Conditions: Heart Failure
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 5988
Healthy volunteers: no

Brief summary:
This is a study in adults with chronic heart failure. People with chronic heart failure may need to be hospitalised for their condition. Some people with chronic heart failure may eventually die from their condition. The purpose of the study is to find out whether a medicine called empagliflozin lowers the chances of patients having to go to hospital for heart failure and whether it improves their survival. The study is open to patients with a type of chronic heart failure called chronic heart failure with preserved ejection fraction.

Participants stay in the study until researchers have enough information about how effective empagliflozin is. It is expected that participants who enter at the very beginning of the enrolment period may be in the study for over 3 years, while participants who enter near the end of the enrolment period may be in the study for less than 2 years. The participants are put into 2 groups. It is decided by chance who gets into which group. One group gets empagliflozin tablets every day and the other group gets placebo tablets every day. Placebo tablets look like empagliflozin tablets but contain no medicine.

Participants visit the doctors regularly. During these visits, the doctors collect information about the participant's health. The doctors want to know how many patients had to go to hospital because of heart failure or who died from cardiovascular disease.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Empagliflozin intervention 2: Placebo
Intervention descriptions: intervention 1: once daily intervention 2: once daily

Protocol document:
Prot_000.pdf: 
001-MCS-40-106-RD-03 (13.0) / Saved on: 05 Aug 2015
CLINICAL TRIAL PROTOCOL
Document Number:
c03946327-01
EudraCT No.:
2016-002278-11
BI Trial No.:
1245.110
BI 
Investigational 
Product(s):
Empagliflozin
Title:
A phase III randomised, double-blind trial to evaluate efficacy and safety 
of once daily empagliflozin 10 mg compared to placebo, in patients with 
chronic Heart Failure with preserved Ejection Fraction (HFpEF).
Lay title:
EMPagliflozin outcomE tRial in patients with chrOnic heaRt failure
EMPEROR-Preserved
Clinical Phase:
III
Trial Clinical 
Monitor:
Coordinating 
Investigators
Status
Final Protocol
Version and 
Date:
Version: 1.0
Date: 09 NOV 2016
Page 1 of 92
Proprietary confidential information
2016 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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BI Trial No.: 1245.110
c03946327-01
Trial Protocol
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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Boehringer Ingelheim 
Name of finished product:
Jardiance
Name of active ingredient:
Empagliflozin
Protocol date
09 NOV 2016
Trial number:
1245.110
Revision date:
Title of trial:
A phase III randomised, double-blind trial to evaluate efficacy and 
safety of once daily empagliflozin 10 mg compared to placebo, in 
patients with chronic Heart Failure with preserved Ejection Fraction 
(HFpEF)
Coordinating 
Investigator:
Trial site(s):
Multicentre trial in approximately 22 countries.
Clinical phase:
III
Objective(s):
The objective of this event-driven trial is to demonstrate superiority
of empagliflozin 10 mg versus placebo in patients with symptomatic, 
chronic HF and preserved ejection fraction (LVEF > 40%) under 
stable treatment of HF symptoms
Methodology:
Randomised, double blind, placebo controlled, parallel group trial.  
No. of patients:
total entered:
Approximately 4126 randomised
Based on blinded assessment of the event rate of the primary 
endpoint, which is performed during recruitment before any interim


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09 NOV 2016
BI Trial No.: 1245.110
c03946327-01
Trial Protocol
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001-MCS-40-106-RD-03 (13.0) / Saved on: 05 Aug 2015
Name of company:
Boehringer Ingelheim 
Name of finished product:
Jardiance
Name of active ingredient:
Empagliflozin
Protocol date
09 NOV 2016
Trial number:
1245.110
Revision date:
unblinding, the number of patients randomised may be increased up 
to 6000. The number of primary outcome events required is not 
affected by this consideration.
each treatment:
Approximately 2063 (2 treatment groups)
Diagnosis :
Heart failure (HF) with preserved ejection fraction (EF).
Main criteria
for inclusion:

Patients with chronic HF diagnosed for at least 3 months before
Visit 1 and currently in HF NYHA class II-IV

Chronic HF with preserved EF defined as LVEF > 40 % per local
reading (obtained by echocardiography, radionuclide
ventriculography, invasive angiography, MRI or CT), and no prior
measurement of LVEF ≤ 40% under stable conditions. The EF
must have been obtained and documented at Visit 1 or within 6
months prior to Visit 1, and more than 90 days after any
Myocardial Infarction.

Elevated NT-proBNP > 300 pg/ml for patients without AF, OR >
900 pg/ml for patients with AF, analysed at the Central laboratory
at Visit 1

Patients must have at least one of the following evidence of HF:
a) Structural heart disease (left atrial enlargement and/or left
ventricular hypertrophy) documented by echocardiogram at Visit
1, OR
b) Documented hospitalisation for HF (HHF) within 12 months
prior to Visit 1

Oral diuretics, if prescribed to patient according to local guideline
and discretion of the Investigator, should be stable for at least 1
week prior to Visit 2 (Randomisation)

eGFR (CKD-EPI)cr ≥ 20 mL/min/1.73m2 at Visit 1


Boehringer Ingelheim
09 NOV 2016
BI Trial No.: 1245.110
c03946327-01
Trial Protocol
Page 4 of 92
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001-MCS-40-106-RD-03 (13.0) / Saved on: 05 Aug 2015
Name of company:
Boehringer Ingelheim 
Name of finished product:
Jardiance
Name of active ingredient:
Empagliflozin
Protocol date
09 NOV 2016
Trial number:
1245.110
Revision date:
Test product(s):
Empagliflozin
dose:
10 mg q.d.
mode of 
administration:
p.o.
Comparator products:
Placebo
dose:
NA
mode of 
administration:
p.o.
Duration of treatment:

4-21 days screening period

Approximately 20-38 months double-blind treatment until the
required number of adjudicated primary events is reached with
empagliflozin or placebo

Follow-up visit 30 days after end of treatment
The trial will continue until required number of adjudicated primary 
endpoint events have occurred to be able to comply with the objective 
of the trial.
Endpoints
Primary endpoint;
The composite primary endpoint for this trial is the time to first event 
of adjudicated CV death or adjudicated HHF in patients with HFpEF.
Key secondary endpoints; 
The key secondary endpoints which are part of the testing strategy, 
are the following: 
-
Occurrence of adjudicated HHF (first and recurrent)
-
eGFR (CKD-EPI)cr slope of change from baseline
Other secondary endpoints are:
-
Time to first occurrence of sustained reduction of ≥40% eGFR
(CKD-EPI)cr or


Boehringer Ingelheim
09 NOV 2016
BI Trial No.: 1245.110
c03946327-01
Trial Protocol
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001-MCS-40-106-RD-03 (13.0) / Saved on: 05 Aug 2015
Name of company:
Boehringer Ingelheim 
Name of finished product:
Jardiance
Name of active ingredient:
Empagliflozin
Protocol date
09 NOV 2016
Trial number:
1245.110
Revision date:
o
sustained eGFR (CKD-EPI)cr <15 mL/min/1.73 m2 for
patients with baseline eGFR ≥30 mL/min/1.73 m2
o
sustained eGFR (CKD-EPI)cr <10 mL/min/1.73 m2 for
patients with baseline eGFR <30 mL/min/1.73 m2

Time to first adjudicated HHF

Time to adjudicated CV death

Time to all-cause mortality

Time to onset of diabetes mellitus (DM) in patients with pre-DM

Change from baseline in clinical summary score (HF symptoms
and physical limitations domains) of the KCCQ at week 52

Occurrence of all-cause hospitalisation (first and recurrent)
Safety criteria:

Adverse events (AE)

AE of special interest (AESI)

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

Assessment of vital status
Statistical methods:
The overall type one error rate will be preserved at a level of 0.05 (2-
sided). The primary and the key secondary endpoints will be analysed
in the following testing hierarchy:
1. Time to first event of adjudicated CV death or adjudicated
HHF
2. Occurrence of adjudicated HHF (first and recurrent)
3. eGFR (CKD-EPI)cr slope of change from baseline
At the final analysis, after the evaluation of recurrent HHF, alpha will 
be split into 0.001 to be used for the analysis of eGFR slope analysis, 
and the rest will be transferred to the meta-analyses which will 


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09 NOV 2016
BI Trial No.: 1245.110
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Trial Protocol
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Name of company:
Boehringer Ingelheim 
Name of finished product:
Jardiance
Name of active ingredient:
Empagliflozin
Protocol date
09 NOV 2016
Trial number:
1245.110
Revision date:
include this trial and the trial conducted in parallel in patients with 
HFrEF (1245.121). 
For the primary analysis of the primary endpoint a Cox proportional 
hazards regression model of time to first event of adjudicated CV 
death or adjudicated HHF with covariates of age (continuous), gender 
treatment, geographical regions, history of DM (DM, Pre-DM, No
DM), LVEF (continuous) and eGFR (CKD-EPI)cr at baseline 
(continuous) will be used. The primary analysis will be performed on 
the randomised (intention to treat) set.
Approximately 4126 patients will be randomised to accumulate
approximately 841 confirmed primary events within 18 months 
accrual and approximately 20 additional months follow-up period to 
achieve a power of ~90%. The number of patients randomised may be 
increased up to 6000 patients based on a blinded assessment of the 
event rate, which is performed during recruitment before any interim
unblinding. The number of 841 confirmed primary outcome events is 
not affected by this consideration. 
One interim analysis is planned after approximately 500 primary 
adjudicated events have been accrued. If the pre-specified criteria for
stopping for success at the interim analysis has been reached, the 
Executive Steering Committee (ExSC) and the Sponsor will be 
informed. The final decision on whether to stop the trial will be made 
by the Sponsor. 
Safety will be evaluated descriptively on the treated set. 


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FLOW CHART
Trial Period
Scree
ning1
Randomised Treatment Period2
Follow Up
Period 3
Relevant CTP section
Visit
1
2
3
4
5
Phone
call
6
7
Phone
call
8
9
Phone 
call
10
11
Phone 
call
12
13
Phone 
call
14
15
Phone 
call
16
EOT 
Visit
FU 
Visit3
Trial week
-3
1
4
12
22
32
42
52
64
76
88
100
112
124
136
148
EOT 
Visit
EOT + 
30 
days
Days from 
Randomisation Visit 
window4
-21
to -4
1
29±7
85
±7
155 ±7
225
±7
295 ±7
365 
±7
449
±7
533
±7
617
±7
701
±7
785
±7
869
±7
953
±7
1037
±7
---
---
±7
Fasting status5
NF
F
NF
NF
-
NF
NF
-
NF
-
NF
-
NF
-
NF
F
F
Informed Consent 6
X
3, 8
In-/exclusion criteria
X
X
3.3
Medical History/ 
Concomitant 
diagnoses
X
8.3.1
Screening (register in 
IRT)
X
6.2.1
Randomisation (via 
IRT)
X
6.2.2
Demographics7
X
-
NYHA classification
X
X
X
X
X
X
X
X
X
X
X
X
5.2.2
10.3
Physical exam
X
X
X
X
X
X
X
X
5.3.1
Clinical routine exam8
X
X
X
X
X
X
X
X
X
X
5.3.2
Vital signs 9
X
X
X
X
X
X
X
X
X
X
X
X
5.3.3
Height 
X
-


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Trial Period
Screen
ing1
Randomised Treatment Period2
Follow Up
Period 3
Relevant CTP section
Visit
1
2
3
4
5
Phone
call
6
7
Phone
call
8
9
Phone 
call
10 
11
Phone 
call
12
13
Phone 
call
14
15 
Phone 
call
16
EOT 
Visit
FU 
Visit3
Trial week
-3
1
4
12
22
32
42
52
64
76
88
100
112
124
136
148
EOT 
Visit
EOT + 
30 
days
Days from 
Randomisation 
Visit window4
-21 to -
4
1
29±7
85
±7
155 ±7
225
±7
295 ±7
365 
±7
449
±7
533
±7
617
±7
701
±7
785
±7
869
±7
953
±7
1037
±7
---
---
±7
Fasting status5
NF
F
NF
NF
-
NF
NF
-
NF
-
NF
-
NF
-
NF
F
F
Weight
X
X
X
X
X
X
X
X
X
X
X
X
5.2.4
Concomitant 
Therapy 
X
X
X
X
X
X
X
X
X
X
X
X
4.2
Assessment of 
Endpoints10, 11
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
5.2, 5.3
12-lead-ECG 12
X
X
5.3.5
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
5.3.7
KCCQ
X
X
X
X
X
X
5.2.1
EQ-5D
X
X
X
X
X
X
X
X
5.6.1
HCRU 
X
X
X
X
X
X
X
X
X
X
5.6.2
Urine Pregnancy 
Test 13
X
X
X
X
X
X
X
X
X
X
X
5.3.4.2
Safety lab Tests
X14
X
X
X
X
X
X
X
X
X
X
X
5.3.4
NT-proBNP
X
X
X
X
X
X
X
X
5.5
High-sensitivity 
TroponinT
X
5.5
HbA1c 15
X
X
X
X
X
X
X
X
X
X
-


