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)
Phase: PHASE3
Conditions: Heart Failure
Sponsor: Boehringer Ingelheim

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Clinical Trial Protocol
TITLE PAGE
Document Number:
c17550230-03
EudraCT No.:
EU Trial No:
2017-004073-14
BI Trial No.:
1245-0168
BI Investigational 
Product(s):
Empaglifozin
Title:
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)
Lay Title:
This study tests empagliflozin in patients with chronic heart
failure with reduced ejection fraction (HFrEF). The study looks at 
how far patients can walk in 6 minutes and at their heart failure 
symptoms
Clinical Phase:
III
Trial Clinical 
Monitor:
Phone : 
Fax : 
Coordinating 
Investigators:
Phone: 
 / Fax: 
, 

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Phone:
 / Fax:
Status:
Final Protocol (Revised Protocol based on global amendment 2)
Version and Date:
Version:3.0
Date: 20 Jul 2018
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Proprietary confidential information.
2018 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 
Finished product name
Jardiance
Active ingredient name:
Empagliflozin
Protocol date
21 Nov 2017
Revision date
20 Jul 2018
Trial number
1245-0168
Title of trial:
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)
Coordinating 
Investigator
Phone: 
 / Fax: 
Phone:
 / Fax:
Trial site(s):
Multi-centre trial
Clinical phase:
III

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Objective(s):
The primary objective of the study is to evaluate the effect of 
empagliflozin 10 mg versus placebo on exercise ability using the 6 
minute walk test in patients with chronic HF with reduced ejection 
fraction (LVEF ≤ 40%).
Secondary objectives are to assess Patient-Reported Outcome (PRO).
Methodology:
Randomised, double blind, placebo controlled, parallel group trial.
Number of patients
entered: 
300
Number of patients on 
each treatment:
150 (2 treatment groups)
Diagnosis :
Heart failure (HF) with reduced ejection fraction (EF).
Main in- and exclusion 
criteria
Main Inclusion Criteria:

6MWT distance ≤350 m at screening and at baseline.

Patients with chronic HF diagnosed for at least 3 months before 
Visit 1 and currently in NYHA class II-IV

Chronic HF with reduced EF defined as LVEF ≤40 % as per 
echocardiography at Visit 1 per local reading (obtained under 
stable condition)

Elevated NT-proBNP > 450 pg/ml for patients without atrial 
fibrillation (AF) OR > 600 pg/ml for patients with AF as analysed
at the Central laboratory at Visit 1

Patients must be clinically stable and on appropriate and stable 
dose of medical therapy for HF (such as ACEi, ARB, β-blocker, 
oral diuretics, MRA, ARNI, ivabradine), consistent with 
prevailing CV guidelines, stable for at least 4 weeks prior to Visit 
1(screening) with the exception of diuretics which must have 
been stable for at least two weeks prior to Visit 1. The 
investigator must document the reason in case the patient is not 
on such medication or if not on target dose as per local 
guidelines.

Clinically stable at randomization with no signs of heart failure 
decompensation (as per investigator judgement).  

Appropriate use of medical devices such as cardioverter 
defibrillator (ICD) or a cardiac resynchronization therapy (CRT) 
consistent with prevailing local or international CV guidelines, 
and if a device is required, it must have been implanted for at 
least 3 months prior to visit 1 for CRT and 1 month prior to visit 
1 for ICD. 

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Main Exclusion Criteria:

Myocardial infarction (increase in cardiac enzymes in 
combination with symptoms of ischaemia or newly developed 
ischaemic ECG changes), coronary artery bypass graft surgery or 
other major cardiovascular surgery, stroke or TIA in past 90 days 
prior to Visit 1

Acute decompensated HF (exacerbation of chronic HF) requiring
intravenous (i.v.) diuretics, i.v. inotropes or i.v. vasodilators, or
left ventricular assist device within 4 weeks to Visit 1, and during 
screening period until Visit 2

Previous or current randomisation in another Empagliflozin Heart 
Failure trial (i.e. studies 1245.110, 1245.121, 1245-0167) 

Type 1 Diabetes Mellitus (T1DM)

eGFR < 20 mL/min/1.73 m2  (CKD-EPIcr) at Visit 1

Symptomatic hypotension or a SBP < 100 mmHg at Visit 1 or 2

Systolic blood pressure (SBP) ≥ 180 mmHg at Visit 1 or 2, or 
SBP >160mmHg at both Visit 1 and 2

Atrial fibrillation or atrial flutter with a resting heart rate >110 
bpm

Unstable angina pectoris in past 30 days prior to Visit 1

Largest distance walked in 6 minutes (6MWTD) at baseline 
<100m.

Any presence of condition that precludes exercise testing such as:
•
claudication,
•
uncontrolled (according to investigator judgement) 
bradyarrhythmia, or tachyarrhythmia,
•
significant musculoskeletal disease,
•
primary pulmonary hypertension,
•
severe obesity (body mass index ≥40.0 kg/m2),
•
orthopedic conditions that limit the ability to walk (such as 
arthritis in the leg, knee or hip injuries)
•
amputation with artificial limb without stable prosthesis 
function for the past 3 months 
•
Any condition that, in the opinion of the investigator, would 
contraindicate the assessment of 6MWT

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
Patients in a structured (according to Investigator judgement) 
exercise training program in the 1 month prior to screening or 
planned to start one during the course of this trial.

Patients with planned implantation of ICD or CRT during the 
course of the trial.

Treatment with i.v. iron therapy or erythropoietin (EPO) within 3 
months prior to screening. 
Test product(s):
Empagliflozin
dose:
10 mg q.d.
mode of administration:
p.o.
Comparator products:
Placebo
dose:
Not applicable
mode of administration:
p.o.
Duration of treatment:
12 weeks
Endpoints
Primary Endpoints:

Change from baseline to week 12 in exercise capacity as 
measured by the distance walked in 6 minutes 
Key Secondary Endpoints:

Change from baseline to week 12 in Kansas City 
Cardiomyopathy Questionnaire (KCCQ) Total Symptom Score 
(TSS)  

Change from baseline to week 12 in Chronic Heart Failure 
Questionnaire Self-Administered Standardized format (CHQ-
SAS) dyspnea score  
Other Secondary Endpoints: 

Change from baseline to week 6 in exercise capacity as measured 
by the distance walked in 6 minutes 

Change from baseline in Clinical Congestion Score at week 12.

Change from baseline in Patient Global Impression of Severity of 
Heart Failure Symptoms at week 12.

Change from baseline in Patient Global Impression of Dyspnea
Severity at week 12.

Patient Global Impression of Change in Heart Failure Symptoms 
at week 12.

Patient Global Impression of Change in Dyspnea at week 12.

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
Change from baseline in N-terminal pro-brain natriuretic peptide 
(NT-proBNP) at week 12
Safety criteria:

Adverse events (AE)

Serious adverse events (SAE)

AE of special interest (AESI) (hepatic injury, decreased renal 
function and ketoacidosis)

Incidence and intensity of AE including serious AE (SAE)

Withdrawal from trial medication due to AE

Clinically relevant new finding or worsening of existing 
condition on physical examination

Clinically relevant changes in laboratory measurements from
baseline

Heart rate and blood pressure in conjunction with exercise testing

ECG findings at scheduled visits reported as AEs
Statistical methods:
The primary model will be a Wilcoxon rank test on change from 
baseline to week 12 in 6MWT. 
The primary model will be conducted on all randomized patients.
Both key secondary endpoints will be tested using a Wilcoxon rank 
test, and both will be tested if the primary endpoint revealed a 
significant result in favour of empagliflozin. For adjustment of 
multiplicity of the two key secondary endpoints a Hochberg 
procedure will be followed. 
The other secondary endpoints will not be part of the testing 
hierarchy.
Change from baseline to week 6 in exercise capacity as measured by 
the distance walked in 6 minutes will be evaluated using the same 
model as for the primary endpoint
Change from baseline to week 12 of Clinical Congestion Score will 
be evaluated using a mixed model repeated measure analysis over 
time. The model will include the factor treatment and the linear 
covariate of baseline Clinical Congestion Score.
Proportion of patients in every category of global impression of 
change at week 12 will be evaluated using Cochran-Mantel-Haenszel 
test.
Proportions of patients categorized by the shift in scores between 
baseline and week 12 in patient global impression of severity score 
will be evaluated using Cochran-Mantel-Haenszel test.

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The endpoint “Change from baseline in NT-proBNP at week 12” 
(after log-transformation) will be evaluated using a mixed model 
repeated measure analysis over time with baseline log-transformed 
NT-proBNP as a covariate without imputation of missing values.

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FLOW CHART
Trial Period
Screening*
Randomized Treatment Period
FU Period
Visit
1
2
3
4 (EOT) 
Early 
Discontinuati
on Visit11
FU Visit
Trial week
-3
1
6
12
EOT/early 
d/c + 7 
days
Days of treatment 
-21 to -4
1
43
85
Time Window
-
-
±7 
±7
+7
Informed consent
X
In/exclusion criteria
X
X
Demographics
X
Medical history/Concomitant 
diagnoses
X
Vital signs1
X
X
X
X
X
X
Physical examination
X
X
X
X
Height
X
Weight
X
X
X
X
Urine Pregnancy test2
X
X
X
X
X
HbA1c
X
X
X
eGFR (CKD-EPIcr formula)
X*
X
X
X
X
X
Safety lab: blood tests
X3*
X
X4
X
X
X
Safety lab: urinalysis including 
ketones
X* 
X
X
X
X
X
ECG exam5
X*
X
X
Echocardiogram6
X
NT-proBNP
X*
X
X
X
X
6 min walk test7
X8
X9
X
X9
X
Concomitant therapy
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
KCCQ10
X
X
X
X
CHQ-SAS10
X
X
X
X
Clinical Congestion Score
X
X
X
X
Patient Global Impression of 
Severity of Heart Failure 
Symptoms10
X
X
X
X
Patient Global Impression of 
Severity of Dyspnea10
X
X
X
X
Patient Global Impression of 
Change in Heart Failure 
Symptoms10
X
X
X

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Trial Period
Screening*
Randomized Treatment Period
FU Period
Visit
1
2
3
4 (EOT) 
Early 
Discontinuati
on Visit11
FU Visit
Trial week
-3
1
6
12
EOT/early 
d/c + 7 
days
Days of treatment 
-21 to -4
1
43
85
Time Window
-
-
±7 
±7
+7
Patient Global Impression of 
Change in Dyspnea10
X
X
X
Clinician Global Impression  of 
Severity of  CHF
X
X
X
X
Clinician Global Impression  of 
Change in CHF Severity
X
X
X
NYHA Classification
X
X
X
X
X
HCRU 
X
X
X
X
Randomization (IRT)
X
Dispense trial medication
X
X
Return medication / Medication 
compliance check
X
X
X
* The screening procedures can be performed on different days within the time window. 
Specifically it is recommended to have the NT-proBNP and safety lab measures (via 
central lab) measured as first step, especially in patients with no previous natriuretic 
peptide value available from clinical routine assessment in the past 6 months (refer to 
section 6.2.1).  The baseline rhythm (e.g. sinus rhythm, AF) of the patient must be 
clarified (i.e. ECG) and documented at the time the NT-proBNP sample is collected.
1. Blood pressure and heart rate will be measured with the patient seated and rested for at 
least 5 minutes.
2. For female patients of child-bearing potential, local urine pregnancy test should be 
performed.
3. For the screening Visit 1, the safety laboratory is limited to liver transaminases, alkaline 
phosphatase, haemoglobin, serum creatinine, eGFR calculation. Patients do not have to be 
fasting.
4. For Visit 3, the safety laboratory is limited to liver transaminases, bilirubin and serum 
creatinine, eGFR calculation
5. A 12-lead ECG will be performed at screening and EOT visits. For this 12-lead ECG, the 
interpretation of the tracing must be made locally by the investigator or designee. In case 
of any cardiac symptom (indicating rhythm disorders or cardiac ischaemia), additional 12-
lead ECG(s) should be done and any abnormal findings will be reported as AEs. 
6. An echocardiogram should be performed on all patients at Visit 1 to assess left ventricular 
ejection fraction (LVEF) for eligibility.
7. 6MWT to be performed by qualified and experienced personnel. The assessments should 
be performed by the same qualified and experienced personnel at all visits, where possible.

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Testing of the 6MWT at each clinic visit should be preferably performed about the same 
time of day to minimize intraday variability. Prior to performing the 6MWT, the relative 
contraindications to exercise should be assessed as per appendix 10.1.3. Heart rate and 
blood pressure will be measured before exercise, at end-exercise, five minutes after 
termination of exercise and when, for clinical reasons, it is required.
8. One 6 minute walk test (6MWT) will be performed at the screening visit.  The 6MWT will 
be performed after vital signs have been captured and prior to any other study procedures
at this visit.  If the distance walked is > 350m the patient will be considered a screen 
failure.
9. Two 6 minute walk tests will be performed at visits 2 and 4 at least 1 hour apart.  The 
largest distance measured will be used for the analysis. If at Visit 2 the distance walked on 
any test is > 350m or the largest distance walked is < 100m the patient will be considered 
a screen failure. 
10.
For the order of completion of patient reported outcome measures please refer to 
section 6.2.2.
11.
Patients who prematurely discontinue from trial medication will be required to return 
to the study site as soon as possible after treatment discontinuation for the early 
discontinuation visit and the follow up visit.  In addition, the patient should return to clinic 
for their regularly scheduled week 12 study visit as outlined in section 3.3.4.1.

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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................3
FLOW CHART........................................................................................................................9
TABLE OF CONTENTS ......................................................................................................12
ABBREVIATIONS................................................................................................................16
1.
INTRODUCTION...............................................................................................19
1.1
MEDICAL BACKGROUND.............................................................................19
1.2
DRUG PROFILE................................................................................................20
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................21
1.4
BENEFIT - RISK ASSESSMENT.....................................................................23
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................27
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........27
2.1.1
Main objectives....................................................................................................27
2.1.2
Primary endpoint(s)............................................................................................27
2.1.3
Secondary endpoint(s) ........................................................................................27
2.2
FURTHER OBJECTIVES AND FURTHER ENDPOINTS ..........................28
2.2.1
Further objectives ...............................................................................................28
2.2.2
Further endpoints ...............................................................................................28
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................30
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................30
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................30
3.3
SELECTION OF TRIAL POPULATION .......................................................33
3.3.1
Main diagnosis for trial entry ............................................................................34
3.3.2
Inclusion criteria .................................................................................................34
3.3.3
Exclusion criteria ................................................................................................35
3.3.4
Withdrawal of patients from therapy or assessments .....................................37
3.3.4.1
Withdrawal from trial treatment ...........................................................................38
3.3.4.2
Withdrawal of consent for trial participation........................................................38
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................39
4.
TREATMENTS...................................................................................................40
4.1
INVESTIGATIONAL TREATMENTS ...........................................................40
4.1.1
Identity of the Investigational Medicinal Products..........................................40
4.1.2
Selection of doses in the trial..............................................................................40
4.1.3
Method of assigning patients to treatment groups...........................................41
4.1.4
Drug assignment and administration of doses for each patient......................41
4.1.5
Blinding and procedures for unblinding...........................................................42
4.1.5.1
Blinding.................................................................................................................42
4.1.5.2
Unblinding and breaking the code ........................................................................42

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4.1.6
Packaging, labelling, and re-supply...................................................................43
4.1.7
Storage conditions...............................................................................................43
4.1.8
Drug accountability.............................................................................................43
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................44
4.2.1
Other treatments and emergency procedures..................................................44
4.2.2
Restrictions ..........................................................................................................45
4.2.2.1
Restrictions regarding concomitant treatment ......................................................45
4.2.2.2
Restrictions on diet and life style..........................................................................46
4.2.2.3
Restrictions regarding women of childbearing potential......................................46
4.3
TREATMENT COMPLIANCE........................................................................46
5.
ASSESSMENTS..................................................................................................48
5.1
ASSESSMENT OF EFFICACY........................................................................48
5.1.1
Six Minute Walk Test .........................................................................................48
5.1.2
Kansas City Cardiomyopathy Questionnaire...................................................48
5.1.3
Chronic Heart Failure Questionnaire Self Administered Standardized .......49
5.1.4
NT-proBNP..........................................................................................................49
5.1.5
New York Heart Association classification.......................................................49
5.1.6
Clinical Congestion Score...................................................................................49
5.1.7
Patient Global Impression of Change in Heart Failure Symptoms................50
5.1.8
Patient Global Impression of Change in Dyspnea ...........................................50
5.1.9
Patient Global Impression of Severity of Heart Failure Symptoms...............51
5.1.10
Patient Global Impression of Severity of Dyspnea ..........................................51
5.1.11
Clinician Global Impression of Change in CHF Severity ...............................52
5.1.12
Clinician Global Impression of Severity of CHF .............................................52
5.2
ASSESSMENT OF SAFETY.............................................................................53
5.2.1
Physical examination ..........................................................................................53
5.2.2
Vital signs.............................................................................................................53
5.2.3
Body weight and height ......................................................................................53
5.2.4
Safety laboratory parameters ............................................................................53
5.2.4.1
Renal Function......................................................................................................55
5.2.4.2
Pregnancy Testing.................................................................................................56
5.2.4.3
Criteria for hypoglycaemic events........................................................................56
5.2.4.4
Urinary tract infection and genital infections .......................................................56
5.2.5
Electrocardiogram ..............................................................................................56
5.2.6
Other safety parameters.....................................................................................56
5.2.7
Assessment of adverse events.............................................................................57
5.2.7.1
Definitions of AEs ................................................................................................57
5.2.7.2
Adverse event collection and reporting ................................................................60
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................62
5.3.1
Assessment of pharmacokinetics .......................................................................62
5.4
ASSESSMENT OF BIOMARKER(S) ..............................................................62
5.5
OTHER ASSESSMENTS...................................................................................62
5.5.1
Echocardiogram..................................................................................................62
5.5.2
Health Care Resource Utilisation (HCRU).......................................................62

