapy started after baseline (similar to worst case rules 
applied for adverse events).
All other cases or conflicting cases resulting from these imputation rules need to be assessed 
by the trial team on an individual patient basis.  
Missing measurement to confirm “sustained” decrease
An eGFR (Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)cr) reduction is 


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considered sustained, if it is determined by two or more consecutive post-baseline central 
laboratory measurements separated by at least 30 days (first to last of the consecutive eGFR 
values). If there is no additional measurement >= 30 days after the eGFR reduction is 
observed and the patient dies within 60 days of this measurement, then the eGFR reduction is 
also considered sustained.
Hospital discharge date
Missing hospital discharge dates will be replaced with the date of the last follow-up. 
6.6.3
Longitudinal Analyses
There will be different methods of analysing continuous longitudinal data. 
Observed case on-treatment (OC-OT):
Only the available data that were observed while patients were on study medication (defined 
as time from first drug intake until last permanent treatment stop date plus the endpoint 
specific follow-up time (as defined in Table 6.1: 2)) are considered. 
Measurements are assigned to planned weeks according to Table 6.7: 1
Imputed records are not included.
Observed case including data after treatment discontinuation (OC-AD):
All available data are considered, including values obtained on treatment or post-treatment. 
Imputed records are not included.
Measurements are assigned to planned weeks according to Table 6.7: 1.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Baseline will be defined as the last available measurement before start of randomised trial 
medication for all endpoints. For laboratory data (e.g. NT-proBNP), baseline will use central 
laboratory data.
Since the protocol specifies that all measurements are taken at Visit 2a before any intake of 
trial medication, all measurements at the first day of drug intake are assumed to qualify as 
baseline assessments. 
For randomised patients without any treatment intake: Baseline will be defined as the last 
available measurement before or on the day of randomisation. 
Measurements taken after the first intake of randomised trial medication will be considered 
on-treatment values if they have been obtained up to the end of the parameter specific follow-
up period as defined in Table 6.7: 1 below and will be assigned to the randomised study drug 
for efficacy and safety analyses. Measurements taken after the end of the parameter specific 
follow-up period after the last intake of study drug will be considered post-treatment values.
Efficacy and safety measurements will be assigned to visits based on time windows around 
the planned visit dates. These time windows are defined based on the planned number of days 
after the date of first administration of study drug. 


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The time window for the first visit after randomisation starts on the day after the first intake of 
study drug. The midpoint between two on-treatment visits defines the end of a time window, 
with the midpoint being included in the time window of the preceding visit. 
Table 6.7: 1
Time windows 
Time window (days after 
baseline)
Visit number
Visit label
Planned days
Start
End
Endpoints assessed at each on-site visit (e.g. creatinine / eGFR)
2a
Baseline 1
1
NA
1
2b
Day 3
3
2
4
2c
Day 5
5
5
10
3
Day 15
15
11
22
4
Day 30
30
23
60
5
Day 90
90
61
Trt stop + x*
days
Endpoints that are not assessed on Visit 2b and 2c (e.g. weight)
2a
Baseline 1
1
NA
1
3
Day 15
15
2
22
4
Day 30
30
23
60
5
Day 90
90
61
Trt stop + x*
days
1 Only values taken prior to the start of treatment with randomised study drug can be considered baseline values. Time windows will be used 
for assignment of measurements to scheduled visits.
* See Table 6.1: 2
Only one observation per time window will be selected for analysis at an on-treatment visit –
the non-missing value will be selected which is closest to the protocol planned visit day. If 
there are two observations which have the same difference in days to the planned day or if 
there are two observations on the same day, the first value will be used. 
Baseline definition for concomitant therapies
Concomitant medication taken at baseline is any medication with start date ‘continued’ or 
before date of first study medication intake (randomisation date will be used for patients not 
treated) and end date continued on or after date of first study medication intake 
(randomisation date will be used for patients not treated). 


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6.8 
CALCULATION OF TIME TO EVENT
This section describes the calculation of the time to event and the time that patients without an 
event are in the study (under risk). 
Consistent with that approach, the respective time intervals determine the start and end for the 
derivation of occurrence of a specific event.
For those patients with an event, the time to event is calculated as: 
<date of event> - < start date> + 1
For those patients without an event, the time at risk is calculated as:
<date of censoring> - < start date > + 1
6.8.1
Start date
In general, the time to event will be derived from the date of randomisation. 
For the following endpoints (analysed as occurrence or time to first event), the date of first 
drug intake will be used as the start date:
•
AE analyses according to Section 7.8.1
•
Endpoints purely based on laboratory measurements or concomitant medications, 
that include a relation to baseline (such as decrease from baseline >= 40%, 
doubling vs baseline, etc. )
Please note, that for composite endpoints, that include component(s) using randomisation date 
and other component(s) using first drug intake date as start date, the time at risk for the 
composite will start with date of randomisation (which may be earlier). For the individual 
components, the component specific start date will be used.
6.8.2
Date of event
For time-to-death endpoints, the respective death date will be used rather than time to the first 
onset of the fatal AE.
For composite outcomes, e.g. time to first occurrence of cardiovascular (CV) death or HFE 
until end of trial visit, the earliest onset date of the corresponding components will be used.
The time to first occurrence type of endpoints based on laboratory data including endpoints 
which have the requirement of a “sustained” measurement are determined by the date of the 
first measurement that fulfils this condition.
For events with multiple possible episodes, such as HFE or all-cause hospitalisation, the 
admission date of the first hospitalisation will be used, unless noted otherwise. The same 
applies to time-to-AE analysis, where the onset date of the first episode will be used.