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Trial Period
Screen
ing1
Randomised Treatment Period2
Follow Up
Period 3
Relevant CTP section
Visit
1
2
3
4
5
Phone
call
6
7
Phone
call
8
9
Phone 
call
10 
11
Phone 
call
12
13
Phone 
call
14
15 
Phone 
call
16
EOT 
Visit
FU 
Visit3
Trial week
-3
1
4
12
22
32
42
52
64
76
88
100
112
124
136
148
EOT 
Visit
EOT + 
30 
days
Days from 
Randomisation 
Visit window4
-21 to -
4
1
29±7
85
±7
155 ±7
225
±7
295 ±7
365 
±7
449
±7
533
±7
617
±7
701
±7
785
±7
869
±7
953
±7
1037
±7
---
---
±7
Fasting status5
NF
F
NF
NF
-
NF
NF
-
NF
-
NF
-
NF
-
NF
F
F
Lipid profile panel 
X
X
X
X
X
5.3.4
eGFR (CKD-EPIcr
formula)
X
X
X
X
X
X
X
X
X
X
X
X
5.3.4.1
UACR
X
X
X
X
X
X
X
X
X
X
X
X
5.3.4
PK sampling 
(substudy)16
X
5.4.1
Sampling for 
biobanking of 
serum/plasma/urine/
DNA (optional, 
requires  separate 
informed consent)17
X18
X
X
5.5.1
Dispense trial 
medication19
X
X
X
X
X
X
X
X
X
4.1.4
6.2.2
Return Medication/ 
medication 
compliance check
X
X
X
X
X
X
X
X
X
4.3


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1.
The screening procedures can be done on different days within the time window
2.
From Visit 8 and onwards, on-site visits will be scheduled every 24 weeks until end of trial. 
Patients who prematurely discontinue trial medication will perform EOT visit and Follow Up visit, and then continue with scheduled visits until the trial is stopped. 
For patients not willing to attend scheduled visits, telephone calls must be made regularly (ref. Section 3.3.4.1) to document any occurrence of outcome events and vital 
status. 
If the trial continues beyond 148 weeks, visits are to be repeated with same intervals as from week 64 and onwards.
3.
Timepoint for the EOT will be communicated via an Investigator letter when the Sponsor is confident that required number of events will be reached within a reasonable 
timeframe (ref. Section 3.1 and 6.2.3). All patients will have a follow up visit 30 days following regular or premature completion of the treatment period. 
4.
Visit dates are determined per the date of randomisation.  If a visit is missed, the patient should be returned to the original visit schedule at the next visit.
5.
NF = non fasting, F=fasting. Fasting means no food or liquid intake except for water the last 10-16 hours
6.
Informed consent may be obtained prior to visit 1 in order to give time to collect medical records. Visit 1 should be performed within 30 days of signing the informed 
consent form (ICF).
7.
If accepted by local authorities or ethic committees, demographics to be collected in this trial are gender, year of birth, ethnicity and race. 
8.
The Investigator will be asked to record results from clinical routine examinations like ECG, echocardiography or similar procedures (MRI, CT-scan, etc.), and if 
applicable information gathered from interrogations of the ICD in the eCRF.
9.
Vital signs measurements in this trial are blood pressure and pulse rate. 
10. Protocol specified outcome events should be collected on the appropriate eCRF page only. The outcome events which are exempted from SAE reporting are listed in
Section 5.3.6.
11. For patients with non-fatal stroke the Modified Rankin Scale (MRS) should be scored by the investigator based on an interview at the next regular on-site visit after the 
onset of the stroke. In those cases where MRS assessment occurred within 90 days after the stroke, a repeat MRS-assessment should be performed at the next on-site 
visit..
12. For the 12-lead ECG done at the baseline and EOT visit, the interpretation of the tracing must be made locally by a qualified physician and documented on the ECG 
section of the eCRF. In case of any cardiac symptoms (indicating rhythm disorders or cardiac ischaemia), additional 12-lead ECG(s) should be done to document a 
potential outcome event.
13. For female patients of child-bearing potential, local urine pregnancy test should be performed according to the Flow Chart. More frequent testing should be performed if 
required by local regulations/authorities.
14. For the screening Visit 1, the safety laboratory is limited to liver transaminases, alkaline phosphatase, serum creatinine and urinalysis. Patients do not have to be fasting.
15. HbA1c to be analysed in all patients, e.g. diabetics and non-diabetics.
16. For PK analysis, one blood sample will be collected prior to the next scheduled dose of trial medication at Visit 4 and between 22 to 26 h after the most recent drug 
intake. 
17. Collection of biobanking samples (plasma, serum, urine, DNA) is optional. Participating patients are required to give informed consent specifically for biobanking. 
Samples will be stored at a biobanking facility for future research. 
18. DNA biobanking requires only one blood sample to be taken, preferably at Visit 2 (Randomisation). However, collection at later visits is permitted as long as the 
informed consent for biobanking remains valid. 
19. At all visits; the respective kit number has to be allocated to the patient via IRT. Trial medication should be taken after all trial related procedures are completed at an on-
site visit.


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TABLE OF CONTENTS
CLINICAL TRIAL PROTOCOL.....................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................7
TABLE OF CONTENTS .................................................................................11
ABBREVIATIONS...........................................................................................15
1
INTRODUCTION................................................................................18
1.1
MEDICAL BACKGROUND............................................................................18
1.2
DRUG PROFILE ...............................................................................................19
1.2.1
Non-clinical assessment of safety .................................................................19
1.2.2
Clinical pharmacokinetics ............................................................................19
1.2.3
Clinical efficacy and safety...........................................................................19
2
RATIONALE, OBJECTIVES, AND BENEFIT-RISK 
ASSESSMENT .....................................................................................22
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................22
2.2
TRIAL OBJECTIVES.......................................................................................23
2.3
BENEFIT-RISK ASSESSMENT......................................................................23
3
DESCRIPTION OF DESIGN AND TRIAL POPULATION..........25
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................25
3.1.1
Administrative structure of the trial ...........................................................26
Clinical Event Committee ..........................................................................27
3.1.1.1
Hepatic external adjudication.....................................................................27
3.1.1.2
Adjudication of ketoacidosis ......................................................................27
3.1.1.3
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S) .....................................................................................27
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
Removal of patients from therapy or assessments .....................................33
Removal of individual patients...................................................................33
3.3.4.1
Discontinuation of the trial by the Sponsor................................................35
3.3.4.2
4
TREATMENTS....................................................................................36
4.1
INVESTIGATIONAL TREATMENTS ..........................................................36
4.1.1
Identity of the investigational Medicinal product and comparator..........36
4.1.2
Selection of doses in the trial ........................................................................36
4.1.3
Method of assigning patients to treatment groups.....................................37
4.1.4
Drug assignment and administration of doses for each patient................37
4.1.5
Blinding and procedures for unblinding.....................................................38
Blinding ......................................................................................................38
4.1.5.1
Unblinding and breaking the code..............................................................38
4.1.5.2
4.1.6
Packaging, labelling and re-supply..............................................................38
4.1.7
Storage conditions .........................................................................................39
4.1.8
Drug accountability.......................................................................................39


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4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................39
4.2.1
Other treatments and emergency procedures ............................................39
4.2.2
Restrictions.....................................................................................................41
4.3
TREATMENT COMPLIANCE .......................................................................41
5
VARIABLES AND THEIR ASSESSMENT.....................................42
5.1
TRIAL EFFICACY ENDPOINTS...................................................................42
5.1.1
Primary endpoint(s) ......................................................................................42
5.1.2
Secondary endpoint(s)...................................................................................42
5.1.3
Further endpoints..........................................................................................42
5.2
ASSESSMENT OF EFFICACY.......................................................................44
5.2.1
KCCQ.............................................................................................................44
5.2.2
New York Heart Association classification.................................................45
5.2.3
NT-proBNP....................................................................................................45
5.2.4
Body weight....................................................................................................45
5.2.5
Blood pressure ...............................................................................................45
5.3
ASSESSMENT OF SAFETY............................................................................45
5.3.1
Physical examination.....................................................................................45
5.3.2
Clinical routine examination........................................................................46
5.3.3
Vital signs.......................................................................................................46
5.3.4
Safety laboratory parameters.......................................................................46
Renal function.............................................................................................47
5.3.4.1
Pregnancy testing........................................................................................48
5.3.4.2
Criteria for hypoglycaemic events..............................................................48
5.3.4.3
Urinary tract infections and genital infections ...........................................48
5.3.4.4
5.3.5
Electrocardiogram.........................................................................................49
5.3.6
Other safety assessments...............................................................................49
Outcome of non-fatal stroke.......................................................................49
5.3.6.1
Hepatic events.............................................................................................49
5.3.6.2
5.3.7
Assessment of adverse events .......................................................................49
Definitions of AEs......................................................................................49
5.3.7.1
Adverse event collection and reporting......................................................53
5.3.7.2
5.4
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS (SUBSTUDY).........................................................56
5.4.1
Pharmacokinetic endpoints ..........................................................................56
5.4.2
Methods of sample collection........................................................................57
5.4.3
Analytical determinations.............................................................................57
5.5
ASSESSMENT OF BIOMARKERS................................................................57
5.5.1
Biobanking (optional)....................................................................................57
Methods and timing of sample collection...................................................58
5.5.1.1
5.6
OTHER ASSESSMENTS..................................................................................58
5.6.1
EQ-5D.............................................................................................................58
5.6.2
Health Care Resource Utilisation (HCRU).................................................59
5.7
APPROPRIATENESS OF MEASUREMENTS.............................................59
6
INVESTIGATIONAL PLAN .............................................................60
6.1
VISIT SCHEDULE............................................................................................60


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6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................60
6.2.1
Screening........................................................................................................60
6.2.2
Treatment period...........................................................................................60
6.2.3
End of Treatment, Follow Up Period and Trial Completion ....................61
6.2.4
Early discontinuation of trial medication and trial termination ..............62
7
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE.....................................................................................63
7.1
STATISTICAL DESIGN – MODEL ...............................................................63
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................63
7.3
PLANNED ANALYSES....................................................................................65
7.3.1
Primary endpoint analyses ...........................................................................65
7.3.2
Secondary endpoint analyses........................................................................66
7.3.3
Further endpoint analyses............................................................................67
7.3.4
Safety analyses...............................................................................................67
7.3.5
Pharmacokinetic analyses.............................................................................68
7.3.6
Prespecified meta-analysis............................................................................68
7.4
INTERIM ANALYSES .....................................................................................68
7.5
HANDLING OF MISSING DATA ..................................................................69
7.6
RANDOMISATION ..........................................................................................70
7.7
DETERMINATION OF SAMPLE SIZE ........................................................70
8
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY......................................72
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ..........................................................................................................72
8.2
DATA QUALITY ASSURANCE .....................................................................73
8.3
RECORDS ..........................................................................................................73
8.3.1
Source documents..........................................................................................73
8.3.2
Direct access to source data and documents...............................................75
8.3.3
Storage period of records..............................................................................75
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................75
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY.......76
8.6
TRIAL MILESTONES......................................................................................76
8.7
PROTOCOL VIOLATIONS ............................................................................77
8.8
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
TRIAL RELATED INJURY.............................................................................77
9
REFERENCES.....................................................................................78
9.1
PUBLISHED REFERENCES...........................................................................78
9.2
UNPUBLISHED REFERENCES.....................................................................82
10
APPENDICES......................................................................................83
10.1
INCLUSION OF ILLITERATE PATIENTS..................................................83
10.1.1
Patient reported outcome forms ..................................................................83
10.1.2
Patient information and informed consent (including biobanking) .........83
10.2
PATIENT REPORTED OUTCOMES ............................................................85
10.2.1
EQ-5D.............................................................................................................85
10.2.2
KCCQ.............................................................................................................88