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5.6
APPROPRIATENESS OF MEASUREMENTS..............................................63
6.
INVESTIGATIONAL PLAN.............................................................................64
6.1
VISIT SCHEDULE.............................................................................................64
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................64
6.2.1
Screening and run-in period(s)..........................................................................64
6.2.2
Treatment period(s)............................................................................................65
6.2.3
Follow up period and trial completion..............................................................66
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................67
7.1
STATISTICAL DESIGN - MODEL.................................................................67
7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................67
7.3
PLANNED ANALYSES.....................................................................................68
7.3.1
Primary endpoint analyses.................................................................................68
7.3.2
Secondary endpoint analyses .............................................................................69
7.3.3
Further endpoint analyses..................................................................................70
7.3.4
Safety analyses.....................................................................................................71
7.3.5
Pharmacokinetic and pharmacodynamic analyses..........................................72
7.4
INTERIM ANALYSES ......................................................................................72
7.5
HANDLING OF MISSING DATA ...................................................................72
7.6
RANDOMISATION ...........................................................................................74
7.7
DETERMINATION OF SAMPLE SIZE .........................................................74
7.7.1
Power estimation for key secondary endpoints................................................75
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........79
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................79
8.2
DATA QUALITY ASSURANCE ......................................................................80
8.3
RECORDS...........................................................................................................80
8.3.1
Source documents ...............................................................................................80
8.3.2
Direct access to source data and documents.....................................................81
8.3.3
Storage period of records ...................................................................................81
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................82
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........82
8.6
TRIAL MILESTONES.......................................................................................82
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................83
9.
REFERENCES....................................................................................................85
9.1
PUBLISHED REFERENCES............................................................................85
9.2
UNPUBLISHED REFERENCES......................................................................91
10.
APPENDICES.....................................................................................................92
10.1
SIX MINUTE WALK TEST..............................................................................92
10.1.1
General considerations for exercise testing ......................................................92
10.1.2
Exercise performance variability ......................................................................92
10.1.3
Safety issues .........................................................................................................93

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10.1.4
Conduct of the 6MWT........................................................................................94
10.2
INCLUSION OF ILLITERATE PATIENTS...................................................98
10.2.1
Patient Reported Outcome Measures ...............................................................98
10.3
PATIENT REPORTED OUTCOME................................................................99
10.3.1
KCCQ (Kansas City Cardiomyopathy Questionnaire)...................................99
10.3.2
Chronic Heart Failure Questionnaire Self Administered - Standardized 
(CHQ-SAS) ........................................................................................................101
10.3.3
Patient Global Impression of Change in Heart Failure Symptoms: shortness 
of breath, fatigue and swelling.........................................................................107
10.3.4
Patient Global Impression of Change in Dyspnea .........................................107
10.3.5
Patient Global Impression of Severity of Heart Failure Symptoms: shortness 
of breath, fatigue and swelling.........................................................................107
10.3.6
Patient Global Impression of Severity of Dyspnea ........................................108
10.4
CLINICIAN GLOBAL IMPRESSION ..........................................................108
10.4.1
Clinician Global Impression of Change in CHF Severity .............................108
10.4.2
Clinician Global Impression of Severity of CHF ...........................................108
10.5
NYHA FUNCTIONAL CLASSIFICATION..................................................109
10.6
BLOOD PRESSURE MEASUREMENT PROCEDURE.............................109
10.7
ACCEPTED FORMS OF CONTRACEPTION FOR PATIENTS IN 
PORTUGAL......................................................................................................110
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .......................................111
11.1
GLOBAL AMENDMENT 1 ............................................................................111
11.2
GLOBAL AMENDMENT 2 ............................................................................121

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ABBREVIATIONS
ACEi
Angiotensin converting enzyme inhibitor
AE
Adverse Event
AESI
Adverse Event of Special Interest
AF
Atrial Fibrillation
ALT
Alanine-Aminotransferase
ARB
Angiotensin receptor blocker
ARNI
Angiotensin receptor-neprilysin inhibitor
AST
Aspertate-Aminotransaminase
BI
Boehringer Ingelheim
BMI
Body Mass Index
CA
Competent Authority
CEC
Clinical event committee
CHF
Chronic Heart Failure
CHQ-SAS
Chronic Heart Failure Questionnaire Self-Administered Standardized 
format
CKD-EPIcr
Chronic Kidney Disease Epidemiology Collaboration Equation
CML
Clinical Monitor Local
CPET
Cardiopulmonary Exercise Testing
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
CRO
Contract Research Organization
CRT
Cardiac resynchronization therapy
CT
Computed Tomography
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Cardiovascular
DILI
Drug Induced Liver Injury
DKA
Diabetic Ketoacidosis
DMC
Data Monitoring Committee
ECG
Echocardiogram
eDC
Electronic Data Capture
EF
Ejection Fraction
eGFR
Estimated Glomerular Filtration Rate
EMPA-REG
Empaglifozin – reducing excess glucose
EOT
End of Trial
EPO
Erythropoietin
EU
European Union
EudraCT
European Clinical Trials Database
ExC
Executive Committee
FDA
US Food and Drug Administration
FC
Flow Chart
GCP
Good Clinical Practice

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GMP
Good Manufacturing Practice
HF
Heart Failure
HFpEF
Heart Failure with Preserved Ejection Fraction
HFrEF
Heart Failure with Reduced Ejection Fraction
HHF
Hospitalization for Heart Failure
IB
Investigator’s Brochure
ICD
Implantable Cardioverter Defibrillator
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
ITT
Intention to Treat
i.v.
intravenous
JVD
Jugular Venous Distension
KCCQ-CSS
Kansas City Cardiomyopathy Questionnaire – Clinical Summary Score
KCCQ-TSS
Kansas City Cardiomyopathy Questionnaire – Total Symptom Score
LVEF
Left Ventriclar Ejection Fraction
MACE
Major Adverse Cardiovascular Events
MedDRA
Medical Dictionary for Drug Regulatory Activities
MMRM
Mixed Model Repeated Measure
MRA
Mineralcorticoid Receptor Antagonist
MRI
Magnetic Resonance Imaging
NT-proBNP
N-Terminal Pro-Brain Natriuretic Peptide
NYHA
New York Heart Association
OPU
Operative Unit
PGI-C
Patient’s Global Impression of Change
PGI-S
Patient’s Global Impression of Severity
PRO
Patient Reported Outcome
PROM
Patient Reported Outcome Measures
p.o.
per os (oral)
q.d.
quaque die (once a day)
QoL
Quality of Life
REP
Residual Effect Period
SAE
Serious Adverse Event
SGLT-2
Sodium Glucose Co-Transporter 2
SOP
Standard Operating Procedures
6MWT
Six Minute Walk Test
6MWTD
Distance walked in six minutes
SC
Steering Committee
SMQ
Standardised MedDRA Query
SUSAR
Suspected Unexpected Serious Adverse Reactions
T1DM
Type 1 Diabetes Mellitus
T2DM
Type 2 Diabetes Mellitus
TCM
Trial Clinical Monitor

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TMF
Trial Master File
TSAP
Trial Statistical Analysis Plan
ULN
Upper Limit of Normal
UTI
Urinary Tract Infections
WHO
World Health Organization
WOCBP
Woman of childbearing potential

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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Chronic heart failure (HF) is a progressive syndrome characterised by the inability of
the   heart to provide adequate blood supply to meet the metabolic demand of different
tissues or do it at the expense of elevated left ventricle filling pressure. HF is a
prevalent disease     affecting an estimated 26 million people worldwide. In the United
States alone the prevalence is 5.7 million, and there are 670,000 new cases per year
[R16-1527]. HF is associated with premature mortality and frequent hospitalisation.
Approximately 50% of patients who develop HF die within 5 years after diagnosis
[P16-03952]. HF is the most common cause of hospitalisation among individuals
above 65 years of age in the Western countries [P16-03760].
Two main types of HF have been defined mainly based on the LV ejection fraction
(EF) and also other structural changes in heart muscle. 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 current empagliflozin exercise capacity trials patients 
with HFmrEF is covered under HFpEF protocol. It should be noted that the current trial and 
the companion trial in HFpEF patients will allow participation of the full spectrum of HF 
patients with reduced, mid-range, or preserved EF.  Amongst patients with HF who
require hospitalisation, the proportion of HFpEF is rising. Analysis of a large HF 
registry showed that the proportion of patients hospitalised with HF (HHF) who had 
HFpEF increased from 33% in 2005 to 39% in 2010 [R16-1529]. The readmission 
rate among patients with HFrEF is close to 29% within 60-90 days post discharge 
which is equal to HFpEF [R16-1527]. After HHF, the one year mortality rate is high
and essentially not different between patients with preserved or reduced left ventricular
ejection fraction (LVEF) [R16-2217], underscoring a high unmet medical need in this
population.
Despite the current standard of care for treatment of HFrEF such as medical therapy
[angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers
(ARB), beta blockers, mineralocorticoid receptor antagonists (MRA), ivabradine and
angiotensin receptor blocker-neprilysin inhibitor (ARNI)] or device therapy the
treatment of HFrEF still appears suboptimal as evidenced by the high mortality rate 
(6-7% / year) and high hospitalization and re-admission for heart failure (9-10% / 
year) hospitalization and up to 30% re-admissions within 90 days post discharge).  
For HFpEF, however, no specific therapy exists and therefore control of congestive
symptoms during acute episodes is the mainstay of management of these patients. No
class of drugs have shown to increase survival or reduce hospitalisations for HFpEF
[P16-03760, P16-05920, R17-1584; R17-0953; R16-1527].

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About 25 to 45% of patients with HF have concomitant type 2 diabetes mellitus
(T2DM), and nearly 15-25% has borderline diabetes (pre-diabetes), indicating a
potential link between heart failure and glucometabolic disturbances [R16-2382, R16-
2384].
Empagliflozin is an orally available inhibitor of the renal dependent glucose co-
transporter 2 (SGLT-2) indicated for, reduction of blood glucose in patients with
T2DM by promoting urinary glucose excretion. It also reduces blood pressure, arterial
stiffness and measures of the 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 Boehringer Ingelheim (BI) initiated the EMPA-REG OUTCOME trial to
explore CV benefit of the drug as well as to establish the safety profile of
empagliflozin [P15-09840].
This trial was completed in 2015 and showed that empagliflozin, when given in addition
to standard care treatment in high CV risk patients with T2DM, reduces the risk of 3-
point MACE by 14% mostly driven by a 38% reduction in CV death. Furthermore this
trial demonstrated reduction in the prespecified and adjudicated composite outcome of
“CV death or hospitalisation for heart failure (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, empagliflozin showed reduction in CV death, HHF, and composite of
“HHF or CV death”
[P16-01253].
Currently, two large clinical outcome trials are ongoing in patients with HFpEF 
(EMPEROR-preserved) or HFrEF (EMPEROR-reduced) to evaluate the effect of 
empagliflozin for the reduction of cardiovascular death and heart failure 
hospitalization.
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 normal within 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®.

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For a more detailed description of the drug profile please refer to the current
Investigator’s Brochure (IB) [c01678844-09] and local prescribing information for
empagliflozin.
1.3
RATIONALE FOR PERFORMING THE TRIAL
In addition to impacting cardiovascular outcomes (death and hospitalization), heart 
failure also leads to a substantial reduction in Quality of Life (QoL) and a high 
symptom burden on a daily basis due to limitation of physical activity (increasing 
from NYHA Class I to IV).  
Therefore, improving heart failure symptoms and assessing the activity of daily living 
such as exercise ability continues to be an unmet medical need in HF patients [R17-
1588].
Further, some HF medications (e.g. Digoxin, Beta blocker, Spironolactone) 
demonstrated discordant results in exercise ability test versus mortality and morbidity 
outcomes [R17-1587]. Empagliflozin, by inhibiting SGLT2 transporter in kidneys, 
induces glucosuria and natriuresis through the decreased reabsorption of glucose and 
sodium and consequent osmotic diuresis [P13-16965].  The glucosuric effect of 
empagliflozin is persistent for as long as the medications is used [P16-01830].  This is 
important as in case of other diuretics such as thiazide or loop diuretics, natriuresis 
may be compensated within days of drug administration through changes in tubulo-
glomerular feedback resulting in reduced efficacy. Also, no clinically significant 
change in serum Na+ or K+ was observed with empagliflozin as shown in the EMPA-
REG-OUTCOME trial [P15-09840], while these changes are common with loop or 
thiazide diuretics (hypokalemia), with mineralocorticoid receptor antagonists (MRAs) 
(hyperkalemia), or with vasopressin antagonists / vaptans (hypernatremia).
For empagliflozin, the MOA suggests a potential for improving of exercise capacity 
tests and patients` symptoms:

The glucosuria mediated osmotic diuresis, is thought to result in long-lasting 
hemodynamic changes associated with modest osmotic diuresis, less 
extracellular volume, increase of hemoglobin (hemoconcentration), shift in 
fuel supply from glucose to fat oxidation and towards more energy-efficient 
ketones, possible reduction of vascular wall stress, decrease ventricular load 
and improving cardiac function as well as improving symptom and functional 
capacity [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 administrations [P16-01830], which 
would be in line with the observed earlyeffects 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 hospitalization in 
patients with baseline cardiac failure (narrow 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 anemia 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; anemia: reduced cardiac oxygen supply).  Due to the 
combination of positive effects, empagliflozin is expected to address the unmet 
medical need of improving exercise ability in this patient population.
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 weighing of the individual beneficial 
effects.  In HFrEF, reducing congestion by osmodiuresis is considered as a 
prominent beneficial effect that may contribute to improved exercise ability.
Taken together, it is anticipated that empagliflozin will show effects on exercise 
ability and mortality & morbidity in both HF subpopulations and supports the 
scientific rationale of performing this trial to explore the effect of empagliflozin on 
exercise ability in patients with HFrEF.

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1.4
BENEFIT - RISK ASSESSMENT
The overall benefits and safety profile of empagliflozin have been outlined in 
previous sections. A pharmacologic rationale for the use of empagliflozin in HF can 
be found in section 1.1.
It has been shown in healthy volunteers dosing with empagliflozin results in 
glycosuria summing up to about 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.  Because in the EMPA REG Outcome study no difference in CV benefit 
was detected for patients with renal impairment vs the overall population, it is 
hypothesized that this amount of glucosuria is not the main factor for obtaining CV 
effects with empagliflozin.
There are no long-term safety data for empagliflozin in patients without diabetes.  
Data in non-diabetic subjects is limited to healthy volunteers, without significant co-
morbidities or concomitant medications.  Exposure in healthy volunteers is from 
single dose and multiple dose studies with exposure up to 28 days.  However, while 
limited, such data does include over 500 healthy volunteers exposed to empagliflozin 
during the clinical development for treatment of T2DM.  No specific safety concern 
was identified and no occurrence of symptomatic hypoglycaemia was detected [U12-
2707-01].  It is noted that in patients with T2DM, the risk of hypoglycaemia was only 
increased with empagliflozin compared to the placebo group in patients who were 
concomitantly treated with insulin or a sulfonylurea.  Further, in a mechanistic study 
[c11963611-01], subjects without DM were shown to increase endogenous glucose 
production in response to glucosuria after administration with empagliflozin.  As a 
result, blood glucose levels remained in the normal range for these individuals [P16-
01830].  Therefore it seems scientifically reasonable to hypothesize that in non-
diabetic patients, with no medical indication for insulin or sulfonylurea treatment the
risk of hypoglycaemia associated with empagliflozin treatment would be lower than 
in patients with T2DM.
Because of the mode of action, blockade of the SGLT-2 with consequent glucosuria, 
is the same in patients with and without diabetes, although of different average daily 
amounts, it is considered likely that the tolerability of empagliflozin in non-diabetic 
patients may be no less favourable than in patients with T2DM.
There is also currently limited therapeutic experience with empagliflozin in patient 
aged 85 years and older.  The prevalence of chronic heart failure increases with age 
and the therapeutic options in the elderly above 85 years are limited.  The inclusion of 
this population in the clinical trial setting will help support the assessment of benefit-
risk of empagliflozin for patients over 85 years.  Special caution should be used in 

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these patients, who may be at increased risk of adverse consequences attributed to 
empagliflozin related volume depletion.
Many patients with CHF have renal impairment, and to ensure that the trial results 
reflect this population, patients with 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 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].  Renal safety will be closely monitored throughout the trial.  Refer to 
section 5.2.7.1.
The overall tolerability and safety profile as outlined in section 1.2, and the current IB, 
supports chronic safe administration of empagliflozin 10 mg in human studies. 
Potential benefits:
Patients with HF are thought to benefit from combined beneficial effects of 
empagliflozin such as persistent osmodiuresis, reduction in blood pressure, weight 
loss, increase in hematocrit, and changes in cardiometabolic parameters as early as the 
first few weeks of empagliflozin administrations.  In HFrEF, reducing congestion by 
osmodiuresis is considered as a prominent beneficial effect that may contribute to 
improved exercise ability.
The details of the potential benefits of empagliflozin in addressing short-term 
symptoms and exercise ability of patients wih HFrEF was discussed in section 1.3.
Lack of correlation between blood glucose lowering effects and CV outcome 
improvement in EMPA-REG-OUTCOME [P15-09840] as well as a 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.
Due to the combination of several positive effects, empagliflozin is expected to 
address the unmet medical need of improving exercise ability in the HFrEF patient 
population.
Known and potential risks:
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 

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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. In addition, approximately 550 healthy volunteers were exposed 
to empagliflozin (up to 800 mg single dose and up to 50 mg multiple dosing)
[c01678844-09]. 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 than in the patients with T2DM [P17-
04479].
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 
AEs, AEs leading to discontinuation and serious Adverse Events (SAEs) were 
comparable to placebo. There was no significant increase in frequency of 
hypoglycaemia with empagliflozin compared to placebo except when used in 
combination with a sulphonylurea or basal insulin.It is not expected that patients 
without DM use insulin and/or sulfonylurea. 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
[c01678844-09].
Empagliflozin causes intravascular volume contraction. Patients with known 
cardiovascular disease, patients on antihypertensive therapy with a history of 
hypotension or patients aged 75 years and older are at increased risk of volume 
depletion.
Rare cases of DKA were observed in patients with T2DM treated with empagliflozin
[c01678844-09].
Based on the findings in the nonclinical trials conducted to date and in accordance 
with international regulatory guidelines, the inclusion of women of childbearing 
potential (WOCBP) in this trial is justified. To minimise the risk of unintentional 
exposure of an embryo or foetus to the investigational drug, women of child bearing 
potential must agree to the requirements for pregnancy testing and contraceptive 
methods described in this protocol
As with all drugs, the potential for hypersensitivity and allergic reactions has to be 
taken into consideration when empagliflozin is administered. Other risks to the 
patients are the risks inherent to any investigational medicinal product used in a 
clinical trial setting, such as unexpected adverse clinical or laboratory events.
Although rare, a potential for drug-induced liver injury (DILI) is under constant 
surveillance by sponsors and regulators. Therefore, this trial requires timely detection, 
evaluation, and follow-up of laboratory alterations in selected liver laboratory 
parameters to ensure patients´ safety, see also section 5.2.6, adverse events of special 
interest.