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6.8.3
Censoring
The underlying principle is that the censoring date should be the last date a patient was known 
to be free of an endpoint event (e.g. free of each component of CV death and HFE).
For all endpoints except all-cause mortality and cause-specific death, patients without 
occurrence of a specific endpoint (composite endpoint or individual components) will be 
considered censored at the individual day of end-of-study. 
The individual day of trial completion will be the latest of:

last onset of an AE or date of death

onset dates of adjudicated events

end of treatment

last visit date (NYHA class, KCCQ, pregnancy test, vital signs, ECG, or central 
laboratory)
Censoring is considered independent from study drug intake.
All-cause mortality
A patient without the event will be censored at the latest of:
•
individual day of trial completion (without the restrictions defined above for 
patients with withdrawn consent or lost to follow-up)
•
last date known alive from the vital status page
Endpoints of any cause-specific death, e.g. CV death 
The same censoring rule as for all-cause mortality applies, and in addition, date of death if 
died from other causes than the one specified in the endpoint.
Endpoints based on laboratory data only 
Patients who already fulfil the respective condition at baseline are not considered in the 
number of patients at risk for this endpoint. 
If a baseline laboratory measurement is not available for the parameter of interest, it is 
assumed that the patient did not experience the condition corresponding to the endpoint at 
baseline and the patient is included in the patients at risk for this endpoint. Patients without an 
event and available post-baseline laboratory measurement will be considered censored at the 
date of last laboratory sampling of the corresponding parameter. Patients with a missing 
baseline laboratory value required to derive a change from baseline and patients without 
laboratory data following the baseline measurement will be censored on the date of 
randomisation. 


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Composite endpoints (analysed using a time-to-event approach)
Only patients that are included in the analyses for all components of the composite endpoint 
will be included in the analysis of the composite.
Of those, a patient with at least one event in any of the components of the composite will be 
considered to have an event and the date of the first event will be used for the composite 
endpoint. A patient without an event will be considered censored at the earliest of all 
censoring dates of the component endpoints.


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7.
PLANNED ANALYSIS
For End-Of-Text (EoT) tables, the set of summary statistics is: N / Mean / Standard Deviation 
(SD) / Standard Error (SE) / Minimum (Min) / lower quartile (Q1)/ Median / upper quartile
(Q3)/ Maximum (Max). The 1st and 99th percentiles might be substituting minimum and 
maximum in tables with open-ended values to safeguard against implausible extremes.
Geometric means and ranges will be added to the presentation or replace the presentation of 
mean and standard deviation for parameters that follow a log-normal distribution rather than a 
normal distribution. 
Statistical parameters will be displayed to a defined number of decimal places as specified in 
the BI guideline “Standards for Reporting of Clinical Trials and Project Summaries” (3)
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group (unless otherwise specified, all patients in the respective patient set 
whether they have non-missing values or not). Percentages will be rounded to one decimal 
place. The category missing will be displayed only if there are actually missing values.
Disposition of the patient population participating in the trial will be analysed by treatment 
groups, and stratum and presented in the clinical trial report as a frequency-distribution. 
Disposition as required for reporting for the trial in European Clinical Trials Database
(EudraCT) will be provided. Enrolment will be summarised by country and by age group for 
reporting in EudraCT.
The reason for not randomising screened patients will be summarized descriptively. 
The frequency of patients with iPDs will be presented by treatment group for the randomised 
set (RS). The frequency of patients in different analysis sets will also be presented for each 
treatment group.
Descriptive statistics on the impact of COVID-19 on study visits as well as study medication 
intake will be provided.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Demographics and baseline characteristics will be analysed based on the RS. Demographics 
will be repeated on the TS if the analysis sets differ by more than 1%. Standard descriptive 
analysis and summary tables will be presented. 
 
 Descriptive analysis of the following variables 
measured at baseline will be presented: Age, BMI, time since diagnosis, systolic blood 
pressure (SBP), diastolic blood pressure (DBP), heart rate, weight, eGFR, NT-proBNP, 
LVEF, KCCQ-TSS and hematocrit. 


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A summary of the number of patients in each randomisation stratum (de novo or 
decompensated chronic HF) per treatment will also be shown. The information will be based 
upon the data received from the IRT provider.  
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report using the RS. Concomitant 
medication use will be summarised by Anatomical-Therapeutic-Chemical classification level 
3 (ATC3) and preferred name. Summaries will be presented for concomitant therapies taken 
before initial hospitalisation, taken at baseline and separately for concomitant medications.
Separate summaries of use of heart failure-related drugs (e.g. ARNi, beta-blockers, 
ivabradine, diuretics, ACE-inhibitors, ARBs, MRAs, cardiac glycosides), anticoagulants, 
acetylsalicylic acid (ASA), or lipid lowering drugs will be presented. Use of devices and other 
non-medication therapy taken before initial hospitalisation and separately for those newly 
introduced after initial hospitalisation will also be summarised. 
Concomitant diseases will be summarised by system organ class and preferred term. Relevant 
medical history by treatment group will also be presented.
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the report. The number and 
percentage of patients with overall compliance 
 
 will be reported. Overall compliance will be calculated as a 
weighted average of reported compliance. The sum of all reported compliance over the 
planned visits will be divided by the total duration. The TS will be considered.
7.4
PRIMARY ENDPOINT
The efficacy analysis will be based on the RS, including all randomised patients. Analyses 
will be performed according to the intention-to-treat principle, with the use of all available 
data (on and off-treatment) through the trial period. This equates to a treatment-policy style 
estimand. Treatment will be evaluated as randomised.
The primary endpoint is clinical benefit (4 and 5) assessed using a stratified win ratio 
approach. The statistical model will be a non-parametric generalised pairwise comparison 
within HF status strata. The variance of the stratified win ratio will be calculated using the 
asymptotic normal U statistics approach (5).
Superiority of empagliflozin vs. placebo will be evaluated with one-sided tests, at a 
significance level of 0.025.


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7.4.1
Primary analysis of the primary endpoint
The primary endpoint is clinical benefit, a composite of death, number of HFEs, time to first 
HFE and change from baseline in KCCQ-TSS after 90 days of treatment.  This will be 
assessed using a stratified win ratio approach.
All patients randomised to empagliflozin are compared to all patients randomised to placebo 
within their stratum. 
For any two patients, a patient will win, i.e. achieve a better clinical outcome, as determined 
by assessing the following criteria sequentially, stopping when an advantage for either patient 
is shown:
1. Death within common follow-up time

death is worse than no death

earlier death is worse

tied, if not possible to determine
2. Number of HFEs within common follow-up time

more HFEs is worse

tied, if same number of HFEs
3. Time to first HFE within common follow-up time

earlier HFE is worse

tied, if not possible to determine
4. KCCQ-TSS change from baseline at Day 90

more positive change from baseline is better

the threshold for the difference is >= 5 for a win

tied, if difference < 5
Note, priority is therefore given to death over HFE, and both of these over changes in KCCQ-
TSS. Below are some examples:
1.
Death, e.g.:

Patient A dies 30 days after randomisation (loses)

Patient B dies 40 days after randomisation (wins)
2. If no winner based on death, number of HFEs within common follow-up time, 
e.g.:

Patient A had two HFEs (loses)

Patient B had one HFE (wins)
3. If no winner based on number of HFEs, time to first HFE, e.g.:

Patient A had an HFE 30 days after randomisation (loses)

Patient B had an HFE 50 days after randomisation (wins)


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4. If no winner based on time to first HFE, KCCQ-TSS change from baseline at Day 
90, e.g.:

Patient A: KCCQ-TSS change from baseline at Day 90 is 5 (loses)

Patient B: KCCQ-TSS change from baseline at Day 90 is 11 (wins)
The implemented generalised pairwise comparisons approach compares all patients in one 
treatment group to all other patients within their strata in the other treatment group. The 
stratified win ratio is then calculated as the total number of wins in the empagliflozin group 
across all strata divided by the total number of losses.
Applying weights that are analogous to a Mantel-Haenszel approach (10), the stratified win 
ratio is:
 = ∑
	
()/()


∑

()/()


where m is the stratum number (m = 1, 2), ne(m) is the number of wins in the empagliflozin 
group in the mth stratum, np(m) is the number of wins in the placebo group in the mth stratum 
and N(m) is the total number of patients in the mth stratum.
The variance is calculated by the asymptotic normal U statistic approach (5)
Separate summaries for each component of this endpoint will also be presented.
The method of handling missing KCCQ-TSS values for this analysis is described in Section 
6.6.1.


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7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoint
This section is not applicable, as no key secondary endpoint has been specified in the 
protocol.
7.5.2
Secondary endpoints
Other secondary endpoints are exploratory. No correction for multiple hypotheses testing will 
be made.
Change from baseline in continuous endpoints, such as KCCQ-TSS, will be analysed using 
restricted maximum likelihood estimation based on a mixed-effect model for repeated 
measures (MMRM) analysis to obtain adjusted means for the treatment effects. This model
will include discrete fixed effects for treatment group (empagliflozin or placebo) and HF
status (de novo or decompensated chronic HF) at each visit and continuous fixed effects for
baseline value at each visit. Missing data caused by patient withdrawal or other reasons will
be handled implicitly by the MMRM approach. An unstructured covariance structure will be 
used to model the within-patient errors.  
Area under the curve (AUC) of change from baseline in log-transformed NT-proBNP level
over 30 days of treatment will be analysed by an analysis of covariance (ANCOVA). Based
on literature reviews, NT-proBNP level is regarded as log-normally distributed, therefore
values will be log-transformed prior to analysis (6). The linear trapezoidal rule will be used to 
calculate the AUC after the log-transformation has been applied to each value.
ANCOVA with a discrete fixed effect for HF status (de novo or decompensated chronic HF) 
and a continuous fixed effect for baseline NT-proBNP level (log-transformed) will be used to 
compare treatment groups. The method of handling missing NT-proBNP levels for this 
analysis is described in Section 6.6.1.
Comparisons between treatment groups regarding the binary endpoint variable (improvement
in KCCQ-TSS of ≥ 10 points after 90 days of treatment) will be performed using a logistic
regression model adjusting for the binary covariate HF status (de novo or decompensated
chronic HF) and continuous covariate baseline KCCQ-TSS score. The likelihood-ratio test 
will be used to test for a difference between treatments. Adjusted odds ratios together with 1-
sided 97.5% confidence limits will be used to quantify the effect of treatment, comparing 
empagliflozin to placebo as the reference.


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Time to event endpoints will be analysed using the Cox proportional hazards model (7) with 
HF status (de novo or decompensated chronic HF) as a covariate. Hazard ratios (HRs) and 
their associated one-sided 97.5% confidence limits will be estimated for evaluating the 
superiority of empagliflozin to placebo.  All time-to-event endpoints will be reported in days. 
Other secondary endpoints will be summarised descriptively [including days alive and out of
hospital (DAOH)].  DAOH will be summarised as a percentage (12).
The follow-up time for DAOH analyses is defined as the minimum of 90 days after 
randomisation, or time between randomisation and date of censoring for non-fatal events
except for patients who died within the first 90 days, where 90 days is considered as the 
DAOH follow-up time. Days alive and out of hospital (DAOH) for each patient is calculated 
as follow-up time subtracted by the number of days in hospital during the 90 days after 
randomisation as well as the number of days being dead within the first 90 days.  Percentage 
DAOH is defined as DAOH divided by the DAOH follow-up time of each patient multiplied 
by 100.
Additionally, a negative binomial model (including HF status [de novo or decompensated 
chronic HF] as a factor) will be fitted to the data of recurrent HFE. The rate ratio and 
confidence interval will be reported.
The endpoints “diuretic effect as assessed by weight loss per mean daily loop diuretic dose 
after 15 days of treatment” and “diuretic effect as assessed by weight loss per mean daily loop 
diuretic dose after 30 days of treatment” will be defined as follows:
Change in weight (kg) from baseline to Day T
Mean daily i. v. dose
40 mg
or mean daily oral dose
80 mg
furosemide# up to Day T
# or equivalent loop diuretic dose
where the mean daily dose is defined as:
∑
1 2 31
4
1
T
and N = number of days on dose level x, d = dose level and T = day of the weight 
measurement.
The equivalent loop diuretic dose to a single dose of 40 mg of furosemide is defined as 20 mg 
of torasemide or 1 mg of bumetanide.
The dose level will be counted as 0 mg, if patients do not take loop diuretics for part of the 
time period.  Patients not taking loop diuretics at all will be excluded from the calculation.  
Missing data will be handled according to the rules set out in Section 6.6.2.