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10.3
NYHA FUNCTIONAL CLASSIFICATION...................................................90
10.4
MODIFIED RANKIN SCALE .........................................................................90
10.5
STRUCTURAL HEART DISEASE.................................................................90
10.6
BLOOD PRESSURE MEASURMENT PROCEDURE.................................91
11
DESCRIPTION OF GLOBAL AMENDMENT(S)..........................92


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ABBREVIATIONS 
ACE
Angiotensin Converting Enzyme
ACR
Albumin Creatinine Ratio
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine-Aminotransferase
ARB
Angiotensin Receptor Blocker
ARNI
Angiotensin Receptor blocker-Neprilysin Inhibitor
AST
Aspertate-Aminotransaminase
BI
Boehringer Ingelheim
BMI
Body Mass Index
BNP
B-type Natriuretic Peptide
CA
Competent Authority
CEC
Clinical Event Committee
CHF
Congestive Heart Failure
CI
Confidence Interval
CK
Creatine Kinase
CKD
Chronic Kidney Disease
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration Equation
CL
Clinical Lead (title refers to CRO’s Project Leader on national/regional
level)
CML
Local Clinical Monitor (title refers to Sponsor’s Project Leader on
national/regional level)
CRA
Clinical Research Associate
CRO
Clinical Research Organisation
CRT
Cardiac Resynchronisation 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
DNA
Deoxyribonucleic acid
EDC
Electronic Data Capture
ExSC
Executive Steering Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EF
Ejection Fraction
eGFR
Estimated Glomerular Filtration Rate
EOT
End of treatment
EQ5D
EuroQol 5 dimensions
eTMF
Electronic Trial Master File


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EudraCT
European Clinical Trials Database
GCP
Good Clinical Practice
GI
Gastrointestinal
HbA1c
Glycated Haemoglobin
HCRU
Health Care Resource Utilisation
HDL
High Density Lipoprotein
HF
Chronic Heart Failure
HHF
Hospitalisation for Heart Failure
HFpEF
Heart Failure with Preserved Ejection Fraction
HFrEF
Heart Failure with Reduced Ejection Fraction
HR
Heart Rate
IB
Investigator’s Brochure
ICD
Implantable Cardioverter Defibrillator
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
i.v.
Intravenous
KCCQ
Kansas City Cardiomyopathy Questionnaire
LA
Left Atrial
LDL
Low Density Lipoprotein
LPDD
Last Patient Drug Discontinuation
LVEF
Left Ventricular Ejection Fraction
MACE
Major Adverse Cardiovascular Event
MedDRA
Medical Dictionary for Drug Regulatory Activities
MI
Myocardial Infarction
MMRM
Mixed Model Repeated Measures
MRA
Mineralocorticoid Receptor Antagonist
MRI
Magnetic Resonance Imaging
MRS
Modified Rankin Scale
NT-proBNP
N-terminal of the prohormone brain natriuretic peptide
NYHA
New York Heart Association Classification
PK
Pharmacokinetics
p.o.
per os (oral)
PSA
Prostate-Specific Antigen
q.d.
quaque die (once a day)
RBC
Red Blood Cells
REP
Residual Effect Period, after the last dose of medication with measureable
drug levels or pharmacodynamic effects still likely to be present
RI
Renal Impairment
RS
Randomisation Set
SAE
Serious Adverse Event
SBP
Systolic blood Pressure
SEC
Scientific Excellence Committee
SGLT-1
Sodium-glucose co-transporter 1


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SGLT-2
Sodium-glucose co-transporter 2
SMQ
Standardised MedDRA Query
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
T1DM
Type 1 diabetes mellitus
T2DM
Type 2 diabetes mellitus
TDMAP
Trial Data Management and Analysis Plan
TIA
Transient Ischaemic Attack
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
UACR
Urine Albumin Creatinine Ratio
UGE
Urine Glucose Excretion
ULN
Upper limit of normal
UTI
Urinary Tract Infection
VAS
Visual Analogue Scale
WBC
White Blood Cells
WOCBP
Women of childbearing potential


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1
INTRODUCTION
1.1
MEDICAL BACKGROUND
Chronic heart failure (HF) is a progressive syndrome characterised by the inability of the 
heart to provide adequate blood supply to meet the metabolic demand of different tissues or 
do it at the expense of elevated left ventricle filling pressure. HF is a prevalent disease
affecting an estimated 26 million people worldwide. In the United States alone the prevalence 
is 5.7 million, and there are 670,000 new cases per year [R16-1527]. HF is associated with 
premature mortality and frequent hospitalisation. Approximately 50% of patients who 
develop HF die within 5 years after diagnosis [P16-03952]. Annually, more than 1 million 
patients are hospitalised with a primary diagnosis of HF. HF is the most common cause of 
hospitalisation among individuals above 65 years of age in the western countries [P16-
03760]. Two types of HF have been defined mainly based on the LV ejection fraction (EF) 
and also other structural changes in heart muscle. They consist of heart failure with reduced 
EF (HFrEF) <40% and heart failure with preserved EF (HFpEF) ≥40%. Relative prevalence 
of HFpEF among HF patients is approximately 50% [R16-1528]. 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 rate of rehospitalisation among 
patients with HFrEF is close to 29% within 60-90 days of hospitalisation discharge which is 
equal to HFpEF [R16-1527].
Despite advances in therapy and management, HF remains a deadly clinical syndrome. After 
HHF, the one year mortality rate is high and not different between patients with preserved or 
reduced left ventricular ejection fraction (LVEF) [R16-2217], underscoring a high unmet 
medical need in this population. 
About 25 to 45% of patients with HF have concomitant type 2 diabetes mellitus (T2DM), and 
nearly 15-25% have borderline DM (pre-diabetes), indicating a potential link between the HF 
syndromes and glucometabolic disturbances [R16-2382, R16-2384]. 
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 mortality and morbidity remains 
high. For HFpEF, however, control of congestive symptoms during acute episodes is the 
mainstay of management of these patients and no class of drugs have shown to increase 
survival or reduce HHF [P16-03760, P16-05920]. 
Empagliflozin is an orally available inhibitor of the renal dependent glucose co-transporter 2 
(SGLT-2) indicated for, reduction of blood glucose in patients with T2DM by promoting 
urinary glucose excretion. It also reduces blood pressure, arterial stiffness and measures of 
the myocardial workload, likely through various mechanisms, as well as improving other CV 
risk factors (uric acid, visceral fat mass, albuminuria) [P15-00589, P15-09541].  


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In 2010 Boehringer Ingelheim (BI) initiated the EMPA-REG OUTCOME trial to explore CV 
benefit of the drug as well as to establish the safety profile of empagliflozin [P15-09840]. 
This trial completed in 2015 and showed empagliflozin, when given in addition to standard 
care treatment in high CV risk patients with T2DM, reduces the risk of 3-point MACE by 
14% mostly driven by a 38% reduction in CV death. Furthermore this trial demonstrated 
reduction in the prespecified and adjudicated composite outcome of “CV death or HHF” and 
HHF by 34%.
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 significant reduction in CV death, HHF, and composite of “HHF or CV death” [P16-
01253]. 
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 the urinary sodium excretion returns 
to normal within few days of empagliflozin administration, the effect on urinary glucose 
continues.
Empagliflozin has been developed for the treatment of T2DM, and has received marketing 
approval in various regions including the European Union, Latin America, 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) [c01678844-06] and local prescribing information for empagliflozin.
1.2.1
Non-clinical assessment of safety
For further information regarding pre-clinical evaluation, please refer to the current version 
of the IB for empagliflozin.
1.2.2
Clinical pharmacokinetics
In humans, empagliflozin predominantly showed linear pharmacokinetic (PK). Empagliflozin 
reaches peak levels at approximately 1.5 hours and showed a biphasic decline with the 
terminal elimination half-life of 12.4 hours ranging from 10 to 19 hours.
Empagliflozin exposure increases with renal or hepatic impairment; however, no dose 
adjustment is recommended as the observed changes in exposure were not clinically 
meaningful. No clinically relevant PK interactions were observed with other oral 
antidiabetics, warfarin, verapamil, ramipril, simvastatin, digoxin, hydrochlorothiazide, 
torasemide, emfibrozil, rifampicin, probenecid and oral contraceptives (Microgynon®). 
For further details refer to the current version of the IB for empagliflozin.
1.2.3
Clinical efficacy and safety
Approximately 550 healthy volunteers were exposed to empagliflozin (up to 800 mg single 
dose and up to 50 mg multiple dosing). Approximately 8500 patients with T2DM have been 
treated with empagliflozin in research studies, of which approximately 4400 have been 


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treated for more than 52 weeks. Also, empagliflozin was tested in over 4600 patients with 
T2DM and high CV risk for median treatment duration of 2.6 years.
The EMPA-REG OUTCOME trial was a randomised, placebo-controlled trial of 
empagliflozin 10 and 25 mg in 7020 patients with T2DM and high CV risk. It ended in 2015 
after accruing the minimum prespecified 691 major adverse CV events. Empagliflozin was 
associated with significant risk reduction of all-cause mortality by 32% (HR 0.68; 95% CI 
0.57, 0.82 p<0.0001) and CV death by 38% (HR 0.62; 95% CI 0.49, 0.77, p value <0.0001). 
In addition, the EMPA-REG OUTCOME trial showed reduction in the prespecified and 
adjudicated composite outcome of “CV death or HHF” by 34% (HR 0.66; 95% CI 0.55, 0.79, 
p value <0.0001). This result was consistent across various predefined sensitivity analysis and 
internal consistency was confirmed by showing overall homogeneity over a wide range of 
subgroups, including patients with and without history of HF at baseline. There was no 
significant difference in improving CV outcomes between the 10 and 25 mg dose.
The Phase III studies in T2DM showed that treatment with empagliflozin 10 mg or 25 mg 
once daily for up to 24 weeks results in a reduction of HbA1c up to 1%, body weight 
reduction between 2-3 kg, and a decrease in systolic blood pressure (SBP) between 3-5 
mmHg compared with placebo. This was consistently observed with empagliflozin as 
monotherapy, add on to metformin, metformin and sulphonylurea, pioglitazone with or 
without metformin, and to basal insulin with metformin and/or sulphonylurea. Phase III 
studies up to 104 weeks in T2DM support the sustained effect of empagliflozin.
In clinical studies, empagliflozin was well tolerated in both healthy volunteers and patients 
with T2DM including patients with high CV risk up to a median duration of 2.6 years. The 
frequency of overall Adverse Events (AEs), AEs leading to discontinuation and Serious AE 
(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. In general there was a small increase in frequency of 
urinary tract infection (UTI) compared to placebo. There was an increase in frequency of 
genital infections with the use of empagliflozin. There was a small increase in total 
cholesterol, low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) 
cholesterol and no significant changes in triglycerides. No changes in electrolytes were 
observed with empagliflozin. 
In the EMPA-REG OUTCOME trial renal function over time, as measured by the eGFR, is 
shown in Figure 1.2.3:1 [P16-06807].  After the initial decrease, eGFR remained steady in the 
empagliflozin group and was reversed after the cessation of the trial medication (Figure 
1.2.3:2). At the follow-up visit, the adjusted mean difference from placebo in the change from 
baseline in the eGFR with each of the two doses of empagliflozin was 4.7 ml per minute per 
1.73 m2 (95% confidence interval, 4.0 to 5.5; P<0.001 for both comparisons) (Figure 
1.2.3:2). The data indicated that the initial drop in eGFR after administration of empagliflozin 
is reversible and most likely due to hemodynamic carnages. This is very similar to what have 
been observed with ACEi and ARBs. The EMPA-REG OUTCOME trial also generated the 
hypothesis that the expected deterioration in renal function in patients with T2DM slowed 
down after using empagliflozin, and this will be further tested in the HF trials using the eGFR 
slope analysis and composite renal endpoints (see Section 5.1.2 and 5.1.3).


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Figure 1.2.3:1
Change in eGFR over192 weeks in the EMPA-REG OUTCOME 
trial.
Figure 1.2.3:2
Change in eGFR from baseline to last measurement during treatment 
and follow-up in the EMPA-REG OUTCOME trial.