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Special attention will be paid to prevent metabolic acidosis, ketoacidosis and diabetic 
ketoacidosis (DKA). For further details refer to Section 4.2.1.
To continue the assessment of the safety of empagliflozin, adjudication of certain 
hepatic events and ketoacidosis will be performed in this trial. The progress of the 
trial will also be assessed at regular intervals by an independent Data Monitoring 
Committee (DMC). Further details are described in Section 8.7, the adjudication 
charter and the DMC charter.
6MWT risks:
The 6MWT is a standard procedure to assess the functional capacity of patients with 
chronic heart failure. The exercise testing and the safety measures during the test 
(including the conditions to stop the test) are based on the recommendations outlined 
by the American Thoracic Society (2002) [R03-0725]. The selection of the sites will 
ensure that the sites are well equiped and qualified to perform the 6MWT.
Overall the potential benefits, coupled with an acceptable safety profile and a well 
controlled environment during the exercise testing, 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 primary objective of this trial is to evaluate the effect of empagliflozin 10 mg 
versus placebo on exercise ability using the 6 minute walk test in patients with chronic
HF with reduced ejection fraction (LVEF ≤40%).
Secondary objectives are to assess Patient-Reported Outcome.
This trial is part of an investigational clinical trial program of empagliflozin in 
patients with chronic HF. A comparable trial (study number 1245-0167) to investigate
the same objectives in patients with preserved EF (LVEF > 40%) is ongoing in parallel.
2.1.2
Primary endpoint(s)
The primary endpoint is the change from baseline to week 12 in exercise capacity as 
measured by the distance walked in 6 minutes in standardised conditions as described 
in the 6-minute walk test (MWT) appendix (appendix 10.1).
2.1.3
Secondary endpoint(s)
Key secondary endpoints are:

Change from baseline to week 12 in Kansas City Cardiomyopathy Questionnaire 
(KCCQ) Total Symptom Score (TSS)

Change from baseline to week 12 in Chronic Heart Failure Questionnaire Self-
Administered Standardized format (CHQ-SAS) dyspnea score  
Other secondary endpoints are: 

Change from baseline to week 6 in exercise capacity as measured by the distance 
walked in 6 minutes

Change from baseline in Clinical Congestion Score at week 12.

Change from baseline in Patient Global Impression of Severity of Heart Failure 
Symptoms at week 12.

Change from baseline in Patient Global Impression of Dyspnea Severity at week 
12.

Patient Global Impression of Change in Heart Failure Symptoms at week 12.

Patient Global Impression of Change in Dyspnea at week 12.

Change from baseline in N-terminal pro-brain natriuretic peptide (NT-proBNP) at 
week 12

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2.2
FURTHER OBJECTIVES AND FURTHER ENDPOINTS
2.2.1
Further objectives
Further objectives are to evaluate additional details of PRO, heart failure class and 
exercise ability. 
2.2.2
Further endpoints
Further endpoints are: 

Increase in 6MWT ≥ 30 m from baseline at week 12

Response in KCCQ domains at week 12*

Response in CHQ domains at week 12*

Change from baseline in Patient Global Impression of Severity of Heart Failure 
Symptoms at week 6.

Change from baseline in Patient Global Impression of Dyspnea Severity at week 
6.

Patient Global Impression of Change in Heart Failure Symptoms at week 6.

Patient Global Impression of Change in Dyspnea at week 6.

Change from baseline in Clinician Global Impression of Severity of CHF at Week 
6 and week 12

Clinician Global Impression of Change in CHF Severity at Week 6 and week 12

Change from baseline in KCCQ overall summary score, CSS, and individual 
domains at Week 6 and week 12

Change from baseline in KCCQ TSS at Week 6

Change from baseline in CHQ individual domains at week 6 and week 12

Change from baseline in Clinical Congestion Score at week 6.

Change from baseline in N-terminal pro-brain natriuretic peptide (NT-proBNP) at 
week 6

Changes in NYHA class at Week 6 and week 12

Change from baseline to week 6 and week 12 in patient-rated assessment of 
dyspnea and fatigue by the Borg scale as part of the 6MWT

Occurrence of HHF and CV death

Occurrence of all-cause mortality

Occurrence of CV death

Occurrence of all-cause hospitalization (first and recurrent)

Occurrence of hospitalization for HF (first and recurrent)

Occurrence of all-cause emergency room visits (first and recurrent)

Emergency room visit for HF (requires use of i.v. diuretics; first and recurrent)

Occurrence of unscheduled outpatient visit (first and recurrent)

Intensification of diuretic therapy (adding a new diuretic, increase of dose)

Occurrence of MI (fatal or non-fatal)

Occurrence of Stroke (fatal or non-fatal)

Occurrence of TIA

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* Criteria for response will be explored based on anchor-based methods – further detail 
will be specified in the TSAP.

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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This is a randomised, double-blind, parallel-design, placebo controlled, multinational 
and multi center study.
A total of approx. 300 male and female patients with chronic heart failure will be 
randomized (1:1) in the study in about 8 countries. 
The screening period will last up to 3 weeks and patients will receive the study drug 
for 12 weeks. 
Figure 3.1:1 Overview of trial design
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE 
OF CONTROL GROUP(S)
A variety of medications have been tested in patients with HFrEF with beneficial 
effect in morbidity (specifically reduction of hospitalizations for heart failure) and 
mortality. The aim of this trial is to recruit patients with HFrEF on various HF 
Follow-up 
Empaglifozin 10 mg N =150
Placebo N = 150
13
12
6
Screening
Visit 1
End of 
treatment
End of trial
R
Randomization
Up to -3 
Visit 3
-4d to -21d
weeks
1

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background therapies to evaluate the effect of empagliflozin on exercise ability in a 
real life clinical setting. 
Choice of endpoint:
Various tests are available to assess exercise ability, which can be grouped in two 
main categories: self-paced submaximal exercise capacity tests (e.g. 6MWT), and 
maximal exercise capacity tests (e.g. Cardiopulmonary Exercise Testing (CPET)).  
For CPET, which measures peakVO2 as primary variable, patients must reach their 
maximal exercise ability which implies a high burden on patients with HF and 
requires centers with advanced exercise equipment and highly experienced staff.  In 
addition, peak VO2 testing is not widely available, is time consuming and costly, and 
is difficult to implement as an endpoint in large scale clinical trials [R17-1588].  
Evaluating HF patients and their limitations in daily activities, however, does not 
require these patients to reach their maximal exercise ability and these limitations 
could be identified after mild to moderate exertion during a self-paced 6MWT [R17-
1341]. The 6MWT, therefore, better reflects activities of daily living that are mostly 
done at submaximal levels of exertion [R17-1340; R17-1367].
In a systematic review of the literature, 6MWT showed concordance (positive or 
neutral) in 41 out of 47 studies with patient’s symptoms, indicating the relevance of 
this test in assessing short term symptoms improvement [P17-05077].  Pulmonary 
hypertension trials routinely assess 6MWT as a primary endpoint, supported by a 
secondary efficacy endpoint of time to clinical worsening, which has served as the 
basis for approval of investigational drugs in that specific indication.  Despite the 
outlined differences, studies have shown good correlations between PeakVO2 and 
6MWT [R17-1592] with up to 80% positive or neutral concordance. The 6MWT was 
also found to be reliable and valid in patients with mild-to-moderate CHF and to have 
good correlation with the maximal exercise capacity supporting the validity of the test
[R17-1367]. These findings indicate the clinical utility of the 6MWT for HF clinical
trials and emphasize its reliability by being concordant to the peakVO2 test, without 
burdening HF patients with maximal exercise testing.  The 6MWT has limitations as 
it is self-paced (the patient may limit her/his performance which is not objectively 
assessable as a performance marker such as peakVO2), but adhering to certain 
recommendations such as providing standard phrases of encouragement during the 
test will help reducing variability of the test and increase chance of assessing a 
clinical effect. 
Patient Related Outcome Measures (PROM):
PRO is any report of the status of a patient’s health condition that comes directly from 
the patient, without interpretation of the patient’s response by a clinician or anyone 
else [R12-5607].

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PRO can provide information on a range of patients’ health status outcome including 
the following: symptoms; functional limitations; impacts on daily activities; social,
emotional, psychological and overall well-being [R17-1342].
The Kansas City Cardiomyopathy Questionnaire (KCCQ) is one of the most widely 
used HF PRO instruments [R17-2687].
KCCQ has prognostic significance, which may aid in their clinical interpretation and 
decision making based on risk stratification.
The Chronic Heart Failure Questionnaire (self-administered standardized format) 
(CHQ-SAS) is a heart failure-specific PRO measure with 16-items, designed to assess 
PRO [R17-2668], [R17-2969] in adult heart failure patients and specifically evaluates 
longitudinal change over time. The subscales of the CHQ-SAS are: dyspnea, fatigue
and emotional function. Items are rated on a 7-point Likert scale ranging from 1 (e.g. 
extremely short of breath) to 7 (e.g. not at all short of breath) [R17-2969].
Control group: 
Due to its mode of action empagliflozin has the potential be efficacious in treating 
patients with HF and could provide additional efficacy in combination with any given 
background therapy. However, the effect of empagliflozin in patients with heart 
failure has not yet been systematically assessed in a randomized 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 hospitalization.
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 level of hemodynamic and 
glycemic control 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. 
This includes, but is not limited to (if indicated and not contraindicated)
acetylsalicylic acid , statins, a diuretic, an inhibitor of the renin-angiotensin system, 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 ICDs and 
CRT. This should be conducted 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 above for mode of action and 
EMPA-REG-OUTCOME results) empagliflozin is expected to exert its effect within 

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the early weeks of administration and therefore the peak effect on improving exercise 
ability is expected to be seen as early as approximately 4-8 weeks from baseline. 
Thus, a 12 week time point is considered suitable for the assessment of the primary 
endpoint.
3.3
SELECTION OF TRIAL POPULATION
A sufficient number of patients will be screened to ensure that an adequate number of 
patients will be randomized. It is planned that approximately 300 male and female 
patients who meet the eligibility criteria will be randomized in the study. The planned 
number of patients per site is approximately 4 (at approximately 80 sites). 
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 ISF at the investigational site irrespective of whether they 
have been treated with investigational drug or not.
Re-screening and/or re-testing (of assessments) should be discussed with Local 
Clinical Monitor (CML). Whilst the information provided below is not an exhaustive 
list, it provides some guidance as to when such re-screening and/or re-testing would 
be considered appropriate
Re-testing:
Re-testing for eligibility criteria is only to be performed once for blood pressure, 
electrocardiogram (ECG) measurements and laboratory result which is obviously 
received beyond stability at the central laboratory or thought to be a spurious or 
transient result based on previously available laboratory results or in the opinion of 
the investigator. The re-test should be carried out as soon as possible so the laboratory 
test results will be received within the next planned visit windows in order to avoid 
protocol window violations. If the retest is for the NT-proBNP, the baseline rhythm 
(e.g. sinus rhythm, AF) of the patient must be clarified (i.e. ECG) and documented at 
the time the NT-proBNP sample is collected.
Re-screening will be allowed on a case-by-case basis.
Patients must be clinically stable with no signs of heart failure decompensation when 
entering the study. If the patient is not clinically stable, rescreening is allowed:
Re-screening of the same patient is only allowed once.

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The patient must be clinically stable for at least 4 weeks and satisfy all 
eligibility criteria.
The patient should be declared a screening failure in the electronic Case Report 
Form (eCRF) and IRT with their original patient number.
Upon re-screening, the IRT system will allocate a new screening number for the 
patient
The patient must be re-consented using the current approved version of the 
information sheet and consent form
If a patient is a screen failure in one of the other Heart Failure trials with Empagliflozin
they could be considered for this trial as long as they meet all eligibility criteria.
In instances where a patient is a screen failure in 1245-0167, all relevant completed 
screening procedures can be used for the eligibility assessment of the patient in 1245-
0168 as long as they are completed during the original screening timeframe. The decision 
to screen the patient in the 1245-0167 trial should be based on Investigator judgement and 
in consultation with the Sponsor.
3.3.1
Main diagnosis for trial entry
The trial will be performed in patients with chronic heart failure with an ejection fraction 
≤ 40%.
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, usually ≥ 18 years) at screening.
2. Male or female patients. Women of childbearing potential (WOCBP)1 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. For sites in Portugal please refer to the contraception methods described 
in appendix 10.7.
3. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial
4. 6MWT distance ≤350 m at screening and at baseline.
                                                
1 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile. 
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
Please note that tubal ligation is NOT accepted as a method of permanent sterilisation and therefore a woman who 
underwent tubal ligation is still considered as WOCBP. However tubal ligation is considered as a method of highly effective 
birth control. 

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5. Patients with chronic HF diagnosed for at least 3 months before Visit 1 and currently 
in NYHA class II-IV
6. Chronic HF with reduced EF defined as LVEF ≤ 40 % as per echocardiography at 
Visit 1 as per local reading (obtained under stable condition).
7. Elevated NT-proBNP > 450 pg/ml for patients without atrial fibrillation (AF) OR NT-
proBNP > 600 pg/ml for patients with AF as analysed at the Central laboratory at 
Visit 1
8. Patients must be clinically stable and on appropriate and stable dose of medical 
therapy for HF (such as ACEi, ARB, β-blocker, oral diuretics, MRA, ARNI, 
ivabradine), consistent with prevailing CV guidelines, stable for at least 4 weeks prior 
to Visit 1(screening) with the exception of diuretics which must have been stable for
at least two weeks prior to Visit 1. The investigator must document the reason in case 
the patient is not on such medication or if not on target dose of any heart failure 
medication as per local guidelines.
9. Clinically stable at randomization with no signs of heart failure decompensation (as 
per investigator judgement).  
10. Appropriate use of medical devices such as cardioverter defibrillator (ICD) or a 
cardiac resynchronization therapy (CRT) consistent with prevailing local or 
international CV guidelines, and if a device is required, it must have been implanted 
for at least 3 months prior to visit 1 for CRT and 1 month prior to visit 1 for ICD. 
3.3.3
Exclusion criteria
1. Myocardial infarction (increase in cardiac enzymes in combination with symptoms of 
ischaemia or newly developed ischaemic ECG changes), coronary artery bypass graft 
surgery or other major cardiovascular surgery, stroke or TIA in past 90 days prior to 
Visit 1
2. Acute decompensated HF (exacerbation of chronic HF) requiring intravenous (i.v.) 
diuretics, i.v. inotropes or i.v. vasodilators, or left ventricular assist device within 4
weeks prior to Visit 1, and/or during screening period until Visit 2
3. Previous or current randomisation in another Empagliflozin Heart Failure trial (i.e.
studies 1245.110, 1245.121, 1245-0167)
4. Type 1 Diabetes Mellitus (T1DM)
5. Impaired renal function, defined as eGFR < 20 mL/min/1.73 m2 (CKD-EPIcr) or 
requiring dialysis, as determined  at Visit 1
6. Symptomatic hypotension or a SBP < 100 mmHg at Visit 1 or 2
7. Systolic blood pressure (SBP) ≥ 180 mmHg at Visit 1 or 2, or SBP >160mmHg at 
both Visit 1 and 2
8. Atrial fibrillation or atrial flutter with a resting heart rate >110 bpm documented by 
ECG at Visit 1 (Screening) 
9. Unstable angina pectoris in past 30 days prior to Visit 1
10. Largest distance walked in 6 minutes (6MWTD) at baseline <100m.
11. Any presence of condition that precludes exercise testing such as:
o claudication,
o uncontrolled (according to investigator judgement) bradyarrhythmia or 
tachyarrhythmia,
o significant musculoskeletal disease,

