Clinical trial NCT03448406
Conditions: Heart Failure
Sponsor: Boehringer Ingelheim
Start date: 2018-03-20; Completion date: 2019-10-09
Enrollment: 315 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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 (6MWT) in patients with chronic heart failure (CHF) with preserved ejection fraction (LVEF \> 40%).

Secondary objectives are to assess Patient-Reported Outcome (PRO)

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Empagliflozin intervention 2: Placebo
Intervention descriptions: intervention 1: Film-coated tablet intervention 2: Film-coated tablet

Protocol documents:
Prot_001.pdf: 
001-MCS-40-106-RD-03 (14.0) / Saved on: 17 October 2016
TITLE PAGE
Clinical Trial Protocol
Document Number:
c17450485-02
EudraCT No.:
EU Trial No:
2017-004072-59
BI Trial No.:
1245-0167
BI Investigational 
Product(s):
Empagliflozin
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 preserved Ejection 
Fraction (HFpEF) (EMPERIAL – preserved)
Lay Title:
This study tests empagliflozin in patients with chronic heart failure 
with preserved ejection fraction (HFpEF). 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: 
Phone:
, Fax:
Status:
Final Protocol (Revised protocol based on Global Amendment 1)
Version and Date:
Version: 2.0
Date: 16 May 2018
Page 1 of 120
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:
Empaglifozin
Protocol date
10 Nov 2017
Revision date
16 May 2018
Trial number
1245-0167
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 preserved Ejection Fraction
(HFpEF) (EMPERIAL – preserved)
Principal Investigator 
< for single-centre trial 
or > Coordinating 
Investigator< for multi-
centre trial if 
applicable >:
Phone: 
; Fax: 
Phone: 
 , Fax: 
Trial site(s):
Multi-centre trial 
Clinical phase:
III 
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 (6MWT) in patients with chronic heart failure (CHF)
with preserved ejection fraction (LVEF > 40%).
Secondary objectives are to assess Patient-Reported Outcome (PRO).
Methodology:
Randomised, double blind, placebo controlled, parallel group trial.


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Number of patients
entered: 
300 
Number of patients on 
each treatment:
150 (2 treatment groups)
Diagnosis :
Heart failure with preserved ejection fraction (EF)
Main in- and exclusion 
criteria
Main Inclusion Criteria:
•
6MWT distance ≤350 m at screening and at baseline.
•
Patients with CHF diagnosed for at least 3 months before Visit 
1 and currently in NYHA class II-IV
•
CHF with preserved EF defined as left ventricular ejection 
fraction (LVEF) > 40 % as per echocardiography at Visit 1 per 
local reading and no prior measurement of LVEF ≤ 40% under 
stable conditions. 
•
Elevated NT-proBNP > 300 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 have at least one of the following evidence of HF:

Structural heart disease (left atrial enlargement and/or left 
ventricular hypertrophy) documented by echocardiogram at 
Visit 1, OR

Documented hospitalisation for HF within 12 months prior 
to Visit 1
•
Consistent with prevailing cardiovascular (CV) guidelines, if 
oral diurectics are prescribed to control symptoms, patients 
must be on an appropriate and stable dose for at least 2 weeks 
prior to Visit 1.
•
Clinically stable at randomization with no signs of heart failure 
decompensation (as per investigator judgement).  
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 CHF) 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


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•
Previous or current randomisation in another Empagliflozin Heart 
Failure trial (i.e. studies 1245.110, 1245.121, 1245-0168) 
•
Type 1 Diabetes Mellitus (T1DM)
•
Impaired renal function, defined as eGFR < 20 mL/min/1.73 m2  
(CKD-EPIcr) or requiring dialysis, as determined at Visit 1
•
Symptomatic hypotension and/or a systolic blood pressure (SBP)
< 100 mmHg at Visit 1 or 2
•
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 documented by ECG at Visit 1 
•
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
•
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.
•
ICD implantation within 1 month prior to Visit 1 or planned 
during the course of the trial
•
Implanted cardiac resynchronisation therapy (CRT)
•
Treatment with i.v. iron therapy or erythropoietin (EPO) within 3 
months prior to screening. 


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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
(PGI-S) 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 (PGI-C) 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
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 


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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.
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
X*,3
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


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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 Heart Failure 
Symptoms10
X
X
X
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).
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.


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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. 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 .....................................................................2
FLOW CHART........................................................................................................................7
TABLE OF CONTENTS ......................................................................................................10
ABBREVIATIONS................................................................................................................14
1.
INTRODUCTION...............................................................................................17
1.1
MEDICAL BACKGROUND.............................................................................17
1.2
DRUG PROFILE................................................................................................18
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................19
1.4
BENEFIT - RISK ASSESSMENT.....................................................................20
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................24
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........24
2.1.1
Main objectives....................................................................................................24
2.1.2
Primary endpoint(s)............................................................................................24
2.1.3
Secondary endpoint(s) ........................................................................................24
2.2
FURTHER OBJECTIVES AND FURTHER ENDPOINTS ..........................25
2.2.1
Further objectives ...............................................................................................25
2.2.2
Further endpoints ...............................................................................................25
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................26
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................26
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................26
3.3
SELECTION OF TRIAL POPULATION .......................................................28
3.3.1
Main diagnosis for trial entry ............................................................................30
3.3.2
Inclusion criteria .................................................................................................30
3.3.3
Exclusion criteria ................................................................................................31
3.3.4
Withdrawal of patients from therapy or assessments .....................................33
3.3.4.1
Withdrawal from trial treatment ...........................................................................34
3.3.4.2
Withdrawal of consent for trial participation........................................................34
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................35
4.
TREATMENTS...................................................................................................36
4.1
INVESTIGATIONAL TREATMENTS ...........................................................36
4.1.1
Identity of the Investigational Medicinal Products..........................................36
4.1.2
Selection of doses in the trial..............................................................................37
4.1.3
Method of assigning patients to treatment groups...........................................37
4.1.4
Drug assignment and administration of doses for each patient......................38
4.1.5
Blinding and procedures for unblinding...........................................................38
4.1.5.1
Blinding.................................................................................................................38


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4.1.5.2
Unblinding and breaking the code ........................................................................38
4.1.6
Packaging, labelling, and re-supply...................................................................39
4.1.7
Storage conditions...............................................................................................39
4.1.8
Drug accountability.............................................................................................39
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................40
4.2.1
Other treatments and emergency procedures..................................................40
4.2.2
Restrictions ..........................................................................................................42
4.2.2.1
Restrictions regarding concomitant treatment ......................................................42
4.2.2.2
Restrictions on diet and life style..........................................................................42
4.2.2.3
Restrictions regarding women of childbearing potential ......................................42
4.3
TREATMENT COMPLIANCE........................................................................43
5.
ASSESSMENTS..................................................................................................44
5.1
ASSESSMENT OF EFFICACY........................................................................44
5.1.1
Six Minute Walk Test .........................................................................................44
5.1.2
Kansas City Cardiomyopathy Questionnaire...................................................44
5.1.3
Chronic Heart Failure Questionnaire Self Administered Standardized .......45
5.1.4
NT-proBNP..........................................................................................................45
5.1.5
New York Heart Association classification.......................................................45
5.1.6
Clinical Congestion Score...................................................................................45
5.1.7
Patient Global Impression of Change in Heart Failure Symptoms................46
5.1.8
Patient Global Impression of Change in Dyspnea ...........................................46
5.1.9
Patient Global Impression of Severity of Heart Failure Symptoms...............47
5.1.10
Patient Global Impression of Severity of Dyspnea ..........................................47
5.1.11
Clinician Global Impression of Change in CHF Severity ...............................48
5.1.12
Clinician Global Impression of Severity of CHF .............................................48
5.2
ASSESSMENT OF SAFETY.............................................................................49
5.2.1
Physical examination ..........................................................................................49
5.2.2
Vital signs.............................................................................................................49
5.2.3
Body weight and height ......................................................................................49
5.2.4
Safety laboratory parameters ............................................................................49
5.2.4.1
Renal function.......................................................................................................51
5.2.4.2
Pregnancy testing..................................................................................................51
5.2.4.3
Criteria for hypoglycaemic events........................................................................51
5.2.4.4
Urinary tract infection and genital infections .......................................................51
5.2.5
Electrocardiogram ..............................................................................................51
5.2.6
Other safety parameters.....................................................................................52
5.2.7
Assessment of adverse events.............................................................................52
5.2.7.1
Definitions of AEs ................................................................................................52
5.2.7.2
Adverse event collection and reporting ................................................................55
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................57
5.3.1
Assessment of pharmacokinetics .......................................................................57
5.4
ASSESSMENT OF BIOMARKER(S) ..............................................................57
5.5
OTHER ASSESSMENTS...................................................................................57


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5.5.1
Echocardiogram..................................................................................................57
5.5.2
Health Care Resource Utilisation (HCRU).......................................................58
5.6
APPROPRIATENESS OF MEASUREMENTS..............................................58
6.
INVESTIGATIONAL PLAN.............................................................................59
6.1
VISIT SCHEDULE.............................................................................................59
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................59
6.2.1
Screening and run-in period(s)..........................................................................59
6.2.2
Treatment period(s)............................................................................................60
6.2.3
Follow up period and trial completion..............................................................61
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................62
7.1
STATISTICAL DESIGN - MODEL.................................................................62
7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................62
7.3
PLANNED ANALYSES.....................................................................................63
7.3.1
Primary endpoint analyses.................................................................................64
7.3.2
Secondary endpoint analyses .............................................................................64
7.3.3
Further endpoint analyses..................................................................................65
7.3.4
Safety analyses.....................................................................................................66
7.3.5
Pharmacokinetic and pharmacodynamic analyses..........................................67
7.4
INTERIM ANALYSES ......................................................................................67
7.5
HANDLING OF MISSING DATA ...................................................................67
7.6
RANDOMISATION ...........................................................................................69
7.7
DETERMINATION OF SAMPLE SIZE .........................................................69
7.7.1
Power estimation for key secondary endpoints................................................70
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........74
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................74
8.2
DATA QUALITY ASSURANCE ......................................................................75
8.3
RECORDS...........................................................................................................75
8.3.1
Source documents ...............................................................................................75
8.3.2
Direct access to source data and documents.....................................................76
8.3.3
Storage period of records ...................................................................................77
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................77
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........77
8.6
TRIAL MILESTONES.......................................................................................77
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................78
9.
REFERENCES....................................................................................................81
9.1
PUBLISHED REFERENCES............................................................................81
9.2
UNPUBLISHED REFERENCES......................................................................87
10.
APPENDICES.....................................................................................................88
10.1
SIX MINUTE WALK TEST..............................................................................88


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10.1.1
General considerations for exercise testing ......................................................88
10.1.2
Exercise performance variability ......................................................................88
10.1.3
Safety issues .........................................................................................................90
10.1.4
Conduct of the 6MWT........................................................................................91
10.2
INCLUSION OF ILLITERATE PATIENTS...................................................94
10.2.1
Patient Reported Outcome Measures ...............................................................94
10.3
PATIENT REPORTED OUTCOME................................................................95
10.3.1
KCCQ (Kansas City Cardiomyopathy Questionnaire)...................................95
10.3.2
Chronic Heart Failure Questionnaire Self Administered – Standardized 
(CHQ-SAS) ..........................................................................................................97
10.3.3
Patient Global Impression of Change in Heart Failure Symptoms: shortness 
of breath, fatigue and swelling.........................................................................103
10.3.4
Patient Global Impression of Change in Dyspnea .........................................103
10.3.5
Patient Global Impression of Severity of Heart Failure Symptoms: shortness 
of breath, fatigue and swelling.........................................................................103
10.3.6
Patient Global Impression of Severity of Dyspnea ........................................104
10.4
CLINICIAN GLOBAL IMPRESSION ..........................................................105
10.4.1
Clinician Global Impression of Change in CHF Severity .............................105
10.4.2
Clinician Global Impression of Severity of CHF ...........................................105
10.5
NYHA FUNCTIONAL CLASSIFICATION..................................................106
10.6
BLOOD PRESSURE MEASUREMENT PROCEDURE.............................106
10.7
STRUCTURAL HEART DISEASE................................................................107
10.8
ACCEPTED FORMS OF CONTRACEPTION FOR PATIENTS IN 
PORTUGAL......................................................................................................108
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .......................................109
11.1
GLOBAL AMENDMENT 1 ............................................................................109
11.2
GLOBAL AMENDMENT 2 ............................................................................119


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ABBREVIATIONS
6MWT
Six Minute Walk Test
6MWTD
Distance walked in six minutes
AE
Adverse Event
AESI
Adverse Event of Special Interest
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
Chronic Heart Failure Questionnaire
CHQ-SAS
Chronic Heart Failure Questionnaire – Self-Administered Standardized
format
CK
Creatine Kinase
CKD-EPIcr
Chronic Kidney Disease Epidemiology Collaboration Equation
CML
Clinical Monitor Local
CPET
Cardiopulmonary Exercise Testing
CRA
Clinical Research Associate
CRF
Case Report Form, electronic
CRO
Contract Research Organization
CRT
Cardiac Resynchronization Therapy
CT
Computed Tomography
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Cardiovascular
DBP
Diastolic Blood Pressure
DILI
Drug Induced Liver Injury
DKA
Diabetic Ketoacidosis
DM
Diabetes Mellitus
DMC
Data Monitoring Committee
DOMS
Delayed Onset Muscular Soreness
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
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


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EudraCT
European Clinical Trials Database
ExC
Executive Committee
FC
Flow Chart
FDA
US Food and Drug Administration
FEV1
Forced Expiratory Volume at 1 Second
GCP
Good Clinical Practice
GI
Gastrointestinal
GMP
Good Manufacturing Practice
HA
Health Authority
HCRU
Health Care Resource Utilisation
HDL
High Density Lipoprotein
HF
Heart Failure
HFmrEF
Heart Failure with mid-range Ejection Fraction
HfpEF
Heart Failure with Preserved Ejection Fraction
HfrEF
Heart Failure with Reduced Ejection Fraction
HHF
Hospitalization for Heart Failure
i.v.
intravenous
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
JVD
Jugular Venous Distension
KCCQ
Kansas City Cardiomyopathy Questionnaire
KCCQ-CSS
Kansas City Cardiomyopathy Questionnaire - Clinical Summary Score
KCCQ-TSS
Kansas City Cardiomyopathy Questionnaire - Total Symptom Score
LA
Left Atrium
LDL
Low-Density Lipoprotein
LPDD
Last Patient Drug Discontinuation
LV
Left Ventricle
LVEF
Left Ventriclar Ejection Fraction
LVMI
Left Ventricle Mass Index
MACE
Major Adverse Cardiovascular Events
MedDRA
Medical Dictionary for Drug Regulatory Activities
MI
Myocardial infarction
MMRM
Mixed Model Repeated Measure
MOA
Mode of Action
MRA
Mineralcorticoid Receptor Antagonist
MRI
Magnetic Resonance Imaging
NT-proBNP
N-Terminal Pro-Brain Natriuretic Peptide
NYHA
New York Heart Association
OPU
Operative Unit
p.o.
per os (oral)


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PGI-C
Patient Global Impression of Change
PGI-S
Patient Global Impression of Severity
PRO
Patient Reported Outcome
PROM
Patient Reported Outcome Measures
q.d.
quaque die (once a day)
QoL
Quality of Life
RA
Regulatory Authority
RS
Randomised Set
REP
Residual Effect Period
SAE
Serious Adverse Event
SBP
Systolic Blood Pressure
SC
Steering Committee
SD
Standard Deviation
SGLT-1
Sodium Glucose Co-Transporter 1
SGLT-2
Sodium Glucose Co-Transporter 2
SMQ
Standardised MedDRA Query
SOP
Standard Operating Procedures
SUSAR
Suspected Unexpected Serious Adverse Reactions
T1DM
Type 1 Diabetes Mellitus
T2DM
Type 2 Diabetes Mellitus
TCM
Trial Clinical Monitor
TIA
Transient Ischemic Attack
TMF
Trial Master File
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
UGT
Uridine 5'-diphospho-glucuronosyltransferase
ULN
Upper Limit of Normal
UTI
Urinary Tract Infections
VAS
Visual Analogue Scale
VO2
Volume of Oxygen - oxygen consumption
WHO
World Health Organization
WOCBP
Woman of childbearing potential


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Chronic heart failure (CHF) 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. Heart Failure (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 left ventricle (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 HFpEF 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 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 readmission for heart failure (9-10% / year) hospitalization and up to 30% readmissions
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 hospitalizations 
for HFpEF [P16-03760, P16-05920, R17-1584; R17-0953; R16-1527].
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


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heart failure and glucometabolic disturbances [R16-2382, R16-2384].
Empagliflozin is an orally available inhibitor of the renal dependent sodium 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 cardiovascular (CV) risk factors (e.g. uric acid, visceral fat mass,
albuminuria) [P15-00589, P15-09541].
In 2010 Boehringer Ingelheim (BI) initiated the EMPA-REG (Empaglifozin – Reducing 
Excess Glucose) 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
major adverse cardiovascular event (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 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 empaglifozin 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®.
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.