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In a dedicated trial in patients with moderate and severe RI (eGFR between 15-60 
mL/min/1.73 m2 [Chronic Kidney Disease (CKD3 and CKD4)]) treatment with empagliflozin 
was well tolerated and in patients with CKD3 led to statistically significant reduction of 
HbA1c and clinically meaningful improvement in body weight and BP compared to placebo 
at Week 24, these results were sustained for up to 52 weeks [P14-01211]. In patients with 
CKD4 renal impairment, while there was not change in the glycaemic response, the reduction 
in BP and renal hemodynamic changes (similar to what was observed in the EMPA-REG 
OUTCOME trial) were preserved. In the EMPA-REG OUTCOME trial a similar reduction in 
CV risk was observed in the subgroup of patients with different degree of RI, including 
patients with eGFR between >45-60 and >30-45 mL/min/1.73 m2.
2
RATIONALE, OBJECTIVES, AND BENEFIT-RISK ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
Heart failure is an important public health problem, and one of the leading causes of 
hospitalisation in the Western countries. With the increasingly aging population and
increasing incidence of obesity, the scope and cost to society associated with this condition 
will progressively rise. There is an unmet medical need in treatment of patients with HFpEF.  
Despite advances in the management of HF, no new therapies have been found to improve 
outcomes by reducing mortality or morbidity (i.e. CV death or HHF) in these patients [P16-
03760]. HF also significantly decreases health-related quality of life (HRQOL) and 
pharmacological therapies have not shown consistent improvement in HRQOL.
Empagliflozin improves survival in patients with high cardiovascular risk by mechanisms 
which go beyond the blood glucose lowering effect. There was no heterogeneity by baseline 
HbA1c categories in HHF or “CV death and HHF” risk reduction in the EMPA-REG 
OUTCOME trial. Empagliflozin exerts its glucose lowering effect by preventing sodium and 
glucose reabsorption. The initial natriuresis will be compensated within days of drug 
administration through changes in tubulo-glomerular feedback. However, the glucosuria lasts 
as long as the medication is used.  This leads to consequent hemodynamic changes associated 
with a modest osmotic diuresis, blood pressure lowering effect, improvement in arterial 
stiffness, reduction in oxidative stress, and decrease in heart rate (HR) x Pressure product, a 
measure of myocardial oxygen consumption, with no increase in HR and no effect on 
sympathetic nerve activity [P15-00589, P15-09541]. Of note, the effect of empagliflozin on 
improving CV outcomes is evident even at low urinary glucose excretion demonstrated in 
those with low HbA1c as well as in those with reduced renal function (i.e. eGFR < 60
mL/min/1.73 m2). Subgroup analysis of the EMPA-REG OUTCOME trial showed no 
difference in patients with baseline HbA1c <7%, 7% to 8%, 8% to 9%, or >9% for CV death 
or HHF risk reduction. In addition, patients who had no HbA1c change or only modest 
change up to 0.2% throughout the trial have shown to have a similar risk reduction of HHF as 
the patients with at least 0.3% or higher reduction in HbA1c. Also as noted changes in BP 
reduction and hemodynamic changes were preserved in patients with CKD4, despite loss of 
glycaemic efficacy. Lack of correlation between CV outcome improvement and blood 
glucose levels provides supporting evidence that the benefit of empagliflozin in HHF or CV 
death risk reduction should also be expected in patients without DM [P16-01253, c09670340, 
c11764168]. The beneficial CV effects of empagliflozin cannot be explained by the modest 


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glucose control achieved in the EMPA-REG OUTCOME trial. Other outcome trials with the 
goal of tight glycaemic control (ADVANCE, ACCORD, and VADT) have failed to show 
significant CV benefit [R16-1560] and decrease in incident HF or mortality [R16-0736]. 
It should be noted that in a mechanistic study, non-DM subjects showed metabolic changes 
such as, increase in endogenous glucose production, and substrate shift from glucose to lipid 
oxidation similar to those observed in patients with T2DM after one dose and up to 4 weeks 
of daily administration of empagliflozin [P16-01830]. Furthermore, in a trial of healthy 
volunteers, empagliflozin 10 mg resulted in approximately 50 g glucosuria per day [P13-
04190]. This amount of glucose excretion is similar to what had been observed in patients 
with eGFR between 30-60 mL/min 1.73 m2 (CKD3) which was close to 55 g glucosuria per 
day. In the EMPA-REG OUTCOME trial patients with CKD3 showed a trend for the CV 
death or HHF risk reduction very similar to the risk reduction in the main cohort and in 
patients with CKD2 and 1. While the higher level of glucosuria is associated with a higher 
HbA1c reduction and better glycaemic control, this correlation is lacking for the CV benefits 
associated with empagliflozin, and in fact a lower glucose excretion similar to what has been 
observed in patients with CKD3 or in healthy volunteers seems to be sufficient to improve 
the CV outcomes. Therefore, the expected benefit of empagliflozin such as BP reduction, 
weight loss, improvement in arterial stiffness, and hemodynamic changes, as well as CV 
benefits seen in patients with T2DM is also speculated to be seen in HF patients without DM
and in patients with CKD3 and 4. These findings further support the rationale of exploring 
the effect of empagliflozin beyond DM. Although the type of HF was not assessed entering 
the EMPA-REG OUTCOME trial, it is highly likely in this trial both patients with preserved 
and reduced ejection fraction were included, considering the high prevalence of both HFrEF 
and HFpEF in patients with DM [R16-1529].
The modes of action described above, and beneficial effect in patients with history of HF in 
the EMPA-REG OUTCOME trial, further supports the scientific rationale of performing this 
trial to explore the effect of empagliflozin in patients with HFpEF.
2.2
TRIAL OBJECTIVES
The objective of this event-driven trial is to demonstrate superiority of empagliflozin 10 mg 
versus placebo in patients with symptomatic, chronic HF and preserved ejection fraction 
(LVEF > 40%) under stable treatment of HF symptoms.
For further description of trial endpoints and statistical analysis, please refer to Section 5 and 
7.
This trial is part of an investigational clinical trial program of empagliflozin in patients with
chronic HF. A trial to investigate the efficacy and safety in patients with reduced EF (LVEF 
≤40%) is ongoing in parallel.
2.3
BENEFIT-RISK ASSESSMENT
The overall benefits and safe 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. 
The overall tolerability and safety profile outlined in Section 1.2, and the current IB, supports 
chronic administration of empagliflozin 10 mg in human studies. 


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Investigators will be encouraged to treat participants to best standard of care in compliance 
with the local guidelines and recommendations for HF, and DM if present.
Based on the putative mechanism of actions (reviewed in Section 2.1) and the result of the 
EMPA-REG OUTCOME trial, it is assumed that patients with HFpEF should benefit from 
empagliflozin treatment on top of guideline-directed therapies. The safety profile of 
empagliflozin in these patients should follow a similar trend which was previously observed 
in over 10000 patients with T2DM treated with empagliflozin, including patients with high 
CV risk.  Safety will be ensured by close monitoring of the subjects for AEs both clinically 
and by laboratory testing. Special attention will be paid to prevent metabolic acidosis, 
ketoacidosis and diabetic ketoacidosis (DKA). For further details refer to Section 4.2.1.
To continue the assessment of the long-term safety of empagliflozin, adjudication of 
cardiovascular events, 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). For further details please refer to Section 3.1.1.
One interim analysis is planned after approximately 500 primary events have been accrued. If 
the prespecified criteria for stopping for success at the interim analysis has been reached, the 
Executive Steering Committee (ExSC) and the Sponsor will be informed. The final decision 
whether to stop the trial will be made by Sponsor. For further details refer to Section 7.4.
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.
Empagliflozin causes intravascular volume contraction. In patients with volume depletion, 
correcting this condition prior to initiation of empagliflozin is recommended. 
Although rare, a potential for drug induced liver injury (DILI) is under constant surveillance 
by the Sponsor 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 5.3.6.1.
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, WOCBP must agree to the requirements for
pregnancy testing and contraceptive methods described in this protocol.


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3
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This randomised, double-blind, multi-national, parallel group trial compares empagliflozin 10 
mg once daily to placebo as add-on to standard of care treatment in patients with HFpEF.
Figure 3.1: 1 
Trial design
Patients are included in the trial once they have signed the informed consent form (ICF). All 
patients suitable after screening and who still meet the inclusion/exclusion criteria when 
returning for Visit 2 approximately 1-3 weeks later will be randomised into one of the 
treatment groups in a 1:1 manner.
Randomisation will be stratified with respect to geographical region (North America, Latin 
America, Europe, Asia and “Other”, history of DM (DM, pre-DM, no DM), LVEF (<50%, 
≥50%) and eGFR (CKD-EPI)cr (<60 mL/min/1.73 m², ≥60mL/min/1.73 m²) at screening.
The trial is event-driven and all randomised patients will remain in the trial until the defined 
number of adjudicated primary endpoint events has been reached. Estimated trial duration is 
38 months with a recruitment period of approximately 18 months. The estimated length of the 
double-blind treatment will vary from approximately 20 to 38 months for each patient. The 
trial duration may be prolonged in case the number of patients and/or primary endpoint 
events is not reached within the planned timelines. The total number of randomised patients 
may be adapted based on assessment of the blinded event rate. For further details refer to 
Section 7.7.
The number of confirmed adjudicated primary endpoint events will be continuously 
monitored during the trial. As soon as the available data reliably suggests that the total 
number of patients with an adjudication confirmed primary endpoint event will be reached 
within a given timeframe, the trial team will initiate required actions to stop the trial. From 
this time point on, all patients are expected to perform their last visit (EOT visit) with the 
proposed time schedule communicated via an investigator letter. See also Section 6.2.3.
Screening
N= 4854
Placebo
N=2063
Empagliflozin 10 mg
N= 2063
F-U
R
N=4126
1-3 weeks                                              ~20-38 months                      30 days 


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3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim (BI). The operational aspects (trial 
management and monitoring) of the trial and Data Management will be outsourced globally 
to a Contract Research Organisation (CRO).
A Coordinating Investigator is responsible to coordinate Investigators at different centres 
participating in this multicentre and multinational trial. Tasks and responsibilities are defined 
in a contract stored in the electronic Trial Master File (eTMF) at the CRO.
An ExSC and a Scientific Excellence Committee (SEC) consisting of independent experts 
and Sponsor representatives will be established to support Sponsor in designing the trials and 
successful execution. The ExSC and SEC will have a scientific and advisory function in the 
trial. The ExSC will be involved with the detailed trial design discussions and decision 
making while the SEC has wide representation of different scientific disciplines and will be 
consulted on the topics requiring broader consensus. The composition of the ExSC and the 
SEC will be documented in the eTMF. The tasks and responsibilities will be agreed in 
contracts between the ExSC and the SEC and the Sponsor, and also summarised in an ExSC-
and SEC-charter filed in the eTMF.
A data-monitoring committee (DMC), independent of the Sponsor and CRO will assess the 
progress of the trial, including an unblinded safety and efficacy assessment at specified 
intervals, and to recommend to the Sponsor whether to continue, modify, or stop the trial. 
Measures are in place to ensure blinding of the Sponsor, ExSC, SEC, CRO and all other trial 
participants. The tasks and responsibilities of the DMC will be specified in a charter. The 
DMC will maintain written records of all its meetings.
Relevant documentation on the participating (Principal) Investigators and other important 
participants, including their curricula vitae, will be filed in the Investigator Site File (ISF).
BI has appointed a Trial Clinical Monitor, responsible for coordinating all required activities, 
in order to

manage the trial in accordance with applicable regulations and applicable BI and CRO 
Standard Operating Procedures (SOPs),

direct the clinical trial team in the preparation, conduct, and reporting of the trial,

ensure appropriate oversight of vendors.
Statistical Evaluation will be done by BI according to BI SOPs, and Data Management will 
be done by the CRO in accordance with CRO SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial will be 
defined according to BI and CRO SOPs, and the applicable SOPs will be listed in the contract 
with the CRO. A list of responsible persons and relevant local information can be found in 
the ISF.
A central laboratory service and an Interactive Voice/Web-based Response System (IRT) -
vendor will be used in this trial. Details will be provided in the IRT Manual and Central 
Laboratory Manual, available in ISF.