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o primary pulmonary hypertension,
o severe obesity (body mass index ≥40.0 kg/m2),
o orthopedic conditions that limit the ability to walk (such as arthritis in the 
leg, knee or hip injuries)
o amputation with artificial limb without stable prosthesis function for the past 
3 months 
o Any condition that, in the opinion of the investigator, would contraindicate 
the assessment of 6MWT
12. Patients in a structured (according to Investigator judgement) exercise training 
program in the 1 month prior to screening or planned to start one during the course of 
this trial.
13. Heart transplant recipient, or listed for heart transplant
14. Currently implanted left ventricular assist device (LVAD)
15. Cardiomyopathy based on 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 or known pericardial constriction
16. Any severe (obstructive or regurgitant) valvular heart disease, that either represents a 
risk for the conduct of the 6MWT or is expected to lead to surgery during the trial in 
the investigator’s opinion
17. Untreated ventricular arrhythmia with syncope in patients without ICD documented 
within the 3 months prior to Visit 1
18. Planned implantation of ICD or CRT during the course of the trial.
19. Diagnosis of cardiomyopathy induced by chemotherapy or peripartum within the 12 
months prior to Visit 1
20. Symptomatic bradycardia or second or third degree heart block without a pacemaker 
after adjusting beta-blocker therapy, if appropriate
21. Chronic pulmonary disease i.e. with known FEV1 < 50% requiring home oxygen, or 
oral steroid therapy or hospitalisation for exacerbation within 12 months, or 
significant chronic pulmonary disease in the opinion of the investigator, or primary 
pulmonary arterial hypertension
22. Indication of liver disease, defined by serum levels of either ALT (SGPT), AST 
(SGOT), or alkaline phosphatase above 3 x upper limit of normal (ULN) as 
determined at Visit 1
23. Haemoglobin (HgB) <9  g/dl at Visit 1
24. History of ketoacidosis
25. Major surgery (major according to the investigator’s assessment) performed within 90 
days prior to Visit 1, or scheduled major elective surgery (e.g. hip or knee
replacement) duringthe course of the trial 
26. Gastrointestinal surgery or gastrointestinal disorder that could interfere with trial
medication absorption in the investigator’s opinion
27. 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, 
in situ carcinoma of uterine cervix, or low risk prostate cancer (biopsy Gleason score 
of ≤ 6 and clinical stage T1c or T2a)

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28. 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
29. Current use or prior use of a SGLT-2 inhibitor or combined SGLT-1 and 2 inhibitor 
within 12 weeks prior to Visit 1 or during screening period until Visit 2 
(Randomisation).  Discontinuation of a SGLT-2 inhibitor or combined SGLT-1 and 2 
inhibitor for the purposes of study enrolment is not permitted.
30. Treatment with i.v. iron therapy or erythropoietin within 3 months prior to screening
31. Currently enrolled in another investigational device or drug study, or less than 30 days 
since ending another investigational device or drug study(s), or receiving other 
investigational treatment(s). Patients participating in a purely observational trial will 
not be excluded
32. Known allergy or hypersensitivity to empagliflozin or other SGLT-2 inhibitors
33. Chronic alcohol or drug abuse or any condition that, in the investigator’s opinion,
makes them an unreliable trial subject or unlikely to complete the trial
34. Women who are pregnant, nursing, or who plan to become pregnant while in the trial
35. Any other clinical condition that would jeopardise patients safety while participating 
in this trial, or may prevent the subject from adhering to the trial protocol.
3.3.4
Withdrawal of patients from therapy or assessments
Patients may potentially be withdrawn from trial treatment or from the trial as a whole
(“withdrawal of consent”) with very different implications, please see sections 3.3.4.1 and 
3.3.4.2 below.
Every effort should be made to keep the randomised 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 randomization, as well as the
explanation of the consequences of withdrawal. 
The decision to withdraw from trial treatment or from the whole trial as well as the reason
must be documented in the patient files and CRF.
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
as scheduled. This includes careful patient selection and appropriate explanation of the
trial requirements and procedures prior to enrolment as well as an explanation of the
consequences of premature withdrawal.

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3.3.4.1
Withdrawal from trial treatment
An individual patient is to be withdrawn from trial treatment if:

The patient wants to withdraw from trial treatment, without the need to justify the 
decision.

The patient needs to take concomitant drugs that interfere with the investigational 
product or other trial medication (see 4.2.2.1 for restricted medication).

The patient can no longer be treated with trial medication for other medical reasons 
(such as surgery, adverse events, other diseases, or pregnancy).

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 comply with the trial requirements in the future.
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 (FC) and section 6.2.3. In addition, if the patient
discontinues early, the patient should return to clinic for their regularly scheduled week 
12 study visit and have all study procedures performed except those pertaining to drug 
intake.
Every effort should be made for the patient to attend the regularly scheduled study visits, 
however if this is not possible, then the remaining visits should be conducted by phone.  
For all patients the reason for withdrawal from trial treatment (e.g. adverse events) must 
be recorded in the CRF. These data will be included in the trial database and reported.
Pregnancy
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 5.2.7.2).  As pregnancy is not a contraindication for the 6MWT, the
patient will be expected to attend the regularly scheduled study visits as outlined above.
3.3.4.2
Withdrawal of consent for trial participation
Patients may withdraw their consent for 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.
The Investigator must be involved in the discussions with the patient regarding a
withdrawal of consent and should explain the difference between treatment withdrawal 
and withdrawal of consent for trial participation and explain the options for continued 
follow up after withdrawal from trial treatment, 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. Violation of GCP, the trial protocol, or the contract impairing the appropriate conduct 
of the trial
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 products:
Substance:
empagliflozin
Pharmaceutical formulation:
Film-coated tablet
Source:
Boehringer Ingelheim
Unit strength:
10 mg
Posology
1 tablet once daily
Route of administration:
oral
Substance:
Placebo matching empagliflozin
Pharmaceutical formulation:
Film-coated tablet
Source:
Boehringer Ingelheim
Unit strength:
-
Posology
1 tablet once daily
Route of administration:
oral
4.1.2
Selection of doses in the trial
Empagliflozin 10 mg and 25 mg are approved for the treatment of T2DM.
Empagliflozin exerts its effect by promoting glucosuria and consequent hemodynamic
changes associated with diuresis, improvement in arterial stiffness, blood pressure
lowering effect with no increase in HR and reduction in HR 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.

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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 subgroup analysis empagliflozin improved the main outcome of CV death and HHF 
with the similar magnitude in patients with low or high levels of HbA1c at baseline. This
indicates the risk reduction for HF 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 as well. 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 10 mg empagliflozin and similar general safety, and 
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 [c01678844-09].
4.1.3
Method of assigning patients to treatment groups
During visit 2 eligible patients will be randomised to receive empagliflozin 10 mg, or 
matching placebo, in a 1:1 ratio according to a randomization plan. The assignment will 
occur in a blinded fashion via Interactive Response Technology (IRT).
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 the 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.
4.1.4
Drug assignment and administration of doses for each patient
Patients who qualify will be randomised to one of the dosages described in Section 4.1.1.
Trial medication will be dispensed by the pharmacist or the investigator in a double-blind 
and single-dummy manner.
IRT will be used to allocate study medication to patients at visit 2 and 3 for a 6 week 
period and one week reserve ( i.e. 49 tablets total) each time. Treatment starts on the day 
of visit 2 and ends on the day of visit 4 (or early discontinuation visit). For further details
regarding packaging (e.g. number of tablets per container) please refer to Section 4.1.6.

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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. 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.
Patients should be instructed to take their medication on the morning of trial visits 3 and 
4. Visits should be routinely scheduled at approximately the same time of day for each 
visit. The actual date and time of administration of the trial medication at the trial visit 
will be recorded in the eCRF.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
Patients, investigators 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 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.
The randomization code will be kept secret by Clinical Trial Support up to database lock.
4.1.5.2
Unblinding and breaking the code
Emergency unblinding will be available to the investigator / pharmacist / investigational 
drug storage manager via IRT. It must only be used in an emergency situation when the 
identity of the trial drug must be known to the investigator 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 
along with the date and the initials of the person who broke the code.
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 representatives and not be 
shared further. 

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4.1.6
Packaging, labelling, and re-supply
The investigational products will be provided by BI or a designated 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 local clinical 
monitor (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 and/or pharmacist and/or investigational drug storage manager will 
receive the investigational drugs delivered by the sponsor when the following 
requirements are fulfilled:

Approval of the clinical trial protocol by the IRB / ethics committee ,

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,

Availability of FDA Form 1572 (if applicable).
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 and/or pharmacist and/or investigational drug storage manager 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 product and trial

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patients. The investigator / pharmacist / investigational drug storage manager will 
maintain records that document adequately that the patients were provided the doses 
specified by the CTP and reconcile all investigational products received from the sponsor. 
At the time of return to the sponsor and/or appointed CRO, the investigator / pharmacist / 
investigational drug storage manager 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
Concerning the 6MWT, the following is required:
The test should be performed in a location where a rapid, appropriate response to an 
emergency is possible. Adequate safety equipment must be readily available at the test 
site according to local institutional requirements and emergency medications are to be 
administered at the discretion of the Investigator, such as oxygen, fast acting nitrate,
antiplatelets agent, sphyngomanometer and telephone.
The 6MWT should be immediately stopped in case of acute chest pain, sudden pallor, 
loss of coordination / staggering, mental confusion, extreme dyspnea, leg cramps, 
diaphoresis.  The subject should be monitored in the unit until the signs / symptoms / 
ECG modifications have been completely cleared.
The use of medication for the treatment of HF will be in accordance with 
local/international guidelines and at the discretion of the Investigator. 
All concomitant (additional) medications and other therapies should be recorded on the 
appropriate pages of the eCRF.
Concomitant antidiabetic medications should be adjusted individually as clinically 
indicated by the patient’s usual diabetes care provider. 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. 

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Cases of DKA have been reported in T2DM 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). 
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., 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. 
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 day period between the EOT and the Follow Up Visit.  
Patients must be on appropriate and stable dose of oral diuretics, consistent with prevailing 
CV guidelines for 2 weeks prior to Visit 1 to control volume status and symptoms.
Patients must be on appropriate and stable dose of concomitant medications, consistent 
with prevailing CV guidelines for 4 weeks prior to Visit 1 to control HF symptoms.

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The investigator must document the reason in case a patient is not on such medication or
if not on target dose of any heart failure medication as per local guidelines.
Patients should not receive treatment with i.v. iron therapy and EPO during the course of 
the trial.
If any restricted treatment is given during the conduct of the trial, the trial medication 
must 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.
4.2.2.2
Restrictions on diet and life style
Prior to each visit during which a 6MWT is performed, patients should be advised not to 
perform vigorous exercise on the day of testing. Patients should be advised to take only a 
light meal prior to a 6MWT.
Patients must remain in the building where the exercise testing is performed and must 
return to the study personnel at least 10 minutes prior to the start of the 6MWT.
For further details on restrictions on diet and life style please refer to Appendix 10.1.
4.2.2.3
Restrictions regarding women of childbearing potential 
Women of childbearing potential must use the contraception methods described in the 
patient information. For sites in Portugal please refer to the contraception methods 
described in Appendix 10.7.
4.3
TREATMENT COMPLIANCE
Patients are requested to bring all remaining trial medication including empty package 
material with them when attending visits.
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 since last tablet count 
100
Number of  tablets which should have been taken in the 
same period
Compliance should be between 80% and 120%. 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.

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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
Six Minute Walk Test
At all sites, patients will perform an exercise capacity assessment using the 6 minute walk 
test (6MWT). One 6MWT will be performed at the screening visit, visit 3 and the early 
discontinuation visit (if applicable). At visits 2 and 4, two 6MWTs will be performed at 
least 1 hour apart for increasing reliability of the test as well as for decreasing variability.  
The distances from both tests will be recorded in the eCRF and the largest distance 
measured will used for analysis.  Testing of the 6MWT at each clinic visit should be 
preferably performed about the same time of day to minimize intraday variability.
The 6MWTs at Visit 1 and 2 will be performed to assess patient eligibility and as well the 
screening test will serve as the training test to familiarize patients with the procedure.  If 
the distance walked during any of these 6MWTs is > 350m the patient will be considered 
a screen failure. If the largest distance walked at Visit 2 is < 100m, the patient will be 
considered a screen failure. The 6MWT of largest distance performed at Visit 2, will be 
the baseline result.  
Prior to and at the end of the 6MWT, patients will be asked to rate their breathing 
discomfort and overall fatigue using the Borg Scale. 
The 6MWT methodology is described in detail in the ISF and Appendix 10.1. Please refer 
to section 6.2.2 for preferred order of completion of assessments.
5.1.2
Kansas City Cardiomyopathy Questionnaire
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 10.3.1).
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.

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5.1.3
Chronic Heart Failure Questionnaire Self Administered Standardized
The Chronic Heart Failure Questionnaire Self Administered Standardized (CHQ-SAS) is 
a heart failure-specific PRO measure that assesses the patients’ perception of their heart 
failure and measures the impact of heart failure symptoms. The CHQ-SAS refers to the 
CRQ-self-administered format and contains 16 standardised questions pertaining to 3 
domains: dyspnea, fatigue and emotional function. Items are rated on a 7-point Likert 
scale ranging from 1 (e.g. extremely short of breath) to 7 (e.g. not at all short of breath) 
[R17-2969].
Patients will complete the first administration of the questionnaire at Visit 2 and complete 
the follow-up administration questionnaire at Visits 3 and 4 and early discontinuation (if 
applicable).
Please refer to section 6.2.2 for order of completion of patient reported outcome
measures.
Please refer to Appendix 10.3.2 for the first administration of the questionnaire and the 
ISF for the follow-up administration of the questionnaire.
5.1.4
NT-proBNP
Samples for NT-proBNP will be collected at Visit 1 (Screening) to determine whether the
patient is eligible for the trial. Further samples for NT-proBNP will be collected at later
time points in the trial (see Flow Chart) to investigate a potential effect of the trial
medication. Samples for NT-proBNP will be analysed at the Central Laboratory.
5.1.5
New York Heart Association classification
The New York Heart Association (NYHA) functional classification will be used to
classify the severity of the patients’ heart failure (ref. Appendix 10.5). The investigator
should place the patients in one of the four categories based on how limited their physical
activity are.
Candidates for screening are required to have a NYHA functional class II, III or IV.
The classification of patient’s physical activity according to NYHA will be performed at
all on-site and if needed, telephone visits, until end of the trial.
5.1.6
Clinical Congestion Score
Patient’s congestion will be assessed using a clinician-based outcome assessment of 6 
different signs and symptoms: dyspnea, orthopnea, fatigue, jugular venous distention (as 
assessed by the investigator), rales, and edema. 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 below:

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Signs/Symptoms
0
1
2
3
Dyspnea
None
Seldom
Frequent
Continuous
Orthopnea
None
Seldom
Frequent
Continuous
Fatigue
None
Seldom
Frequent
Continuous
JVD (cm H2O)
(jugular venous 
distension)
≤6
6 <JVD <10
10 ≤ JVD 
<15
≥15
Rales
None
Bases
From base to 
<50%
From base 
to >=50%
Edema
Absent/ trace
Slight
Moderate
Marked
The Clinical Congestion Score will be completed according to the Flowchart. Please refer 
to section 6.2.2 for preferred order of completion of assessments.
5.1.7
Patient Global Impression of Change in Heart Failure Symptoms
The patient global impression of change (PGI-C) in Heart Failure Symptoms is a 1-item 
questionnaire to assess patient’s impression of change in heart failure symptoms, 
specifically: shortness of breath, fatigue and swelling.
The patient global impression of change asks the patient to choose one response that best 
describes the overall change (if any) in his/her Heart Failure Symptoms, specifically: 
shortness of breath, fatigue and swelling since he/she started taking the trial medication
!" #$% &!''!()"* +,-.#%*!/0 1-.'%2

Very much better (+3)

Much better (+2)

A little better (+1)

No change (0)

A little worse (-1)

Much worse (-2)

Very much worse (-3)
Please refer to section 6.2.2 for order of completion of patient reported outcome measures
and Appendix 10.3.3.
5.1.8
Patient Global Impression of Change in Dyspnea
The patient global impression of change (PGI-C) in dyspnea is a 1-item questionnaire 
designed to assess the patient’s impression of change in dyspnea.

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The patient global impression of change asks the patient to choose one reponse that best 
describes the change (if any) in his/her shortness of breath when performing usual 
activities since he/she started taking the trial medication on the following 7-category 
scale:

Very much better (+3)

Much better (+2)

A little better (+1)

No change (0)

A little worse (-1) 

Much worse (-2)

Very much worse (-3)
Please refer to section 6.2.2 for order of completion of patient reported outcome
measures and Appendix 10.3.4.
5.1.9
Patient Global Impression of Severity of Heart Failure Symptoms
Patient global Impression of Severity (PGI-S) of Heart Failure Symptoms 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.
5.1.10
Patient Global Impression of Severity of Dyspnea
Patient global Impression of Severity (PGI-S) of Dyspnea is a 1-item questionnaire 
designed to assess patient’s impression of symptom severity, specifically dyspnea.
The PGI-S item asks the patient to choose one response that best describes how his/her
dyspnea is now on a 5-point scale:

Not at all (1)

Mild (2)

Moderate (3)

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
Severe (4) 

Very severe (5)
Please refer to section 6.2.2 for order of completion of patient reported outcome
measures and Appendix 10.3.6.
5.1.11
Clinician Global Impression of Change in CHF Severity 
Clinician Global Impression of Change in CHF Severity is a 1-item questionnaire 
designed to assess Investigator's (physician’s) overall impression of change in the 
patient’s chronic heart failure (CHF) severity related to his/her participation in the study; 
specifically signs and symptoms associated with chronic heart failure on a 7-point scale.
This questionnaire is assessing change from baseline.  For consistency, the same 
Investigator should assess the patient at each visit.  If this is not possible, then the 
response ‘N/A = cannot be assessed’ should be selected.
N/A = Cannot be assessed
1 =  Very much improved
2 =  Much improved
3 =  Minimally improved
4 =  No change
5 =  Minimally worse
6 =  Much worse
7 =  Very much worse
Please refer to section 6.2.2 for preferred order of completion of assessments and 
Appendix 10.4.1.
5.1.12
Clinician Global Impression of Severity of CHF
Clinician Global Impression of Severity of CHF is a 1-item questionnaire designed to 
assess Investigator's overall impression of severity of chronic heart failure, specifically 
signs and symptoms associated with chronic heart failure now (at the time-point of 
assessment) on the 5-point scale:
Normal, not at all ill (1)
Mildly ill (2)
Moderately ill (3)
Severely ill (4) 
Very severely ill (5)
Please refer to section 6.2.2 for preferred order of completion of assessments and 
Appendix 10.4.2.