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1.3
RATIONALE FOR PERFORMING THE TRIAL
In addition to impacting cardiovascular outcomes (death and hospitalization), HF 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 [increasingly from New York Heart Association 
(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].
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 MRAs (hyperkalemia), or with vasopressin 
antagonists / vaptans (hypernatremia).
For empagliflozin, the mode of action (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 early effects on reduction in HHF as shown in the EMPA-REG 
OUTCOME trial. See figure 1.3:1.


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Figure 1.3:1 Kaplan-Meier estimates of time to first heart failure requiring hospitalization in 
patients with baseline cardiac failure [narrow standardized MedDRA query (SMQ)], pooled 
empagliflozin doses versus placebo-treated set. X-axis: study day [c02695839-01].

Patients with HFpEF are thought to benefit from combined beneficial effects of 
empagliflozin (see above). This benefit is expected based on the increased prevalence 
of obesity, hypertension, and 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 
HFpEF.


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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 Diabetes Mellitus (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 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 estimated glomerular filtration rate (eGFR) ≥20 ml/min/1.73m2 can 
be included. In the EMPA-REG Outcome trial, the cardiovascular benefits for empagliflozin 
were not driven by its pharmacological effect of lowering blood glucose and were 


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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 5.2.4.1 and 5.2.7.1.
The overall tolerability and safety profile as outlined in section 1.2, and the current 
Investigator’s Brochure (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. Due to the combination of positive effects, empagliflozin is 
expected to address the unmet medical need of improving exercise ability in this patient 
population. The details of the potential benfits of empagliflozin in addressing short-term 
symptoms and exercise ability of patients wih HFpEF 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 empaglifozin 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 HFpEF 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 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). 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 adverse events 
(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. 


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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 Diabetic Ketoacidosis (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.
Special attention will be paid to prevent metabolic acidosis, ketoacidosis and 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 6 minute walk test (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 CHF with preserved 
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
CHF. A comparable trial (study number 1245-0168) to investigate the same objectives in 
patients with reduced 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 
6MWT 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 (PGI-S) 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 (PGI-C) 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 patient reported outcome (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
* 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 approximately 300 male and female patients with chronic heart failure will be 
randomised (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 HFpEF without showing benefit in 
morbidity (specifically reduction of hospitalizations for heart failure) and mortality. The aim 
of this trial is to recruit patients with HFpEF on various background therapies for 
concomitant diseases 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 
Follow-up 
Empaglifozin 10 mg N =150
Placebo N = 150
13
12
6
Screening
Visit 1
End of 
treatment
End of trial
R
Rando
Up to -3 
Visit 3
-4d to -21d
weeks
1


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exercise capacity tests (e.g. Cardiopulmonary Exercise Testing (CPET)).  For CPET, which 
measures peak volume O2 (VO2) 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 
assessed 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 peak VO2 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 peak VO2 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 peak VO2), 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].
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-


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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 empaglifozin in patients with heart failure has not yet been 
systematically assessed in a randomised clinical trial. Currently, two large clinical outcome 
trials are ongoing in patients with HFpEF (EMPEROR-preserved) or HFrEF (EMPEROR-
reduced) to evaluate empaglifozin 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 implantable cardioverter defibrillators (ICDs). 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 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 randomised. It is planned that approximately 300 male and female patients 
who meet the eligibility criteria will be randomised in the study. The planned number of 
patients per site is approximately 4 (at approximately 80 sites). 


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Screening of patients for this trial is competitive, i.e. screening for the trial will stop at all 
sites at the same time once a sufficient number of patients has been screened. Investigators 
will be notified about screening completion and will then not be allowed to screen additional 
patients for this trial.
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the Investigator Site File (ISF) 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 Clinical Monitor 
Local (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 window in order to avoid protocol window violations. 
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.
-
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 1245-0168, all relevant completed screening 
procedures can be used for the eligibility assessment of the patient in 1245-0167 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. 


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3.3.1
Main diagnosis for trial entry
The trial will be performed in patients with chronic heart failure with a left ventricular 
ejection fraction > 40 % (this includes patients with preserved and mid-range heart failure).  
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. WOCBP1 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 10.8.
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.
5. Patients with CHF diagnosed for at least 3 months before Visit 1, and currently in NYHA
class II-IV
6. CHF with preserved EF defined as LVEF > 40 % as per echocardiography at Visit 1 per 
local reading and no prior measurement of LVEF ≤ 40% under stable conditions. 
7. Elevated NT-proBNP > 300 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
8. Patients must have at least one of the following evidence of HF:
a.
Structural heart disease2 (left atrial enlargement and/or left ventricular
hypertrophy) documented by echocardiogram at Visit 1, OR 
b. Documented HHF3 within 12 months prior to Visit 1
                                                
1 A woman is considered of childbearing potential, 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. 
2 Structural heart disease is further defined in appendix 10.7
3 The main reason for HHF must be HF. Documentation for HHF must be provided in the source documents


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9. Consistent with prevailing CV guidelines, if oral diuretics are prescribed to control 
symptoms, patients must be on an appropriate and stable dose of oral diuretics for at least
2 weeks prior to Visit 1 to control symptoms.
10. Clinically stable at randomization with no signs of heart failure decompensation (as per 
investigator judgement).  
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 transient ischemic attack in past 
90 days prior to Visit 1
2. Acute decompensated HF (exacerbation of CHF) 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, 1245-0168).
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 systolic blood pressure (SBP) < 100 mmHg at Visit 1 or 2 
7. 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,
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 


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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. ICD implantation within 1 month prior to Visit 1 or planned during the course of the trial
15. Implanted cardiac resynchronisation therapy (CRT)
16. 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
17. 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
18. 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 Investigator’s opinion, or primary pulmonary arterial 
hypertension
19. 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
20. Haemoglobin < 9 g/dl at Visit 1
21. History of ketoacidosis
22. 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.
23. Gastrointestinal (GI) surgery or GI disorder that could interfere with trial medication
absorption in the investigator’s opinion
24. Any documented active or suspected malignancy or history of malignancy within 2 years
prior to screening, except appropriately treated basal cell carcinoma of the skin or in situ 
carcinoma of uterine cervix or low risk prostate cancer (biopsy Gleason score of ≤ 6 and 
clinical stage T1c or T2a)


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25. 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
26. 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.
27. Treatment with i.v. iron therapy or erythropoietin (EPO) within 3 months prior to 
screening.
28. Currently enrolled in another investigational device or drug trial, or less than 30 days 
since ending another investigational device or drug trial(s), or receiving other 
investigational treatment(s). Patients participating in a purely observational trial will not
be excluded
29. Known allergy or hypersensitivity to empagliflozin or other SGLT-2 inhibitors
30. Chronic alcohol or drug abuse or any condition that, in the investigator’s opinion, makes 
them an unreliable trial patient or unlikely to complete the trial
31. Women who are pregnant, nursing, or who plan to become pregnant while in the trial
32. 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 section 3.3.4.1 and 
section 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


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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.
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 section 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 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 section 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.


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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.
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 Good Clinical Practice (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


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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 heart rate and reduction in heart rate multiplied by pressure 
product, an index of myocardial oxygen consumption. These modes of actions support the 
scientific rationale of testing empagliflozin in patients with HF.
In the EMPA-REG-OUTCOME trial both doses were administered to patients with T2DM
and showed to be equally effective in reducing CV death, HHF, and composite of HHF or 
CV death in patients with HF at baseline.
In 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 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 section 4.1.5.2.
Using this procedure, relevant parties will be blinded to the treatment group assignment.


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4.1.4
Drug assignment and administration of doses for each patient
Patients who qualify will be randomised to one of the 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.
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 


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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. 
4.1.6
Packaging, labelling, and re-supply
The investigational products will be provided by BI or a designated contract research 
organization (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 Institutional Review Board (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 Food and Drug Administration (FDA) Form 1572 (if applicable).


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Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. Patients should be instructed to return 
unused investigational drug.
The investigator 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 patients. The 
investigator / pharmacist / investigational drug storage manager will maintain records that 
document adequately that the patients were provided the doses specified by the Clinical Trial 
Protocol (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, 
antiplatelet 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 monitord 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.


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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. 
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.


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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 End of Trial (EOT) and the Follow Up Visit. 
Consistent with prevailing CV guidelines, if oral diuretics are prescribed, patients must be on 
an appropriate and stable dose for 2 weeks prior to Visit 1 to control volume status and 
symptoms.
Concomitant diseases should be treated according to best standard of care in accordance with 
local guidelines and recommendations.
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 10.8.


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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 Clinical Research Associate (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.
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. 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 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 CHQ-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 NYHA functional classification will be used to classify the severity of the patients’
heart failure (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 (JVD) 
(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 in table 5.1.6:1.


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Table 5.1.6:1
Clinical congestion score
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 Flow Chart. 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
!"# Patient $%&'(% )*+,#--.&/ &0 1 "(/2# ./ 3#(,4 5(.%6,# 78*+4&*- .- ( 9:.4#* 
;6#-4.&//(.,# 4& (--#-- +(4.#/4<- .*+,#--.&/ &0 ="(/2# ./ "#(,4 0(.%6,# -8*+4&*-> -+#=.0.=(%%8? 
-"&,4/#-- &0 ',#(4"> 0(4.26# (/@ -A#%%./2B 
The PGI-C 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 &/ 4"# 0&%%&A./2 C
:=(4#2&,8 -=(%#?

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 in dyspnea is a 1-item questionnaire designed to 
assess the patient’s impression of change in dyspnea.


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The PGI-C asks the patient to choose one response 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 of Heart Failure Symptoms .- ( 9:.4#* ;6#-4.&//(.,# 4& 
(--#-- +(4.#/4<- .*+,#--.&/ &0 -8*+4&*- -#D#,.48>-+#=.0.=(%%8? 
-"&,4/#-- &0 ',#(4"> 0(4.26# 
(/@ -A#%%./2B 
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 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)


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
Mild (2)

Moderate (3)

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 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)


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Please refer to section 6.2.2 for preferred order of completion of assessments and appendix 
10.4.2.
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
A complete physical examination will be performed at the time points specified in the Flow
Chart. Complete physical examination will include general appearance as well as evaluation 
of organ systems including an assessment of the cardiovascular system. 
The results must be included in the source documents available at the site. 
5.2.2
Vital signs
Vital signs will be evaluated at the time points specified in the Flow Chart. 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 
Flow Chart.
Body Mass Index (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 Flow Chart.


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All analyses will be performed by a central laboratory, the respective reference ranges will be 
provided in the ISF. 
Patients do not have to be fasted for the blood sampling for the safety laboratory. 
Instructions regarding sample collection, sample handling/ processing and sample shipping 
are provided in the Laboratory Manual in the ISF. 
The central laboratory will send reports to the investigator. It is the responsibility of the 
investigator to evaluate the laboratory reports. Clinically relevant abnormal findings as 
judged by the investigator will be reported as adverse events (please refer to section 5.2.7.1).
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 
electronic data capture (eDC) system. The amount of blood taken from the patient concerned 
will be increased due to this additional sampling.
The central laboratory will transfer the results of the analysis to the sponsor.
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


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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 Chronic Kidney Disease Epidemiology creatinine (CKD-EPIcr) 
equation [R12-1392].
5.2.4.2
Pregnancy testing
Pregnancy testing (urine) will be performed in female patients of child bearing potential
according to the time points indicated in the Flow Chart. Pregnancy kits will be provided by
the Central Laboratory. For reporting of pregnancy event refer to section 5.2.7.2.
5.2.4.3
Criteria for hypoglycaemic events
All symptomatic hypoglycaemia events, or severe hypoglycaemias (e.g. if the patient
required assistance of another person), or any hypoglycaemia episode with glucose values <
54 mg/dl (< 3.0 mmol/l), or if the investigator considered the event to be an AE should be
documented as an AE "hypoglycaemic event". In non-diabetic or pre-diabetic patients, the
investigator should consider and rule out other alternative causes for such symptoms and can
perform blood glucose levels to confirm the diagnosis of hypoglycaemia.
5.2.4.4
Urinary tract infection and genital infections
Patients having a history of chronic/recurrent UTIs 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. 


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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.
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.


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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 section 5.2.7.2, subsections “AE Collection” and AE reporting to 
sponsor and timelines”
Adverse events of special interest
The term adverse event of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this 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 ULN.


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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.
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).


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Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).

Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.
5.2.7.2
Adverse event collection and reporting
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


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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.
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.


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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.
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
•
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
•
Left Atrium (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


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For details on echocardiographic parameters please refer to appendix 10.7.
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 Flow Chart. 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)

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 6MWT 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 Flow Chart.The assessments must all fall within the acceptable screening 
visit window but do not need to be performed on the same day. The patient should be 
registered in IRT as a screened patient.
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)
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.


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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.  Resceening will be considered 
on a case-by-case basis as described in section 3.3.
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 at 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 Flow Chart:

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 


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adjusted and optimised according to local and international guidelines.
If any additional therapy is considered necessary for the patient’s welfare during the
treatment period it may be given at the discretion of the Investigator (see also restrictions 
in section 4.2.2.
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 Flow
Chart. 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 


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following hierarchical order:
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. 


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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 
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


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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.
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.


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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. 
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 


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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.
The details of the analysis will be specified in the Trial Statistical Analysis Plan (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 stardard deviation (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. 


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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
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


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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 %.
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.


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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 
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 %. 


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Table 7.1.1: 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 7.1.1: 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%
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 
European Union (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.
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-


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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 
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 


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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.
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 


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must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). They may review all CRFs and informed consents. The accuracy of the data will 
be verified by direct comparison with the source documents described in section 8.3.1. The 
sponsor will also monitor compliance with the protocol and GCP.
8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
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 World Health 
Organization (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 


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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.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
(HA) 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 1245-0168 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 


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appropriate Regulatory Authorities (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.
Events may either be defined by abnormal laboratory values and/or relevant adverse events or 
both. 
For qualifying events, relevant source documents generated from any medical evaluations of 
these events will be requested including for example laboratory values, histological analysis, 
reports from ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), 
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 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 (TCM), 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 CMLs, 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 (Operative Unit, [OPU]) in accordance with applicable 
regulations and BI SOPs, or by a 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.


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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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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), 
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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
Empagliflozin and clinical outcomes in patients with type 2 diabetes, 
established cardiovascular disease and chronic kidney disease.
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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)
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)
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 
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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 (2005)
R16-1529
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.
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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 
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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)
R17-1226
Ponikowski P, Veldhuisen DJ van, Comin-Colet J, Ertl G, Komajda M, Mareev 
V, et al, CONFIRM-HF Investigators
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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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R17-1341
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patients with heart failure.
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Utility of patient-reported outcome instruments in heartfailure.
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HP, Pitta F, et al
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performance in patients with chronic heart failure.
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R17-1562
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characteristics and targets for therapy.
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Redfield MM
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Wessler BS, Kramer DG, Kelly JL, Trikalinos TA, Kent DM, Konstam MA, et 
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Drug and device effects on peak oxygen consumption, 6-minute walk distance, 
and natriuretic peptides as predictors of therapeutic effects on mortality in 
patients with heart failure and reduced ejection fraction.
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R17-1588
Butler J, Hamo CE, Udelson JE, Pitt B, Yancy C, Shah SJ, et al
Exploring new endpoints for patients with heart failure with preserved ejection 
fraction.
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Cahalin LP, Mathier MA, Semigran MJ, Dec GD, DiSalvo TG
The six-minute walk test predicts peak oxygen uptake and survival in patients 
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Guyatt GH, Nogradi S, Halcrow S, Singer J, Sullivan MJJ, Fallen EL
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Comparison of quality of life measures in heart failure.
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R17-3097
Comin-Colet J, Lainscak M, Dickstein K, Filippatos GS, Johnson P, Luescher 
TF, et al
The effect of intravenous ferric carboxymaltose on health-related quality of life 
in patients with chronic heart failure and iron deficiency: a subanalysis of the 
FAIR-HF study.
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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 


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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 testing environment surroundings.
•
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 the 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 
cardiopulmonary resuscitation (CPR) should be present throughout the test (see 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.