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Clinical Event Committee
3.1.1.1
An independent external committee (Clinical Event Committee, [CEC]) will be established to 
adjudicate centrally and in a blinded fashion whether pre-specified criteria for adjudication 
endpoints are met.
For any events that qualify for adjudication, trial sites will be required to provide in a timely 
manner clinical documentation such as (but not limited to) electrocardiograms (ECGs), 
laboratory values, angiography reports, echocardiography reports, CT and/or Magnetic 
Resonance Imaging (MRI) reports, discharge summaries, and autopsy reports to support the 
external event adjudication. If the CEC requests more data, all efforts must be made by the 
site to collect all available data to support adjudication. 
For reporting of events and exemption from expedited reporting refer to Section 5.3.7.2.
The tasks and responsibilities of the CEC, and the pre-specified criteria for adjudication will 
be specified in a charter. The CEC will maintain the adjudication results in writing.
Hepatic external adjudication
3.1.1.2
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 laboratory values, histological analysis, reports from
ultrasound, CT, MRI, scintigraphy, hospital discharge letters, and medical reports from other 
physicians. All evaluations will be performed in a blinded fashion. The assessments will be 
analysed based on empagliflozin data combined from multiple trials (i.e. on project level).
Adjudication of ketoacidosis
3.1.1.3
Events suspected to be metabolic acidosis, ketoacidosis and DKA will be adjudicated by 
independent external experts in a blinded fashion.
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 and mortality. The aim of this trial is to recruit patients with HFpEF on various HF 
background therapies to evaluate the long term effect of empagliflozin on CV death and HHF 
in a real life clinical setting.
Due to its mode of action empagliflozin should be efficacious in treating patients with HF 
and could provide additional efficacy in combination with any given background therapy. 


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The placebo-controlled design is considered ethically acceptable on the basis of appropriate 
criteria for patient discontinuation, ability to change background therapy to maintain, or 
obtain, sufficient level of hemodynamic control as defined in relevant local and regional 
guidelines for optimised standard of care.
The double-blind treatment period is planned until the necessary number of events is 
observed to evaluate efficacy of empagliflozin compared to standard of care. The 30 days
follow-up period is considered to be sufficient for assessment of adverse events and efficacy 
outcomes after stopping trial medication.
Patients should be receiving appropriate care as defined by their physician or practitioner for 
all cardiovascular conditions according to the prevailing guidelines. This should be conducted 
in the context of local or regional guidance for primary or secondary CV prevention.
The rationale for dose and dose-interval selection is described in Section 4.1.2.
3.3
SELECTION OF TRIAL POPULATION
An appropriate number of patients will be screened for the trial in approximately 22
countries. Approximately 500 trial centres will participate to ensure that the estimated 4126
patients are randomised to trial medication and complete the trial. Investigators who fail to 
randomise at least one patient in the first 12 weeks from centre initiation may be excluded 
from further participation. If enrolment is delayed, additional centres may be initiated. The 
total number of randomised patients may be adapted based on assessment of the blinded 
event rate. For further details refer to Section 7.7.
Clinical trials contribute toward reducing health disparities through improved knowledge 
about treatment among diverse populations. Greater diversity in clinical trial samples allows 
for broader generalisation of trial results, increased minority access to trials, improved 
standards of care, decreased disparities in disease treatment and outcomes, and improved 
external validity supported by a more representative sample. Greater number of African-
Americans as an example, suffer from HF and all efforts must be made to have adequate 
representation of this minority population from the USA [P15-10667]. Each Investigator
should develop a recruitment strategy that ensures the recruitment of a representative patient 
population and takes into consideration gender, race and ethnicity.
According to previous heart failure trials and registries the prevalence of DM amongst 
patients with HF varies from 25% to 40%. Prevalence of pre-DM is not clearly understood 
but it is estimated to vary from 15% to 50% [R16-2382, R16-2384]. In a recent large HF 
outcome trial, 35% of the patients reported to have DM, another 15% found to have 
undiagnosed DM and around 27% had pre-DM [R16-2383]. 
Since there is a chance that empagliflozin, as a diabetes drug, when used in CV outcome 
trials recruits more patients with T2DM, capping on trial level will be used to aim for a 
similar distribution of patients with DM, pre-DM or no DM as it is expected in the population 
of patients with the chronic heart failure in real life. 


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Via IRT it will be ensured that approximately a minimum of 35 % of the trial population will 
be patients with DM, a minimum of 15 % will be patients with pre -DM and a minimum of 
20 % will be non-diabetic patients. 
Additionally recruitment to the three categories of DM, pre-DM or no DM will be monitored 
on regional level. Capping on regional level may be applied to achieve a contribution of each 
region to each category of diabetes status. DM in this context is defined as active treatment 
with antidiabetic medication (for indication of DM) or screening HbA1c ≥6.5% or history of 
DM. Pre-DM is defined as screening HbA1c ≥5.7% and <6.5% without the intake of 
antidiabetic medication (unless taken for a non-DM indication) and no history of DM, and 
patients with no DM is defined as screening HbA1c < 5.7 % without any intake of 
antidiabetic medication (unless taken for a non-DM indication) and no history of DM [R16-
2261].
IRT will be used to aim for a trial population consisting of approximately 35% to 50% with 
an LVEF >50%. To ensure adequate enrolment of patients the final decision on capping will 
be based on the recommendation from the ExSC during the recruitment period.
Screening of patients for this trial is competitive, i.e. screening for the trial will stop at all 
centres when a sufficient number of patients have been randomised to trial treatment. 
Investigators will be notified when screening is complete and will not be allowed to recruit 
additional patients thereafter. Patients who have completed visit 1 procedures prior to 
notification of the termination of recruitment will be allowed to be randomised in the trial, if 
they meet all eligibility criteria. Patient eligibility will be based upon a complete medical 
history including a physical examination and clinical laboratory tests. Judgment of the 
clinical relevance of a concomitant disease is at the discretion of the Investigator.
Re-screening and/or re-testing (of assessments) is permitted if approved by Local Clinical 
Monitor (CML)/Clinical Lead (CL) or delegate. 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 a laboratory result which is 
obviously received beyond stability at the central laboratory or thought to be a spurious result 
based on previously available laboratory results. The re test should be carried out as soon as 
possible so the laboratory test results will be received within the next planned visit windows 
in order to avoid protocol window violations. 
Re-screening:
-
Re-screening of the same patient is only allowed once.
-
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.


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-
The patient must be re-consented using the current approved version of the 
information sheet and consent form.
A log of all patients enrolled into the trial (i.e. who have signed ICF) will be maintained in 
the ISF at the investigational site irrespective of whether they have been treated with 
investigational drug or not.
3.3.1
Main diagnosis for trial entry
The trial will be performed in patients with chronic heart failure with an ejection fraction     
> 40 %. 
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
1. Age ≥18 years at screening. For Japan only: Age ≥20 years at screening
2. Male or female patients. WOCBP a must be ready and able to use highly effective 
methods of birth control per ICH M3 (R2) [R09-1400] 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
3. Patients with chronic HF diagnosed for at least 3 months before Visit 1, and currently 
in HF NYHA class II-IV
4. Chronic HF with preserved EF defined as LVEF > 40 % per local reading (obtained 
by echocardiography, radionuclide ventriculography, invasive angiography, MRI or
CT), and no prior measurement of LVEF ≤ 40% under stable conditionsb. The EF 
must have been obtained and documented at Visit 1 or within 6 months prior to Visit 
1, and more than 90 days after any myocardial infarction (as defined in exclusion 
criterion No. 1)
5. Elevated NT-proBNP > 300 pg/ml for patients without AF, OR > 900 pg/ml for 
patients with AF, analysed at the Central laboratory at Visit 1
________________________________
aWomen of childbearing potential are defined as:
-
having experienced menarche and
-
not postmenopausal (12 months with no menses without an alternative medical cause) and 
-
not permanently sterilised (e.g., tubal occlusion, hysterectomy, bilateral oophorectomy or bilateral 
salpingectomy).
b In the Investigator’s opinion


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6. Patients must have at least one of the following evidence of HF: 
a.
Structural heart diseasec (left atrial enlargement and/or left ventricular 
hypertrophy) documented by echocardiogram at Visit 1 or within 6 months 
prior to Visit 1, OR
b. Documented HHFd within 12 months prior to Visit 1
7. Oral diuretics, if prescribed to patient according to local guidelines and discretion of 
the Investigator, should be stable for at least 1 week prior to Visit 2 (Randomisation)
8. Body Mass Index (BMI) < 45 kg/m2 at Visit 1
9. Signed and dated written ICF in accordance with GCP and local legislation prior to 
admission to the trial
3.3.3
Exclusion criteria
1. Myocardial infarction (increase in cardiac enzymes in combination with symptoms of 
ischaemia or newly developed ischaemic ECG changes), coronary artery bypass graft 
surgery or other major cardiovascular surgery, stroke or TIA in past 90 days prior to 
Visit 1
2. Heart transplant recipient or listed for heart transplant
3. Implantation of cardioverter defibrillator (ICD) within 3 months prior to Visit 1
4. Implanted cardiac resynchronisation therapy (CRT)
5. 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
6. Any severe (obstructive or regurgitant) valvular heart disease expected to lead to 
surgery during the trial in the Investigator’s opinion
7. Acute decompensated HF (exacerbation of chronic HF) requiring intravenous (i.v.)
diuretics, i.v. inotropes or i.v. vasodilators, or left ventricular assist device within 1 
week from discharge to Visit 1, and during screening period until Visit 2 
(Randomisation)
8. Atrial fibrillation or atrial flutter with a resting heart rate > 110 bpm documented by 
ECG at Visit 2 (Randomisation)
9. Systolic blood pressure (SBP) ≥ 180 mmHg at Visit 2. If SBP >150 mmHg and <180 
mmHg at Visit 2, the patient should be receiving at least 3 antihypertensive drugs
10. Symptomatic hypotension and/or a SBP < 100 mmHg at Visit 1 or Visit 2
________________________________
c Structural heart disease is further defined in Appendix 10.5
d The main reason for HHF must be HF. Documentation for HHF must be provided in the source documents


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11. Chronic pulmonary disease requiring home oxygen, 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
12. 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
13. Impaired renal function, defined as eGFR < 20 mL/min/1.73 m2 (CKD-EPI)cr or 
requiring dialysis, as determined at Visit 1
14. Haemoglobin < 9 g/dl at Visit 1
15. History of ketoacidosis
16. 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 replacement ) 
within 90 days after visit 1
17. Gastrointestinal (GI) surgery or GI disorder that could interfere with absorption of 
trial medication in the investigator’s opinion 
18. Any documented active or suspected malignancy or history of malignancy within 2
years prior to screening, except appropriately treated basal cell carcinoma of the skin, 
in situ carcinoma of uterine cervix or low risk prostate cancer (patients with pre-
treatment PSA < 10 ng/mL and biopsy Gleason score of ≤ 6  and clinical stage T1c or 
T2a)
19. Presence of any other disease than heart failure with a life expectancy of <1 year in 
the investigator’s opinion
20. 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
21. Treatment with any SGLT-2 inhibitor or combined SGLT-1 and 2 inhibitor within 1 
week prior to Visit 1 or during screening period until Visit 2 (Randomisation)
22. 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
23. Known allergy or hypersensitivity to empagliflozin or other SGLT-2 inhibitors
24. Chronic alcohol or drug abuse or any condition that, in the investigator’s opinion, 
makes them an unreliable trial subject or unlikely to complete the trial
25. Women who are pregnant, nursing, or who plan to become pregnant while in the trial
26. 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 


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3.3.4
Removal of patients from therapy or assessments
Removal of individual patients
3.3.4.1
This is a long-term outcome trial and every effort should be made by the site staff to 
encourage patients to remain in the trial and on trial medication unless medical condition 
substantially changes to alter the safety profile. If a patient is withdrawn from the trial the 
ExSC and the Sponsor should be informed immediately about each individual case.
Prematurely discontinuation of trial medication
For patients who prematurely discontinue trial medication all efforts should be made to 
observe these patients and ask them to continue to attend the scheduled visits until the end of 
trial. It is expected that all efforts are made to follow up on the collection of all adverse 
events, outcome events and concomitant therapy, and to have a complete dataset without 
missing data.
If a patient who prematurely discontinued trial medication is not willing to return to the 
predefined trial visits, at minimum a telephone call every 24 weeks (preferably every 12
weeks) and a telephone call at trial end will be required, to document the occurrence of 
outcome events and vital status. If possible, other AE’s and concomitant therapy changes 
since last visit must be recorded. 
Every attempt must be made by the Investigator to ensure patients continue participating in 
the trial during trial medication interruptions and after discontinuation of trial medication.
Patients who prematurely discontinue trial medication are allowed to restart treatment, at any 
time if appropriate in the opinion of the Investigator. At every visit following trial medication 
discontinuation Investigators must consider if trial medication can be re-started.
Patients that are not actively taking trial medication may be less motivated to adhere to the 
scheduled trial visits. Investigators and site staff should work to detect early signs of losing 
interest and readily present such patients (not actively taking trial medication) with the 
following options to encourage continued participation:
Option 1 
Continue to attend regularly scheduled trial visits at the centre until the trial 
ends
Option 2 
Conduct all remaining trial visits over the phone
Option 3
Discontinue participation in remaining trial activities but permit collection of 
vital status and CV outcome events at the end of the trial through the patient or 
alternative person designated by the patient (e.g., family, spouse, partner, legal 
representative, or physician) even if only by telephone
Option 4 
Discontinue participation in remaining trial activities but permit collection of 
vital status at the end of the trial through the patient, alternative person 
designated by the patient, or through review of patient’s medical information 
from alternative sources (e.g., doctor’s notes, hospital records, etc.)
Patients will be asked to choose the most rigorous form of follow-up that they are willing to 
comply with.