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5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
A complete physical examination will be performed at the time points specified in the 
flowchart. 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 flowchart. 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. 
All recordings should be made using a similar type of and validated certified blood
pressure recording instrument on the same arm. Further details on blood pressure
measurement procedure are provided Appendix 10.6.
5.2.3
Body weight and height
Measurements of body weight and height will be performed at the time points specified in 
the flowchart.
BMI (kg/m2) will be calculated for determination of eligibility at Visit 1.
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 to be assessed are listed in Table 5.2.4:1. For the sampling 
time points please see the flowchart.
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. 

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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 
5.2.7.1).
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
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
-
Reticulocyte Count (reflex test if Hb outside normal range)

Red Blood Cells (RBC) / Erythrocytes

WBC / Leukocytes

Platelet Count / Thrombocytes

Differential Automatic (relative and absolute count): Neutrophils, Eosinophils, Basophils,
Monocytes, Lymphocytes
Clinical chemistry

Albumin

Alkaline phosphatase
-
-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)

Hs Troponin I (reflex tests if CK is elevated)

Glucose

Potassium

Protein total

Sodium

Urea (BUN)

Uric acid
Urine

Urinalysis: standard dipstick test including ketones semi-quantitative measurement
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 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 the screening and EOT Visits as indicated in the Flow
Chart. The investigator or a designee will evaluate whether the ECG is normal or
abnormal and whether it is clinically relevant, if abnormal. ECGs may be repeated for 
quality reasons and the repeated recording used for analysis. 
In case of any cardiac symptom (indicating rhythm disorders or cardiac ischaemia), or for 
safety reasons additional 12-lead ECG(s) should be done and any abnormal findings will 
be reported as AEs. 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 adverse events 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 
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or 
clinical investigation subject administered a medicinal product and which does not 
necessarily have 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.
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 
-
requires prolongation of existing hospitalisation,
-
results in persistent or significant disability or incapacity, or
-
is a congenital anomaly / birth defect,
or
-
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. 
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical 
Events, Boehringer Ingelheim has set up a list of further 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.
The latest list of “Always Serious AEs” can be found in the eDC system. These events 
should always be reported as SAEs as described above.
Note: Cancers of new histology and exacerbations of existing cancer must be classified as 
a serious event regardless of the duration between 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”

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Adverse events of special interest (AESIs)
The term 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 below.
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 and/or ALT >3 fold ULN combined with an elevation of total 
bilirubin >2 fold ULN measured in the same blood draw sample, and/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 “DILI checklist” provided in the 
ISF.
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.
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
<15mmol/L and measurement of serum beta-hydroxybutrate levels. Other diagnostic 
criteria which can support the diagnosis of ketoacidosis are urine ketones and anion gap
>10mmol/L.

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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.
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
Causal relationship of AEs
Medical judgement should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 
Arguments that may suggest 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 diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is 
evident (e.g. pre-treatment cases, diagnosis of cancer or chronic disease within
days / weeks of drug administration; an allergic reaction weeks after 
discontinuation of the drug concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).

Of note, this criterion may not be applicable to events whose time course is 
prolonged despite removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation 
(e.g. situations where other drugs or underlying diseases appear to provide a more 
likely explanation for the observed event than the drug concerned).

Disappearance of the event even though the trial drug treatment continues or 
remains unchanged.

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5.2.7.2
Adverse event collection and reporting
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: 
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 AEs but should only 
report related SAEs and related AESIs of which the investigator may become aware 
of by any means of communication, e.g. phone call. Those AEs should however, not 
be reported in the CRF.
Figure 5.2.7.2:1
Adverse Event Collection Periods
AE reporting to 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 via fax immediately (within 24 hours ) to 
the sponsor’s 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 fax 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.

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Information required
For each AE, the investigator should provide the information requested on the appropriate 
eCRF pages and the BI SAE form, if applicable. The investigator should determine the 
causal relationship to the trial medication.
The following should also be recorded as an (S)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 pre-exist prior to trial inclusion they will be considered as 
baseline conditions and should be collected in the eCRF only. 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.
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
•
Genital infection
•
Acute pyelonephritis
•
Sepsis
•
Urinary tract infection
•
Bone fracture
•
Hypotension
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 Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (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 Trials 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.

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5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
This study will not analyse pharmacokinetic or pharmacodynamics parameters.
5.4
ASSESSMENT OF BIOMARKER(S)
This study will not analyse exploratory biomarkers.  Please refer to section 5.1.4 for 
details on NT-proBNP.
5.5
OTHER ASSESSMENTS
5.5.1
Echocardiogram
An echocardiogram will be performed on all patients as part of the screening procedures.  
The standard methodology of the institution will be used and the following clinical 
information will be recorded:
•
Left Ventricular Ejection Fraction (LVEF)
•
Left ventricular end-diastolic and end-systolic diameters
•
Left ventricular end-diastolic and end-systolic volumes
•
Wall motion abnormalities (if any)
•
Septal and posterior wall thickness
•
LA diameter
•
Heart valve status
•
Any other abnormal findings (according to investigator judgement)
Optional measurements:
•
LV mass index (LVMI)
•
E/e′
•
LA volume
•
LA area
5.5.2
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 chronic heart failure (first and recurrent)

All-cause emergency room visits (first and recurrent)

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
Emergency room visits due to worsening of chronic 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)
5.6
APPROPRIATENESS OF MEASUREMENTS
The primary endpoint measurement will be consistent with the recognized standard for 
conducting the 6 MWT to assess treatment changes in heart failure patients (R03-0725).
All secondary and further endpoint measurements performed during this trial are standard
measurements and will be performed in order to determine empagliflozin efficacy in an
appropriate way. The scheduled measurements are appropriate to see drug induced changes in
vital signs, standard laboratory values and biomarkers specific to efficacy of treatment of HF.
The endpoints are widely used and accepted for evaluation of efficacy on an oral HF drug.
Patient Reported Outcome measures are an essential part for this phase III trial.
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 these time windows.
All trial visits should take place at approximately the same time of day and preferably before
noon.
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)
Screening Period
Following informed consent, the patient will undergo visit 1/screening assessments as
indicated in the Flowchart. 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.
For patients with no BNP or NT-proBNP measurement available from clinical routine in the 
past 6 months indicative of the likelihood of eligibility for this study, it is recommended to 
split the screening visit into two steps and start with the measurement of NT-proBNP and 
safety lab measures (via central laboratory), wait for the results, and do the remaining 
screening assessments on a separate day (within the allowed visit window). The baseline 
rhythm (e.g. sinus rhythm, AF) of the patient must be clarified (i.e. ECG) and documented at 
the time the screening NT-proBNP sample is collected.
One 6MWT will be performed at the screening visit (visit 1) to assess patient eligibility and if 
the distance walked during the 6MWT is > 350m, the patient will be considered a screen 
failure. If the distance walked during the 6MWT is < 100m at screening, the patient is 
allowed to return to the baseline assessment to account for a learning effect that may result in 
some improvement of the walking distance.
If the patient meets the entry criteria, Visit 2 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.
Re-testing for certain eligibility criteria can be performed once for abnormal laboratory, 
blood pressure and / or ECG results as outlined in section 3.3.  Rescreening will be 
considered on a case-by-case basis as described in section 3.3.

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6.2.2
Treatment period(s)
Randomisation will occur at Visit 2 using IRT. The patients will return to the clinic for
regularly scheduled visits 6 and 12 weeks after randomisation as specified in the Flow Chart.
These on-site visits will assess the occurrence of safety and efficacy endpoints, trial 
medication compliance, concomitant therapy or intervention.
All visit 2 assessments must be performed before the first dose is taken in the site. The 
assessments at visits 3 and 4 must be performed post-dose. Patients should be instructed to
take their medication on the morning of trial visits 3 and 4. Visits should be routinely
scheduled at approximately the same time of day for each visit. 
At all treatment visits (visits 2, 3 and 4/EOT) and the early discontinuation visit, patient 
reported outcome measures should be completed first. 
Patient reported outcome measures should be completed in the following order:

KCCQ 

PGI – Severity – Heart Failure Symptoms

PGI – Change –  Heart Failure Symptoms

PGI - Severity - Dyspnea

PGI - Change – Dyspnea

CHQ-SAS
The order of the remaining assessments should be preferably completed as follows and 
according to the visits specified in the Flowchart:

Physical examination, body weight, height and vital signs

Completion of clinician impression scales and clinical congestion score by 
Investigator

ECG 

6MWT conducted in duplicate (at visits 2 and 4 only) at least 1 hour apart. At visits 1, 
3 and the early discontinuation visit, only one 6MWT will be conducted.

Laboratory sample, urine pregnancy
Testing of the 6MWT at each clinic visit should be performed about the same time of day to 
minimize intraday variability. Prior to performing the 6MWT the relative contraindications to 
exercise should be assessed as per appendix 10.1.3.
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.

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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. 
Patients will be dispensed medication at visits 2 and 3 and allocation of new kit number(s)
will be managed through the IRT. Visit 4 is the last day of treatment and the patient should 
return all remaining medication during this visit.
Permanent trial medication discontinuation is only justified when clear persistent
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.
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 
Flowchart. The follow-up visit marks the completion of the study for the individual patient.
See Section 3.3.4.1 for procedures to be followed in case a patient prematurely discontinues 
trial treatment.

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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
The eligible patients for this trial will be randomised to empagliflozin 10 mg and placebo in 
1:1 ratio.
The primary endpoint is the change from baseline to week 12 in exercise capacity as 
measured by the distance walked in 6 minutes. The statistical model will be a Wilcoxon rank 
test on change from baseline to week 12 in distance walked in the 6MWT. 
The primary model will be conducted on all randomized patients. Where more than one
measurement is available on the same day (duplicate measurements), the highest distance 
walked will be used for analysis. 
The two key secondary endpoints ‘Change from baseline to week 12 in KCCQ-TSS’ and 
‘Change from baseline to week 12 in CHQ-SAS dyspnea score’ are part of the testing 
strategy. 
Both key secondary endpoints will be tested using a Wilcoxon rank test, and both will be 
tested if the primary endpoint revealed a significant result in favour of empagliflozin. For 
adjustment of multiplicity of the two key secondary endpoints a Hochberg procedure will be 
followed. 
The other secondary endpoints will not be part of the testing hierarchy.
7.2
NULL AND ALTERNATIVE HYPOTHESES
Both key secondary endpoints will be tested if the primary endpoint revealed a significant 
result in favour of empagliflozin. For adjustment of multiplicity of the tests of the two key 
secondary endpoints a Hochberg procedure will be followed. The trial is designed to achieve 
a power of 90% for the primary endpoint at level α = 0.05 to detect a difference between 
empagliflozin and placebo.
For all endpoints, superiority of empagliflozin vs. placebo will be evaluated with a two-sided 
test in the following structure:
Null hypothesis: There is no difference between the effect of placebo and the effect of 
empagliflozin in terms of the endpoint in question. 
Alternative hypothesis: There is a difference between the effect of placebo and the effect of 
empagliflozin in terms of the endpoint in question. The tests will be performed in the 
following hierarchical order:

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1. Change from baseline to week 12 in exercise capacity as measured by the distance 
walked in 6 minutes
2.
Hochberg procedure of :
o
Change from baseline to week 12 in KCCQ TSS
o
Change from baseline to week 12 in CHQ-SAS dyspnea score
If the null hypothesis for the primary analysis is rejected, and the result is more
favourable for empagliflozin, superiority is concluded in the primary endpoint, and the 
overall type I error is preserved for the test in the next step. 
In the next step a Hochberg procedure will be applied to account for multiplicity of 
testing of the key secondary endpoints. 
If the primary hypothesis is not rejected, the tests of the key secondary endpoints are
conducted in an exploratory fashion.
The other secondary endpoints will be evaluated in an exploratory manner.
7.3
PLANNED ANALYSES
The efficacy analysis will be based on the randomised set (RS), including all randomised 
patients.
The safety analysis will be based on the treated set (TS), which consists of all patients treated 
with at least one dose of the trial medication. 
For both efficacy and safety analyses, treatment will be evaluated as randomised.
For serum creatinine and values based on upon this measurement such as eGFR, baseline will 
be defined as the mean of all available measurements from the screening visit until start of 
randomised trial medication.
For all other endpoints, baseline will be defined as the last available measurement before start 
of randomised trial medication.
Note that for the primary endpoint the higher measurement for each day is selected as the test 
result for that day. Therefore the last available measurement before start of trial medication 
will refer to the higher value on the day of the last measurement before treatment intake. 
7.3.1
Primary endpoint analyses
The primary endpoint ‘change from baseline to week 12 in exercise capacity’ will be 
evaluated using a normal approximation of the Wilcoxon rank test using the randomized set. 
For estimation of effect the non-parametric Hodges-Lehmann estimate for the median 
difference will be calculated. Any confirmatory conclusion such as for hierarchical testing 

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will be based on the result of the Wilcoxon rank test and will not consider the Hodges-
Lehmann estimate or the corresponding confidence interval, which are given to support 
interpretation. 
If repeated distance walked in 6 minutes (6MWTD) measurements on the same day are 
available the longest distance will be used for this day.
Change from baseline will be defined as distance walked in 6 minutes (6MWTD) at week 12 
assessment minus the distance walked at baseline.
If no value for the 6MWTD is available at week 12, an imputed value as defined in table 7.5: 
1 will be used. 
Sensitivity analysis for the primary endpoint will include using a mixed model repeated 
measure analysis (MMRM) with baseline 6MWT as a covariate without imputation of 
missing values.
7.3.2
Secondary endpoint analyses
Key secondary endpoints
Both key secondary endpoints ‘Change from baseline to week 12 in heart failure symptoms
as measured by the KCCQ TSS’ and ‘Change from baseline to week 12 in CHQ-SAS dyspnea 
score’ will be evaluated using a normal approximation of the Wilcoxon rank test using the 
randomized set. For estimation of effect the non-parametric Hodges-Lehmann estimate for 
the median difference will be calculated.
Change from baseline in both scores will be defined as the endpoint value at week 12 minus 
the last available endpoint value before start of randomised trial medication.
If no questionnaire is available at week 12, an imputed value as defined similar to the 
imputation for the primary endpoint will be used. 
Sensitivity analysis for the key secondary endpoint will include using a mixed model 
repeated measure analysis with baseline of the key secondary endpoint as a covariate without 
imputation of missing values.
Other secondary endpoints
Change from baseline to week 6 in exercise capacity as measured by the distance walked in 6 
minutes will be evaluated using the same model as for the primary endpoint.
Change from baseline of Clinical Congestion Score at week 12 will be evaluated using an 
mixed model repeated measure analysis (MMRM) analysis over time. The model will include 
the factor treatment and the linear covariate of baseline Clinical Congestion Score.

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Proportion of patients in every category of global impression of change at week 12 will be 
evaluated using Cochran-Mantel-Haenszel test. Details on combining categories if the 
proportion of patients in one of the categories is small will be given in the TSAP.
Proportions of patients categorized by the shift in scores between baseline and week 12 in 
patient global impression of severity score will be evaluated using Cochran-Mantel-Haenszel 
test. Details on combining categories if the proportion of patients in one of the categories is 
small will be given in the TSAP.
The endpoint “Change from baseline in NT-proBNP at week 12” (after log-transformation) 
will be evaluated using a MMRM analysis over time with baseline log-transformed NT-
proBNP as a covariate without imputation of missing values.
7.3.3
Further endpoint analyses
Endpoints describing responders such as increase in 6MWT ≥ 30 m or response in KCCQ or 
CHQ domains will be evaluated using a Chi-Square test.
Proportions of patients categorized by the shift in scores between baseline and week 6 in 
patient global impression of severity score will be evaluated using Cochran-Mantel-Haenszel 
test. Details on combining categories if the proportion of patients in one of the categories is 
small will be given in the TSAP.
Proportion of patients in every category of patient global impression of change at week 6 will 
be evaluated using Cochran-Mantel-Haenszel test. Details on combining categories if the 
proportion of patients in one of the categories is small will be given in the TSAP.
Proportion of patients in every category in clinician global impression of change at week 6 
and week 12 will be evaluated using Cochran-Mantel-Haenszel test. Details on combining 
categories if the proportion of patients in one of the categories is small will be given in the 
TSAP.
Proportions of patients categorized by the shift in scores between baseline and week 6 (week 
12) in clinician global impression of severity score will be evaluated using Cochran-Mantel-
Haenszel test. Details on combining categories if the proportion of patients in one of the 
categories is small will be given in the TSAP.
Change from baseline continuous endpoints such as KCCQ domains or CHQ domains at week 
6 and Week 12 will be evaluated using a MMRM analysis over time. The model will include 
treatment as fixed categorical effect and baseline of the respective endpoint as fixed 
continuous effect.
Change from baseline in Clinical Congestion Score at week 6 will be evaluated by the same 
MMRM used to evaluate Clinical Congestion Score at week 12 described for the secondary 
endpoint. 

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Change from baseline in NT-proBNP at week 6 will be evaluated by the same MMRM used 
to evaluate NT-proBNP at week 12 described for the secondary endpoint. 
Proportions of patients categorized by the shift in scores between baseline and week 12 in 
NYHA class will be evaluated using Cochran-Mantel-Haenszel test. Details on combining 
categories if the proportion of patients in one of the categories is small will be given in the
TSAP.
Change from baseline to week 12 in patient-rated assessment of dyspnea and fatigue by the 
Borg scale as part of the 6MWT will be presented descriptively.
Other further endpoints will be analysed descriptively.
7.3.4
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.
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.