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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 diastolic blood pressure (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
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 


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requirements and emergency medications are to be administered at the discretion of the 
Investigator such as:
• Oxygen,
• Fast-acting nitrate 
• Anitplatelet 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 
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.


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•
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:
•
“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.
•
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.”
•
Demonstrate by walking one lap yourself.  Walk and pivot around a cone briskly.
•
“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.  
•
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.  
•
After the first minute, tell the patient the following (in even tones): “You are doing 
well.  You have 5 minutes to go.”
•
When the timer shows 4 minutes remaining, tell the patient the following: “Keep up 
the good work.  You have 4 minutes to go.”


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•
When the timer shows 3 minutes remaining, tell the patient the following: “You are 
doing well.  You are halfway done.”
•
When the timer shows 2 minutes remaining, tell the patient the following: “Keep up 
the good work.  You have only 2 minutes left.”
•
When the timer shows only 1 minute remaining, tell the patient: “You are doing well.  
You have only 1 minute to go.”
•
Do not use other words of encouragement (or body language to speed up).
•
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 seconds: “Please resume walking whenever you feel 
able.” The time that the patient stopped and the time that walking is recommenced 
should be recorded.  
•
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.
•
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.”
•
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 or a piece of tape 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 symptoms.


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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 


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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
STRUCTURAL HEART DISEASE
Left atrial (LA) enlargement is defined by at least one of the following measurements:

LA width ≥4.0 cm, or

LA length ≥5.0 cm, or

LA area ≥20 cm2, or 

LA volume ≥55 ml, or

LA volume index ≥34 ml/m2
Left ventricular hypertrophy is defined by at least one of the following measurements:

Septal thickness or posterior wall thickness ≥ 1.1 cm. 

LV mass index (LVMI) ≥115 g/m2 for males and ≥95 g/m2 for females

E/e′ (mean septal and lateral) ≥13 

e’ (mean septal and lateral) <9 cm/s


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10.8
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
2017-004072-59
BI Trial number
1245-0167
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 
preserved Ejection Fraction (HFpEF) 
(EMPERIAL – preserved)
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
Clinical Trial Protocol Cover Page and Synopsis.
Description of change
Phone:
, Fax:
Was changed to:
Phone:
, Fax:
Rationale for change
The contact information for the Coordinating
Investigator was updated.
Section to be changed
Clinical Trial Protocol Synopsis: Main Inclusion
Criteria, Section 3.3.2 Inclusion Criteria 9 and
Section 4.2.2.1.


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Description of change
Patients must be on appropriate and stable dose 
of oral diuretics, consistent with prevailing 
cardiovascular (CV) guidelines for at least 2 
weeks prior to Visit 1.
Was changed to:
Consistent with prevailing CV guidelines, if oral 
diuretics are prescribed to control symptoms, 
patients must be on an appropriate and stable dose 
of oral diuretics, consistent with prevailing 
cardiovascular (CV) guidelines for at least 2 weeks 
prior to Visit 1 to control symptoms.
Rationale for change
To clarify that it is not mandatory for patients to be 
on diurectics to be included in the trial.  If diurectics 
are prescribed to relieve symptoms and volume 
overload as per heart failure guidelines, the dose 
must be appropriate and stable as per the inclusion 
criterion.
Section to be changed
Clinical Trial Protocol Synopsis: Main Exclusion
Criteria, Section 3.3 and Section 3.3.3 Exclusion
Criteria 3.
Description of change
Clinical Trial Protocol Synopsis: Main
Exclusion Criteria and Section 3.3.3 Exclusion
Criteria 3:
Previous or current participation in another 
Empaglifozin Heart Failure trial (i.e. studies 
1245.110, 1245.121, 1245-0168) 
Was changed to:
Previous or current participation randomisation in 
another Empagliflozin Heart Failure trial (i.e. 
studies 1245.110, 1245.121, 1245-0168). 
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
Flowchart and Section 6.2.1.
Description of change
The following footnote was added to the 
flowchart for eGFR, safety labs, NT-proBNP:


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
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 
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
Section 3.2, Section 5.1.3, Appendix 10.3.2
Description of change
Section 3.2:
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


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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 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 


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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
Description of change
The following text was added:
In instances where a patient is a screen failure in 
1245-0168, all relevant completed screening 
procedures can be used for the eligibility 
assessment of the patient in 1245-0167 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 HFrEF trial 
to be considered for the HFpEF trial without need 
to have all screening examinations performed 
again.  
Section to be changed
Section 3.3.3 Exclusion Criteria 22
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
Description of change
Section 4.2.1:
The test should be performed in a location where a 


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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 4.2.2.1
Description of change
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 and concomitant 
diseases.
Was changed to:
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 and concomitant 
diseases.
Concomitant diseases should be treated 
according to best standard of care in accordance 
with local guidelines and recommendations.
Rationale for change
In accordance with prevailing guidelines, 
concomitant diseases (such as hypertension and 
coronary artery disease) should be treated 
according to the best possible standard of care and 
according to respective guidelines for these 
concomitant diseases.
Section to be changed
Table 5.1.6:1
Description of change
JVD (cm 
H2O)
(jugular 
venous 
distension)
<=6
6-9
10-
15
>=15
Was changed to:
JVD (cm 
H2O)
(jugular 
venous 
distension)
≤6
6 <
JVD
9 < 
10
10 ≤
JVD
<15
≥15
Rationale for change
The JVD categories were corrected to avoid any
overlap across the categories.
Section to be changed
Section 5.2.1
Description of change
Complete physical examination will include 
general appearance as well as evaluation of organ 


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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
For details on echocardiographic parameters please 
refer to appendix 10.6 and the ISF.
Was changed to:
For details on echocardiographic parameters please 
refer to appendix 10.7.
Rationale for change
All details of requested parameters are provided in 
the protocol and appendix reference corrected.
Section to be changed
Section 6.2.2
Description of change
The following text was added:
All Visit 2 assessments must be performed 
before the first dose is taken at 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. 
Rationale for change
This text was added to clarify performing of the 
procedures in relation to dosing.
Section to be changed
Section 5.1.8 and Section 7.7
Description of change
The following links were updated:
To appendix 10.3.4
Table 7.7:2
Table 7.7.1:1
Table 7.7.1:3
Rationale for change
Updated links.
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 


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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 
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:


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• 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
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 


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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.
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.
11.2
GLOBAL AMENDMENT 2
Date of amendment
EudraCT number
EU number
BI Trial number
BI Investigational Product(s)
Title of protocol
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard –
IRB / IEC / Competent Authority to be notified of change with request for 
approval


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Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
Description of change
Rationale for change


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c17450485
2.0
clinical-trial-protocol-version-2
A phase III randomised, double-blind trial to evaluate the effect of 12 weeks
treatment of once daily EMPagliflozin 10 mg compared with placebo on ExeRcise
ability and heart failure symptoms, In patients with chronic HeArt FaiLure with
preserved Ejection Fraction (HFpEF) (EMPERIAL – preserved)
Author-Trial Clinical Monitor
17 May 2018 14:41 CEST
Approval-Team Member Medicine
17 May 2018 14:44 CEST
Author-Trial Statistician
17 May 2018 16:33 CEST
Approval-Therapeutic Area 
19 May 2018 18:20 CEST
Verification-Paper Signature
Completion
23 May 2018 21:14 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c17450485
2.0

SAP_000.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c21037235-05
BI Trial No.:
1245-0167
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 preserved Ejection 
Fraction (HFpEF) (EMPERIAL – preserved)
Revised protocol version 2.0 including Protocol Amendment 1
[c17450485-02]
Investigational
Product(s):
Empagliflozin
Responsible trial 
statistician(s):
Phone: 
Fax: 
Date of statistical 
analysis plan:
21 OCT 2019 REVISED
Version:
REVISED
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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................9
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY....................10
4.1 
CHANGES NEWLY INTRODUCED FROM THE CLINICAL TRIAL 
PROTOCOL........................................................................................................10
5.
ENDPOINTS .......................................................................................................11
5.1
PRIMARY ENDPOINT .....................................................................................11
5.2
SECONDARY ENDPOINTS.............................................................................11
5.2.1
Key secondary endpoints....................................................................................11
5.2.2
Secondary endpoints...........................................................................................11
5.3
FURTHER ENDPOINTS...................................................................................11
5.4
OTHER VARIABLES........................................................................................11
5.4.1
Demographic and other baseline characteristics .............................................11
5.4.2
Treatment compliance........................................................................................11
5.4.3
Treatment exposure............................................................................................12
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................13
6.1
TREATMENTS...................................................................................................13
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................14
6.3
SUBJECT SETS ANALYSED...........................................................................18
6.4
SUBGROUPS ......................................................................................................19
6.5
POOLING OF CENTRES .................................................................................22
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................22
6.6.1
Primary endpoint................................................................................................23
6.6.2
Key Secondary endpoint.....................................................................................23
6.6.3
Secondary endpoints...........................................................................................25
6.6.4
Longitudinal Analyses ........................................................................................26
6.6.5
Safety Analyses....................................................................................................27
6.6.6
Missing dates .......................................................................................................27
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................29
7.
PLANNED ANALYSIS......................................................................................32
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........32
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................33
7.3
TREATMENT COMPLIANCE........................................................................33
7.4
PRIMARY ENDPOINT .....................................................................................33
7.4.1
Primary analysis of the primary endpoint........................................................33
7.4.2
Sensitivity analysis of the primary endpoint ....................................................34
7.4.3
Subgroup analysis of the primary endpoint .....................................................34
7.5
SECONDARY ENDPOINTS.............................................................................34


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7.5.1
Key secondary endpoints....................................................................................34
7.5.1.1
Primary analysis of the key secondary endpoints .................................................35
7.5.1.2
Sensitivity analysis of the key secondary endpoints.............................................35
7.5.1.3
Subgroup analysis of the key secondary endpoints ..............................................35
7.5.1.4
Further exploratory analyses of the key secondary endpoints..............................36
7.5.2
Other Secondary endpoints................................................................................36
7.6
FURTHER ENDPOINTS...................................................................................37
7.6.1
Binary endpoints .................................................................................................37
7.6.2
Ordinal endpoints ...............................................................................................37
7.6.3
Continuous endpoints .........................................................................................38
7.7
EXTENT OF EXPOSURE.................................................................................39
7.8
SAFETY ANALYSIS..........................................................................................39
7.8.1
Adverse events.....................................................................................................39
7.8.1.1
Assignment of AEs to treatment...........................................................................39
7.8.1.2
AE summaries.......................................................................................................40
7.8.1.3
Adverse events of special interest (AESIs)...........................................................41
7.8.1.4
Specific AEs..........................................................................................................42
7.8.1.5
Events qualifying for external adjudication by the adjudication committee ........44
7.8.1.6
AEs while patients taking wrong medication .......................................................45
7.8.1.7
Adverse event incidence rates...............................................................................45
7.8.2
Laboratory data ..................................................................................................46
7.8.3
Vital signs.............................................................................................................49
7.8.4
ECG and physical examination .........................................................................49
7.8.5
Others...................................................................................................................49
8.
REFERENCES....................................................................................................50
9.
ADDITIONAL SECTIONS ...............................................................................51
9.1
REGIONS AND COUNTRIES..........................................................................51
9.2
DIABETES STATUS AT BASELINE..............................................................52
9.3
DERIVATION OF RESPONDER THRESHOLD FOR KCCQ-TSS AND 
CHQ-SAS DYSPNEA.........................................................................................53
9.4
DERIVATION OF KCCQ AND CHQ-SAS DOMAINS ................................54
9.4.1
Kansas City Cardiomyopathy Questionnaire (KCCQ)...................................54
9.4.2
Chronic Heart Failure Questionnaire (CHQ) Self-Administered 
Standardised format (SAS)................................................................................60
9.5
DERIVATION OF CLINICAL CONGESTION SCORE ..............................60
10.
HISTORY TABLE..............................................................................................62


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LIST OF TABLES
Table 6.1: 1
Treatment regimens / study intervals ...............................................................13
Table 6.1: 2
Endpoint-specific assignment to the on-treatment phase.................................14
Table 6.2: 1
Important protocol deviations ..........................................................................14
Table 6.3: 1
Subject sets analysed........................................................................................19
Table 6.4: 1
Categories of covariates for displays of baseline characteristics and 
subgroup analyses ............................................................................................20
Table 6.6.2: 1 Imputation Rules for missing KCCQ-TSS Assessments at Week 12 ..............24
Table 6.6.2: 2 Imputation Rules for missing CHQ-SAS Assessments at Week 12 ................25
Table 6.6.3: 1 Imputation rules for missing exercise capacity at week 6................................26
Table 6.7: 1
Time windows for primary analysis of primary and key secondary 
endpoints and Sensitivity analyses using Wilcoxon model .............................30
Table 6.7: 2
Time windows for measurements except primary analysis of primary and 
key secondary endpoints [OC-OT] ..................................................................30
Table 6.7: 3
Time windows for measurements except primary analysis of primary and 
key secondary endpoints [OC-AD]..................................................................31
Table 7.8.2: 1 CKD staging.....................................................................................................48
Table 9.1: 1
Regions and countries ......................................................................................51
Table 9.2: 1
DM at baseline .................................................................................................52
Table 10: 1
History table .....................................................................................................62


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
6MWT
Six-minute walking test
6MWTD
Six-minute walking test distance
ACE
Angiotensin converting enzyme
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine transaminase
ANCOVA
Analysis of covariance
ARB
Angiotensin Receptor Blocker
ARNI
Angiotensin Receptor-Neprilysin Inhibitor
ASA
acetylsalicylic acid
AST
Aspartate transaminase
ATC
Anatomical-Therapeutic-Chemical classification
AUC
Area Under the receiver operating characteristic Curve
BI
Boehringer Ingelheim
BIcMQ
Boehringer Ingelheim customised MedDRA Query
BMI
Body Mass Index
BP
Blood Pressure
bpm
beats per minute
BRPM
Blinded Report Planning Meeting
CEC
Clinical event committee
CHF
Chronic Heart Failure
CHQ
Chronic Heart Failure Questionnaire
CHQ-SAS
Chronic Heart Failure Questionnaire - Self-Administered Standardised 
format
CKD
Chronic Kidney Disease
CKD-EPIcr
Chronic Kidney Disease Epidemiology Collaboration Equation
CML
Local Clinical Monitor
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report


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Term
Definition / description
CRA
Clinical Research Associate
CRT
Cardiac Resynchronisation Therapy
CV
Cardiovascular
DBL
Database lock
DBP
Diastolic Blood Pressure
DKA
Diabetic ketoacidosis
DM
Diabetes Mellitus
DM&SM
Boehringer Ingelheim Data Management And Statistics Manual
ECDF
Empirical cumulative distribution functions
ECG
Electrocardiogramm
eCRF
Electronic Case Report Form
EF
Ejection Fraction
eGFR
Estimated Glomerular Filtration Rate
EMA
European Medicines Agency
EoT
End-of-Text
gCV
Geometric coefficient of variation
HF
HFpEF
HHF
Heart Failure
Heart Failure with preserved Ejection Fraction
Hospitalisation for Heart Failure
HLT
High-Level Term
IC
Informed Consent
ICD
Implantable Cardioverter Defibrillator
ICH
International Conference On Harmonisation
iPD
Important Protocol Deviation
JVD
Jugular Venous Distension
KCCQ
Kansas City Cardiomyopathy Questionnaire
KCCQ-CSS
Kansas City Cardiomyopathy Questionnaire – Clinical Summary Score
KCCQ-TSS
Kansas City Cardiomyopathy Questionnaire - Total Symptom Score
LLT
Lowest Level Term
LVEF
Left Ventricular Ejection Fraction
MedDRA
Medical Dictionary For Regulatory Activities