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7.7
EXTENT OF EXPOSURE
There will be three methods of calculating exposure:
a.
First intake to last intake of study drug, including off-treatment periods
b. First intake to last intake of study drug, excluding off-treatment periods
c.
Overall observational period (randomisation until end of follow-up for primary 
endpoint, see censoring for non-fatal events in Section 6.8.3)
Descriptive statistics tables with mean, SD, median and range of the number of days a patient 
was on treatment will be provided. These tables will also provide the sum-total of the time (in 
years) that all patients were on treatment.
Frequency tables of number and percentage of patients belonging to categorical ranges of 
exposure weeks will be provided as well. Following are the categories of exposure-ranges (in 
days): >= 0 days, >= 30 days, >= 60 days, >= 83 days.
7.8
SAFETY ANALYSIS
The safety analysis will be based on the TS. Treatment will be evaluated as randomised.
While tables will generally display results by randomised treatment, listings will reflect 
whether a measurement/AE occurred on or off treatment.
7.8.1
Adverse Events
Unless otherwise specified, the analyses of AEs will be descriptive in nature and will be based 
on the number of patients with AEs and not on the number of AEs.
AEs will be coded using the current version of the Medical Dictionary for Regulatory 
Activities (MedDRA) coding dictionary. 
Definitions of BI customised MedDRA Queries (BIcMQs) for new MedDRA versions are 
maintained by the BI dictionary maintenance group. 


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For analysis of multiple AE occurrences, data from the eCRF will be collapsed into an AE 
provided that all of the following applies:
•
All AE attributes are identical (including Lowest Level Term (LLT), intensity, action 
taken, therapy required, seriousness, reason for seriousness, relationship, outcome, AE of 
special interest and also additional information of specific AEs or AESIs such as whether 
a bone fracture is traumatic.
•
The occurrences were time-overlapping or time-adjacent (time-adjacency of 2 occurrences 
is given if the second occurrence started on the same day or on the day after the end of 
the first occurrence).
For further details on summarisation of AE data, please refer to (8).
7.8.1.1 Assignment of AEs to treatment
The analysis of adverse events will be based on the concept of treatment-emergent adverse 
events. That means that all adverse events occurring between first drug intake until 7 days 
after last drug intake will be assigned to the randomised treatment. All adverse events 
occurring before first drug intake will be assigned to ‘pre-treatment’ and all adverse events 
occurring after last drug intake + 7 days will be assigned to ‘follow-up’, except if otherwise 
specified.
In Section 15.3 of the CTR, general AE analysis tables will present only on-treatment AEs 
(applying the rule of 7 days for assignment as on-treatment) for the treatment groups.
Appendix 16.1.13.1 of the CTR will include an analysis (overall summary table, frequency of 
AEs by SOC / PT, frequency of SAEs by SOC/PT) where AEs and SAEs are assigned to the 
following phases: Screening, each treatment group, post-treatment for each treatment group.
For listings, AEs will be assigned to one of the following treatment phases: Screening, 
Placebo, Empa 10, Post Placebo, Post Empa, off-treatment.
7.8.1.2 AE summaries
An overall summary of adverse events will be presented. 
The frequency of patients with adverse events will be summarised by treatment, primary 
system organ class and preferred term. Incidence rates as defined in Section 7.8.1.7 will 
generally be included. 
AEs will also be reported by intensity (without incidence rates). Separate tables will be 
provided for:

for patients with serious adverse events, 

for patients with drug related serious AEs,

for patients with AEs leading to discontinuation,


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
for patients with drug-related AEs.
AEs leading to death will be listed. 
The system organ classes, and preferred terms will be sorted by frequency (within system 
organ class).
Additionally, the following analyses will be reported in Appendix 16.1.13.1 of the CTR for 
disclosure on EudraCT and clinicaltrials.gov:

Frequency [N (%)] of patients with non-serious adverse events occurring with 
incidence in preferred term greater than 5% by treatment,

Adverse events per arm for disclosure on EudraCT by treatment

Non-serious adverse events for disclosure on EudraCT by treatment

Serious adverse events for disclosure on EudraCT by treatment
7.8.1.3 Adverse events of special interest (AESIs)  
Hepatic injury
A frequency table of patients with hepatic injury as defined by the investigator on the eCRF 
tick box by treatment, primary system organ class and preferred term will be provided.
Hepatic injury AEs will be summarised based on a Standardised MedDRA Query (SMQ) 
based definition. From SMQ Drug related hepatic disorders (20000006) the following narrow 
sub-SMQs will be used:

Narrow sub-SMQ Liver related investigations, signs and symptoms (20000008)

Narrow sub-SMQ Cholestasis and jaundice of hepatic origin (20000009)

Narrow sub-SMQ Hepatitis, non-infectious (20000010)

Narrow sub-SMQ Hepatic failure, fibrosis and cirrhosis and other liver damage-related 
conditions (20000013)
A table with frequencies of patients with these AEs by treatment, primary SOC and preferred 
term will be provided. Hepatic injury SAEs based on the above SMQ definition will be 
presented. 
Patients with hepatic injury will be listed.
For presentations on adjudicated hepatic events, refer to Section 7.8.1.5.
Acute renal failure
A frequency table of patients with acute renal failure as defined by the investigator on the 
eCRF tick box by treatment, primary system organ class and preferred term will be provided.


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A frequency table of patients with AEs related to acute renal failure by treatment, primary 
SOC and preferred term will be provided based on the narrow SMQ Acute renal failure 
(20000003). 
SAEs and AEs leading to discontinuation based on the narrow SMQ Acute renal failure 
(20000003) will be presented. 
In addition, frequency tables will be produced for patients with elevated creatinine ≥ 2 x 
baseline and > 1 x upper limit of normal (ULN). 
Patients with acute renal failure will be listed.
Ketoacidosis
A frequency table of patients with AEs related to ketoacidosis will be presented by treatment, 
primary SOC and preferred term for investigator reported cases and for the narrow and broad 
BIcMQ definition of diabetic ketoacidosis (DKA).
For presentations on adjudicated events, refer to Section 7.8.1.5.
Patients with DKA based on the broad BIcMQ (30000019) or investigator reported 
ketoacidosis will be listed. 
7.8.1.4 Specific AEs
Hypoglycaemic events
The investigator will record for each AE whether it represents a hypoglycaemic event and, if
so, record additional information to assess the intensity of the hypoglycaemic event. On the 
basis of this information the hypoglycaemic event will be categorised as follows:

severe hypoglycaemic episode: event requiring the assistance of another person to 
actively administer carbohydrate, glucagon or other resuscitative actions

documented symptomatic hypoglycaemia with a measured plasma glucose 
concentration < 3.0 mmol/L (< 54 mg/dL): event accompanied by typical symptoms of 
hypoglycaemia but no need for external assistance

documented symptomatic hypoglycaemia with a measured plasma glucose 
concentration ≥ 3.0 mmol/L and ≤ 3.9 mmol/L (≥ 54 mg/dL and ≤ 70 mg/dL): event 
accompanied by typical symptoms of hypoglycaemia and no assistance required

symptomatic hypoglycaemia and plasma glucose concentration > 3.9 mmol/L (> 70 
mg/dL)

symptomatic hypoglycaemia and plasma glucose concentration not measured

asymptomatic hypoglycaemia: event not accompanied by typical symptoms of 
hypoglycaemia but with a measured plasma glucose concentration ≤ 3.9 mmol/L (≤ 70 
mg/dL)