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The details of the analysis will be specified in the TSAP.
7.3.5
Pharmacokinetic and pharmacodynamic analyses
Not applicable.
7.4
INTERIM ANALYSES
No interim analysis is planned but a DMC will be in place with tasks as described in Section 
8.7.
7.5
HANDLING OF MISSING DATA
Patients with an available week 12 measurement of the 6MWT, regardless of whether on or 
off-treatment, will be ranked based on change from baseline in 6MWT distance at week 12. 
If a patient performs the visit at week 12 but is unable to walk or unable to perform the 
6MWT due to safety concerns, then this will be noted accordingly in the case report form and 
will not be regarded as missing data. This case will be evaluated as a measured distance of 
0m. 
Missing data will be imputed according to the rules outlined in table 7.5: 1, and ranks will be 
assigned based on the imputed data. Imputed data will also be used to calculate the Hodge 
Lehmann estimates for the median difference. Note that no imputation will be used in the 
MMRM analysis that serves as sensitivity analysis in this trial.
All imputed data due to missing data will be lower than measured values. The lowest 
measurable value of the primary endpoint of change from baseline in 6MWT distance is a 
reduction by 350m, i.e. the highest possible baseline value (350 m), and at week 12 the 
lowest possible value of 0m. Therefore, all imputed values for change from baseline for 
patients with missing walking distance at week 12 are below -350 m. 

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Table 7.5: 1 Imputation rules for missing primary endpoint
Category
Ranking
Case description
Imputed change 
from baseline 
in 6MWTD for 
described case
(in m)*
1
Missing data on 6MWT 
at week 12 and no 
clinical event:
Patients with missing 
6MWT at week 12 and 
no event as in category 
2 or 3
If post-baseline
value is available, 
rank by last 
available value. 
Rank below if no 
post-baseline
value is available
Patient has a 
change from 
baseline to last 
available value
of x m, no 
clinical event
-352 +x/1000
No information 
of post-baseline 
6MWT distance 
and no clinical 
event 
-354
2
Missing data and 
clinical event (except 
death).
A clinical event is 
defined as ongoing 
SAE or AE leading to 
treatment 
discontinuation and 
patient is alive at week 
12
Ranked above 
patients who died, 
but below 
patients with 
missing data and 
no clinical event.
Patient has 
ongoing SAE or 
AE leading to 
treatment 
discontinuation, 
no information 
of week 12 
6MWT distance 
and patient alive 
at week 12.
-356
3
Patient died before the 
measurement of 6MWT 
at week 12 was 
conducted.
Ranked by time 
to death from 
randomization
Patient died y
days after 
randomization
-358+y/1000
Similar rules following the same strategy will be defined in the TSAP to impute missing 
values for the key secondary endpoints.

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7.6
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.
No stratification will be performed in this trial.
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.
7.7
DETERMINATION OF SAMPLE SIZE
In clinical studies, 30-50 meters have been variably reported as a meaningful distance 
achieved as a result of therapy [R17-1227].
The SD of 72 m is assumed for sample size considerations of this trial [R17-1225]. The risk 
of observing a higher SD in this trial will be mitigated by using duplicate measurements of 
6MWT at baseline, Week 6 and Week 12 [R17-2791]. For none-missing values a normal
distribution for change from baseline in distance walked in 6 minutes is assumed in all below 
sample size estimations.
The trial is designed to achieve a power of 90% for a two sided test at level α = 0.05 to detect 
a difference between empagliflozin and placebo.
Using a normal distribution to calculate the probability that an observation X in 
Empagliflozin group will be less than an observation Y in the control group under the 
alternative, the following table presents the number of required evaluable patients for 
different assumed means of absolute difference in distance walked within 6 minutes as 
obtained by using the Wilcoxon sample size estimation procedure from commercial software 
nQuery Advisor® 7.0 statistical package by Statistical Solutions Ltd.
Table 7.7: 1
Sample size calculation
True treatment 
difference in 
distance walked in 
6 minutes
SD
P(X<Y)
Required number 
of patients per 
group
30 m
72 m
0.384
131
40 m
72 m
0.347
76
50 m
72 m
0.312
50

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A true treatment difference of 30 m is used as a conservative measure for sample size 
calculation to ensure that the study could detect the lowest effect size reported to be 
meaningful.
Therefore, a total of 131 evaluable patients per group are needed in order show a significant 
result for a two-sided test at level α = 0.05 with a power of 90% not considering missing data. 
To assess the impact of missing data a simulation with 100000 iterations was performed. A
normal distribution for 6MWT distance was assumed and a total of 5%, 8% and 10% patients
imputed to worst case as outlined in section 7.5 in each treatment group were investigated. 
The results are summarized in Table 7.7: 2.
Table 7.7: 2
Simulation of imputation rules
N per 
group
Simulated true 
treatment 
difference for 
non-missing 
data
[mean SD]
Percentage of 
missing data
imputed to 
worst case
Power
150
30 72
5%
90%
150
30 72
8%
87%
150
30 72
10%
85%
Therefore, a total of 150 patients per treatment group will allow for a drop-out and imputation
of about 5% of the patients in order to show a significant result for a two-sided test at level α 
= 0.05 with a power of 90%. With a drop-out rate of 10%, a total of 150 patients per 
treatment group would still yield a power of 85%.
7.7.1
Power estimation for key secondary endpoints
KCCQ
For power estimation of the KCCQ-TSS a treatment difference of 5 points is assumed. In 
patients with heart failure previous studies have reported a standard deviation of the KCCQ 
TSS between 13 in the CONFIRM-HF trial and 19-21in the FAIR-HF trial [R17-1226, R17-
3097].
Using a normal distribution to calculate the probability that an observation X in 
Empagliflozin group will be less than an observation Y in the control group under the 
alternative, a sample size of 150 per treatment group will result in approximately 55% to 90% 
power to detect a 5 point difference between treatment groups at an alpha-level of 5% using a 
Wilcoxon test, if all questionnaires are available at the end of the trial (see Table 7.7.1: 1).
Due to the Hochberg procedure, if CHQ dyspnea is not significant, an alpha-level of 2.5% 
will become applicable. Table 7.7.1:1 therefore additionally shows an alpha-level of 2.5 %.

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Table 7.7.1: 1 – Power Estimation for KCCQ-TSS
SD
P(X<Y)
Power for α = 5%
Power for α = 
2.5%
13
0.393
89%
83%
15
0.407
79%
71%
17
0.418
69%
59%
20
0.430
55%
44%
While every effort will be made to collect the questionnaire for randomized patients 
regardless of being on or off treatment, about 5% missing questionnaires may be assumed 
and are considered for power evaluation in analogy with the primary endpoint. 
Results of a simulation of the power with 100000 iterations to detect a 5 point difference 
between treatment groups in a Wilcoxon test with imputation rules analogously to the 
primary endpoint, assuming 5% missing questionnaires at week 12 in each treatment arm, a 
normal distribution for non-missing scores, and alpha of 5% is summarized in the Table 
7.7.1: 2 below.
Table 7.7.1: 2 – Simulation of Imputation Rules for KCCQ-TSS
SD
Power for α = 5%
Power for α = 2.5%
13
85%
76%
15
73%
61%
17
61%
49%
20
47%
35%
Overall power is reasonable to evaluate superiority of empagliflozin versus placebo assuming 
a treatment effect of 5 points and a standard deviation that does not exceed 15 points.
CHQ
For power estimation of the CHQ dyspnea a treatment difference of 0.5 points is assumed
[R99-1220].  CHQ and CRQ (an instrument almost identical to CHQ used in respiratory 
disease) are reported as performing similarly [R99-1220]. A standard deviation of the change 

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from baseline of the standardized CRQ dyspnea score of 1.15 has been reported [R05-1404]. 
Similar data were also reported for CHQ [R17-2917]. Therefore, for power estimation, a 
standard deviation of 1 to 1.4 is assumed.
Using a normal distribution to calculate the probability that an observation X in 
Empagliflozin group will be less than an observation Y in the control group under the 
alternative, a sample size of 150 per treatment group will result in approximately 84% to 98% 
power per score to detect a 0.5 point difference between treatment groups at an alpha-level of 
5% using a Wilcoxon test, if all questionnaires are available at the end of the trial (see Table 
7.7.1:3). 
Due to the Hochberg procedure, if KCCQ-TSS is not significant, an alpha-level of 2.5% will 
become applicable. Table 7.7.1: 3 therefore additionally shows an alpha-level of 2.5 %. 
Table 7.7.1: 3 – Power Estimation for CHQ-SAS
SD
P(X<Y)
Power for α = 5%
Power for α = 2.5%
1
0.362
98%
97%
1.2
0.384
93%
89%
1.4
0.400
84%
77%
While every effort will be made to collect the questionnaire for randomized patients 
regardless of being on or off treatment, about 5% missing questionnaires may be assumed 
and are considered for power evaluation in analogy with the primary endpoint. 
Results of a simulation of the power with 100000 iterations  to detect a 0.5 point difference 
between treatment groups in a Wilcoxon test with above imputation rules, assuming 5% 
missing questionnaires at week 12 in each treatment arm, a normal distribution for non-
missing scores, alpha of 5%  is summarized in the Table 7.7.1:4 below.
Table 7.7.1: 4 – Simulation of Imputation Rules for CHQ-SAS
SD
Power for α = 5%
Power for α = 2.5%
1
98%
95%
1.2
90%
83%
1.4
79%
69%

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Overall a power of approximately 70% or higher is expected to detect a difference of 0.5 for 
each score given the planned sample size of 150 patients per treatment group.
Calculations were performed using nQuery Advisor® 7.0 statistical package by Statistical 
Solutions Ltd and simulation was performed using R version 3.3.2 by The R Foundation for 
Statistical Computing.

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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE
The trial will be carried out in accordance with the Medical Devices Directive 
(93/42/EEC) and the harmonised standards for Medical Devices (ISO 14155, current 
version).
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 Tripartite Guideline 
for Good Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU 
regulation 536/2014 and other relevant regulations.
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 finalization 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 obtains written consent of the patient’s own free will with the informed consent 

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form after confirming that the patient understands the contents. The investigator (or 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.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
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 good documentation practices 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 three documented attempts to retrieve 
previous medical records. If this fails a verbal history from the patient, documented in their 
medical records, would be acceptable.
During the site visit the sponsor’s CRA or auditor must be granted access to the original 
patient file (please see section 8.3.2). The investigator must ensure that all patient identifiers
(e.g. patient’s name, initials, address, phone number, social security number) have properly 
been removed or redacted from any copy of the patients’ source documents before sending 
them to the sponsor.

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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 which must be stored 
appropriately, 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 (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, images and report of echocardiogram (from Visit 
1) for the assessment of LVEF, ECG tracings and other imaging or testing results, with 
proper documented medical evaluation (in validated electronic format, if available)

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 sponsor will monitor the conduct of the trial by regular on-site monitoring visits and in-
house data quality review. The frequency of site monitoring will be determined by assessing 
all characteristics of the trial, including its nature, objective, methodology and the degree of 
any deviations of the intervention from normal clinical practice.
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):

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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.
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
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted below. Patient privacy will 
be ensured by using patient identification code numbers.
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the 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 insent.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial
(“Last Patient Out”).
The “Last Patient Drug Discontinuation” (LPDD) date is defined as the date on which the 
last patient at an individual trial site ends trial medication (as scheduled per protocol or 
prematurely). Individual investigators will be notified of SUSARs occurring with the trial
medication until 30 days after LPDD 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.

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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).
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 (ExC) consisting of independent experts (the Coordinating 
Investigators of this trial and of the 1245-0167 trial) and sponsor representatives will be 
established to support the Sponsor in designing the trials and successful execution.  The 
composition of the ExC will be documented in the Trial Master File (TMF). The tasks and 
responsibilities will be agreed in contracts between the ExC members and the sponsor.
A Steering Committee (SC) consisting of independent experts and sponsor representatives
will be established to support the Coordinating Investigators who will be the chairs of the SC. 
The composition of the SC will be documented in the Trial Master File (TMF). The tasks and 
responsibilities will be agreed in contracts between the SC members 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 RAs/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 hepatic charter.

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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, CT, MRI, 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.
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the (Investigator Site File) ISF. The investigators will have access to the 
BI clinical trial portal (Clinergize) to facilitate document exchange and maintain electronic 
ISF. 
BI has appointed a Trial Clinical Monitor, 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 Local Clinical Monitors (CML), 
Clinical Research Associates (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
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M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE, EMPA-REG 
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Fitchett D, Zinman B, Wanner C, Lachin JM, Hantel S, Salsali A, Johansen 
OE, Woerle HJ, Broedl UC, Inzucchi SE, EMPA-REG OUTCOME Trial 
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Heart J 37 (19), 1526 – 1534 (2016)
P16-01830
Ferrannini E, Baldi S, Frascerra S, Astiarraga B, Heise T, Bizzotto R, Mari A, 
Pieber TR, Muscelli E. 
Shift to fatty substrate utilization in response to sodium.glucose cotransporter 2 
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Diabetes 65 (5), 1190 - 1195 (2016)
P16-03760
Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Drazner MH, Fonarow 
GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, 
Masoudi FA, McBride PE, McMurray JJV, Mitchell JE, Peterson PN, Riegel 
B, Sam F, Stevenson LW, Tang WHW, Tsai EJ, Wilkoff BL.
2013 ACCF/AHA guideline for the management of heart failure: a report of 
the American College of Cardiology Foundation/ American Heart Association 
Task Force on Practice Guidelines. J Am Coll Cardiol 62 (16), e147 - e239 
(2013)
P16-03952
Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das 
SR, de Ferranti S, DesprésJ-P, Fullerton HJ, Howard VJ, Huffman MD, Isasi 
CR, Jiménez MC, Judd SE, Kissela BM, LichtmanJH, LisabethLD, Liu S, 
Mackey RH, Magid DJ, McGuire DK, Mohler ER III, Moy CS, Muntner P, 
Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, 
Reeves MJ, Rodriguez CJ, Rosamond W, Sorlie PD, Stein J, TowfighiA, Turan 
TN, Virani SS, Woo D, Yeh RW, Turner MB; on behalf of the American Heart 
Association Statistics Committee and Stroke Statistics Subcommittee. Heart 
disease and stroke statistics - 2016 update: a report from the American Heart 
Association.
Circulation 133 (4), e38 – e360 (2016)
P16-05920
Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, Falk 
V, Gonza´lez-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, 
Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GMC, Ruilope 
LM, Ruschitzka F, Rutten FH, van der Meer P. 
2016 ESC Guidelines for the diagnosis and treatment of acute and chronic 
heart failure: the Task Force for the Diagnosis and Treatment of Acute and 
Chronic Heart Failure of the European Society of Cardiology (ESC), 
developed with the special contribution of the Heart Failure Association (HFA) 
of the ESC.
Eur Heart J 18 (8), 891 - 975 (2016) 
P17-04479
Al-Jobori H, Daniele G, Cersosimo E, Triplitt C, Mehta R, Norton L, et al. 
Empagliflozin and kinetics of renal glucose transport in healthy individuals and 
individuals with type 2 diabetes. 
Diabetes 66 (7), 1999 - 2006 (2017)
P17-05077
Olsson LG, Swedberg K, Clark AL, Witte KK, Cleland JGF
Six minute corridor walk test as an outcome measure for the assessment of 
treatment in randomized, blinded intervention trials of chronic heart failure: a 
systematic review.
Eur Heart J 26, 778 - 793 (2005)
P17-10453
Wanner C, Lachin JM, Inzucchi SE, Fitchett D, Mattheus M, George J, et al, 
EMPA-REG OUTCOME Investigators