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Term
Definition / description
MMRM
mixed model repeated measure analysis
MRA
Mineralocorticoid receptor antagonist
NT-proBNP
N-Terminal Pro-Brain Natriuretic Peptide
NYHA
New York Heart Association
OC-AD
Observed Case including data After Discontinuation
OC-OT
Observed Case On Treatment
PD
Protocol Deviation
PDMAP
Project Data Management and Analysis Plan
PGI-C
Patient Global Impression of Change
PGI-S
Patient Global Impression of Severity
PRO
Patient Reported Outcome
PT
Preferred Term
pt-yrs
patient years
Q1
Lower Quartile
Q3
Upper Quartile
ROC
Receiver Operating Characteristic
RS
Randomised Set
SAE
Serious Adverse Events
SBP
Systolic Blood Pressure
SCR
Screened Set
SD
Standard Deviation
SE
Standard Error
SEM
Standard Error of Measurement
SensRS
Sensitivity analysis set
SMQ
Standardised MedDRA Query
SOC
System Organ Class
T1DM
Type 1 Diabetes Mellitus
TBILI
Total Bilirubin
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
ULN
Upper Limit of Normal


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Term
Definition / description
UTI
Urinary Tract Infections
WCI
Worst Case Imputation
WHO DD
World Health Organization Drug Dictionary
Y/N
Yes/No


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


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
4.1 
CHANGES NEWLY INTRODUCED FROM THE CLINICAL TRIAL 
PROTOCOL
Analyses of the following endpoints have been added:

Systolic blood pressure 

Diastolic blood pressure

Body weight


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
The primary endpoint is defined in CTP Section 2.1.2.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
The key secondary endpoint is defined in CTP Section 2.1.3. The scoring algorithm for 
KCCQ-TSS and CHQ-SAS dyspnea can be found in Appendix 9.4.
5.2.2
Secondary endpoints
Secondary endpoints are listed in CTP Section 2.1.3. The scoring algorithm for the clinical 
congestion score can be found in Appendix 9.5.
5.3
FURTHER ENDPOINTS
Further endpoints are listed in CTP Section 2.2.2.
Response in KCCQ domains at week 12: Response will be defined as an improvement of at 
least 5 points.
Response in CHQ domains at week 12: Response will be defined as an improvement of at 
least 0.5 points. Scoring algorithm for all KCCQ domains and CHQ-SAS domains can be 
found in Appendix 9.4.
5.4
OTHER VARIABLES
5.4.1
Demographic and other baseline characteristics
Blood pressure: Baseline SBP and DBP are taken from the vital signs assessment. If no vital 
signs assessment is available, the value before the start of the 6MWT will be used.
Region will be defined according to Table 9.1:1
Heart rate will display values entered in the electronic case report form (eCRF) as ‘pulse’. 
5.4.2
Treatment compliance
Overall compliance (%) to study medication will be calculated as a weighted average of 
reported compliance. Weights will be determined based on actual visit dates. Compliance will
be displayed for the treated set.


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5.4.3
Treatment exposure
Duration of exposure will be calculated as day of last intake of study drug – day of first 
intake of study drug + 1 day. 


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
There will be 3 study intervals in this trial: screening, study treatment phase (with either 
empagliflozin 10mg or matching placebo) and follow-up. The purpose of the definitions 
below is to describe the different study intervals.
Table 6.1: 1
Treatment regimens / study intervals
Label in database
Label in tables 
and listings
Interval
Start date 
SCREENING
Screening
Screening
Date of informed consent
PLACEBO/
BI 10773 10 MG
Placebo/Empa 
10 mg
Treatment
Date of first administration of 
double-blind study treatment
FOLLOW-UP
Post Pbo/Post
Empa
Follow up
Date of last administration of 
study drug + 1 day
Details on the definition of the treatment period for different endpoints are listed in 
Table 6.1:2. The efficacy analyses will follow the intention-to-treat (ITT) principle. For the
assignment of patients to treatment groups this means that patients will be analysed as 
randomised. 
For safety analyses, patients will be also assigned to the treatment groups as randomised.
If a patient erroneously receives the wrong trial drug, all future medication packs will be 
dispensed as scheduled for the treatment group to which the patient was randomised. 
Therefore, the adverse events will be analysed as per randomised treatment, which is 
expected to reflect the prevailing treatment. In exceptional cases that a patient took the wrong 
treatment, all adverse events that occur while being on the wrong treatment will be listed and 
analyses of this data are described in section 7.8.1.6. 


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Table 6.1: 2
Endpoint-specific assignment to the on-treatment phase
Endpoint
Last day of assignment to on-
treatment phase
(days after last intake of study 
medication)
6MWT distance
1
PRO endpoints (key secondary endpoints)
7
Adverse events
7
Safety laboratory measurements
3
Heart rate
1
Body weight
1
Creatinine and estimated glomerular filtration 
rate (eGFR)
1
Blood pressure
1
6.2
IMPORTANT PROTOCOL DEVIATIONS
A protocol deviation (PD) is important, if it affects the rights or safety of the study patients or 
if it can potentially influence the primary outcome measures for the respective patients in a 
way that is neither negligible nor in accordance with the study objectives. 
Important protocol deviations (iPDs) will be described in the clinical trial report (CTR). A 
listing of patients with medication code broken will be provided.
Table 6.2: 1
Important protocol deviations
Category / 
Code
Description
Requirements
Excluded 
from
A
Entrance criteria not met
A1
Target indication not met
A1.06
No chronic HF or no NYHA 
class II-IV
Inclusion criterion #5 not met
None
A1.07
Conditions on ejection 
fraction (EF) not met
Inclusion criterion #6 not met
None
A1.08
Conditions on NT-proBNP 
not met
Inclusion criterion #7 not met
None
A1.09
Conditions on HF not met
Inclusion criterion #8 not met
None


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Table 6.2: 1
Important protocol deviations (cont.)
Category / 
Code
Description
Requirements
Excluded 
from
A2/3
Other entrance criteria not 
met
A2.02
Age out of range
Inclusion criterion #1 not met
None
A2.08
Specific inclusion criterion 
for women of child-bearing 
potential not met
Inclusion criterion #2 not met
None
A2.14
6MWT distance above 350m 
at screening or baseline or 
below 100m at baseline
Inclusion criterion #4 or exclusion criterion 
#10 not met
SensRS1
A2.12
Inclusion criterion on stable 
concomitant medication not 
met
Inclusion criterion #9 not met
None
A3.44
Patient with unstable 
conditions
Exclusion criteria #1, #2, #6. #9, #13, #18 
or #22 not met, inclusion criterion #10 not 
met
None
A3.49
Participation in another 
Empagliflozin HF trial
Exclusion criterion #3 not met
None
A3.51
Type 1 diabetes
Exclusion criterion #4 not met
None
A3.09
Renal insufficiency or renal 
impairment (assessed by 
eGFR)
Exclusion criterion #5 not met
None
A3.33
Systolic blood pressure at 
visit 1 or 2 out of range
Exclusion criterion #7 not met
None
A3.31
Atrial fibrillation or atrial 
flutter with a resting heart 
rate >110bpm 
Exclusion criterion #8 not met
None
A3.48
Presence of condition that 
precludes exercise testing
Exclusion criterion #11 not met
None
A3.47
Participation in structured 
Exercise training
Exclusion criterion #12 not met
None
A3.42
Recently implanted ICD 
Exclusion criterion #14 not met
None
A3.43
Implanted CRT
Exclusion criterion #15 not met
None
A3.29
Patients with 
cardiomyopathies excluded 
by the protocol 
Exclusion criterion #16 not met
None
A3.30
Any severe (obstructive or 
regurgitant) valvular heart 
disease excluded by the 
protocol
Exclusion criterion #17 not met
None
A3.06
Indication of liver disease
Exclusion criterion #19 not met
None
A3.34
Haemoglobin at visit 1 below 
cut-off
Exclusion criterion #20 not met
None
A3.35
History of Ketoacidosis
Exclusion criterion #21 not met
None
A3.36
Gastrointestinal (GI) surgery 
or GI disorder that could 
interfere with study 
medication absorption in the
investigator’s opinion
Exclusion criterion #23 not met
None


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Table 6.2: 1
Important protocol deviations (cont.)
Category / 
Code
Description
Requirements
Excluded 
from
A3.37
Documented or active 
malignancy
Exclusion criterion #24 not met
None
A3.39
Intake of restricted 
medications or any drug 
considered likely to interfere 
with the safe conduct of the 
trial
Exclusion criterion #25  not met
None
A3.40
Treatment with any SGLT-2 
inhibitor
or SGLT-1 and 2 inhibitor
Exclusion criterion #26 not met
None
A3.50
Treatment with i.v. iron 
therapy or erythropoietin 
(EPO) within 3 months prior 
to screening
Exclusion criterion #27 not met
None
A3.11
Intake of an investigational 
drug in another trial within 30 
days prior to intake of study 
medication in this trial
Exclusion criterion #28 not met
None
A3.41
Known allergy or 
hypersensitivity to
empagliflozin
Exclusion criterion #29 not met
None
A3.13
Relevant alcohol or drug 
abuse and other conditions 
affecting study compliance 
Exclusion criterion #30 not met
None
A3.12
Specific exclusion criterion 
for pre-menopausal women 
not met
Exclusion criterion #31 not met
None
A3.14
Any other clinical condition 
unsafe for participation that 
would jeopardise patient 
safety while participating in 
this clinical trial
Exclusion criterion #32 not met
None
B
Informed consent
B1
Informed consent not 
available/not done
Informed consent date missing
All
B2
Informed consent too late
Informed consent date <actual consent 
date> was after Visit 1 date <Visit 1 date>
None


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Table 6.2: 1
Important protocol deviations (cont.)
Category / 
Code
Description
Requirements
Excluded 
from
C
Trial medication and 
randomisation
C1.02
Incorrect trial medication 
taken
Wrong medication taken for more than 20% 
of the overall treatment duration. Can only 
be finally judged after data base lock 
(DBL) since unblinding information is 
required.
None
C3.01
Non-compliance with study 
drug intake
Compliance <80% or >120%
None
C4.011
Medication code broken 
inappropriately
Medication code was broken for no valid 
reason.
Final decision at the DBL meeting based on 
medical judgement. 
None
D
Concomitant medication
D2.01
Prohibited medication use
Review of eCRF for prohibited medication.
Final decision at the DBL meeting based on 
medical judgement.
None
G
Study-specific analysis
G3.481
Unsuitable set up or conduct 
for 6MWT at baseline or 
week 12
Important deviations from the set-up or 
conduct as defined in the protocol
SensRS1
G3.491
Not compliant with 
contraindications of the 
6MWT
6MWT not stopped when it should have 
been based on stopping criteria, 6MWT not 
rescheduled appropriately when patient 
presents with relative contraindications 
SensRS1
G3.501
Assessment order not 
followed that could influence 
PRO at baseline or week 12
PRO measurements not before any other 
assessment at baseline or week 12
None
I
Other safety-related 
deviations
I2.01
Pregnancy
None
KEY: 6MWT= six minute walk test, HF=Heart Failure, NT-proBNP=N-Terminal Pro-Brain Natriuretic Peptide, NYHA= 
New York heart association, EF=ejection fraction, T1DM=Type 1 diabetes mellitus, bpm=beats per minute, 
ICD=implantable cardioverter defibrillator, CRT= cardiac resynchronisation therapy.
1 needs to be checked at site by Local Clinical Monitors (CMLs) / Clinical Research Associates (CRAs) as these cannot be 
checked programmatically


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6.3
SUBJECT SETS ANALYSED
The following patient sets are defined in section 7.3 of the protocol:
•
Randomised set (RS)
This patient set includes all randomised patients, whether treated or not. Treatment 
will be evaluated as randomised.
•
Treated set (TS)
This patient set includes all patients who were dispensed study medication and were 
documented to have taken at least one dose of investigational treatment. Treatment 
will be evaluated as randomised.
In addition the following patient set is defined:
•
Screened Set (SCR)
Consists of all patients screened for the trial, with informed consent given and who 
completed at least one screening procedure at Visit 1.
For sensitivity analyses the following patients set is defined:
•
Sensitivity analysis set 1 (SensRS1)
Randomised patients excluding patients with an iPD related to 6MWT, i.e. iPD 
categories A2.14, G3.48 and G3.49 of Table 6.2: 1
•
Sensitivity analysis set 2 (SensRS2)
Randomised patients excluding patients for which at least one on-treatment value of 
urine glucose test result was included in the safety laboratory reports posted to a 
portal by the central laboratory, and the reports were accessed before database lock.
•
Sensitivity analysis set 3 (SensRS3)
Randomised patients excluding non-diabetic patients for which at least one on-
treatment value of urine glucose test result was included in the reports posted and 
accessed before database lock.
Demographics and baseline characteristics as well as the efficacy analysis will be based on 
the RS. Demographics will be repeated on the TS if the number of patients in the analysis sets 
differ by more than 5%. The safety analysis will be based on the TS.
Overall number of patients participating in the study (screened, randomised, screened but not 
randomised, etc.) by region and country will be based on the SCR.


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Table 6.3: 1
Subject sets analysed
Subject set
Class of endpoint
Screened 
Set
Randomised 
set
Treated set
Primary and key secondary 
endpoints 
X
X
(other) Secondary and further 
endpoints 
X
Safety endpoints 
X
Demographic/baseline 
endpoints
X
X1
Extent of exposure
X
Disposition
X
1 Demographics will be repeated on the TS if the number of patients in the analysis sets 
differ by more than 5%.
6.4
SUBGROUPS
Subgroups are provided in Table 6.4: 1. Missing categories for subgroup variables will not be 
considered in the respective analysis. 
Subgroups with fewer than 14 patients in total (yielding approximately 7 patients per 
treatment group) will generally not be included in the analyses of subgroups. Small 
subgroups can be combined into other subgroups. Final decision will be made at final 
Blinded Report Planning Meeting (BRPM).
Although several subgroup analyses are prespecified in Table 6.4: 1, the subgroup analysis by 
Diabetes at baseline (diabetic, non-diabetic) is the medically and academically most 
important subgroup analysis.