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A patient could be instructed to permanently stop the trial medication only after discussion 
with Investigator, if eligibility criteria are being violated, or if the patient fails to comply with 
the protocol (e.g. non-attendance at trial assessments).
Withdrawal of informed consent
A patient has the right to withdraw informed consent for participation at any time for any 
reason. However, withdrawal of consent from trial participation should be very rare and 
unusual. Because of this, the Investigator must be involved in the discussions with the patient 
regarding a withdrawal of consent. Additionally, the Investigator must discuss the withdrawal 
of consent with the Sponsor’s/CRO’s representative prior to stopping trial participation.
Early discontinuation of trial medication is not a criterion for withdrawal of consent for 
participation in the trial.
The right to withdraw informed consent at any time for any reason also applies to the optional 
informed consent to biobanking (including DNA sampling), which is separate from the 
consent for trial participation.
If the patient withdraws informed consent for participation in the trial, the trial will end for 
that patient. The patient should stop taking trial medication and should be asked to complete 
the end of treatment (EOT) visit and follow-up procedures as described in the Flow Chart. 
Completing these procedures is strongly recommended for the patient’s safety. Patients that 
withdraw informed consent will not be replaced.
Vital status must be collected at the end of trial for patients that withdraw consent from trial 
participation, if allowed by local regulations.
Patients lost to follow-up
If a patient is lost, every effort will be made by the Investigator and site staff to contact and 
locate the patient before the patient is declared lost to follow-up. Investigators and site staff 
must use every possible allowable means, according to local regulations, to locate patients 
who have missed visits. Efforts to contact the patient may include but are not limited to:
•
Calling all numbers for patient and listed contacts (including in the evening and on
weekends).
•
Calling primary care physician, referring specialist and/or other listed physicians for
more recent information, date of last office visit or to determine vital status.
•
Sending an email and follow up with mailing certified letters (return receipt requested) 
to all known patient addresses and all listed contacts (e.g., relatives, friends, 
neighbours) that were provided by the patient.
•
Reviewing patient’s records and medical notes for any details of a hospitalisation,
doctor’s visit or other procedure that may indicate location or status of subject.
•
Use Internet to search for possible contact information for the patient.
•
Try reverse directory for phone numbers to get possible addresses and/or new contact
details.
•
Utilise social networking sites.


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•
Check local, regional, and national public records to locate the patient or search for
vital status in accordance with local law.
•
Consider home visit.
•
Contact patient finder service.
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 5.3.4.2).
An excessive withdrawal rate can have a severe negative impact on the scientific value of the 
trial. The Intention To Treat analysis requires that all randomised patients be followed until 
trial end even if the trial medication was temporarily interrupted, discontinued or never 
started. Every effort should be made to keep the patients in the trial as scheduled. This 
includes careful patient selection and appropriate explanation of the trial requirements and 
procedures prior to enrolment as well as an explanation of the consequences of premature 
withdrawal.
Discontinuation of the trial by the Sponsor
3.3.4.2
BI reserves the right to discontinue the trial overall or at a particular trial centre at any time 
for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial centre
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial (see also
Section 3.1.1).
3. Violation of GCP, the Clinical Trial Protocol (CTP), or the contract disturbing the
appropriate conduct of the trial
The Investigator / the trial centre 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 BI.
4.1.1
Identity of the investigational Medicinal product and comparator
The characteristics of test products are below:
Substance:
empagliflozin
Pharmaceutical formulation:
film-coated tablet
Source:
Boehringer Ingelheim
Unit strength:
10 mg
Posology:
1 tablet once daily
Rout of administration:
oral
Substance:
placebo matching empagliflozin
Pharmaceutical formulation:
film-coated tablet
Source:
Boehringer Ingelheim
Unit strength:
-
Posology:
1 tablet once daily
Rout of administration:
oral
4.1.2
Selection of doses in the trial
Empagliflozin 10 mg and 25 mg are approved for the treatment of T2DM.
Empagliflozin exerts its effect by promoting glucosuria and consequent hemodynamic 
changes associated with diuresis, improvement in arterial stiffness, blood pressure lowering 
effect with no increase in HR and reduction in HR x Pressure product, an index of myocardial 
oxygen consumption. These modes of actions support the scientific rationale of using 
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 


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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 about 50g glucosuria. 
Given the lower exposure with 10 mg empagliflozin similar general safety, and CV effects 
similar for both doses, empagliflozin 10 mg once daily has been selected in this trial.
For further details see current version of the IB.
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 the randomisation plan. The assignment will 
occur in a blinded fashion via Interactive Response Technology (IRT).
To facilitate the use of the IRT, the Investigator will receive a manual including all necessary 
instructions for using the system. A copy of the manual will be available in the ISF.
Patient assignment to the treatment group will be determined by a computer generated 
random sequence. Access to the randomisation code will be controlled and documented - for 
further details please refer to Section 4.1.5.1. and 4.1.5.2.
Using this procedure, relevant parties will be blinded to the treatment group assignment.
For information on stratification and capping please refer to Section 3.3.
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 in a double-blind and single-dummy manner. 
Dispensing of kits for the double-blind treatment period will begin at Visit 2 and continue at 
every visit until end of trial.  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.  On days before the next 
visit, the dose should be taken 22-26 hours before the planned dose at the visit. No double 
doses should be taken.
Patients should be instructed not to take their medication on the morning of trial visits as they 
will be dosed whilst in the clinic. 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.


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4.1.5
Blinding and procedures for unblinding
Blinding
4.1.5.1
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 randomisation code will be kept secret by Clinical Trial Support up to database lock.
Unblinding and breaking the code
4.1.5.2
Emergency unblinding will be available to the Investigator via the IRT. It must only be used 
in an emergency situation when the identity of the trial medication must be known to the 
Investigator in order to provide appropriate medical treatment or otherwise assure safety of 
trial participants. Whenever possible and if time allows, the need for unblinding will be 
discussed with the medical representative from the Sponsor or delegate before the unblinding 
of trial medication takes place. The reason for unblinding must be documented in the source 
documents and/or appropriate eCRF page along with the date and the initials of the person 
who broke the code.
The patient could continue with trial medication after unblinding.
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 to be shared 
further.
For Japan only: In this blinded trial, an emergency code break will be available to the 
Investigator / the sub-Investigators via the IRT. This code break may only be accessed in 
emergency situations when the identity of the trial medication must be known to the 
Investigator /the sub-Investigators in order to provide appropriate medical treatment or if 
required to assure the safety of trial participants. Each site receives a manual from the IRT 
provider that contains instructions on how to unblind the treatment of a patient via the IRT 
(via 24-hour Emergency helpline). If the code break for a patient is accessed, the Sponsor or 
delegate must be informed immediately. The reason for accessing the code break, together 
with the date, must be documented on the appropriate eCRF page. In case third party needs to 
break the code, however, when the Investigator cannot be reached, the code can be opened by 
calling emergency code manager.
4.1.6
Packaging, labelling and re-supply
The investigational products will be provided by BI or a designated CRO. They will be 
packaged and labelled in accordance with the principles of Good Manufacturing Practice 


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(GMP). Re-supply to the sites will be managed via the IRT, which will also monitor expiry 
dates of supplies available at the sites.
For details of packaging and the description of the label, please refer to the ISF.
4.1.7
Storage conditions
Trial medication must be stored under the recommended storage conditions indicated on the 
label. A temperature log must be maintained by the investigator / pharmacist / investigational 
drug storage manager to make certain that the drug supplies are stored at the correct 
temperature. 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 or delegate when the following 
requirements are fulfilled:

Approval of the trial protocol by the Institutional Review Board (IRB) / ethics committee 

Availability of a signed and dated clinical trial contract between the Sponsor or delegate 
and the head of 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 

For USA; Availability of Form 1572
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, CRO or warehouse / drug distribution centre or 
alternative disposal of unused products. If applicable, the Sponsor, CRO 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 CTP and 
reconcile all investigational products received from the Sponsor or delegate. At the time of 
return to the Sponsor/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
The use of medication for the treatment of HF will be at the discretion of the Investigator and 
should be in accordance with local/international guidelines. 


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All concomitant (additional) medications and other therapies should be recorded on the 
appropriate pages of the eCRF. 
Concomitant antidiabetic medications should be adjusted individually as clinically indicated 
by the patient’s usual diabetes care provider. Restrictions of antidiabetic background therapy 
are described in Section 4.2.2. 
Patients without a diagnosis of DM experiencing repeated or severe symptoms such as 
nervousness, sweating, intense hunger, trembling, weakness and palpitations should contact 
the Investigator or other healthcare professional, as these symptoms might be suggestive of 
hypoglycaemia. In the case of hypoglycaemia, in patients with or without DM, that may put 
the patient at risk (e.g. repeated symptomatic hypoglycaemia or severe hypoglycaemia), 
appropriate care should be provided at the discretion of the Investigator.
Special attention must be paid to the prevention of ketoacidosis. All patients must be made 
aware of this risk and need to be instructed to contact the Investigator or other healthcare 
professional in case of symptoms of metabolic acidosis, ketoacidosis and DKA. Cases of 
DKA have been reported in patients treated with empagliflozin, including fatal cases. In a 
number of reported cases, the presentation of the condition was atypical with only moderately 
increased blood glucose values; below 14 mmol/l (250 mg/dl).
The risk of DKA must be considered in the event of non-specific symptoms such as nausea, 
vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing, confusion, unusual 
fatigue or sleepiness. 
Patients should be assessed and treated for ketoacidosis immediately according to local 
guidelines if these symptoms occur, regardless of blood glucose level. If ketoacidosis is 
suspected, the trial medication should be discontinued, the patient should be evaluated, and 
prompt treatment should be initiated.
Patients who may be at higher risk of ketoacidosis while taking empagliflozin include 
patients on a very low carbohydrate diet (as the combination may further increase ketone 
body production), patients with an acute illness, pancreatic disorders suggesting insulin 
deficiency (e.g. Type 1 diabetes mellitus (T1DM), history of pancreatitis or pancreatic 
surgery), insulin dose reduction (including insulin pump failure), alcohol abuse, severe 
dehydration, and patients with a history of ketoacidosis. Empagliflozin should be used with 
caution in these patients. In patients requiring insulin, caution should be taken when the dose 
of insulin is reduced.
In clinical situations known to predispose to ketoacidosis (e.g. prolonged fasting due to acute 
illness or surgery), the Investigator should consider monitoring for ketoacidosis and 
temporarily discontinue the trial medication. 
There are no trial specific emergency procedures to be followed.


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4.2.2
Restrictions
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 30 days 
period between the EOT and the Follow Up Visit.
If any restricted treatment is given during the conduct of the trial, the trial medication can be 
discontinued temporarily, or if needed permanently.
If the patient is in need of any additional treatment during this period, this may be given at 
the discretion of the Investigator. The patient can still remain on trial medication.
WOCBP must use the contraception methods as described in the patient information.
4.3
TREATMENT COMPLIANCE
Patients are requested to bring all remaining trial medication including empty package 
material with them when attending visits.
The Investigator or his/her designate will count the number of the returned tablets and 
calculate the compliance based on the number of tablets taken, divided by the number of 
tablets that should have been taken since last visit, multiplied by 100. See formula below.
Compliance (%) = 
Compliance should be between 80% and 120%. Compliance should be emphasised with a
goal of at least 80% compliance rate. 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.
Number of tablets actually taken since last tablet count x 100
Number of tablets which should have been taken in the same period


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5
VARIABLES AND THEIR ASSESSMENT
5.1
TRIAL EFFICACY ENDPOINTS
5.1.1
Primary endpoint(s)
The composite primary endpoint for this trial is the time to first event of adjudicated CV 
death or adjudicated HHF in patients with Heart Failure with preserved Ejection Fraction 
(HFpEF).
5.1.2
Secondary endpoint(s)
The key secondary endpoints which are part of the testing strategy, are the following: 
1. Occurrence of adjudicated HHF (first and recurrent),
2. eGFR (CKD-EPI)cr slope of change from baseline
Other secondary endpoints (not part of confirmatory testing hierarchy on trial level) are the 
following:

Time to first occurrence of sustained* reduction of ≥40% eGFR (CKD-EPI)cr or
o
sustained eGFR (CKD-EPI)cr <15 mL/min/1.73 m2 for patients with baseline 
eGFR ≥30 mL/min/1.73 m2
o
sustained eGFR (CKD-EPI)cr <10 mL/min/1.73 m2 for patients with baseline 
eGFR <30 mL/min/1.73 m2
*An eGFR (CDK-EPI)cr reduction is considered sustained, if it is determined by 
two or more consecutive post-baseline central laboratory measurements separated by 
at least 30 days (first to last of the consecutive eGFR values).