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Empagliflozin and clinical outcomes in patients with type 2 diabetes, 
established cardiovascular disease and chronic kidney disease.
Circulation, (2017)
R05-1404
Schunemann HJ, Griffith L, Jaeschke R, Goldstein R, Stubbing D, Austin P, 
Guyatt GH
A comparison of the original chronic respiratory questionnaire with a 
standardized version.
Chest 124 (4), 1421 - 1429 (2003)
R99-1220
Jaeschke R, Singer J, Guyatt GH
Measurement of health status: ascertaining the minimal clinically important 
difference.
Controlled Clin Trials 10, 407 - 415 (1989)
R03-0725
Crapo RO, Enright PL, Zeballos RJ
ATS statement: guidelines for the six-minute walk test. This official statement 
of the American Thoracic Society was approved by the ATS Board of 
Directors March 2002.
Am J Respir Crit Care Med 166, 111 - 117 (2002)
R12-1392
Levey AS, Stevens LA, Schmid CH, Zhang Y, Castro AF, Feldman HI, Kusek 
JW, Eggers P, Lente F van, Greene T, Coresh J, Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI)cr
A new equation to estimate glomerular filtration rate.
Ann Intern Med 150 (9), 604 - 612 (2009)
R12-5607
Guidance for industry: patient-reported outcome measures: use in medical 
product development to support labeling claims (December 2009, 
clinical/medical).
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tion/Guida nces/UCM193282.pdf (access date: 14 December 2012) ; U.S. 
Department of Health and Human Services, Food and Drug Administration, 
Center for Drug Evaluation and Research (CDER), Center for Biologics 
Evaluation and Research (CBER), Center for Devices and Radiological Health 
(CDRH) (2009)
R16-1527
Ambrosy AP, Fonarow GC, Butler J, Chioncel O, Greene SJ, Vaduganathan 
M, Nodari S, Lam CSP, Sato N, Shah AN, Gheorghiade M. 
The global health and economic burden of hospitalizations for heart failure: 
lessons learned from hospitalized heart failure registries. J Am Coll Cardiol 63 
(12), 1123 - 1133 (2014)
R16-1528
Owan TE, Redfield MM. 
Epidemiology of diastolic heart failure. Prog Cardiovasc Dis 47 (5), 320 - 332 
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Steinberg BA, Zhao X, Heidenreich PA, Peterson ED, Bhatt DL, Cannon CP, 
Hernandez AF, Fonarow GC, Get With the Guidelines Scientific Advisory 
Committee and Investigators. 
Trends in patients hospitalized with heart failure and preserved left ventricular 
ejection fraction: prevalence, therapies, and outcomes. Circulation 126 (1), 65 -
75 (2012)
R16-2217
Cheng RK, Cox M, Neely ML, Heidenreich PA, Bhatt DL, Eapen ZJ,
Hernandez AF, Butler J, Yancy CW, Fonarow GC
Outcomes in patients with heart failure with preserved, borderline, and
reduced ejection fraction in the Medicare population.
Am Heart J 168 (5), 721 – 730.e3 (2014)
R16-2382
Goode KM, John J, Rigby AS, Kilpatrick ES, Atkin SL, Bragadeesh T, Clark 
AL, Cleland JG.
Elevated glycated haemoglobin is a strong predictor of mortality in patients 
with left ventricular systolic dysfunction who are not receiving treatment for 
diabetes mellitus. Heart (Lond) 95, 917 - 923 (2009)
R16-2384
Suskin N, McKelvie RS, Burns RJ, Latini R, Pericak D, Probstfield J, Rouleau 
JL, Sigouin C, Solymoss CB, Tsuyuki R, White M, Yusuf S.
Glucose and insulin abnormalities relate to functional capacity in patients with 
congestive heart failure, Eur Heart J, 21 (16), 1368-75 (2000)
R17-0953
Hoekstra T, Jaarsma T, Veldhuisen DJ van, Hillege HL, Sanderman R, 
Lesman-Leegte I
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Eur J Heart Fail 15 (1), 94 - 102 (2013)
R17-0954
Anker SD, Colet JC, Filippatos G, Willenheimer R, Dickstein K, Drexler H, et 
al, FAIR-HF Trial Investigators Ferric carboxymaltose in patients with heart 
failure and iron deficiency. 
N Engl J Med 361 (25), 2436 – 2448 (2009)
R17-1225
Ponikowski P, Veldhuisen DJ van, Comin-Colet J, Ertl G, Komajda M, Mareev 
V, et al
Rationale and design of the CONFIRM-HF study: a double-blind, randomized, 
placebo-controlled study to assess the effects of intravenous ferric 
carboxymaltose on functional capacity in patients with chronic heart failure 
and iron deficiency.
ESC Heart Fail 1, 52 - 58 (2014)
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Ponikowski P, Veldhuisen DJ van, Comin-Colet J, Ertl G, Komajda M, Mareev 
V, et al, CONFIRM-HF Investigators
Beneficial effects of long-term intravenous iron therapy with ferric 
carboxymaltose in patients with symptomatic heart failure and iron deficiency.
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Shoemaker MJ, Curtis AB, Vangsnes E, Dickinson MG
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activity in individuals with chronic heart failure.
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R17-1340
Ferreira JP, Duarte K, Graves TL, Zile MR, Abraham WT, Weaver FA, et al
Natriuretic peptides, 6-min walk test, and quality-of-life questionnaires as 
clinically meaningful endpoints in HF trials.
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Rostagno C, Gensini GF
Six minute walk test: a simple and useful test to evaluate functional capacity in 
patients with heart failure.
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Kelkar, John Spertus, Peter Pang, Renee F. Pierson, Robert J. Cody, Ileana L. 
Pina, Adrian Hernandez, Javed Butler JACC: Heart Failure Mar 2016, 4 (3) 
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HP, Pitta F, et al
Reliability, construct validity and determinants of 6-minute walk test 
performance in patients with chronic heart failure.
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R17-1562
Bishu K, Redfield MM
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characteristics and targets for therapy.
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R17-1584
Redfield MM
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Wessler BS, Kramer DG, Kelly JL, Trikalinos TA, Kent DM, Konstam MA, et 
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R17-1592
Cahalin LP, Mathier MA, Semigran MJ, Dec GD, DiSalvo TG
The six-minute walk test predicts peak oxygen uptake and survival in patients 
with advanced heart failure.
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Spertus J, Peterson E, Conard MW, Heidenreich PA, Krumholz HM, Jones P, 
et al
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Guyatt GH, Nogradi S, Halcrow S, Singer J, Sullivan MJJ, Fallen EL 
Development and testing of a new measure of health status for clinical trials in 
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Yusuf S, Tsuyuki R
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Evans RA, Singh SJ, Williams JE, Morgan MDL
The development of a self-reported version of the Chronic Heart 
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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 
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Repir J 44, 1428 – 1446 (2014)

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9.2
UNPUBLISHED REFERENCES
c01678844-09
Empagliflozin Investigator’s Brochure, Current Version
c02695839-01
 
 Clinical Trial Report: Empagliflozin (BI 10773). The EMPA-REG 
OUTCOME® Trial 1245.25. 
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.
U12-2707-01
SCS appendix and integrated summary of safety 08 Feb 2013

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10.
APPENDICES
10.1
SIX MINUTE WALK TEST
10.1.1
General considerations for exercise testing
The methodology of the six minute walk test protocol is based on recommendations outlined 
by the American Thoracic Society (2002) [R03-0725, R17-3628].
10.1.2
Exercise performance variability
A number of physiological and psychological factors are known to affect exercise 
performance.  Lack of attention to controlling these extraneous factors may result in a certain 
degree of variability in exercise performance.  As such, the following pre-defined 
requirements have been put in place to reduce exercise performance variability:
Physiological:
•
The patient’s usual medical regimen should be continued
•
Pre-exercise diet: Subjects are to be encouraged to eat breakfast before coming to the 
clinic.  However, subjects should not eat within 2 hours of exercise tests.
•
Hydration state: Subjects are to be encouraged to maintain an adequate hydration state 
during the morning of the exercise tests.
•
Environmental conditions (temperature, humidity): Temperature and humidity should be 
controlled within the testing environment at comfortable levels. 
Previous exercise:
•
Fatigue: Subjects should be encouraged to stay well-rested and to refrain from any 
strenuous, fatiguing or exhausting activities (e.g., walking up hills, walking up many 
flights of stairs, running, cycling, shovelling snow, strenuous household chores) on the 
morning of exercise tests.
•
Delayed onset muscular soreness (DOMS): Very strenuous, heavy type of activities, 
especially activities to which the subject is unaccustomed, can lead to muscle soreness 
24-48 hours after the activity.  Subjects should be encouraged to refrain from any type of 
heavy lifting, exhaustive digging in the garden etc., for 2-3 days prior to each clinic visit, 
especially if the subject has not performed these activities recently.
Psychological:
•
Verbal encouragement: During exercise testing, the wording and intensity of verbal 
encouragement provided to the subject will be standardized, and will preferably only be 
provided by one member of the trial team.  Appropriate positive words should be used to 
encourage the patient to continue walking.
•
Familiarity with surroundings: Trial staff should allow as much time as necessary for the 
subject to become comfortable with the test environment surroundings.

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•
Distractions: During the exercise tests, access to the testing environment should be 
restricted to trial staff as much as possible.  The noise level in the testing environment 
should be kept to a minimum, except for those sounds specifically related to the conduct 
of the test.  This will ensure that the subject is able to concentrate on the task at hand, and 
will also ensure that the subject is attentive to the verbal encouragement provided by the 
designated member of the trial team.
•
Comfort during test: Subjects should be appropriately dressed for exercise (e.g., shorts or 
track pants, gym shoes, T-shirt or sweat shirt), and should use their usual walking aids 
during the test (cane, walker, etc.).  Trial staff should ensure that the subject is 
comfortable with the environment prior to starting the exercise.
•
Familiarity with test: Before starting exercise, a member of the trial team should make 
sure that the subject is completely familiar with the type of exercise that is to be 
performed.
•
Performance incentives: No external incentives for performance (i.e., rewards for 
performance) should be given to the subject, especially as the subject nears the point of 
limitation, but also prior to or at any time during the exercise.
Heart rate and safety monitoring:
•
Heart rate and blood pressure will be measured before exercise, at end-exercise, five 
minutes after termination of exercise and when, for clinical reasons, it is required.
Personnel qualifications:

Exercise challenges should be conducted by adequately trained personnel with a basic 
knowledge of exercise physiology.

Technicians familiar with normal and abnormal responses during exercise and trained in 
CPR should be present throughout the test (see also Section 3, Safety Issues).

Medically qualified personnel are required to be present for the first test. However, the 
supervising physician must be readily available during all tests to respond as needed.  The 
degree of subject supervision should be increased if warranted by the clinical status of the 
subject.
10.1.3
Safety issues
Relative Contraindications:
The following conditions that preclude exercise testing should be assessed at each site visit
prior to the 6MWT and patients with any of these findings can return to the study site within 
the visit window to complete the 6MWT if these measurements are resolved:
•
Acute decompensated heart failure,
•
A resting heart rate > 120bpm, SBP > 180mmHg and DBP > 100mmHg.
•
Symptomatic hypotension and symptomatic bradycardia
•
Any condition that, in the opinion of the investigator, would impact the ability of the 
patient to perform the 6MWT

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Stable exertional angina is not an absolute contraindication for a 6MWT, but patients with 
these symptoms should perform the test after using their antiangina medication, and rescue 
nitrate medication should be readily available.
Stopping rules:
Cardiac (e.g. bradyarrhythmias, ventricular tachycardia, myocardial infarction, heart failure, 
hypotension, and shock) and non-cardiac (musculoskeletal trauma, severe fatigue, dizziness, 
fainting, body aches) complications of exercise challenges have been reported.
Consequently during the test, study personnel should be alert to any abnormal event.
Indications to stop the test must be clearly established and known by the personnel involved 
in testing.  Such symptoms are listed below:
•
Acute chest pain,
•
Sudden pallor,
•
Loss of co-ordination / staggering,
•
Mental confusion,
•
Extreme dyspnea,
•
Leg cramps,
•
Diaphoresis.
The subject will be withdrawn from performing the 6MWT should any of these symptoms 
occur.
Safety requirements and rescue medication:
If the exercise test has been stopped for one of these reasons, the subject should be monitored 
in the laboratory until signs / symptoms / ECG modifications have completely cleared.  
Adequate safety equipment must be available at the test site according to local institutional 
requirements and emergency medication are to be used at the Investigator’s discretion such 
as:
•
Oxygen,
•
Fast acting nitrate,
•
Antiplatelets agent
•
Sphygmomanometer
•
Telephone
•
Automated electronic defibrillator or other safety measures as per institutional 
requirements
10.1.4
Conduct of the 6MWT
Location of the 6MWT:
The 6MWT should be performed indoors, along a long, flat, straight, enclosed corridor with a 
hard surface that is seldom traveled.  The walking course must be 30 m in length and 

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therefore a 100-ft hallway is required.  The length of the corridor should be marked every 1m 
to 3m however the recommendation is to mark the course every 1m.  The turnaround points 
should be marked with a cone (such as an orange traffic cone) and placed 0.5m from each 
extremity to enable the subject to not have to turn too abruptly. A starting line, which marks 
the beginning and end of each 60-m lap, should be marked on the floor using brightly colored 
tape.
Required equipment for the 6MWT:
The following equipment is required by the staff:
•
Countdown timer
•
Mechanical lap counter
•
Two cones to mark the turnaround points
•
A chair that can be easily moved along the walking course
•
Worksheet on a clipboard
•
Borg CR-10 scale
•
30 meters measuring tape
•
safety requirements as outlined in Section 10.1.3
Measurements:
•
Repeat testing should be performed about the same time of day to minimize intraday 
variability.
•
A “warm-up” period before the test should not be performed.
•
The patient should sit at rest in a chair, located near the starting position, for at least 5 
minutes before the test starts.  During this time, check for contraindications, measure 
heart rate and blood pressure, and make sure that clothing and shoes are appropriate.
•
Set the lap counter to zero and the timer to 6 minutes.  Assemble all necessary 
equipment (e.g. lap counter, timer, worksheet, BORG CR-10 scale) and move the 
patient to the starting point.
•
The patient should be asked to rate their baseline breathing discomfort and overall 
fatigue using the Borg Scale.
•
The patient should be instructed as follows:
o
“The object of this test is to walk as far as possible for 6 minutes. You will walk 
back and forth in this hallway.  Six minutes is a long time to walk, so you will be 
exerting yourself.  You will probably get out of breath or become exhausted. You 
are permitted to slow down, to stop, and to rest as necessary.  You may lean 
against the wall while resting, but resume walking as soon as you are able.

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o
You will be walking back and forth around the cones.  You should pivot briskly 
around the cones and continue back the other way without hesitation.  Now I’m 
going to show you.  Please watch the way I turn without hesitation.”
o
Demonstrate by walking one lap yourself.  Walk and pivot around a cone briskly.
o
“Are you ready to do that?  I am going to use this counter to keep track of the 
number of shuttles (distance between the two cones) you complete.  I will click it 
each time you turn around at this starting line.  Remember that the objective is to 
walk AS FAR AS POSSIBLE for 6 minutes, but don’t run or jog.”  
o
Do you have any questions? Are you ready to start? Start now.”
•
You should stand near the starting line during the test.  Do not walk with the patient.  
As soon as the patient starts to walk, start the timer.
•
Do not talk to anyone during the walk.  Use an even tone of voice when using the 
standard phrases of encouragement.  Watch the patient.  Do not get distracted and lose 
count of the shuttles. Each time the patient walks one length of the corridor, click the 
lap counter once (and mark the shuttle on the worksheet).  Let the participant see you 
do it.  
o
After the first minute, tell the patient the following (in even tones): “You are 
doing well.  You have 5 minutes to go.”
o
When the timer shows 4 minutes remaining, tell the patient the following: “Keep 
up the good work.  You have 4 minutes to go.”
o
When the timer shows 3 minutes remaining, tell the patient the following: “You 
are doing well.  You are halfway done.”
o
When the timer shows 2 minutes remaining, tell the patient the following: “Keep 
up the good work.  You have only 2 minutes left.”
o
When the timer shows only 1 minute remaining, tell the patient: “You are doing 
well.  You have only 1 minute to go.”
o
Do not use other words of encouragement (or body language to speed up).
o
If the patient stops walking during the test and needs a rest, say this: “You can 
lean against the wall if you would like; then continue walking whenever you feel 
able.”  Do not stop the timer. While the patient is stopped, standardised 
encouragement should be provided every 30 s: “Please resume walking whenever 
you feel able.” The time that the patient stopped and the time that walking is 
recommenced should be recorded.

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o
If the patient stops before the 6 minutes are up and refuses to continue (or you 
decide that they should not continue), wheel the chair over for the patient to sit on, 
discontinue the walk, and note on the worksheet the distance, the time stopped, 
and the reason for stopping prematurely.
o
When the timer is 15 seconds from completion, say this: “In a moment I’m going 
to tell you to stop.  When I do, just stop right where you are and I will come to 
you.”
o
When the timer rings (or buzzes), say this: “Stop!” Walk over to the patient.  
Consider taking the chair if they look exhausted.  Mark the spot where they 
stopped by placing a bean bag on the floor.
•
At the end of exercise the blood pressure and heart rate should be recorded.  Repeat 
blood pressure and heart rate measurements will be taken 5 minutes later to assess 
recovery rate.
•
The patient should be asked to rate their end of exercise breathing discomfort and 
overall fatigue using the Borg Scale.
•
Record the number of shuttles from the counter (or tick marks on the worksheet).
•
Record the additional distance covered (the number of meters in the final partial 
shuttle) using the course distance markers.  Calculate the total distance walked, 
rounding to the nearest meter, and record it on the worksheet.
•
Congratulate the patient on good effort and ask if they have any symptom.

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10.2
INCLUSION OF ILLITERATE PATIENTS 
10.2.1
Patient Reported Outcome Measures
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.

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10.3
PATIENT REPORTED OUTCOME 
10.3.1
KCCQ (Kansas City Cardiomyopathy Questionnaire)

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10.3.2
Chronic Heart Failure Questionnaire Self Administered - Standardized 
(CHQ-SAS)
First Administration:

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10.3.3
Patient Global Impression of Change in Heart Failure Symptoms: shortness 
of breath, fatigue and swelling. 
Please choose one response below that best describes the overall change in your Heart Failure 
Symptoms specifically shortness of breath, fatigue and swelling, since you started taking the 
trial medication:
Very much better 
Much better 
A little better 
No change 
A little worse 
Much worse 
Very much worse 
10.3.4
Patient Global Impression of Change in Dyspnea 
Please choose one response below that best describes the overall change in your shortness of 
breath (dyspnea) since you started taking the trial medication:
Very much better 
Much better 
A little better 
No change 
A little worse 
Much worse 
Very much worse 
10.3.5
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 

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10.3.6
Patient Global Impression of Severity of Dyspnea
Please choose one response below that best describes your most recent experience of 
shortness of breath (dyspnea) when performing your usual activities:
Not at all 
Mild 
Moderate 
Severe  
Very severe 
10.4
CLINICIAN GLOBAL IMPRESSION
10.4.1
Clinician Global Impression of Change in CHF Severity 
Considering your total clinical experience with this particular population, compared to the 
patient's condition at the baseline, this patient's condition is:
N/A =  Cannot be assessed
1 =  Very much improved
2 =  Much improved
3 =  Minimally improved
4 =  No change
5 =  Minimally worse
6 =  Much worse
7 =  Very much worse
If the same Investigator is not able to assess the patient at each visit then please select the 
response ‘N/A = cannot be assessed’.
10.4.2
Clinician Global Impression of Severity of CHF 
Considering your total clinical experience with this particular population, how severely ill is 
the patient at this time:
Normal, not at all ill
Mildly ill
Moderately ill
Severely ill 
Very severely ill

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10.5
NYHA FUNCTIONAL CLASSIFICATION
Class
Patient symptoms
I
No limitation of physical activity. Ordinary physical activity does not cause undue
fatigue, palpitation, dyspnea (shortness of breath)
II
Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity
results in fatigue, palpitation, dyspnea (shortness of breath)
III
Marked limitation of physical activity. Comfortable at rest. Less than ordinary
activity causes fatigue, palpitation, or dyspnea
IV
Unable to carry on any physical activity without discomfort. Symptoms of heart
failure at rest. If any physical activity is undertaken, discomfort increases
10.6
BLOOD PRESSURE MEASUREMENT PROCEDURE
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 1, 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 device should be used throughout the 
trial for a patient.
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 DBP of 109.4 would be rounded to 109 mmHg).