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Table 6.4: 1
Categories of covariates for displays of baseline characteristics and subgroup 
analyses
Variable
Categorisation
Demo-
graphics1
Subgroups for 
Efficacy 
endpoints2
Safety
Age (years)
<50
50 to <65
65 to <75
75 to <85
≥85
X
< 65
≥65
X
X
Sex
Male
Female
X
X
Region3
Europe, Australia, North 
America
X
Europe or Australia
North America
X
Ethnicity
Hispanic/ Latino
Not Hispanic/ Latino
X
X
Race
American Indian or Alaska 
Native
Asian
Black or African-American
Native Hawaiian or other 
Pacific Islander
White
X
White
Black/ African-American
Asian
Other including mixed race
X
BMI (kg/m2)
<30
≥30
X
X
eGFR at baseline 
(mL/min/1.73m²)
≥90
60 to <90
45 to <60
30 to <45
20 to <30
<20
X
≥60 
45 to <60
30 to <45
<30
X


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Table 6.4: 1
Categories of covariates for displays of baseline characteristics and subgroup 
analyses (cont.)
Variable
Categorisation
Demo-
graphics1
Subgroups for 
Efficacy 
endpoints2
Safety
Diabetes at baseline4
DM, 
pre-DM, 
non-DM (excl. pre-DM)
X
DM, non-DM
X
X (only 
hypoglycemia)
History of hypertension
Yes / No
X
Baseline BP
SBP<140 and DBP<90 vs. 
SBP≥ 140 or DBP≥90
X
X
Atrial Fibrillation at 
baseline5
Yes/ No
X
X
Baseline LVEF
</≥50
X
<50, 50 to <60, ≥60
X
History of HHF within the 
last 12 months 
Yes / No
X
History of valvular disease
Yes / No
X
Cause of HF
Ischemic
Hypertensive
Valvular heart disease
Diabetic
Alcoholism
Idiopathic
Cardiomyopathy
Other
X
Time since diagnosis of HF
≤ 1 year, >1 to ≤ 5 years, > 5 
to ≤ 10years, > 10 years
X
NYHA at baseline
I/II/III/IV
X
II6 vs. III/IV
X
NT-proBNP (separated by 
atrial fibrillation status) at 
baseline7
atrial fibrillation at baseline 
and < / ≥ median;
no atrial fibrillation at 
baseline and < / ≥ median 
X


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Table 6.4: 1
Categories of covariates for displays of baseline characteristics and subgroup 
analyses (cont.)
Variable
Categorisation
Demo-
graphics1
Subgroups for 
Efficacy 
endpoints2
Safety
Baseline KCCQ-TSS
By quartiles
X (only 
KCCQ-TSS 
and 6MWT)
Baseline CHQ-SAS 
Dyspnea domain
By quartiles
X (only CHQ-
SAS dyspnea 
and 6MWT)
Baseline PGI-S Dyspnea
5 categories
X
X (only CHQ-
SAS dyspnea)
Baseline PGI-S HF 
symptoms
5 categories
X
X (only 
KCCQ-TSS)
Baseline distance walked in 
6 minutes
< / >= median 
X (only 
6MWT)
Baseline use of ACE-
inhibitor, ARB or ARNi
Yes / No
X8
X
Baseline use of diuretics 
other than MRA
Yes / No
X8
X
Baseline use of MRA
Yes / No
X8
X
Baseline use of loop or 
high-ceiling diuretics
Yes / No
X8
X
baseline haemoglobin 
< / >= median
X
1 The column demographics shows categories displayed for overall demographics. 
Demographics are not planned by subgroup. 
2 Subgroups planned for the following endpoints: primary and key secondary endpoints. 
3 Region categorisation: see Table 9.1: 1. 
4 Diabetes at baseline categorisation: see Table 9.2: 1; for subgroup analysis ‘pre-DM’ and 
‘non-DM (excluding pre-DM)’ will be combined into the category ‘non-DM’
5 atrial fibrillation at baseline means atrial fibrillation in last ECG before treatment intake
6 patients with NYHA class I are counted in subgroup NYHA class II
7 Median NT-proBNP will be calculated for randomised patients with/without atrial 
fibrillation at baseline separately and subgroups will be defined based on the respective 
median for patients with/without atrial fibrillation at baseline accordingly
8 part of the presentation of baseline concomitant therapy as outlined in Section 7.2
6.5
POOLING OF CENTRES
Not applicable because centre/country is not included in the statistical model.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
The imputation strategy for all confirmatory analyses, i.e. primary analysis of primary and 
key secondary endpoints, will be based on the following principle:


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Patients with an available week 12 measurement of the endpoint, regardless of whether on or 
off-treatment, will be ranked based on change from baseline at week 12. If a patient performs 
the visit but the 6MWT is not done this will not be regarded as missing data. This case will be 
evaluated as a measured distance of 0m. 
All imputed data due to missing data will be lower than the measured values and will be 
ranked in the following orders: Patients who do not have a clinical event (death, serious 
adverse event or any AE leading to discontinuation) and have a value at week 6 are ranked by 
their values. Patients who do not have a clinical event and have no valid post-baseline value 
are ranked below. Patients who have a clinical event are given a lower rank and death is 
ranked below any other clinical event by time to death from randomisation. 
A treatment-emergent SAE with outcome “recovered with sequelae” leading to an 
amputation is considered to be an ongoing clinical event.
Imputation will not be applied for any parametric analysis, descriptive statistics and 
derivation of responder thresholds for the key secondary endpoints.
6.6.1
Primary endpoint
Handling of missing data is described in section 7.5 of the clinical trial protocol for the 
primary analysis and subgroup analysis of the primary endpoint change from baseline in 
6MWTD.
6.6.2
Key Secondary endpoint
Missing individual items within a questionnaire will be handled according to the rules in
Appendix 9.4.
Patients with an available week 12 measurement, regardless of whether on or off treatment, 
will be ranked based on change from baseline at week 12 regardless of clinical events. 
For any missing week 12 assessment of the KCCQ-TSS, the below imputation will be applied
for the primary analysis and subgroup analysis in accordance to the strategy for the primary 
endpoint:
Since the lowest possible value for change from baseline in KCCQ-TSS is 0 minus the 
highest possible baseline value (100), all imputed values for change from baseline are 
below -100 as described in Table 6.6.2: 1 below.


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Table 6.6.2: 1 Imputation Rules for missing KCCQ-TSS Assessments at Week 12
Category
Ranking
Case description
(Imputed) 
Change from 
baseline in 
KCCQ-TSS for 
described case 
1
Missing data on KCCQ-
TSS at week 12 and no 
clinical event:
Patients with missing 
KCCQ-TSS 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
score is available
Patient has a 
change from 
baseline to last 
available value
of x points, no 
clinical event
-102 +x/1000
No information 
of post-baseline 
KCCQ-TSS and 
no clinical event 
-104
2
Missing data and 
clinical event (except 
death).
A clinical event is 
defined as ongoing SAE 
at week 12 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 week 12 
KCCQ-TSS 
assessment and 
patient alive at 
week 12.
-106
3
Patient died before the 
assessment of KCCQ-
TSS at week 12 was 
conducted. 
Ranked by time to 
death from 
randomisation
Patient died y 
days after 
randomisation
-108+y/1000
For any missing week 12 assessment of the CHQ-SAS, the below imputation will be applied
for the primary analysis and subgroup analysis in accordance to the strategy for the primary 
endpoint:
Since the lowest possible value for change from baseline in CHQ-SAS dyspnea (fatigue) 
score is 1 minus the highest possible baseline value (7) all imputed values for change from 
baseline are below -6 as described below in Table 6.6.2: 2.


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Table 6.6.2: 2 Imputation Rules for missing CHQ-SAS Assessments at Week 12
Category
Ranking
Case description
(Imputed) 
Change from 
baseline in 
CHQ-SAS for 
described case 
1
Missing data on CHQ-
SAS at week 12 and no 
clinical event:
Patients with missing 
CHQ-SAS 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 
score is available
Patient has a 
change from 
baseline to last 
available value of x 
points, no clinical 
event
-12 +x/1000
No information of 
post-baseline CHQ 
and no clinical 
event 
-14
2
Missing data and 
clinical event (except 
death).
A clinical event is 
defined as ongoing 
SAE at week 12 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 
week 12 CHQ 
assessment and 
patient alive at 
week 12.
-16
3
Patient died before the 
assessment of CHQ at 
week 12 was 
conducted. 
Ranked by time to 
death from 
randomisation
Patient died y days 
after randomisation
-18+y/1000
Missing change from baseline due to missing baseline questionnaire will not be imputed.
6.6.3
Secondary endpoints
Handling of missing data for the change from baseline to week 6 in exercise capacity as 
measured by the distance walked in 6 minutes will be analogous to the primary endpoint, see 
Table 6.6.3:1


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Table 6.6.3: 1 Imputation rules for missing exercise capacity at week 6
Category
Ranking
Case description
Imputed change 
from baseline 
in 6MWTD for 
described case 
(in m)*
1
Missing data on 6MWT 
at week 6 and no 
clinical event:
Patients with missing 
6MWT at week 6 and 
no event as in category 
2 or 3
Ranked above 
patients who died 
or patients with a 
clinical event, but 
below patients 
with available 
measurement at 
week 6.
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 
6
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 6 
6MWT distance 
and patient alive 
at week 6.
-356
3
Patient died before the 
measurement of 6MWT 
at week 6 was 
conducted. 
Ranked by time 
to death from 
randomisation
Patient died y 
days after 
randomisation
-358+y/1000
6.6.4
Longitudinal Analyses
There will be different methods of analysing continuous longitudinal data. 
Observed case on-treatment (OC-OT):
Only the available data that were observed while patients were on study medication (defined 
as time from first drug intake until last permanent treatment stop date plus the endpoint 
specific follow-up time (as defined in Table 6.1:2)) are considered. 
Measurements are assigned to planned weeks according to Table 6.7: 2
Imputed records are not included
Observed case including data after treatment discontinuation (OC-AD):


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All available data are considered, including values obtained on treatment or post-treatment.
Imputed records are not included.
Measurements are assigned to planned weeks according to Table 6.7: 1 and Table 6.7: 2
Worst case imputation (WCI):
All available data as described for OC-AD and additionally including worst case imputation 
as described in Sections 6.6.1 – 6.6.3. This imputation will only be considered in non-
parametric analyses.
6.6.5
Safety Analyses
There will be no imputation of data for safety analyses. 
6.6.6
Missing dates
Adverse event data 
Missing or partial date information for AEs will be replaced according to general Boehringer 
Ingelheim (BI) rules described in the BI guidance for handling of missing and incomplete AE 
dates (2).
Partial onset dates from clinical event committee (CEC):
In the unlikely case that only the year is documented, the day and month will be imputed as 
01 Jan unless the subsequently derived date is before randomisation; in this case the date of 
randomisation will be used as start date. 
If year and month is present the day will be imputed as first of the month unless the 
subsequently derived date is before randomisation; in this case the date of randomisation will 
be used.
Death date
For patients with a record of death captured on the electronic case report form (eCRF) with 
missing or only partial death date from all available sources, the death date will be derived as 
the latest date of any dates as of: event onset and end dates from either the AE page, or CEC 
adjudicated onset dates, by using also imputed AE dates, range or of possible days based on 
partial death date and date of last contact. 
Missing information on the date of first administration of trial drug
If the date of first drug administration is missing but the patient was randomised, the date of 
the first drug administration will be set to the date of randomisation. If the date of first 
administration is partially missing with the month and year present, the day will be set to the 
date of randomisation if randomisation was in the same month. If randomisation was in the 
month prior to the first drug administration the missing day will be imputed as the first day of 
the month. 
Missing date of last contact date:


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If the date is partially or completely missing, use the minimum of the following dates:

the date of Informed Consent (IC) withdrawal (if applicable)

date of death 

If the patient did not die and did not withdraw consent, the latest of: 
o
visit end dates, 
o
drug administration dates, 
o
last drug stop date, 
o
last assessment date (ECG date, date of KCCQ, date of CHQ)  
o
AE onset and AE end dates

(in case for partially missing date) Last day of the year/month given as partial date
In case of a partially missing date, if the imputed date is before the first day of the month/year 
given as partial date, the first day of the month/year will be used. 
All other cases need to be assessed by the trial team on an individual patient basis, using the 
above points as guidance.
Missing information on the date of trial medication stop
If the date is partially or completely missing, use the minimum of the following dates:

End of treatment visit date (if available)

Date of death (if applicable)

Trial completion (last contact date)

Longest treatment duration (assuming 1 tablet/day)

(in case for partially missing date) Last day of the year/month given as partial date
In case of a partially missing date, if the imputed date is before the first day of the month/year 
given as partial date, the first day of the month/year will be used. 
All other cases need to be assessed by the trial team on an individual basis, using the points 
above as guidance.  
Missing information on concomitant therapy dates
For incomplete date information the midpoint of the possible interval will be used. If only the 
year is present the day and month will be imputed as 01 July, if year and month is present the 
day will be imputed as 15. If the year is missing, the date will be considered missing. 
If this leads to contradictions for the start or end date of a concomitant therapy (e.g. imputed 
end date before documented start date) a partial end date will be imputed as the end of the 
interval or a partial start date will be imputed as the start of the interval in the database to 
resolve this contradiction. 
All other cases or conflicting cases resulting from these imputation rules need to be assessed 
by the trial team on an individual basis.  


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6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
For serum creatinine and values based 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. 
Since the protocol specifies that all measurements are taken at visit 2 before any intake of 
trial medication, all measurements at the first day of drug intake are assumed to qualify as 
baseline measurements. For laboratory values, clock time is recorded. If a lab measurement is 
done after treatment start, this will not qualify as baseline measurements, except in case of 
HbA1c, which is considered to be a stable measurement and qualifies for baseline on the 
whole day of first treatment intake.
For randomised patients without any treatment intake: For serum creatinine and values based 
upon this measurement such as eGFR, baseline will be defined as the mean of all available 
measurements from the screening visit until and including the day of randomisation. For all 
other endpoints, baseline will be defined as the last available measurement before or on the 
day of randomisation.
Medication taken at baseline is any medication with start date continued or before date of 
first study medication intake (randomisation for patients not treated) and end date continued 
or on or after date of first medication intake (randomisation for patients not treated).  
Measurements taken after the first intake of randomised trial medication will be considered 
on-treatment values if they have been obtained up to end of the parameter specific follow-up 
period as defined in Table 6.7: 1 below and will be assigned to the randomised study drug for 
efficacy and safety analyses. 
Measurements taken after the end of the endpoint specific follow-up period after the last 
intake of study drug will be considered post-treatment values.
On-treatment (for OC-OT analysis) or all post-randomisation (for OC-AD analysis) efficacy 
and safety measurements will be assigned to visits based on time windows around the 
planned visit dates. These time windows are defined based on the planned number of days 
after the date of first administration of study drug. 
The time window for the first visit after randomisation starts on the day after the first intake 
of study drug. For the primary analysis of the primary endpoint and the key secondary 
endpoints, the start of the time window of week 12 assessment will follow the protocol 
defined time window (refer to Table 6.7: 1 for details). For all sensitivity analyses and all 
other endpoints the midpoint between two on-treatment visits defines the end of a time 
window, with the midpoint being included in the time window of the preceding visit (Table 
6.7: 2). 


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Table 6.7: 1
Time windows for primary analysis of primary and key secondary endpoints
and Sensitivity analyses using Wilcoxon model
Time window (days after baseline)
Visit number
Visit label
Planned days
Start
End
2
Baseline1
1
NA
+1
3
Week 6
43
+2
+772
4
Week 12
85
+78
NA2
1 Only values taken prior or on the day of treatment start with randomised study drug can be considered baseline values. To be conservative, 
all data on the day of treatment start will be assumed to be before treatment start for 6MWT and PROs. Time windows will be used for 
assignment of measurements to scheduled visits.
2 For patients with no value in the visit 4 window (visit 3 window respectively), determination of imputation categories will be: deaths
before day 92 (day 77 respectively) will be considered for imputation category 3; value for patients with clinical event overlapping at least 
partially with the time window day 78 to day 92 (day 2 to day 77 respectively) will be imputed according to imputation category 2.
Table 6.7: 2
Time windows for measurements except primary analysis of primary and key 
secondary endpoints [OC-OT]
Time window (days after 
baseline)
Visit number
Visit label
Planned days
Start
End
Endpoints assessed at each on-site visit (e.g. creatinine / eGFR)
2
Baseline 1
1
NA
+1
3
Week 6
43
+2
+64
4
Week 12
85
+65
Trt stop + x*
days
FU
FU
Trt stop + 7 days
Trt stop + x* + 
1 day
NA
Endpoints that are not assessed on visit 3 (e.g. weight)
2
Baseline 1
1
NA
+1
4
Week 12
85
+2
Trt stop+ x*
days
FU
FU
Trt stop + 7 days
Trt stop + x* + 
1 day
NA
1 Only values taken prior to the start of treatment with randomised study drug can be considered baseline values. Time windows will be 
used for assignment of measurements to scheduled visits.
* see Table 6.1: 2


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Table 6.7: 3
Time windows for measurements except primary analysis of primary and key 
secondary endpoints [OC-AD]
Time window (days after 
baseline)
Visit number
Visit label
Planned days
Start
End
Endpoints assessed at each on-site visit (e.g. creatinine / eGFR)
2
Baseline 1
1
NA
+1
3
Week 6
43
+2
+64
4
Week 12
85
+65
NA
Endpoints that are not assessed on visit 3 (e.g. weight)
2
Baseline 1
1
NA
+1
4
Week 12
85
+2
NA
1 Only values taken prior to the start of treatment with randomised study drug can be considered baseline values. Time windows will be 
used for assignment of measurements to scheduled visits.
For examinations that are not planned at every on-treatment visit, the time windows will be 
defined according to the same algorithm, based on the midpoint between the planned visit 
day of such an examination. Examples for eGFR and weight can be found in Table 6.7: 2 for 
OC-OT analyses and in Table 6.7: 3 for OC-AD analyses.
Only one observation per time window will be selected for analysis at an on-treatment visit –
the value will be selected which is closest to the protocol planned visit day. 
For the primary endpoint (6MWTD) and any measurement related to the 6MWT assessment
the longest walking distance for each day will be used for the analysis for that day.
If there are two measurements which have the same time difference in days to the planned 
day, or if there are two measurements on the same day (endpoints not related to the 6MWT), 
the first value will be used.
Baseline definition for concomitant therapies
Concomitant medication taken at baseline is any medication with start date continued or 
before date of first study medication intake (randomisation date will be used for patients not 
treated) and end date continued on or after date of first study medication intake 
(randomisation date will be used for patients not treated). 