Time to first adjudicated HHF

Time to adjudicated CV death

Time to all-cause mortality

Time to onset of DM (defined as HbA1c ≥6.5% or as diagnosed by the Investigator)
in patients with pre-DM defined as no history of DM and no HbA1c ≥6.5 before 
treatment, and a pre-treatment HbA1c value of ≥5.7 and <6.5

Change from baseline in clinical summary score (HF symptoms and physical 
limitations domains) of the Kansas City Cardiomyopathy Questionnaire (KCCQ) at 
week 52

Occurrence of  all-cause hospitalisation (first and recurrent)
5.1.3
Further endpoints
-
Time from first to second adjudicated HHF
-
Time to first all-cause hospitalisation
-
Occurrence of adjudicated HHF within 30 days after first adjudicated HHF


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-
Occurrence of adjudicated HHF and CV death. This endpoint will account for clinical 
hierarchies in composite outcomes, i.e. CV death is ascribed greater importance than 
HHF (see win ratio in Section 7.3.3)
-
New onset of atrial fibrillation
-
Adjudicated MI (fatal or non-fatal)
-
Adjudicated stroke (fatal or non-fatal)
-
Adjudicated TIA
-
Composite of time to first event of all-cause mortality and all cause hospitalisation
-
Composite of adjudicated CV death or adjudicated non-fatal MI
-
Composite of adjudicated CV death or adjudicated non-fatal stroke
-
Adjudicated CV death, adjudicated non-fatal MI, adjudicated non-fatal stroke (3-point 
MACE)
-
Progression to macro albuminuria (defined as UACR >300 mg/g) from baseline for 
patients with baseline UACR ≤ 300 mg/g 
-
Time to first new onset of sustained normo− or micro albuminuria (UACR ≤300 
mg/g) in patients with macro albuminuria at baseline
-
Time to first new onset of sustained normo albuminuria (UACR < 30 mg/g) in 
patients with micro- or macro albuminuria at baseline
-
eGFR (CKD-EPI)cr change from baseline to 30 days after treatment stop
-
Composite of sustained reduction of ≥40% eGFR (CKD-EPI)cr or sustained eGFR
(CKD-EPI)cr <15 mL/min/1.73 m2 (< 10 mL/min/1.73 m2 for patients with eGFR 
(CKD-EPI)cr < 30mL/min/1.73 m2 at baseline), or adjudicated CV death
-
Composite of sustained reduction of ≥40% eGFR (CKD-EPI)cr or sustained eGFR
(CKD-EPI)cr <15 mL/min/1.73 m2 (< 10 mL/min/1.73 m2 for patients with eGFR 
(CKD-EPI)cr < 30mL/min/1.73 m2 at baseline), or all-cause mortality
-
Composite of sustained reduction of ≥40% eGFR (CKD-EPI)cr or sustained eGFR 
(CKD-EPI)cr <15 mL/min/1.73 m2 (< 10 mL/min/1.73 m2 for patients with eGFR 
(CKD-EPI)cr < 30mL/min/1.73 m2 at baseline), adjudicated CV death, or adjudicated 
HHF
-
Change from baseline in KCCQ overall summary score at week 52
-
Change from baseline in KCCQ total symptom score at week 52


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-
Change from baseline in KCCQ individual domains at week 52
-
Change from baseline in KCCQ based on patient-preferred outcome at week 52
-
Change in NYHA class from baseline at week 52
-
Change from baseline in Health-related quality of life measured by EQ-5D
-
Health economic analysis by Health Care Resource Utilisation 
-
Changes in NT-proBNP from baseline over time 
-
Change in albuminuria from baseline over time
-
Change in albuminuria from baseline over time by baseline UACR) categories (<30 
mg/g, ≥30mg/g to ≤300mg/g, >300 mg/g)
-
Incidence of acute renal failure (based on narrow SMQ)
-
Time to first acute kidney injury (based on the preferred term)
-
Change from baseline in body weight over time
-
Change from baseline in Systolic Blood Pressure (SBP) over time
-
Change from baseline in Diastolic Blood Pressure (DBP) over time
-
Change from baseline in pulse rate over time
-
Change from baseline in HbA1c over time in the overall population and in 3 
subgroups (non-DM, pre-DM, and DM)
Refer to the trial statistical analysis plan (TSAP) for the complete set of further endpoints. 
5.2
ASSESSMENT OF EFFICACY
The CEC is responsible for the adjudication of all relevant CV events, which could 
potentially fulfil the criteria for the primary, secondary and further endpoints. The CEC 
charter is available in the ISF for details regarding adjudication. Please also refer to Section 
3.1.1.1 for information on the CEC. 
5.2.1
KCCQ
KCCQ is a 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. 
The paper-and-pen version in the required native language of the patient will be used. If the 
required language is not available then the patient is not required to complete the 
questionnaire. 


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The questionnaire takes about 5-8 minutes to complete and will be distributed according to 
the Flow Chart. 
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 10.1.
5.2.2
New York Heart Association classification
The New York Heart Association (NYHA) functional classification will be used to classify 
the severity of the patients’ heart failure (ref. Appendix 10.3). 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 telephone visits until end of the trial.
5.2.3
NT-proBNP
Refer to Section 5.5 Assessment of biomarkers
5.2.4
Body weight
BMI (kg/m2) will be calculated for determination of eligibility at Visit 1.
Body weight will be measured at all on-site visits:

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.).
5.2.5
Blood pressure
SBP and DBP as well as pulse rate (electronically or by palpation, count for 1 minute) will be 
measured after 5 minutes of rest in the seated position according to the Flow Chart. 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 in Appendix 10.6.
5.3
ASSESSMENT OF SAFETY
5.3.1
Physical examination
A complete physical examination will be performed by the Investigator according to the Flow 
Chart. Documentation of, and findings from the physical examination, must be part of the 
source documents available at the site.


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5.3.2
Clinical routine examination
During the course of the trial the patient may undergo examinations that are not trial specific 
but a part of the clinical routine such as:
-
ECG
-
Echocardiography, radionuclide ventriculography, invasive angiography, MRI or CT.
In order to capture arrhythmias and significant changes in ECG, and LVEF measurements in 
echocardiography (or similar), the Investigator will be asked to enter the results from these 
examinations in the eCRF.
If the patient has an ICD the Investigator will be asked to enter information gathered from 
interrogations of the ICD in the eCRF.
5.3.3
Vital signs
Vital signs to be measured are SBP, DBP and pulse rate. 
5.3.4
Safety laboratory parameters
All safety laboratory samples will be collected as described in the Flow Chart. 
All parameters that will be determined during the trial conduct are listed in Table 5.3.4: 1.
The analysis will be performed by a central laboratory. The respective reference range and 
details about sample handling and shipment will be provided in the ISF (Lab Manual).


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Table 5.3.4: 1
Safety laboratory parameters – whole blood, serum or plasma
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
Calcium
Chloride
Creatinine
Creatine kinase (CK)
Hs Troponin I (reflex tests if CK is elevated)
Glucose
Magnesium
Phosphate 
Potassium
Protein total
Sodium
Urea (BUN)
Uric acid
Lipids
Cholesterol (total)
HDL cholesterol
Calculated LDL cholesterol
Triglycerides (reflex test for direct measurement of LDL cholesterol triggered if 
triglycerides are > 400 mg/dl or 4.52 mmol/l)
Renal function
5.3.4.1
Urine albumin/creatinine ratio (UACR) in spot urine will be determined and calculated at the 
central laboratory.
The estimated glomerular filtration rate (eGFR) will be derived from serum creatinine values, 
age, sex and race based on the CKD-EPI equation [R12-1392]:
GFR = 141 × min (Scr /κ, 1)α × max(Scr /κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 1.159 
[if black]
where:
Scr is serum creatinine in mg/dL,
κ is 0.7 for females and 0.9 for males,
α is -0.329 for females and -0.411 for males,
min indicates the minimum of Scr /κ or 1, and
max indicates the maximum of Scr /κ or 1.


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The race of the patient will be entered because of potential differences due to race.  The 
CKD-EPI equation considers the race as an adjustment factor, therefore the race must be 
known for accurate estimation.
In case of an eGFR loss of ≥ 40% since baseline, or when the eGFR drops to < 15 
mL/min/1.73 m2 for patients with an eGFR ≥ 30 mL/min/1.73 m2 at baseline (<10 
mL/min/1.73 m2 for patients with an eGFR < 30 mL/min/1.73 m2 at baseline); an additional 
visit between 30 days to preferably 60 days after detection should be scheduled (unless 
detected at the EOT visit at trial end) to collect a blood sample for repeat central analysis of 
creatinine for calculation of the eGFR. If a signal of abnormal creatinine or eGFR is reported 
to the site by others (e.g. treating physicians from local labs), an additional sample should be 
sent to central lab, and if it is still abnormal, another sample should be sent to central lab 
between 30 days and preferably 60 days.
Kidney function will be classified as described in the table below (Table 5.3.4.1:1):
Table 5.3.4.1: 1
Classification of kidney function
CKD stage
eGFR
1
≥ 90
2
60-89
3a
45-59
3b
30-44
4
15-29
5
< 15
Pregnancy testing
5.3.4.2
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 5.3.7.2.
Criteria for hypoglycaemic events
5.3.4.3
In DM patients, 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.
Urinary tract infections and genital infections
5.3.4.4
Patients having a history of chronic/recurrent urinary tract infections (UTI) or genital 
infections or an acute episode of UTI or genital infection at screening will be identified, and 


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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.
5.3.5
Electrocardiogram
ECGs will be performed at Visit 2, and at the EOT Visit as indicated in the Flow Chart. 
Printed paper traces from 12-lead ECGs (I, II, III, aVR, aVL, aVF, V1-V6) will be collected. 
They should be evaluated, signed, dated and commented upon by the treating 
physician/Investigator and stored locally. The diagnosis and results from the ECG reports
should be collected in the eCRF.
In the event of any cardiac symptoms (i.e. suspicion of heart rhythm disorders or cardiac 
ischaemia) during the course of the trial, if an additional ECG is recorded at time of event, or 
later at the next regular visit, they will be evaluated, signed, dated and commented upon by
the treating physician/Investigator and stored locally. Any clinically relevant new changes in 
the ECG (regardless of patients’ symptoms) should be reported as AEs and followed up 
and/or treated locally until normal or stable condition. ECG associated with cardiovascular 
endpoints must be submitted to the adjudication committee together with the baseline ECG.
Each ECG tracing stored locally should be labelled with trial and patient number, patient 
initials and date. 
5.3.6
Other safety assessments
Outcome of non-fatal stroke
5.3.6.1
For patients experiencing a non-fatal stroke the Modified Rankin Scale (MRS) should be 
used to assess stroke outcome (Appendix 10.4). The scale is widely used in clinical practice 
and consists of grades, from 0 to 6, with 0 corresponding to no symptoms and 6 
corresponding to dead. Investigators will measure and score the MRS based on an interview 
with the patient at the next regular on-site visit after the onset of the stroke. In those cases 
where MRS assessment occurred within 90 days after the stroke, a repeat MRS-assessment 
should be performed at the next on-site visit. Detailed information on the stroke (date and 
time of onset, type, symptoms, method of detection, outcome) will be collected in the eCRF.
Hepatic events
5.3.6.2
For assessment of hepatic events please refer to Section 3.1.1.2.
5.3.7
Assessment of adverse events
Definitions of AEs
5.3.7.1
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.