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10.7
ACCEPTED FORMS OF CONTRACEPTION FOR PATIENTS IN 
PORTUGAL
Women of child-bearing potential* 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. Such methods should be used throughout the study and the
patient must agree to periodic pregnancy testing during participation in the trial.
Highly effective birth control methods include:

Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation:
o
Oral
o
Intravaginal
o
Transdermal

Progestogen-only hormonal contraception associated with inhibition of ovulation:
o
Oral
o
Injectable
o
Implantable

Intrauterine device (IUD)

Intrauterine hormone-releasing system ( IUS)

Bilateral tubal occlusion

Vasectomised partner

Sexual abstinence
*Women of child-bearing potential are defined as follows: Any female who has experience
menarche and is not post-menopausal (defined as at least 12 months with no menses without 
an alternative medical cause) or who is not permanently sterilised (e.g. hysterectomy, 
bilateral oophorectomy or bilateral salpingectomy).

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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
16 May 2018
EudraCT number
EU number
2017-004073-14
BI Trial number
1245-0168
BI Investigational Product(s)
Empagliflozin
Title of protocol
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)
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
X
To be implemented immediately in order to eliminate hazard –
IRB / IEC / Competent Authority to be notified of change with request for 
approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
Flowchart header 
Description of change
Header of second page of flow chart was corrected
Rationale for change
Formatting issue corrected
Section to be changed
Flowchart and Section 6.2.1.
Description of change
The following footnote was added to the 
flowchart for eGFR, safety labs, NT-proBNP:

The screening procedures can be performed on 
different days within the time window.
Specifically, it is recommended to have the 
NT-proBNP and safety lab measures (via 
central lab) measured as first step, especially in 
patients with no previous natriuretic peptide 
value available from clinical routine 
assessment in the past 6 months (refer to 
section 6.2.1)
The following text was added to section 6.2.1:
For patients with no BNP or NT-proBNP 
measurement available from clinical routine in the 
past 6 months indicative of the likelihood of 
eligibility for this study, it is recommended to split 
the screening visit into two steps and start with the 

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measurement of NT-proBNP and safety lab 
measures (via central laboratory), wait for the 
results, and do the remaining screening 
assessments on a separate day (within the allowed 
visit window)
Rationale for change
To allow flexibility for performing screening 
procedures and to reduce screening efforts: By 
measuring NTproBNP first, the remaining 
screening procedures will no longer apply, if the 
NTproBNP result is indicative that the patient does 
not qualify for the study. 
Section to be changed
Inclusion criteria (Synopsis and 3.3.2) and 4.2.2.1
Description of change
In inclusion criteria (synopsis and section 3.3.2), 
inclusion criterion 8: Patients must be clinically 
stable and on appropriate and stable dose of 
medical therapy for HF (such as ACEi, ARB, β-
blocker, oral diuretics, MRA, ARNI, ivabradine), 
consistent with prevailing CV guidelines, stable for 
at least 4 weeks prior to Visit 1(screening) with the 
exception of diuretics which must have been stable 
for at least two weeks prior to Visit 1. The 
investigator must document the reason why the 
patient is not on target dose of any heart failure 
medication as per local guidelines
Was changed to
Patients must be clinically stable and on 
appropriate and stable dose of medical therapy for 
HF (such as ACEi, ARB, β-blocker, oral diuretics, 
MRA, ARNI, ivabradine), consistent with 
prevailing CV guidelines, stable for at least 4 
weeks prior to Visit 1(screening) with the 
exception of diuretics which must have been stable 
for at least two weeks prior to Visit 1. The 
investigator must document the reason in case why 
the patient is not on such medication or if not on 
target dose of any heart failure medication as per 
local guidelines
In section 4.2.2.1 the following text was added:
The investigator must document the reason in case 
a patient is not on such medication or if not on 
target dose of any heart failure medication as per 
local guidelines.
Rationale for change
There are specific medical reasons for a patient not 
receiving a guideline-recommended medication or 
for not receiving the maximum dose (e.g. 

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intolerability) ; if it is medically justified we would 
still include these patients in this trial. The reason 
for not taking a guideline recommended 
medication, or for not taking the maximal possible 
dose, must be documented by the investigator.
Section to be changed
Exclusion criteria (Synopsis and 3.3.3) and section 
3.3
Description of change
Previous or current participation in another 
Empagliflozin Heart Failure trial (i.e. studies 
1245.110, 1245.121, 1245-0167)
Was changed to
Previous or current participation randomisation in 
another Empagliflozin Heart Failure trial (i.e. 
studies 1245.110, 1245.121, 1245-0167)
In section 3.3 the following text was added:
If a patient is a screen failure in one of the other 
Heart Failure trials with Empagliflozin they could 
be considered for this trial as long as they meet all 
eligibility criteria.
Rationale for change
This was clarified as only patients randomized in
another Empagliflozin HF trial are not eligible for
participation and patients who screen-failed in one
of these other trials may be included into this trial.
Section to be changed
Section 3.3
Description of change
The following text was added : 
In instances where a patient is a screen failure in 
1245-0167, all relevant completed screening 
procedures can be used for the eligibility 
assessment of the patient in 1245-0168 as long as 
they are completed during the original screening 
timeframe. The decision to screen the patient in the 
1245-0167 trial should be based on Investigator 
judgement and in consultation with the Sponsor.
Rationale for change
To allow patients screened failed in the HFpEF 
trial, to be considered for the HFrEF trial without 
need to have all screening examinations performed 
again.  
Section to be changed
Section 3.2, Section 5.1.3, Appendix 10.3.2
Description of change
Section 3.2:

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The Chronic Heart Failure Questionnaire (self-
administered standardized format) (CHQ-SAS) is a 
heart failure-specific PRO measure with 20-items, 
designed to assess PRO [R17-2668], [R17-2969] in 
adult heart failure patients and specifically 
evaluates longitudinal change over time. The 
subscales of the CHQ-SAS are: dyspnea, fatigue, 
emotional function, and mastery. 
Was changed to:
The Chronic Heart Failure Questionnaire (self-
administered standardized format) (CHQ-SAS) is a 
heart failure-specific PRO measure with 20 16-
items, designed to assess PRO [R17-2668], [R17-
2969] in adult heart failure patients and 
specifically evaluates longitudinal change over 
time. The subscales of the CHQ-SAS are: dyspnea, 
fatigue and emotional function, and mastery.  
Section 5.1.3:
The CHQ-SAS refers to the CHQ-self-
administered format and contains 20 standardised 
questions pertaining to 4 domains: dyspnea, 
fatigue, emotional function and mastery.
Was changed to:
The CHQ-SAS refers to the CHQ-self-
administered format and contains 20 16
standardised questions pertaining to 4 3 domains: 
dyspnea, fatigue and emotional function and 
mastery.
Appendix 10.3.2: The final version of the 
questionnaire was updated accordingly.
Rationale for change
The questionnaire in its final version does not 
contain the 4 questions pertaining to the Mastery 
domain. 
Section to be changed
Section 3.3
Description of change
Re-testing for eligibility criteria is only to be 
performed once for a laboratory result which is 
obviously received beyond stability at the 
central laboratory or thought to be a spurious or 
transient result based on previously available 
laboratory results or in the opinion of the 
investigator. The re-test should be carried out 
as soon as possible so the laboratory test results 

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will be received within the next planned visit 
window in order to avoid protocol window 
violations. This is also applicable for blood 
pressure and electrocardiogram (ECG) 
measurements.
Was changed to:
Re-testing for eligibility criteria is only to be 
performed once for blood pressure, 
electrocardiogram (ECG) measurements and 
laboratory result which is obviously received 
beyond stability at the central laboratory or 
thought to be a spurious or transient result 
based on previously available laboratory results
or in the opinion of the investigator. The re-test 
should be carried out as soon as possible so the 
laboratory test results will be received within 
the next planned visit window in order to avoid 
protocol window violations. This is also 
applicable for blood pressure and 
electrocardiogram (ECG) measurements.
Rationale for change
To clarify that re-testing can only be performed 
once per patient regardless of the reason for the re-
testing.
Section to be changed
Section 3.3.3 Exclusion Criteria 25
Description of change
Major surgery (major according to the 
investigator’s assessment) performed within 90 
days prior to Visit 1, or scheduled major elective 
surgery (e.g. hip or knee replacement) within 90 
days after Visit 1
Was changed to:
Major surgery (major according to the 
investigator’s assessment) performed within 90 
days prior to Visit 1, or scheduled major elective 
surgery (e.g. hip or knee replacement) during the 
course of the trial within 90 days after Visit 1.
Rationale for change
To clarify the major surgery should not be 
performed while the patient is participating in the 
trial which could be longer than 90 days after Visit 
1.
Section to be changed
Section 4.2.1 and Appendix 10.1.3 Safety 
requirements and rescue medication

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Description of change
Section 4.2.1:
The test should be performed in a location where a 
rapid, appropriate response to an emergency is 
possible. Supplies that must be available are: 
oxygen, sublingual nitroglycerine, acetylsalicylic 
acid, sphyngomanometer and telephone.
Was changed to:
The test should be performed in a location where a 
rapid, appropriate response to an emergency is 
possible. Supplies that Adequate safety 
equipment must be readily available at the test 
site according to local institutional requirements 
and emergency medications are to be 
administered at the discretion of the 
Investigator such as: oxygen, sublingual 
nitroglycerine, fast-acting nitrate, acetylsalicylic 
acid, antiplatelet agent, sphyngomanometer and 
telephone.
Appendix 10.1.3: Safety requirements and 
rescue medication
The following safety equipment should be 
available in the laboratory:
• Oxygen,
• Sublingual nitroglycerine,
• Acetylsalicylic acid
• Sphygmomanometer
• Telephone
Was changed to:
The following Adequate safety equipment should
must be available in the laboratory at the test site 
according to local institutional requirements 
and emergency medications are to be 
administered at the discretion of the 
Investigator such as:
• Oxygen,
• Sublingual nitroglycerine Fast-acting nitrate 
• Acetylsalicylic acid Anitplatelet agent 
• Sphygmomanometer
• Telephone
• Automated electronic defibrillator or other 
safety measures as per institutional 
requirements

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Rationale for change
The class of medication is included instead of the 
individual medication to allow flexibility in what 
the site uses to treat patients in case of an 
emergency and to ensure local institutional 
requirements are followed.
Section to be changed
Section 5.2.1
Description of change
Complete physical examination will include 
general appearance as well as evaluation of organ 
systems according to your routine practice. 
Was changed to:
Complete physical examination will include 
general appearance as well as evaluation of organ 
systems according to your routine practice 
including an assessment of the cardiovascular 
system. 
Rationale for change
A few cardiovascular parameters are to be captured 
in the case report form which are not necessarily 
part of the routine practice.
Section to be changed
Section 5.5.1
Description of change
Details on echocardiographic parameters will be 
specified in the ISF.
Was deleted
Rationale for change
All details of requested parameters are already 
given in the paragraph.
Section to be changed
Appendix 10.1.2
Description of change
Physicians are required to be present for the first 
test and for subsequent tests the supervising 
physician must be readily available to respond as 
needed.  The degree of subject supervision should 
be increased if warranted by the clinical status of 
the subject.
Was changed to:
Medically qualified personnel Physicians are 
required to be present for the first test and for 
subsequent tests. However, the supervising 
physician must be readily available during all tests
to respond as needed.  The degree of subject 
supervision should be increased if warranted by the 
clinical status of the subject.
Rationale for change
To allow for other medically qualified personnel 
(i.e. nurse practitioner) to supervise the first test 
depending on the set-up of the site and tasks 

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delegated by the Investigator.
Section to be changed
Appendix 10.1.4
Description of change
The length of the corridor should be marked every 
1m to 3m. The turnaround points should be marked 
with a cone (such as an orange traffic cone) and 
0.5m from each extremity to enable the subject to 
not have to turn too abruptly.
Was changed to:
The length of the corridor should be marked every 
1m to 3m however the recommendation is to 
mark the course every 1m. The turnaround points 
should be marked with a cone (such as an orange 
traffic cone) and placed 0.5m from each extremity 
to enable the subject to not have to turn too 
abruptly.
Required equipment for the 6MWT:
The following equipment is required by the staff:
• Countdown timer (or stopwatch)
• Mechanical lap counter
• Two small cones to mark the turnaround points
• A chair that can be easily moved along the 
walking course
• Worksheets on a clipboard
• A source of oxygen
• Spygmomanometer
• Telephone
• Automated electronic defibrillator
Was changed to:
Required equipment for the 6MWT:
The following equipment is required by the staff:
• Countdown timer (or stopwatch)
• Mechanical lap counter
• Two small cones to mark the turnaround points
• A chair that can be easily moved along the 
walking course
• Worksheet on a clipboard
• Borg CR-10 scale
• 30 meters measuring tape
• A source of oxygen
• Spygmomanometer
• Telephone
• Automated electronic defibrillator
• Safety requirements as outlined in Section 
10.1.3

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During this time, check for contraindications, 
measure pulse and blood pressure, and make sure 
that clothing and shoes are appropriate.
Was changed to:
During this time, check for contraindications, 
measure pulse heart rate and blood pressure, and 
make sure that clothing and shoes are appropriate.
Assemble all necessary equipment (e.g. lap 
counter, timer) and move the patient to the starting 
point.
Was changed to:
Assemble all necessary equipment (e.g. lap 
counter, timer, worksheet, BORG CR-10 scale) 
and move the patient to the starting point.
The patient should be asked to rate their baseline 
shortness of breath and overall fatigue using the 
Borg Scale.
Was changed to:
The patient should be asked to rate their baseline 
shortness of breath breathing discomfort and 
overall fatigue using the Borg Scale.
Remember that the object is to walk AS FAR AS 
POSSIBLE for 6 minutes, but don’t run or jog.  
Was changed to:
Remember that the objective is to walk AS FAR 
AS POSSIBLE for 6 minutes, but don’t run or jog.  
The following text was moved up to follow 
actual end of test order of procedures:
At the end of exercise the blood pressure and heart 
rate should be recorded.  Repeat blood pressure and 
heart rate measurements will be taken 5 minutes 
later to assess recovery rate.

The patient should be asked to rate their end of 
exercise shortness of breath and overall fatigue 
using the Borg Scale.
Was changed to:

The patient should be asked to rate their end of 
exercise shortness of breath breathing 
discomfort and overall fatigue using the Borg 
Scale.

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Record the additional distance covered (the number 
of meters in the final partial lap) using the markers 
on the wall as distance guides.  
Was changed to:
Record the additional distance covered (the number 
of meters in the final partial lap shuttle) using the 
markers on the wall as distance guides course 
distance markers.  

Congratulate the patient on good effort and offer a 
drink of water.
Was changed to:
Congratulate the patient on good effort and offer a 
drink of water ask if they have any symptoms.
Rationale for change
Editorial changes and clarifications regarding the 
conduct of the 6MWT.

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11.2
GLOBAL AMENDMENT 2
Date of amendment
20 Jul 2018
EudraCT number
EU number
2017-004073-14
BI Trial number
1245-0168
BI Investigational Product(s)
Empagliflozin
Title of protocol
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)
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
X
To be implemented immediately in order to eliminate hazard –
IRB / IEC / Competent Authority to be notified of change with request for 
approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
Abbreviations
Description of change
The following abbreviation was added:
AF – Atrial Fibrillation 
Rationale for change
The abbreviation was added as the term atrial 
fibrillation (AF) was included in the protocol.
Section to be changed
Inclusion criteria (Synopsis and Section 3.3.2)
Description of change
Elevated NT-proBNP > 600 pg/ml as analysed at 
the Central laboratory at Visit 1
Was changed to:
Elevated NT-proBNP > 450 pg/ml for patients 
without atrial fibrillation (AF) OR > 600 pg/ml 
for patients with AF as analysed at the Central 
laboratory at Visit 1
Rationale for change
To take into account the influence of atrial 
fibrillation, the NT-pro BNP threshold has been 
changed to >450 pg/ml for patients without AF and 
kept the same at 600 pg/ml for patients with AF. 
HF guidelines recommend NT-pro BNP >125 
pg/ml to assist diagnosis of HFrEF. A higher 
arbitrary cut-off is selected in clinical trials to 
increase specificity, as it is followed in this study. 
Given the essential part of patient selection in this 

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trial is EF measurement and performance at 6-
minute walk test during screening, the proposed 
change in NT-pro BNP will not affect the integrity 
of the trial.
Section to be changed
Flowchart, Section 3.3, Section 6.2.1 
Description of change
The ECG was marked with footnote * in the 
Flowchart.
The following text was added to Flowchart 
footnote * and Section 6.2.1:
The baseline rhythm (e.g. sinus rhythm, AF) of the 
patient must be clarified (i.e. ECG) and 
documented at the time the NT-proBNP sample is 
collected.
The following text was added to Section 3.3:
If the retest is for the NT-proBNP, the baseline 
rhythm (e.g. sinus rhythm, AF) of the patient must 
be clarified (i.e. ECG) and documented at the time 
the NT-proBNP sample is collected.
Rationale for change
At the time of NT-proBNP measurement, the 
baseline rhythm of the patient (e.g. sinus rhythm, 
AF) must be determined (i.e. by ECG) in order to 
assess, which NT-proBNP cut-off applies for 
eligibility.

 
 
 
 
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c17550230
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clinical-trial-protocol-version-3
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)
Author-Trial Clinical Monitor
24 Jul 2018 18:21 CEST
Author-Trial Statistician
24 Jul 2018 18:25 CEST
Approval-Therapeutic Area 
24 Jul 2018 18:27 CEST
Approval-Team Member Medicine
24 Jul 2018 18:53 CEST
Verification-Paper Signature
Completion
27 Jul 2018 18:34 CEST

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Meaning of Signature  
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Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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