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7.
PLANNED ANALYSIS
For End-Of-Text (EoT) tables, the set of summary statistics is: N / Mean / standard deviation 
(SD) / standard error (SE) / Min / lower quartile (Q1) / Median / upper quartile (Q3) / Max. 
The 1st and 99th percentiles might be substituting minimum and maximum in tables with 
open-ended values to safeguard against implausible extremes. Final decision will be made at 
the final BRPM.
Geometric means and gCV will be added to the presentation or replace the presentation of 
mean, standard error and standard deviation for parameters (e.g. NT-proBNP) that follow a 
log-normal distribution rather than a normal distribution. 
Statistical parameters will be displayed to a defined number of decimal places as specified in 
the BI guideline “Standards for Reporting of Clinical Trials and Project Summaries” (3)
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group (unless otherwise specified, all patients in the respective patient 
set whether they have non-missing values or not). Percentages will be rounded to one decimal 
place. The category missing will be displayed only if there are actually missing values.
Disposition of the patient population participating in the trial will be analysed by treatment 
groups and presented in the clinical trial report as a frequency distribution. The number of 
patients participating (screened, randomised, screened but not randomised, etc.) in the study 
by region, country and, for treated patients, centre, will also be analysed by treatment group 
and presented as a frequency distribution. 
Disposition as required for reporting for the trial in EudraCT will be provided. Enrolment 
will be summarised by country and by age group for reporting in EudraCT. 
The reasons for not randomising screened patients will be summarised descriptively. 
The frequency of patients with iPDs will be presented by treatment group for the randomised 
set. The frequency of patients in different analysis sets will also be analysed for each 
treatment group.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report.
Demographics and baseline characteristics will be analysed based on RS. Demographics will 
be repeated on the TS if the number of patients in the analysis sets differ by more than 5%.
Standard descriptive analysis and summary tables will be presented. These summary tables 
will include description of variables detailed in Section 6.4. In addition, descriptive analyses 
of the following continuous variables measured at baseline will be presented: Age, body mass 
index (BMI), time since HF-diagnosis, systolic blood pressure (SBP), diastolic blood pressure 


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(DBP), weight, eGFR, NT-proBNP, heart rate. For patients with diabetes at baseline, HbA1c
at baseline will be shown descriptively.
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report using the randomised set. 
Concomitant medication use will be summarised by Anatomical-Therapeutic-Chemical 
classification level 3 (ATC1-ATC2-ATC3) and preferred name. Summaries will be presented 
for concomitant therapies taken at baseline and separately those added after baseline.
Separate summaries of use of heart failure-related drugs (e.g. ARNi, beta-blockers, 
ivabradine, diuretics, ACE-inhibitors, ARBs, MRAs, cardiac glycosides), anticoagulants, 
acetylsalicylic acid (ASA), or lipid lowering drugs at baseline and separately those for added 
after baseline will be presented. Definitions of these medication groups are based on World 
Health Organization Drug Dictionary (WHO DD) and are stored in the Project Data 
Management and Analysis Plan (PDMAP).
Use of devices at baseline will also be summarised.
Concomitant diseases will be summarised by system organ class and preferred term. Relevant 
medical history by treatment group will also be presented. Both summaries will be presented 
using the randomised set.
The number and percentage of patients receiving the best tolerated treatment for HF 
symptoms and other common concomitant diseases or symptoms (e.g. hypertension, diabetes, 
cardiac arrhythmia, fluid retention) according to prevailing guidelines in the opinion of the 
investigator will be reported.
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the report. The number and 
percentage of patients with overall study medication compliance will be reported. 
7.4
PRIMARY ENDPOINT
7.4.1
Primary analysis of the primary endpoint
The primary endpoint ‘change from baseline to week 12 in exercise capacity’ as measured by 
the change from baseline to week 12 in distance walked in 6 minutes will be evaluated using 
a normal approximation of the Wilcoxon rank test using the randomised set.
For estimation of effect, non-parametric Hodges-Lehmann estimate for the median difference 
will be used. Corresponding 95% confidence intervals will be displayed. Any confirmatory 
conclusion such as for hierarchical testing 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.


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If no 6MWTD is available at week 12, an imputed value as defined in Section 7.5 of the CTP 
will be used. 
The primary analysis will be conducted on all randomised patients, regardless of whether on 
or off-treatment on the day of 6MWT assessment. Where more than one measurement is 
available for the same day (duplicate measurements), the longest distance walked will be 
used for analysis. In case more than one 6MWT results in the same distance walked, the first 
assessment will be used for analysis.
7.4.2
Sensitivity analysis of the primary endpoint
Sensitivity analysis for the primary endpoint will include;

a mixed model repeated measure analysis (MMRM) without imputation of missing 
values (OC-AD).

an MMRM restricted to on-treatment values (OC-OT).
The model will include visit-by-treatment interaction and baseline-by-visit interaction. An 
unstructured covariance structure will be used to model the within-patient errors. Descriptive 
statistics will be calculated for the value at visit and change from baseline based on OC-AD 
on the randomised set and based on OC-OT on the treated set. The MMRM analyses will also 
be shown graphically.
The primary analysis will be repeated restricted to patient in the sensitivity analysis set
SensRS1, SensRS2 and SensRS3.
If the mean difference between the treatment groups in 6MWTD is above 15m at baseline,
the primary analysis will be repeated, but using the ranks of the residuals from the following 
linear regression model
6MWTD12weeks~6MWTDBaseline
with patients without week 12 data ranked below any patient with week 12 assessment 
similar to the rules for primary analysis.
7.4.3
Subgroup analysis of the primary endpoint
The primary analysis of the primary endpoint will be repeated for each subgroup as defined 
in Table 6.4: 1. A forest plot summarising all subgroup analyses will be shown. 
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
If the null hypothesis for the primary analysis of the primary endpoint 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:


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If the largest p-value of the primary analysis of the two key secondary endpoints is below 
5%, both null hypotheses of the key secondary endpoints will be rejected. Otherwise, if the 
smaller p-value of the primary analysis of the two key secondary endpoints is below 2.5%, 
only the corresponding null hypothesis can be rejected. 
If the primary hypothesis of the primary endpoint is not rejected, the tests of the key 
secondary endpoints are conducted in an exploratory manner.
7.5.1.1 Primary analysis of the key secondary endpoints
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 ‘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 
randomised 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 in Section 6.6 will be 
used. 
7.5.1.2 Sensitivity analysis of the key secondary endpoints
Sensitivity analysis for the key secondary endpoint will include 

a mixed model repeated measure analysis without imputation of missing values (OC-
AD).

a mixed model repeated measure analysis restricted to on treatment values (OC-OT).
The model will include visit-by-treatment interaction and baseline-by-visit interaction. An 
unstructured covariance structure will be used to model the within-patient errors. Descriptive 
statistics will be calculated for the value at visit and change from baseline based on OC-AD 
on the randomised set and based on OC-OT on the treated set.
The primary analysis will be repeated restricted to patients in sensitivity analysis sets 
SensRS2 and SensRS3.
7.5.1.3 Subgroup analysis of the key secondary endpoints
The primary analysis of the key secondary endpoints will be repeated for each subgroup as 
defined in Table 6.4: 1. A forest plot summarising all subgroup analyses will be shown. 


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7.5.1.4 Further exploratory analyses of the key secondary endpoints
A minimal clinically meaningful within-patient change in scores (i.e. responder threshold) 
will be estimated from the trial population (both treatment groups pooled) for KCCQ-TSS 
and CHQ-SAS dyspnea as described in Appendix 9.3.
A responder analysis using a chi-square test will be evaluated in addition. The response 
threshold will be determined as defined in Appendix 9.3. 
An empirical cumulative distribution function of descriptive change from baseline to week 12 
by treatment group on OC-AD on the randomised set will be shown.
7.5.2
Other Secondary endpoints
Other secondary endpoints will not be part of the testing hierarchy. No correction for 
multiple testing of the other secondary endpoints will be made.
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. If no 6MWTD is 
available at week 6, an imputed value as defined in Section 6.6 will be used. 
All other secondary endpoints will take into account all data, regardless of whether the 
patient was on treatment or not, and without imputation of missing values (OC-AD).
The other continuous endpoints are generally analysed in an MMRM, including visit-by-
treatment interaction and baseline-by-visit interaction. An unstructured covariance structure 
will be used to model the within-patient errors. The MMRM analyses will also be shown 
graphically.
Descriptive statistics will be calculated for the value at visit and change from baseline.
Shift from baseline score to 12 week score will be tabulated descriptively for single items 
collected in the context of the clinical congestion score (dyspnea, orthopnea, fatigue, jugular 
venous distension, rales and edema).
The endpoint “Change from baseline in NT-proBNP at week 12” (after log-transformation) 
will be evaluated using an MMRM analysis over time with baseline log-transformed NT-
proBNP by visit interaction and visit by treatment interaction as covariates without 
imputation of missing values. Estimates obtained from the model will then be back-
transformed and reported on the original scale. The MMRM analyses will also be shown 
graphically.
Proportion of patients in every category of global impression of change at week 12 will be 
evaluated using Cochran-Mantel-Haenszel test on the difference in mean treatment scores, 
using modified ridit scores.


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Proportions of patients categorised by the difference in scores between baseline and week 12 
in patient global impression of severity score will be evaluated using a Cochran-Mantel-
Haenszel test on the difference in mean treatment scores, using modified ridit scores.
Difference in score will be defined as the number of categories improved/deteriorated from 
baseline. Shift from baseline score to 12 week score will be tabulated descriptively.
7.6
FURTHER ENDPOINTS
All further endpoints will take into account all data, regardless of whether the patient was on 
treatment or not, and without imputation of missing values (OC-AD).
7.6.1
Binary endpoints
For the following binary endpoints descriptive analyses will be complemented by an 
exploratory chi-square test to compare response between treatment groups.
•
Increase in 6MWT ≥ 30 m from baseline at week 12
•
Response in KCCQ domains at week 12, as defined in Section 5.3. A forest plot of 
response at week 12 for each domain by treatment will be shown. 
•
Response in CHQ domains at week 12, as defined in Section 5.3. A forest plot of response 
at week 12 for each domain by treatment will be shown. 
Descriptive statistics are planned for all other binary endpoints:
•
Occurrence of HHF and Cardiovascular (CV) death
•
Occurrence of all-cause mortality
•
Occurrence of CV death
•
Occurrence of all-cause hospitalisation (first and recurrent)
•
Occurrence of hospitalisation 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
7.6.2
Ordinal endpoints
The following endpoints will be evaluated using the same models as defined for the 
corresponding secondary endpoints:
•
Change from baseline in Patient Global Impression of Severity of Heart Failure 
Symptoms at week 6.
•
Change from baseline in Patient Global Impression of Severity of Dyspnea at week 6.
•
Patient Global Impression of Change in Heart Failure Symptoms at week 6.


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•
Patient Global Impression of Change in Dyspnea at week 6.
•
Change from baseline in Clinician Global Impression of Severity of Chronic Heart Failure 
(CHF) at Week 6 and week 12
•
Clinician Global Impression of Change in CHF Severity at Week 6 and week 12
Frequencies and proportions of patients categorised descriptively by the 

shift in NYHA class from baseline to week 6 and to week 12.
7.6.3
Continuous endpoints
Further continuous endpoints are generally analysed in a mixed model with repeated 
measures (MMRM), including visit-by-treatment interaction and baseline-by-visit interaction. 
An unstructured covariance structure will be used to model the within-patient errors. The 
MMRM analyses will also be shown graphically.
Descriptive statistics will be calculated for the value at visit and change from baseline. 
•
Change from baseline in KCCQ overall summary score, CSS, and individual domains at 
Week 6 and week 12
•
Change from baseline in CHQ individual domains at week 6 and week 12
•
Change from baseline in SBP at Week 6 and week 12
•
Change from baseline in DBP at Week 6 and week 12
The following endpoint is assessed as part of the main analysis or sensitivity analysis of the 
corresponding secondary endpoint:
•
Change from baseline in KCCQ TSS at Week 6
•
Change from baseline in CHQ-SAS dyspnea at Week 6
•
Change from baseline in Clinical Congestion Score at week 6.
•
Change from baseline in NT-proBNP at week 6.
Since bodyweight is only measured at baseline and week 12, an ANCOVA model will be 
presented including baseline weight as a covariate. 
Descriptive statistics are planned for:
•
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
For the following parameters measured at the follow-up visit, additionally descriptive 
statistics at baseline, last value on treatment and follow-up will be presented for patients with 
valid measurements at all three timepoints. . 

SBP

DBP


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7.7
EXTENT OF EXPOSURE
Descriptive statistics tables based on the TS with mean, SD, SE, quartiles, median and range 
of the number of days a patient was on treatment will be provided. These tables will also 
provide the sum-total of the time (in years) that all patients were on treatment.
Frequency tables of number and percentage of patients belonging to categorical ranges of 
exposure weeks will be provided as well. Following are the categories of exposure-ranges (in 
weeks): >= 0 weeks, >=4 weeks, >= 8 weeks, >= 11 weeks.
7.8
SAFETY ANALYSIS
The safety analysis will be based on the treated set (TS). 
While tables will generally display results by randomised treatment, listings will reflect 
whether a measurement/AE occurred on or off treatment.
7.8.1
Adverse events
Unless otherwise specified, the analyses of adverse events (AEs) will be descriptive in nature 
and will be based on the number of patients with AEs and not on the number of AEs.
AEs will be coded using version 22.0 of the Medical Dictionary for Regulatory Activities 
(MedDRA) coding dictionary. 
Definitions of Boehringer Ingelheim customised MedDRA Queries (BIcMQs) for new 
MedDRA versions are maintained by the BI dictionary maintenance group. 
For analysis multiple AE occurrence data in the data from the eCRF will be collapsed into an 
AE provided that all of the following applies:
•
All AE attributes are identical (including Lowest Level Term (LLT), intensity, action 
taken, therapy required, seriousness, reason for seriousness, relationship, outcome, AE of 
special interest and also additional information of specific AEs or AESIs such anatomical 
location of UTI (upper UTI kidney versus Lower UTI bladder and below versus 
asymptomatic bacteriuria) or type of genital infection (fungal balanitis or vulvovaginitis 
versus other than fungal balinitis or vulvovaginitis)).
•
The occurrences were time-overlapping or time-adjacent (time-adjacency of 2 
occurrences is given if the second occurrence started on the same day or on the day after 
the end of the first occurrence).
For further details on summarisation of AE data, please refer to (2).
7.8.1.1 Assignment of AEs to treatment
The analysis of adverse events will be based on the concept of treatment-emergent adverse 
events. That means that all adverse events occurring between first drug intake till 7 days after 
last drug intake will be assigned to the randomised treatment. All adverse events occurring 


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before first drug intake will be assigned to ‘pre-treatment’ and all adverse events occurring 
after last drug intake + 7 days with be assigned to ‘follow-up’, except if otherwise specified.
In Section 15.3 general AE analysis tables will present only on-treatment AEs (applying the 
rule of 7 days for assignment as on-treatment) for the treatments groups. 
Appendix 16.1.13.1 will include an analysis (overall summary table, frequency of AEs by 
system organ class (SOC) / preferred term (PT), frequency of serious adverse events (SAEs) 
by SOC/PT) where AEs and SAEs are assigned to the following phases: Screening, each 
treatment group, post-treatment for each treatment group.
For listings, AEs will be assigned to one of the treatment phases of Screening, Placebo, Empa 
10, Post Placebo, Post Empa. 
7.8.1.2 AE summaries
An overall summary of adverse events will be presented. 
The frequency of patients with adverse events will be summarised by treatment, primary 
system organ class and preferred term. Incidence rates as defined in Section 7.8.1.7 will 
generally be included. 
AEs will also be reported by intensity (without incidence rates). Separate tables will be 
provided for 

for patients with serious adverse events, 

for patients with drug related serious AEs,

for patients with AEs leading to discontinuation

for patients with drug-related AEs.
AEs leading to death will be listed. 
The system organ classes will be sorted according to the standard sort order specified by the 
European Medicines Agency (EMA), preferred terms will be sorted by frequency (within 
system organ class).
Additionally, the following analyses will be reported in Appendix 16.1.13.1 for disclosure on 
EudraCT and clinicaltrials.gov:

Frequency [N(%)] of subjects with non-serious adverse events occurring with 
incidence in preferred term greater than 5% by treatment,

Adverse events per arm for disclosure on EudraCT by treatment

Non-serious adverse events for disclosure on EudraCT by treatment

Serious adverse events for disclosure on EudraCT by treatment


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7.8.1.3 Adverse events of special interest (AESIs) 
Hepatic injury
Hepatic injury AEs will be summarised based on a Standardised MedDRA Query (SMQ)
based definition. From SMQ Drug related hepatic disorders (20000006) the following narrow 
sub-SMQs will be used:

Narrow sub-SMQ Liver related investigations, signs and symptoms (20000008)

Narrow sub-SMQ Cholestasis and jaundice of hepatic origin (20000009)

Narrow sub-SMQ Hepatitis, non-infectious (20000010)

Narrow sub-SMQ Hepatic failure, fibrosis and cirrhosis and other liver damage-
related conditions (20000013)
A table with frequencies of patients with these AEs by treatment, primary SOC and preferred 
term will be provided. Hepatic injury SAEs based on the above SMQ definition will be 
presented. 
Patients with hepatic injury will be listed.
For presentations on adjudicated hepatic events, refer to Section 7.8.1.5.
Acute renal failure
A frequency table of patients with AEs related to acute renal failure by treatment, primary 
SOC and preferred term will be provided based on the narrow SMQ Acute renal failure 
(20000003). 
SAEs and AEs leading to discontinuation based on the narrow SMQ Acute renal failure 
(20000003) will be presented. 
In addition, frequency tables will be produced for patients with elevated creatinine ≥ 2 x 
baseline and > 1 x upper limit of normal (ULN). 
Patients with acute renal failure will be listed.
Ketoacidosis
A frequency table of patients with AEs related to ketoacidosis will be presented by treatment, 
primary SOC and preferred term for investigator reported cases and for the narrow and broad 
BIcMQ definition of diabetic ketoacidosis (DKA).
For presentations on adjudicated events, refer to Section 7.8.1.5.
Patients with DKA based on the broad BIcMQ (30000019) or investigator reported 
ketoacidosis will be listed. 