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Confirmed hypoglycaemic adverse events are defined as hypoglycaemic adverse events that 
had a plasma glucose concentration ≤ 70 mg/dL or required assistance.
Different tables will be shown for (i) patients with investigator-defined hypoglycaemia, and 
(ii) patients with confirmed hypoglycaemic adverse events, i.e. hypoglycaemic adverse events 
that had a plasma glucose concentration ≤ 70 mg/dL or required assistance.
In addition, the number of patients with hypoglycaemia according to SMQ (20000226) will be 
presented.
Patients with hypoglycaemic events will be listed. 
Urinary tract infections (UTI) and genital infections
The following additional specific adverse events will also be assessed and be tabulated by 
treatment group:

Genital infections (BIcMQ  narrow subsearch 1.1 “Genital tract infections predisposed 
to by glucosuria” (30000038))

UTI (BIcMQ  narrow subsearch 2.1 “UTI predisposed by glucosuria” (30000041))
Complicated urinary tract infections defined as serious adverse events of BIcMQ Infection 
narrow, subsearch 2.1 “UTI predisposed by glucosuria” (30000041), all events of subsearch 
2.1.1 ‘Renal infections predisposed by glucosuria’ (30000042), all events of PT Urosepsis 
will be presented. 
Complicated genital infection: defined as all serious events using the BIcMQ Infection narrow 
subsearch 1.1 ‘Genital tract infections predisposed to by glucosuria’ (30000038) and all event 
of the subsearch ‘Complicated genital tract infections predisposed to by glucosuria’ 
(30000129) will also be presented. 
Patients with UTIs or genital infections will be listed. 
Bone fracture events
Frequency tables of patients with bone fracture by treatment, primary system organ class 
(SOC) and preferred term will be provided (based on the narrow BIcMQ “Bone fractures” 
(30000008) and investigator reporting). 
Investigator reported fractures will be reported overall and separately for each type of fracture 
(traumatic and non-traumatic).
Patients with bone fractures will be listed.


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Urinary tract malignancy events
Urinary tract malignancy will be shown based on the BIcMQ  – broad sub-search 14.1 
‘Urinary bladder and tract malignancies’ (30000057) and broad sub-search 14.2 ‘Renal 
malignancies’ (30000103):
Presentation of frequency will be done by treatment, high level term and preferred term.
Patients with urinary tract malignancy will be listed. 
Volume depletion
Volume depletion will be based on the BIcMQ ‘Volume depletion of non-haemorrhagic cause 
and subsequent hypotension’– narrow subsearch 2 ‘Volume depletion and hypotension due to 
dehydration’ (30000090). 
A frequency table of patients with volume depletion by treatment, primary SOC and preferred 
term will be provided. 
A separate table for serious volume depletion events will be presented. 
Patients with volume depletion will be listed.  
Hypotension
Frequency tables of patients with symptomatic hypotension as defined by the investigator on 
the eCRF tick box by treatment, primary system organ class and preferred term will be 
provided.
Symptomatic hypotension episodes will be presented by whether the intensity of diuretic 
medication was reduced and by whether the intensity of non-diuretic antihypertensive therapy 
was reduced. 
A separate table for symptomatic hypotension events, which are serious, will be presented. 
Additionally, hypotension by treatment, primary system organ class and preferred term will 
be provided. Hypotension is defined as preferred terms of the BIcMQ ‘Volume depletion of 
non-haemorrhagic cause and subsequent hypotension’ – narrow sub-search 2 ‘Volume 
depletion and hypotension due to dehydration’ (30000090) but excluding terms of the narrow 
subsearch 1 ‘Volume depletion due to dehydration’(30000089).
A separate table for hypotension events, which are serious, will be presented. 
Patients with hypotension events will be listed.  


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7.8.1.5 Events qualifying for external adjudication by the adjudication committee
An independent external CEC regularly reviews events and evaluates whether pre-specified 
criteria for these adjudication endpoints are met. Details on composition of the CEC, 
responsibilities and clinical event definitions are provided in the separate CEC Charter. 
Adjudication assessments will be incorporated into the database. 
Details of the adjudication process are described in the CEC charter.
Hepatic adverse events
Frequency tables summarising the relatedness and severity will be provided, including a 
listing showing the trigger events and adjudication results. This will include all adjudicated 
events up to 30 days after treatment stop.
Ketoacidosis
Frequency tables showing adjudicated certain ketoacidosis will be provided, including a 
listing showing the trigger events and adjudication results. This will include all adjudicated 
events up to 7 days after treatment stop. 
7.8.1.6 AEs while patients taking wrong medication
A listing will be provided for AEs that occurred while a patient was taking the wrong study 
medication.  If such a patient is identified, an additional adverse event table that assigns the 
adverse events to the actual treatment taken will be presented. A patient who took both the 
assigned treatment and at least one tablet of the wrong treatment, will be counted as at risk in 
both treatment groups for the respective relevant time. The table will include all adverse 
events by SOC and PT. 
7.8.1.7 Adverse event incidence rates
For AE tables showing patients with events, in addition to the frequency tabulations, time-
adjusted adverse event analyses will be performed for all AEs, investigator defined drug-
related AEs, AEs leading to discontinuation, serious AEs, and adverse events of special 
interest by SOC and PT or High-Level Term (HLT) and PT, respectively.
The time at risk in patient years for the on-treatment phase is derived as follows:
Patients with AE: 
time at risk (AE) in days = date of start of AE with specified PT/SOC/HLT – study treatment 
start date + 1 
Patients without AE: 
time at risk (AE) in days = end date of time at risk – study treatment start date + 1, where end 
date of time at risk is the minimum of date of last study drug intake + x days and date of 
death, if applicable.