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7.8.1.4 Specific AEs
Hypoglycaemic events
The investigator will record for each AE whether it represents a hypoglycaemic event and, if 
so, record additional information to assess the intensity of the hypoglycaemic event. On the 
basis of this information the hypoglycaemic event will be categorised as follows:

severe hypoglycaemic episode: event requiring the assistance of another person to 
actively administer carbohydrate, glucagon or other resuscitative actions

documented symptomatic hypoglycaemia with a measured plasma glucose 
concentration < 3.0 mmol/L (< 54 mg/dL): event accompanied by typical symptoms 
of hypoglycaemia but no need for external assistance

documented symptomatic hypoglycaemia with a measured plasma glucose 
concentration ≥ 3.0 mmol/L and ≤ 3.9 mmol/L (≥ 54 mg/dL and ≤ 70 mg/dL): event 
accompanied by typical symptoms of hypoglycaemia and no assistance required

symptomatic hypoglycaemia and plasma glucose concentration > 3.9 mmol/L (70 
mg/dL)

symptomatic hypoglycaemia and plasma glucose concentration not measured

asymptomatic hypoglycaemia: event not accompanied by typical symptoms of 
hypoglycaemia but with a measured plasma glucose concentration ≤ 3.9 mmol/L (≤ 
70 mg/dL)
Confirmed hypoglycaemic adverse event are defined as hypoglycaemic adverse events that 
had a plasma glucose concentration ≤ 70 mg/dL or required assistance.
Different tables will be shown for (i) patients with investigator-defined hypoglycaemia, and 
(ii) patients with confirmed hypoglycaemic adverse events, i.e. hypoglycaemic adverse 
events that had a plasma glucose concentration ≤ 70 mg/dL or required assistance.
Subgroup analyses on confirmed events with respect to DM status at baseline (DM vs non-
DM) will be performed.
In addition the number of patients with hypoglycaemia according to SMQ (20000226) will be 
presented.
Patients with hypoglycaemic events will be listed. 
Urinary tract infections (UTI) and genital infections
The following additional specific adverse events will also be assessed and be tabulated by 
treatment group:

Genital infections (BIcMQ “Infections” (30000036) narrow subsearch 1.1 “Genital 
tract infections predisposed to by glucosuria” (30000038) and investigator 
assessment)


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
UTI (BIcMQ “Infections” (30000036) narrow subsearch 2.1 “UTI predisposed by 
glucosuria” (30000041) and investigator assessment)
Genital infections based on investigator assessment will additionally be summarised by type 
(fungal balanitis or fungal vulvovaginitis, genital infection other than fungal balanitis or 
fungal vulvovaginits), intensity (mild, moderate or severe), how the event was treated (no 
treatment, therapy assigned and number of antimicrobials needed to treat), whether leading to 
discontinuation of treatment, and the number of episodes per patient. 
UTIs based on investigator assessment will additionally be summarised by intensity (mild, 
moderate or severe), anatomical location (upper UTI, lower UTI), occurrence of 
pyelonephritis or urosepsis, how the event was treated (no treatment, therapy assigned and 
number of antimicrobials needed to treat), whether leading to discontinuation of treatment, 
and the number of episodes per patient. 
Complicated urinary tract infections defined as serious adverse events of BIcMQ Infection 
narrow, subsearch 2.1 “UTI predisposed by glucosuria” (30000041), all events of subsearch 
2.1.1 ‘Renal infections predisposed by glucosuria’ (30000042), all events of PT Urosepsis 
will be presented. 
Complicated genital infection: defined as all serious events using the BIcMQ Infection 
narrow subsearch 1.1 ‘Genital tract infections predisposed to by glucosuria’ (30000038) and 
all event of the subsearch ‘Complicated genital tract infections predisposed to by glucosuria’ 
(30000129) will also be presented. 
Patients with UTIs or genital infections will be listed. 
Bone fracture events:
Frequency tables of patients with bone fracture by treatment, primary system organ class 
(SOC) and preferred term will be provided (based on the narrow BIcMQ “Bone fractures”
(30000008) and investigator reporting). 
Investigator reported fractures will be reported overall and separately for each type of 
fracture (traumatic and non-traumatic).
Separate tables for bone fractures based on the BIcMQ, which are serious will be presented. 
Patients with bone fractures will be listed.
Urinary tract malignancy events:
Urinary tract malignancy will be shown based on the BIcMQ ‘Malignancies’ (30000049) –
broad sub-search 14.1 ‘Urinary bladder and tract malignancies’ (30000057) and broad sub-
search 14.2 ‘Renal malignancies’ (30000103):
Presentation of frequency will be done by treatment, high level term and preferred term.


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Patients with urinary tract malignancy will be listed. 
Volume depletion
Volume depletion will be based on the BIcMQ ‘Volume depletion of non-haemorrhagic 
cause and subsequent hypotension’– narrow subsearch 2 ‘Volume depletion and hypotension 
due to dehydration’ (30000090). 
A frequency table of patients with volume depletion by treatment, primary SOC and preferred 
term will be provided. 
A separate table for serious volume depletion events will be presented. 
Patients with volume depletion will be listed.
For the analysis of laboratory data, refer to Section 7.8.2.
Hypotension:
Frequency table of subjects with symptomatic hypotension as defined by the investigator on 
the eCRF tick box by treatment, primary system organ class and preferred term will be 
provided.
Symptomatic hypotension episodes will be presented by whether the intensity of diuretic 
medication was reduced and by whether the intensity of non-diuretic antihypertensive therapy 
was reduced. 
A separate table for symptomatic hypotension events, which are serious, will be presented. 
Additionally hypotension by treatment, primary system organ class and preferred term will be 
provided. Hypotension is defined as preferred terms of the BIcMQ ‘Volume depletion of non-
haemorrhagic cause and subsequent hypotension’ – narrow sub-search 2 ‘Volume depletion 
and hypotension due to dehydration’ (30000090) but excluding terms of the narrow subsearch 
1 ‘Volume depletion due to dehydration’(30000089).
A separate table for hypotension events, which are serious, will be presented. 
Patients with hypotension events will be listed.
7.8.1.5 Events qualifying for external adjudication by the adjudication committee
An independent external CEC regularly reviews events and evaluates whether pre-specified 
criteria for these adjudication endpoints are met. Details on composition of the CEC, 
responsibilities and clinical event definitions are provided in the separate CEC Charter. 
Adjudication assessments will be incorporated into the database. 


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Details of the adjudication process are described in the CEC charter.
Hepatic adverse events:
Frequency tables summarising the relatedness and severity will be provided, including a 
listing showing the trigger events and adjudication results. This will include all adjudicated 
events up to 30 days after treatment stop.
Ketoacidosis:
Frequency tables showing adjudicated certain ketoacidosis will be provided, including a 
listing showing the trigger events and adjudication results. This will include all adjudicated 
events up to 7 days after treatment stop. 
7.8.1.6 AEs while patients taking wrong medication
A listing will be provided for AEs that occurred while a patient was taking the wrong study 
medication.  
If such a patient is identified an additional adverse event table that assigns the adverse events 
to the actual treatment taken will be presented. A patient who took both the assigned 
treatment and also at least one tablet of the wrong treatment will be counted as at risk in both 
treatment groups for the respective relevant time. The table will include all adverse events by 
SOC and PT. 
7.8.1.7 Adverse event incidence rates
For AE tables showing patients with events, in addition to the frequency tabulations, time-
adjusted adverse event analyses will be performed for all AEs, investigator defined drug-
related AEs, AEs leading to discontinuation, serious AEs, and adverse events of special 
interest by SOC and PT or High-Level Term (HLT) and PT, respectively.
The time at risk in patient years for the on-treatment phase is derived as follows:
Patients with AE: 
time at risk (AE) in days = date of start of AE with specified PT/SOC/HLT – study treatment 
start date + 1 
Patients without AE: 
time at risk (AE) in days = end date of time at risk – study treatment start date + 1, where end 
date of time at risk is the minimum of date of last study drug intake + x days and date of 
death, if applicable.
The standard approach will be x=7 days, but for certain AESIs in addition other approaches 
will be used.
Total AE-specific time at risk per treatment group is then derived as: 
Time at risk (AE) [years] = Sum of time at risk [days] over all patients in a treatment group/ 
365.25


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For ‘each row of a table’ (e.g. displaying an SOC), time at risk is calculated using start of 
first AE summarised in this row; e.g. for patient with AE in a specified SOC, time at risk = 
date of start of AE with specified PT in this SOC – start of study treatment + 1.
The AE incidence rate per 100 patient years will then be calculated as follows:
Incidence rate per 100 patient years (pt-yrs) = 100 * number of patients with AE / time at risk 
(AE) [years].
In a similar way the time at risk and incidence rate for the post-treatment period is derived. 
Hereby the start date is the start date of the post-treatment phase instead of the study 
treatment start date.
For some specific outputs showing number of episodes, event rates will be defined as number 
of episodes divided by time at risk. Time at risk will be end date of time at risk – study 
treatment start date + 1, where end date of time at risk is the minimum of date of last study 
drug intake + x days and date of death, if applicable.
7.8.2
Laboratory data
Standard safety tables will not include eGFR or creatinine. Analyses for eGFR and creatinine
will be done separately. 
For continuous safety laboratory parameters, normalised values will be derived as well as the 
differences to baseline. The process of normalisation as well as standard analyses for safety 
laboratory data are described in the BI guidance for the Display and Analysis of Laboratory 
Data (BI-KMED-BDS-HTG-0042 (4)). All analyses considering multiple of times upper limit 
of normal (ULN) will be based on original and not normalised data.
Laboratory parameters will be shown in conventional units. Where conventional units differ 
from SI units, analyses will be repeated on SI units. 
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards [see Data Management and Statistics Manual (DM&SM): Display and Analysis of 
Laboratory Data (BI-KMED-BDS-HTG-0042 (4))].
Laboratory measurements taken up to 3 days after the last administration of randomised study 
drug will be considered as on-treatment.
Default settings will be used for repeated values (using closest and then worst value).
Laboratory values will be compared to their reference ranges and frequency tables will be 
provided for the number of patients within and outside the reference range at baseline and the 
last measurement on treatment.  Descriptive statistics will be provided by treatment group for 
baseline, last value on-treatment and for changes from baseline to last value on treatment.  
For semi-quantitative or categorical laboratory values, shift tables for baseline and last value 
on treatment will also be provided. Frequency tables will summarise the number of patients 
with potentially clinically significant abnormalities. 


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Additionally, for urine ketones a shift table of baseline vs value at visit for each visit will be 
shown. 
For the table on potentially clinically significant abnormalities only patients with at least one 
available on-treatment value will be included in the analysis of an individual laboratory 
parameter.  Other tables are comparing baseline to on-treatment values and will only include 
patients with a baseline value and at least on available on-treatment value. All individual data 
will be presented in listings. 
To support analyses of liver-related adverse drug effects, patients with Aspartate 
transaminase (AST) and/or Alanine transaminase (ALT) ≥3xULN with concomitant or 
subsequent Total Bilirubin (TBILI≥2xULN) in a 30 day period after AST/ALT elevation are 
of special interest. In addition, of these cases, it will be considered whether the alkaline 
phosphatase (AP) is less than 2 x ULN (maximum value in a 30 day period after AST/ALT 
elevation) or not. The start of the 30-day time span is triggered by each liver enzyme 
elevation above the defined thresholds. Patients who fulfil one or two of the criteria for 
ALT/AST or total bilirubin elevations above and have no information available for the 
remaining parameter(s) within the 30 day time window will not be listed under “ALT and/or 
AST ≥ 3xULN with TBILI ≥ 2xULN”. 
In addition ALT/AST will be used to investigate elevated liver enzymes:

ALT/AST ≥ 3 x ULN

ALT/AST ≥ 5 x ULN

ALT/AST ≥ 10 x ULN

ALT/AST ≥ 20 x ULN
All liver enzyme elevations within 30 days of treatment discontinuation will be shown.
Frequency tables of patients with elevated liver enzymes defined by ALT and/or AST, total 
bilirubin and AP combinations will be provided.  Details on patients with elevated liver 
enzymes will be listed.
For the following parameters:

eGFR,

creatinine (only descriptive),
the time course of changes will be assessed. The analysis will be performed by applying 
MMRM models to OC-OT data on the treated set. The MMRM models that will be used are 
specified in Section 7.6. These analyses will be conducted on data before any normalisation.
The MMRM analyses will also be shown graphically. 
For the following parameters:

haemoglobin, and 

haematocrit 


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the change from baseline will be assessed. The analysis will be performed by applying 
ANCOVA models to OC-OT data on the treated set. The ANCOVA model will include 
treatment and baseline as fixed effects. Theses analyses will be conducted on data before any 
normalisation.
To support analysis of renal function, eGFR throughout the trial will be categorised according 
to the following Chronic Kidney Disease (CKD) staging (Table 7.8.2: 1): All calculations for 
the staging of renal function will be based on the originally measured laboratory values, not 
on normalised values with BI standard reference ranges. 
For the following parameters measured at the follow-up visit, additionally descriptive 
statistics at baseline, last value on treatment and follow-up will be provided for patients with 
valid measurements at all three timepoints. 

creatinine

eGFR

haematocrit

haemoglobin
Table 7.8.2: 1 CKD staging
Stage
eGFR 
(mL/min/1.73m²)
Description
Label for 
displays
Additional labels#
1
≥90
Normal or high 
≥90
≥90 (CKD 1)
2
60 to <90
Mildly decreased
60 to <90
60 to <90 (CKD 2)
3A
45 to <60 
Mildly to 
moderately 
decreased
45 to <60 
45 to <60 (CKD 3a)
3B
30 to <45
Moderately to 
severely decreased
30 to <45
30 to <45 (CKD 3b)
4
15 to <30
Severely decreased
15 to <30
15 to <30 (CKD 4)
5
<15
Kidney failure
<15
<15 (CKD 5)
A shift table from baseline to last value on treatment and to minimum value on treatment for 
eGFR (CKD-EPI)cr will be provided.


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7.8.3
Vital signs
Heart rate over time will be summarised descriptively based on OC-OT on the treated set. 
Descriptive statistics will also be shown graphically. 
Additionally descriptive statistics at baseline, last value on treatment and follow-up for 
patients with valid measurements at all three timepoints will be shown. 
7.8.4
ECG and physical examination
Clinically relevant abnormalities found at physical examination will be considered to have 
already existed prior to signing of informed consent and therefore should be considered 
baseline conditions instead of adverse events, unless there is good reason to assume that they 
first appeared after signing of consent.
Outcomes of ECGs will be part of the reporting of medical history or AE reporting. 
Categorical findings as collected in the eCRF will also be summarised descriptively.
7.8.5
Others
Not applicable


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8.
REFERENCES
1 CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic 
E9, Note For Guidance on Statistical Principles for Clinical Trials, current version.
2 BI-KMED-BDS-HTG-0035: "Handling of missing and incomplete AE dates", current 
version; IDEA for CON.
3 BI-KMED-BDS-HTG-0045: "Standards for Reporting of Clinical Trials and Project 
Summaries", current version; IDEA for CON.
4 BI-KMED-BDS-HTG-0042: "Handling, Display and Analysis of Laboratory Data", 
current version; IDEA for CON.
5 Shoemaker MJ, Curtis AB, Vangsnes E, Dickinson MG. Clinically meaningful change 
estimates for the six-minute walk test and daily activity in individuals with chronic 
heart failure. Cardiopulm Phys Ther J 24 (3), 21 - 29 (2013) [R17-1227]
6 Crosby RD, Kolotkin RL, Williams GR. Defining clinically meaningful change in 
health-related quality of life. J Clin Epidemiol 56, 395 - 407 (2003) [R07-1182]
7 Green CP, Porter CB, Bresnahan DR, Spertus JA. Development and evaluation of the 
Kansas City Cardiomyopathy Questionnaire: a new health status measure for heart 
failure. J Am Coll Cardiol 35 (5), 1245 - 1255 (2000) [R17-2666]
8 Bennett SJ, Oldridge NB, Eckert GJ, Embree JL, Browning S, Hou N, et al. 
Comparison of quality of life measures in heart failure. Nurs Res 52 (4), 207 - 216 
(2003) [R17-2917]
9 Ambrosy AP, Pang PS, Khan S, Konstam MA, Fonarow GD, Traver B, Maggioni AP, 
Cook T, Swedberg K, Burnett Jr JC, Grinfeld L, James E. Udelson JE, Faiez Zannad F, 
Gheorghiade M. Clinical course and predictive value of congestion during 
hospitalization in patients admitted for worsening signs and symptoms of heart failure 
with reduced ejection fraction: findings from the EVEREST trial. European Heart 
Journal (2013) 34, 835–843 [R19-0744]


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9.
ADDITIONAL SECTIONS
9.1
REGIONS AND COUNTRIES
Countries will be assigned to regions, as outlined in Table 9.1: 1.  
Table 9.1: 1
Regions and countries
Region
Country
Australia
Australia
Europe
Germany
Greece
Italy
Norway
Poland 
Portugal
Spain
Sweden
North America
Canada
US


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9.2
DIABETES STATUS AT BASELINE
Patients will be assigned to diabetes status category, as outlined in Table 9.2:1.  
Table 9.2: 1
DM at baseline
Diabetes status at 
baseline
Definiton
DM
Patients who fulfil one of the following:
-
investigator-reported medical history of diabetes on the 
medical history page 
OR
-
any pre-treatment HbA1c value >= 6.5%
Pre-DM
Patient who fulfil all of the following:
-
investigator reported ‘no’ for the medical history of 
diabetes on the medical history page 
AND
-
a pre-treatment HbA1c value of >=5.7% and all pre-
treatment HbA1c <6.5%
Missing
Patients who fulfil one of the following:
-
missing assessment of history of diabetes on the medical 
history page AND all pre-treatment HbA1c <6.5%
OR
-
no pre-treatment measurement of HbA1c AND 
investigator reported ‘no’ for the medical history of 
diabetes on the medical history page
OR
-
no pre-treatment measurement of HbA1c and missing 
assessment of history of diabetes on the medical history 
page
Non-DM (excl pre-DM)
Patients not meeting the above criteria 


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9.3
DERIVATION OF RESPONDER THRESHOLD FOR KCCQ-TSS AND 
CHQ-SAS DYSPNEA
A minimal clinically meaningful within patient-change in scores (i.e. responder threshold) 
will be estimated from the trial population (both treatment groups pooled) for KCCQ-TSS 
and CHQ-SAS Dyspnea using the below algorithm. All observed values will be considered in 
this analysis without imputation of missing values (OC-AD).
Anchor
The Patient Global Impression of Severity (PGI-S) of Dyspnea and PGI-S of Heart Failure 
Symptoms will each be used as the primary anchor for the CHQ-SAS Dyspnea scale and 
KCCQ-TSS, respectively. The Patient Global Impression of Change (PGI-C) of Dyspnea and 
PGI-C of Heart Failure Symptoms will be considered as secondary anchor scales for the 
CHQ-SAS Dyspnea scale and KCCQ-TSS, respectively.
A minimal clinically meaningful improvement for each PGI-S scale will be considered to be 
at least a one category improvement in change from baseline in PGI-S at week 12.
A minimal clinically meaningful improvement for each PGI-C scale will be considered to be 
at least “a little better” in PGI-C at week 12.
As an ancillary consideration, the distance walked in 6 minutes will be evaluated as a clinical 
indicator of patient improvement as well. Patients who improve at least 30 meters from 
baseline in distance walked in 6 minutes will be considered to be clinical responders [R17-
1227] (5).
Responder Threshold
To determine the threshold of the Patient Reported Outcome (PRO) measure that best 
identifies patients with minimal clinically meaningful difference as specified above 
(responders / non-responders), the following procedure will be applied:
A receiver operating characteristic (ROC) curve of change from baseline of the PRO measure
will be derived from the logistic regression model with the binary anchor (at least one 
category improvement in PGI-S Y/N) as dependent variable.
The mean of the cut-offs closest to the balance point (i.e. where sensitivity equals specificity)
will be used as the responder threshold for each respective scale’s PRO score.
For further analysis of the key secondary endpoint as defined in Section 7.5.1.4 a patient will 
be considered a responder if the PRO score is greater than or equal to the response threshold 
determined by the anchor of one category improvement in corresponding PGI-S 
questionnaire. 


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Graphical presentations
The ROC curve will be used to illustrate the ability of the PRO score to discriminate between
responders and non-responders. The area under the ROC curve (AUC) will be reported in
addition.
Descriptive empirical cumulative distribution functions (ECDF) will also be plotted by each
anchors categories for each PRO.
Supportive Analyses
Distribution-based analyses will be performed for the CHQ-SAS Dyspnea scale and the
KCCQ-TSS on data of change from baseline to week 12 to support the responder definition
as defined above.
One standard error of measurement (SEM) as well as 0.2*SD and 0.5*SD of the CHQ-SAS
Dyspnea scale and the KCCQ-TSS baseline measurement will be used as benchmarks [R07-
1182](6).
The SEM is defined as  ∗√(1 −) with reliability coefficient r=0.88 for the KCCQ-TSS
(Cronbach’s alpha in [R17-2666] (7)) and r=0.91 for the CHQ-SAS Dyspnea (Cronbach’s 
alpha in [R17-2917] (8)).
For patients who achieved a one-category improvement in PGI-S Dyspnea at week 12 from 
baseline, the descriptive median (with inter-quartile range) of CHQ-SAS Dyspnea will be 
displayed by baseline PGI-S Dyspnea category. The table will be repeated separately for one-
category deterioration, two-category improvement, two category deterioration, and no change 
in PGI-S dyspnea.
For patients who achieved a one-category improvement in PGI-S in heart failure symptoms at 
week 12 from baseline, the median (with inter-quartile range) of KCCQ-TSS will be 
displayed by baseline PGI-S in heart failure symptoms category. The table will be repeated 
for one-category deterioration, two-category improvement, two category deterioration, and no 
change in PGI-S in heart failure symptoms.
9.4
DERIVATION OF KCCQ AND CHQ-SAS DOMAINS
The following algorithm will be used to score the KCCQ-TSS and the CHQ-SAS Dyspnea.
9.4.1
Kansas City Cardiomyopathy Questionnaire (KCCQ)
There are 10 summary scores within the KCCQ, which are calculated as follows:
1. Physical Limitation
Code responses to each of Questions 1a-f as follows:
∀
Extremely limited = 1


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
Quite a bit limited = 2

Moderately limited = 3

Slightly limited = 4

Not at all limited = 5

Limited for other reasons or did not do = <missing value>
If at least three of Questions 1a-f are not missing, then the Physical Limitation Score is 
calculated as follows:
Physical Limitation Score = 100*[(mean of Questions 1a-f actually answered) – 1]/4
2. Symptom Stability
Code the response to Question 2 as follows:

Much worse = 1

Slightly worse = 2

Not changed = 3

Slightly better = 4

Much better = 5

I’ve had no symptoms over the last 2 weeks = 3
If Question 2 is not missing, then the Symptom Stability Score is calculated as follows:
Symptom Stability Score = 100*[(Question 2) – 1]/4
3. Symptom Frequency
Code responses to Questions 3, 5, 7 and 9 as follows:
Question 3

Every morning = 1

3 or more times a week but not every day = 2

1-2 times a week = 3

Less than once a week = 4


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
Never over the past 2 weeks = 5
Questions 5 and 7

All of the time = 1

Several times a day = 2

At least once a day = 3

3 or more times a week but not every day = 4

1-2 times a week = 5

Less than once a week = 6

Never over the past 2 weeks = 7
Question 9

Every night = 1

3 or more times a week but not every day = 2

1-2 times a week = 3

Less than once a week = 4

Never over the past 2 weeks = 5
If at least two of Questions 3, 5, 7 and 9 are not missing, then the Symptom Frequency Score 
is calculated as follows:
S3 = [(Question 3) – 1]/4
S5 = [(Question 5) – 1]/6
S7 = [(Question 7) – 1]/6
S9 = [(Question 9) – 1]/4
Symptom Frequency Score = 100*(mean of S3, S5, S7 and S9)
4. Symptom Burden
Code responses to each of Questions 4, 6 and 8 as follows:

Extremely bothersome = 1


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


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If at least one of Questions 10 and 11 is not missing, then the Self-Efficacy Score is 
calculated as:
Self-Efficacy Score = 100*[(mean of Questions 10 and 11 actually answered) – 1]/4
7. Quality of Life
Code responses to Questions 12, 13 and 14 as follows:
Question 12

It has extremely limited my enjoyment of life = 1

It has limited my enjoyment of life quite a bit = 2

It has moderately limited my enjoyment of life = 3

It has slightly limited my enjoyment of life = 4

It has not limited my enjoyment of life at all = 5
Question 13

Not at all satisfied = 1

Mostly dissatisfied = 2

Somewhat satisfied = 3

Mostly satisfied = 4

Completely satisfied = 5
Question 14

I felt that way all of the time = 1

I felt that way most of the time = 2

I occasionally felt that way = 3

I rarely felt that way = 4

I never felt that way = 5
If at least one of Questions 12, 13 and 14 is not missing, then the Quality of Life Score is 
calculated as:


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Quality of Life Score = 100*[(mean of Questions 12, 13 and 14 actually answered) – 1]/4
8. Social Limitation
Code responses to each of Questions 15a-d as follows:

Severely limited = 1

Limited quite a bit = 2

Moderately limited = 3

Slightly limited = 4

Did not limit at all = 5

Does not apply or did not do for other reasons = <missing value>
If at least two of Questions 15a-d are not missing, then the Social Limitation Score is 
calculated as:
Social Limitation Score = 100*[(mean of Questions 15a-d actually answered) – 1]/4
9. Overall Summary Score
The Overall Summary Score is defined as the mean of the following available summary 
scores:
Physical Limitation Score, Total Symptom Score, Quality of Life Score and Social Limitation 
Score
10. Clinical Summary Score
The Clinical Summary Score is defined as the mean of the following available summary 
scores:
Physical Limitation Score and Total Symptom Score
Note: references to “means of questions actually answered” imply the following.
If there are n questions in a scale, and the subject must answer m to score the scale, but the 
subject answers only n-i, where n-i >= m, calculate the mean of those questions as
(sum of the responses to those n-i questions) / (n-i)
not


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(sum of the responses to those n-i questions) / n
The change from baseline to week 12 in KCCQ-TSS will be calculated as the difference of the 
score at follow-up (week 12) and at baseline. 
9.4.2
Chronic Heart Failure Questionnaire (CHQ) Self-Administered 
Standardised format (SAS)
The CHQ-SAS dyspnea score is defined as the mean of Questions 1-5 within the CHQ-SAS.
The CHQ-SAS fatigue score is defined as the mean of question 7, 9, 12, 14.
The CHQ-SAS emotional function score is defined as the mean of questions 6, 8, 10, 11, 13, 15, 
16.
The scores for each question of each dimension are added together and divided by the number of 
questions. Only items that are answered will be scored. That is items that are scored as “not done” 
or missing will not be included in the summary (average) score. The average score of the 
completed items will be reported.
The change in the score of each domain will be calculated as the difference of the mean score at 
follow-up (week 12) and baseline.
9.5
DERIVATION OF CLINICAL CONGESTION SCORE
Following the scoring algorithm in Ambrosy et al. the clinical congestion score is defined a 
summary score of the 3 items jugular venous distension (JVD), orthopnea and edema [R19-
0744 (9)].
Code responses to orthopnea as follows:

None = 0

Seldom = 1

Frequent = 2

Continuous = 3
Code responses to JVD as follows:

‘≤ 6’ = 0

‘6<JVD<10’ = 1


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
‘10≤JVD<15’ = 2

‘≥15’ = 3
Code responses to Edema as follows:

absent/trace=0

Slight=1

Moderate=2

Marked=3
If at least two of the three items JVD, orthopnea and edema are not missing, then the Clinical 
Congestion Score is calculated as:
Clinical Congestion Score = (mean of items JVD, orthopnea and edema actually answered)*3


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10.
HISTORY TABLE
This is a revised TSAP including the following modifications to the final TSAP
Table 10: 1
History table
Version
Date
(DD-
MMM-YY)
Author
Sections 
changed
Brief description of change
FINAL
5-APR-19
None
This is the final TSAP
REVISED
21-OCT-19
Section 6.3 / 
Section 7.4 / 
Section 7.5
Definition of Senstivity analysis set 2 and 
Sensitivity analysis set 3
Reason for change:
For a subset of patients, on-treatment urine 
dipstick test results for urine glucose had been 
transferred from the central laboratory to the 
sites before DBL. A positive urine glucose test 
can be suggestive of treatment allocation. 
Therefore, an additional sensitivity analysis is 
performed based on the subset of patients who 
did not have an on-treatment urine glucose 
measurement transferred to and accessed by the 
sites before DBL.
In patients with diabetes mellitus at baseline, a 
positive urine dipstick test result is of limited 
value with respect to bearing potential 
information on treatment allocation. Therefore, a 
second additional sensitivity analysis is 
performed, which excludes those non-diabetic 
patients for whom at least one on-treatment 
urine glucose measurement was transferred to 
and accessed by the sites before DBL.
Section 6.4.
Importance of subgroup diabetic vs non diabetic 
highlighted.
Reason for change:
Clarification.
Categorisation of subgroup eGFR at baseline 
updated
Reason for change:
Combine subgroups to avoid small subgroup


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Table 10: 1
History table (cont.)
Version
Date
(DD-
MMM-YY)
Author
Sections 
changed
Brief description of change
Section 6.6
Clarification of 6MWTD if a patient performs 
the visit at week 12 but does not perform the 
6MWT.
Clarification of handling of missing baseline 
questionnaires for WCI analyses.
Clarification of handling of SAE with outcome 
“recovered with sequelae” leading to an 
amputation
Reason for change: Clarifications consistent 
with protocol.
Section 6.7
Clarification of time windows for laboratory 
values at day of treatment start, repeated values,
and time windows for sensitivity analyses using 
primary analysis model.
Reason for Change
For laboratory values, clock time is recorded and
therefore can be taken into account.
All models using Wilcoxon will use the same 
time window
Section 7.8
AEs will be coded using version 22.0 of the 
MedDRA coding dictionary. 
Reason for Change
Clarification
Section 8
Update of References
Reason for change
References have been updated to the current 
versions of BI How to guides 
Section 9.2
Minor and typo corrections
Reason for change:
Clarification