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The standard approach will be x=7 days, but for certain AESIs in addition other approaches 
will be used.
Total AE-specific time at risk per treatment group is then derived as: 
Time at risk (AE) [years] = Sum of time at risk [days] over all patients in a treatment group/ 
365.25
For ‘each row of a table’ (e.g. displaying an SOC), time at risk is calculated using start of first 
AE summarised in this row; e.g. for patients with an AE in a specified SOC, time at risk = 
date of start of AE with specified PT in this SOC – start of study treatment + 1.
The AE incidence rate per 100 patient years will then be calculated as follows:
Incidence rate per 100 patient years (pt-yrs) = 100 * number of patients with AE / time at risk 
(AE) [years].
In a similar way, the time at risk and incidence rate for the post-treatment period is derived. 
Here the start date is the start date of the post-treatment phase instead of the study treatment 
start date.
For some specific outputs showing number of episodes, event rates will be defined as number 
of episodes divided by time at risk. Time at risk will be the end date of time at risk – study 
treatment start date + 1, where the end date of time at risk is the minimum of date of last study 
drug intake + 7 days and date of death, if applicable.
7.8.1.8 COVID-19 related analyses
The subgroup of patients with SARS-COV-2 infection will be analysed. SARS-COV-2 
infections will be defined by the narrow BIcMQ SARS-COV-2 infection. All analyses will be 
repeated using the broad instead of the narrow BIcMQ.
An overview of adverse events will be presented for this subgroup of patients. Additionally,
the number of patients with adverse events, the number of serious AEs and AEs leading to 
discontinuation of study treatment will be presented by treatment, primary SOC and preferred 
term. 
A listing will be prepared presenting all SARS-COV-2 infections.
7.8.2
Laboratory data
Standard safety tables will not include eGFR or creatinine. Analyses for eGFR and creatinine 
will be done separately. 
For continuous safety laboratory parameters, normalised values will be derived, as well as the 
differences to baseline. The process of normalisation as well as standard analyses for safety 
laboratory data are described in the BI guidance for the Display and Analysis of Laboratory 
Data (9). All analyses considering multiples of upper limits of normal (ULN) will be based on 
original and not normalised data.


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Laboratory parameters will be shown in conventional units. Where conventional units differ 
from SI units, analyses will be repeated on SI units. 
Laboratory measurements (not mentioned in Table 6.1: 2) taken up to 3 days after the last 
administration of randomised study drug will be considered as on-treatment.  Default settings 
will be used for repeated values (using closest and then worst value).
Laboratory values will be compared to their reference ranges and frequency tables will be 
provided for the number of patients within and outside the reference range at baseline and the 
last measurement on treatment.  Descriptive statistics will be provided by treatment group for 
baseline, last value on-treatment and for changes from baseline to last value on treatment.  For 
semi-quantitative or categorical laboratory values, shift tables for baseline and last value on 
treatment will also be provided. Frequency tables will summarise the number of patients with 
potentially clinically significant abnormalities. 
Additionally, for urine ketones. a shift table of baseline vs value at each visit will be shown. 
For the table of potentially clinically significant abnormalities, only patients with at least one 
available on-treatment value will be included in the analysis of an individual laboratory 
parameter.  Other tables are comparing baseline to on-treatment values and will only include 
patients with a baseline value and at least one available on-treatment value. All individual 
data will be presented in listings. 
To support analyses of liver-related adverse drug effects, patients with Aspartate transaminase
(AST) and/or Alanine transaminase (ALT) ≥3xULN with concomitant or subsequent Total 
Bilirubin (TBILI) ≥2xULN in a 30 day period after AST/ALT elevation are of special interest. 
In addition, of these cases, it will be considered whether the alkaline phosphatase (AP) is less 
than 2 x ULN (maximum value in a 30 day period after AST/ALT elevation) or not. The start 
of the 30-day time span is triggered by each liver enzyme elevation above the defined 
thresholds. Patients who fulfil one or two of the criteria for ALT/AST or total bilirubin 
elevations above and have no information available for the remaining parameter(s) within the 
30 day time window will not be listed under “ALT and/or AST ≥ 3xULN with TBILI ≥ 
2xULN”. 
In addition, ALT/AST will be used to investigate elevated liver enzymes:

ALT/AST ≥ 3 x ULN

ALT/AST ≥ 5 x ULN

ALT/AST ≥ 10 x ULN

ALT/AST ≥ 20 x ULN
All liver enzyme elevations within 30 days of treatment discontinuation will be shown.
Frequency tables of patients with elevated liver enzymes defined by ALT and/or AST, total 
bilirubin and AP combinations will be provided.  Details on patients with elevated liver 
enzymes will be listed.
For the following parameters:

eGFR,


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
haemoglobin,

haematocrit,

creatinine (only descriptive),
the time course of changes will be assessed. The analysis will be performed by applying 
MMRM models to the TS (on-treatment data) and the RS (all data). No imputation will be 
applied.  The MMRM models that will be used are specified in Section 7.5.2. These analyses 
will be conducted on data before any normalisation. The MMRM analyses will also be shown 
graphically. 
To support analysis of renal function, eGFR throughout the trial will be categorised according 
to the following Chronic Kidney Disease (CKD) staging (Table 7.8.2: 1): All calculations for 
the staging of renal function will be based on the originally measured laboratory values, not 
on normalised values with BI standard reference ranges. 
Table 7.8.2: 1 CKD staging
Stage
eGFR 
(mL/min/1.73m²)
Description
Label for 
displays
Additional labels
1
≥90
Normal or high 
≥90
≥90 (CKD 1)
2
60 to <90
Mildly decreased
60 to <90
60 to <90 (CKD 2)
3A
45 to <60 
Mildly to 
moderately 
decreased
45 to <60 
45 to <60 (CKD 3a)
3B
30 to <45
Moderately to 
severely decreased
30 to <45
30 to <45 (CKD 3b)
4
15 to <30
Severely decreased
15 to <30
15 to <30 (CKD 4)
5
<15
Kidney failure
<15
<15 (CKD 5)
A shift table from baseline to last value on treatment and to minimum value on treatment for 
eGFR (CKD-EPI)cr will be provided.
7.8.3
Vital signs
Heart rate and blood pressure (diastolic and systolic) over time will be summarised 
descriptively based on the RS (all data). Descriptive statistics will also be shown graphically. 


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7.8.4
ECG
Clinically relevant abnormalities found at physical examination will be considered to have 
already existed prior to signing of informed consent and therefore should be considered 
baseline conditions instead of adverse events, unless there is good reason to assume that they 
first appeared after signing of consent.
Outcomes of ECGs will be part of the reporting of medical history or AE reporting. 
Categorical findings as collected in the eCRF will also be summarised descriptively.
7.8.5
Others
Not applicable.


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8.
REFERENCES
1.
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9, 
Note For Guidance on Statistical Principles for Clinical Trials, current version.
2.
BI-KMED-BDS-HTG-0035: "Handling of missing and incomplete AE dates", current 
version; KMED.
3.
BI-KMED-BDS-HTG-0045: "Standards for Reporting of Clinical Trials and Project 
Summaries", current version; IDEA for CON.
4.
Pocock SJ, Ariti CA, Collier TJ, Wang D. The win ratio: a new approach to
the analysis of composite endpoints in clinical trials based on clinical
priorities. Eur Heart J. 2012. 33: 176-182
5.
Dong G, Li D, Ballerstedt S, Vandemeulebroecke M. A generalized
analytic solution to the win ratio to analyze a composite endpoint
considering the clinical importance order among components. Pharm Stat.
2016. 15: 430-437
6.
Schou M, Gustafsson F, Kjaer A, Hildebrandt PM. Long-term clinical
variation of NT-proBNP in stable chronic heart failure patients. European
Heart Journal. 2007. 28(2): 177-182
7.
Collett.D, Modelling Survival Data in Medical Research. A CRC Press
Company. 2003
8.
BI-KMED-BDS-HTG-0041: "Analysis and Presentation of Adverse Event Data from 
Clinical Trials", current version; KMED.
9.
BI-KMED-BDS-HTG-0042: "Handling, Display and Analysis of Laboratory Data", 
current version; IDEA for CON.
10. Dong G, Qiu J, Wang D, Vandemeulebroecke M. The stratified win ratio. Journal of 
Biopharmaceutical Statistics 2018;28:778–96
11. Carpenter JR, Roger JH, Kenward MG. Analysis of longitudinal trials with protocol 
deviation: a framework for relevant, accessible assumptions, and inference via multiple 
imputation. J Biopharm Stat 2013;23(6):1352-1371
12. Ariti CA, Cleland JG, Pocock SJ, et al. Days alive and out of hospital and the patient 
journey in patients with heart failure: Insights from the candesartan in heart failure: 
assessment of reduction in mortality and morbidity (CHARM) program. Am Heart J. 
2011;162(5):900-906. doi:10.1016/j.ahj.2011.08.003
13. Rubin DB. Multiple Imputation for Nonresponse in Surveys. New York: John Wiley 
and Sons; 2004


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9.
ADDITIONAL SECTIONS
9.1
DERIVATION OF KCCQ DOMAINS
The following algorithm will be used to score the KCCQ.
9.1.1
Kansas City Cardiomyopathy Questionnaire (KCCQ)
There are 10 summary scores within the KCCQ, which are calculated as follows:
1. Physical Limitation
Code responses to each of Questions 1a-f as follows:

Extremely limited = 1

Quite a bit limited = 2

Moderately limited = 3

Slightly limited = 4

Not at all limited = 5

Limited for other reasons or did not do = <missing value>
If at least three of Questions 1a-f are not missing, then the Physical Limitation Score is 
calculated as follows:
Physical Limitation Score = 100*[(mean of Questions 1a-f actually answered) – 1]/4
2. Symptom Stability
Code the response to Question 2 as follows:

Much worse = 1

Slightly worse = 2

Not changed = 3

Slightly better = 4

Much better = 5

I’ve had no symptoms over the last 2 weeks = 3
If Question 2 is not missing, then the Symptom Stability Score is calculated as follows:
Symptom Stability Score = 100*[(Question 2) – 1]/4


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3. Symptom Frequency
Code responses to Questions 3, 5, 7 and 9 as follows:
Question 3

Every morning = 1

3 or more times a week but not every day = 2

1-2 times a week = 3

Less than once a week = 4

Never over the past 2 weeks = 5
Questions 5 and 7

All of the time = 1

Several times a day = 2

At least once a day = 3

3 or more times a week but not every day = 4

1-2 times a week = 5

Less than once a week = 6

Never over the past 2 weeks = 7
Question 9

Every night = 1

3 or more times a week but not every day = 2

1-2 times a week = 3

Less than once a week = 4

Never over the past 2 weeks = 5
If at least two of Questions 3, 5, 7 and 9 are not missing, then the Symptom Frequency Score 
is calculated as follows:
S3 = [(Question 3) – 1]/4
S5 = [(Question 5) – 1]/6


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S7 = [(Question 7) – 1]/6
S9 = [(Question 9) – 1]/4
Symptom Frequency Score = 100*(mean of S3, S5, S7 and S9)
4. Symptom Burden
Code responses to each of Questions 4, 6 and 8 as follows:

Extremely bothersome = 1

Quite a bit bothersome = 2

Moderately bothersome = 3

Slightly bothersome = 4

Not at all bothersome = 5

I’ve had no swelling/fatigue/shortness of breath = 5
If at least one of Questions 4, 6 and 8 is not missing, then the Symptom Burden Score is 
defined as follows:
Symptom Burden Score = 100*[(mean of Questions 4, 6 and 8 actually answered) – 1]/4
5. Total Symptom Score
The Total Symptom Score is defined as the mean of the following available summary scores:
Symptom Frequency Score and Symptom Burden Score
6. Self-Efficacy
Code responses to Questions 10 and 11 as follows:
Question 10

Not at all sure = 1

Not very sure = 2

Somewhat sure = 3

Mostly sure = 4

Completely sure = 5
Question 11


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
Do not understand at all = 1

Do not understand very well = 2

Somewhat understand = 3

Mostly understand = 4

Completely understand = 5
If at least one of Questions 10 and 11 is not missing, then the Self-Efficacy Score is calculated 
as:
Self-Efficacy Score = 100*[(mean of Questions 10 and 11 actually answered) – 1]/4
7. Quality of Life
Code responses to Questions 12, 13 and 14 as follows:
Question 12

It has extremely limited my enjoyment of life = 1

It has limited my enjoyment of life quite a bit = 2

It has moderately limited my enjoyment of life = 3

It has slightly limited my enjoyment of life = 4

It has not limited my enjoyment of life at all = 5
Question 13

Not at all satisfied = 1

Mostly dissatisfied = 2

Somewhat satisfied = 3

Mostly satisfied = 4

Completely satisfied = 5
Question 14

I felt that way all of the time = 1

I felt that way most of the time = 2

I occasionally felt that way = 3


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
I rarely felt that way = 4

I never felt that way = 5
If at least one of Questions 12, 13 and 14 is not missing, then the Quality of Life Score is 
calculated as:
Quality of Life Score = 100*[(mean of Questions 12, 13 and 14 actually answered) – 1]/4
8. Social Limitation
Code responses to each of Questions 15a-d as follows:

Severely limited = 1

Limited quite a bit = 2

Moderately limited = 3

Slightly limited = 4

Did not limit at all = 5

Does not apply or did not do for other reasons = <missing value>
If at least two of Questions 15a-d are not missing, then the Social Limitation Score is 
calculated as:
Social Limitation Score = 100*[(mean of Questions 15a-d actually answered) – 1]/4
9. Overall Summary Score
The Overall Summary Score is defined as the mean of the following available summary 
scores:
Physical Limitation Score, Total Symptom Score, Quality of Life Score and Social Limitation 
Score
10. Clinical Summary Score
The Clinical Summary Score is defined as the mean of the following available summary 
scores:
Physical Limitation Score and Total Symptom Score
Note: references to “means of questions actually answered” imply the following.
If there are n questions in a scale, and the subject must answer m to score the scale, but the 
subject answers only n-i, where n-i >= m, calculate the mean of those questions as


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(sum of the responses to those n-i questions) / (n-i)
not
(sum of the responses to those n-i questions) / n
The change from baseline to Day 90 in KCCQ-TSS will be calculated as the difference of the 
score at Day 90 and at baseline. 
9.2
ALGORITHM FOR IMPUTATION ACCORDING TO JUMP-TO-PLACEBO 
METHOD
This algorithm imputes missing on-treatment data as MAR, and then imputes missing off-
treatment data as MNAR by a jump-to-placebo method.
The conceptual approach is described by Carpenter et. al. (11). The implementation is planned 
as follows:
1. Remove any off-treatment data from dataset
2. Non-monotone missing data is imputed under MAR to create a monotone pattern
a.
100 imputations are performed by MCMC-MI, stratified by treatment, with the 
following parameters:
i. Baseline value included as a continuous variable, HF status as a binary 
variable (de novo or decompensated chronic HF)
ii. Multiple chains with 200 burn-in iterations per chain
iii. Jeffrey’s prior
3. SLR-MI is used to impute missing monotone on-treatment data:
a.
All data is imputed using SLR-MI, separately by treatment, with the following 
parameters:
i. Baseline (continuous), HF status (de novo or decompensated HF) 
included as covariates
b. All imputed data for patients at an off-treatment time point is deleted
4. On-treatment group means are calculated for each imputation at each visit
a.
ANCOVA used to calculate adjusted means with the following parameters:
i. Baseline (continuous), HF status (de novo or decompensated chronic 
HF), and treatment included as covariates
ii. Restricted Maximum Likelihood and Kenward-Rogers methods
iii. Least Square Means used
5. Placebo group on-treatment means at each visit are subtracted from all group on-
treatment means at the same visit, to give treatment differences


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a.
Note that these will be 0 for the placebo group
6. Individual data is ‘temporarily saved’ at this point, excluding available off-treatment 
data 
7. Treatment differences are subtracted from the respective (by visit and treatment) data 
values
a.
Results are the ‘residuals’ after removal of treatment effect(s)
b. This is referred to as the residual data
8. Subset of the residual data is created with all patients in placebo group and all patients 
with missing values at first visit requiring imputation. Note that these missing values 
will all be off-treatment.
9. Multiple imputation is performed on the first visit requiring imputation
a.
Linear regression models are used to derive the distributional parameters;
i. One imputation per existing imputation
ii. Residual subset used
iii. Baseline (continuous), HF status (de novo or decompensated chronic 
HF), all previous visits (continuous) included as model covariates
10. Imputed off-treatment values from subset merged with residual data sets.
11. If visits that require imputation remain, go to step 8, else proceed to next step
12. Original data set, saved data sets and residual data sets are merged so that all missing 
values in the saved data set are filled with observed off-treatment measurements where 
available, otherwise the values from corresponding residual data sets are used.
13. The next step depends on the data being imputed:
a. For NT-proBNP, the AUC of change from baseline in log-transformed NT-
proBNP level will be calculated for these imputed data sets.  Then an 
ANCOVA model will be applied (see Section 7.5.2).
b. For KCCQ-TSS, the stratified win ratio will be calculated using these imputed 
data sets, by combining with the non-imputed death and HFE data (see Section
7.4.1).  Then take logs of the stratified win ratios.
14. Estimates and variances are combined using Rubin’s rules (13) to give a single 
estimate and variance for each parameter of interest across all imputations.


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-
YY)
Author
Sections 
changed
Brief description of change
Final
11-Mar-2021
None
This is the final TSAP without any 
modification


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c32295612
1.0
8-01-tsap
A multicentre, randomised, double-blind, 90-day superiority trial to evaluate the
effect on clinical benefit, safety and tolerability of once daily oral EMPagliflozin 10
mg compared to placebo, initiated in patients hospitalised for acUte heart faiLure (de
novo or decompensated chronic HF) who have been StabilisEd (EMPULSE)
Author-Trial Statistician
12 Mar 2021 10:27 CET
Approval-Medical Writer
12 Mar 2021 10:33 CET
Approval-Clinical Trial Leader
12 Mar 2021 12:19 CET
Approval-Project Statistician
13 Mar 2021 12:04 CET
Approval-Team Member Medicine
16 Mar 2021 19:36 CET


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c32295612
1.0