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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.
Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility. Adverse reactions may arise 
from use of the product within or outside the terms of the marketing authorisation or from 
occupational exposure. Conditions of use outside the marketing authorisation include off-
label use, overdose, misuse, abuse and medication errors.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which:

results in death,

is life-threatening, this refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe.

requires inpatient hospitalisation or prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity,

is a congenital anomaly/birth defect,
or

is to be deemed serious for any other reason if it is an important medical event when 
based upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or 
development of dependency or abuse. Any suspected transmission via a medicinal product of 
an infectious agent is considered a serious adverse reaction.
For Japan only: The following events will be handled as “deemed serious for any other 
reason”: AEs which possibly lead to disability will be reported as SAEs.
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
BI has set up a list of AEs, which by their nature, can always be considered to be “serious” 
even though they may not have met the criteria of an SAE as given above.
The latest list of “Always Serious AEs” can be found in the ISF. These events should always 
be reported as SAEs as described above.
Note: Cancers of new histology and exacerbations of existing cancer must be reported as a 
serious event regardless of the duration between discontinuation of the drug and the 
occurrence of the cancer.


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Adverse events of Special Interest (AESIs)
The term AESI relates to any specific AE that has been identified at the substance 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/CRO’s Pharmacovigilance Department 
within the same timeframe that applies to SAE, 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

Marked peak 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.
For the AESI “decreased renal function” the patient needs to be followed-up appropriately 
based on local clinical guidance. 
The Investigator should refer to follow-up schedule for renal endpoint events described in 
Section 5.3.4.1.
Ketoacidosis
If metabolic acidosis, ketoacidosis and DKA is suspected, further investigations should be 
done according to the medical judgment and the clinical course until a diagnosis is made 
and/or the patient is recovered.
Due to its mechanism of action, empagliflozin may potentially modify the clinical 
presentation of ketoacidosis which may occur at lower plasma glucose levels in patients with 
DM and potentially also in non-diabetic patient population. The diagnosis of ketoacidosis in 
these patients can be based on arterial pH≤7.30, serum bicarbonate levels <15 and 
measurement of serum beta-hydroxybutrate levels. Other diagnostic criteria which can 
support the diagnosis of ketoacidosis are urine ketones and anion gap >10. 


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Investigators should note that not all criteria mentioned above need to apply for the diagnosis 
of ketoacidosis, and clinical judgment should also be taken into consideration.
Events leading to lower limb amputation
Any event leading to a lower limb procedure of amputation, auto-amputation or 
disarticulation as defined below is considered as an AESI.  
“Amputation is a resection of a limb through a bone. Disarticulation is a resection of a limb 
through a joint. Auto-amputation is a spontaneous separation of non-viable portion of the 
lower limb.
Not included in this definition are debridement (removal of callus or dead tissue), procedures 
on a stump (like stump revision, drainage of an abscess, wound revision etc.) and other 
procedures (e.g., nail resection or removal) without a concomitant resection of a limb 
(amputation or disarticulation).” (International Working Group of Diabetic Foot, 2015).
Each lower limb amputation, disarticulation, or auto-amputation should be reported 
separately. The SAE report should include the date of the procedure, the level of amputation 
or disarticulation, the medical condition(s) leading to the procedure and if the patient had 
some of the known risk factor(s) for lower limb amputation.
Intensity of AEs
The intensity of the AE should be judged based on the following:
Mild: 
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate: 
Enough discomfort to cause interference with usual activity
Severe: 
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
The definition of an adverse reaction implies at least a reasonable possibility of a causal
relationship between a suspected medicinal product and an adverse event. An adverse
reaction, in contrast to an adverse event, is characterised by the fact that a causal relationship
between a medicinal product and an occurrence is suspected.
Medical judgment should be used to determine the relationship, considering all relevant
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge,
confounding factors such as concomitant medication, concomitant diseases and relevant
history.
Arguments that may suggest 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


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•
No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).
•
The event is typically drug-related and infrequent in the general population not
exposed to drugs (e.g. Stevens-Johnson syndrome).
•
An indication of dose-response (i.e. greater effect size if the dose is increased, smaller
effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship
could be:
•
No plausible time to onset of the event relative to the time of drug exposure is evident
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks
of drug administration; an allergic reaction weeks after discontinuation of the drug
concerned).
•
Continuation of the event despite the withdrawal of the medication, taking into
account the pharmacological properties of the compound (e.g. after 5 half-lives).
•
Of note, this criterion may not be applicable to events whose time course is prolonged
despite removing the original trigger.
•
Additional arguments amongst those stated before, like alternative explanation (e.g.
situations where other drugs or underlying diseases appear to provide a more likely
explanation for the observed event than the drug concerned).
•
Disappearance of the event even though the trial medication continues or remains
unchanged.
For Japan only: The reason for the decision on causal relationship for unlisted AEs needs to 
be provided in the eCRF.
Adverse event collection and reporting
5.3.7.2
AE Collection
The Investigator shall maintain and keep detailed records of all AEs in their patient files. The 
following must be collected and documented on the appropriate eCRF(s) by the Investigator:

From signing the ICF onwards through the Residual Effect Period (REP), until 
individual patient's end of trial participation:
o
all AEs (serious and non-serious), Outcome events and all AESIs.

After the individual patient’s end of trial:
The Investigator does not need to actively monitor the patient for AEs, but must
report relevant SAEs and relevant AESIs of which the Investigator may become 
aware of.
The REP (timeframe after last dose of trial medication when measurable drug levels or 
pharmacodynamic effects are still likely to be present) is defined as 7 days after the last trial 
medication application. All AEs which occurred through the treatment phase and throughout 
the REP will be considered as on treatment. Please also refer to Section 7.3.4.
Events which occurred after the REP will be considered as post treatment events.


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REP (7days)
Report all AEs and all AESIs
Screening/Treatment phase
Remaining F-U (~23days)
End of treatment Visit
F-U visit /
End of Study
Signed 
ICF
Relevant SAEs and AESIs of 
which the investigator may 
subsequently become aware of
Figure 5.3.7.2: 1
Timelines for adverse event collection
AE reporting to the Sponsor/CRO and timelines
The Investigator must report all non-exempted SAEs, AESI and any non-serious AE relevant 
for the reported SAE, immediately (within 24 hours) on the BI SAE form. The same timeline 
applies if follow-up information becomes available.
For Japan only: All SAEs must be reported immediately to the head of the trial site. 
Any protocol exempted event that occurs prior to randomisation and fulfils the criteria of an 
SAE will be reported immediately (within 24 hours) by the Investigator on the BI SAE form 
via fax immediately (within 24 hours) to the Sponsor's/CRO’s unique entry point (country 
specific contact details will be provided in the ISF); however, if the patient has been 
randomised, the exempted events will not be reported as SAEs to the sponsor and no 
causality assessment will be performed. These events will be entered only on the AE 
eCRF pages (within 24 hours). The investigator is also required to provide all defined 
supporting documentation.
In specific occasions the Investigator could inform the Sponsor/CRO upfront via telephone. 
This does not replace the requirement to complete and fax the BI SAE form.
If any exempted event or any other adverse event (serious or non-serious) occurs, the 
investigator or attending physician has the responsibility and will take direct and appropriate 
action to provide care for the patient and to decide whether or not the trial medication should 
be discontinued.
An independent Data Monitoring Committee (DMC) will monitor the safety data in the trial
on an ongoing basis. Reported SAEs occurring after randomisation that are protocol 
exempted events will be collected in the eCRFs and evaluated by the DMC. These events will 
not be collected on SAE forms for expedited review or reporting.
Patient considered “on-
treatment” until end of REP


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Aggregate analysis of endpoint data to determine any potential benefit or risk and to ensure 
patient safety during the clinical trial will be performed on a regular basis by the DMC.
With receipt of any further information to these events, appropriate follow-up forms have 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 paper SAE form. 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 SAE form (if applicable):
Worsening of the underlying disease or of other pre-existing conditions. Exemptions 
are specified in “Exemptions to SAE reporting” and must be adhered to as described 
in that chapter.
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 trial inclusion they will be considered as baseline conditions.
All (S)AEs, including those persisting after individual patient’s end of trial must be followed 
up until they have resolved, have been sufficiently characterised, or no further information 
can be obtained.
For some types of AEs additional information will be collected in the CRF due to the nature 
of the event and mechanisms of action of the trial medication. These listed AEs are distinct 
from AESI:
-
Hypoglycaemic event
-
Genital infection
-
Acute pyelonephritis
-
Sepsis
-
Urinary tract infection
-
Bone fracture
Pregnancy
In rare cases pregnancy may occur in a clinical trial. Once a patient has been enrolled into 
this clinical trial and has taken trial medication, the Investigator must report immediately 
(within 24 hours) a potential drug exposure during pregnancy (DEDP) to the 
Sponsor’s/CRO’s unique entry point (country-specific contact details will be provided in the 
ISF). The Pregnancy Monitoring Form for Clinical Trials (Part A) should be used. 
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the Sponsor’s/CRO’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).


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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.
Exemptions to SAE reporting
A list of serious adverse events that commonly occur in the trial population or which are 
components of trial endpoints are exempted from expedited reporting. These events are 
known consequences of the underlying disease and it is not possible, based on a single case, 
to conclude that there is a reasonable possibility that the investigational drug caused these 
events. Pulmonary complications of heart failure are added to the exemption list, since 
patients with HF commonly experience such complications. Thus these events could be 
reported as pulmonary events, although the underlying aetiology was attributed to HF.
Regardless of relationship to trial medication, these events will not be reported by the 
Sponsor to regulatory agencies or ethics committees in an expedited manner.
These events include: 
Cardiovascular (CV) related death. The CV related death also includes death due to 
undetermined cause, and death due to pulmonary events that may be secondary to 
complications of heart failure such as pulmonary oedema, pulmonary vascular disease 
secondary to heart disease.
HF hospitalisation
Non-fatal MI
Non-fatal stroke and Transient ischemic attack (TIA)
CV hospitalisation events
Pneumonia (fatal and non-fatal)
New or exacerbated COPD (fatal and non-fatal)
Based on the same conclusion that it is not possible to perform a causality assessment on 
these events based on a single case, the trial investigators are exempted from performing a 
causality assessment and reporting these serious adverse events on the SAE form to the 
Sponsor.
All such events will be collected systematically on the eCRF (within 24 hours) from the time 
of randomisation throughout follow up.
This reporting policy assumes global regulatory agency approval.
5.4
DRUG CONCENTRATION MEASUREMENTS AND PHARMACOKINETICS
(SUBSTUDY)
5.4.1
Pharmacokinetic endpoints
The PK sampling will be done from a limited number of randomised patients (approximately 
1650 patients) and at pre-selected sites only. The pre-dose blood samples will be collected at 
visit 4 to determine plasma empagliflozin trough concentrations. These samples will serve to 
determine steady state trough concentrations of empagliflozin.


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The date and exact clock time of trial medication intake the day before this visit will be 
recorded together with the date and exact clock time of drawing the trough pharmacokinetic 
sample.
5.4.2
Methods of sample collection
The time interval for blood sample collection relative to the most recent intake of trial
medication should be between 22 and 26 h. For quantification of empagliflozin trough plasma 
concentrations, 3 mL of blood will be drawn from a forearm vein in an EDTA-anticoagulant 
blood drawing tube at each time-point. Details of sample handling and sample logistics can 
be found in the ISF (Central lab manual).
5.4.3
Analytical determinations
Empagliflozin concentrations in plasma samples will be determined by a validated HPLC
MS/MS assay (high performance liquid chromatography, tandem mass spectrometry). In 
order to identify samples from patients taking placebo, the bioanalyst will be un-blinded so 
that samples from patients receiving placebo will not be analysed for empagliflozin.
5.5
ASSESSMENT OF BIOMARKERS
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. 
Samples for the determination of high-sensitivity cardiac troponin T will be collected at Visit 
2 (Randomisation) and analysed at the Central Laboratory.
5.5.1
Biobanking (optional)
Participation in sampling for biobanking (including DNA) is voluntary and not a prerequisite 
for participation in the trial. Biobanking samples will be taken only after separate informed 
consent has been given in accordance with local ethical and regulatory requirements. Banked 
samples may be analysed in the future for scientific evaluations or to further, for example, the 
mechanistic understanding of drug effects and/or to identify genetic or other factors 
associated with response to therapy or the risk of adverse drug reactions. 
Measures are in place to comply with the applicable rules for the collection, biobanking and 
future use of biological samples and clinical data, in particular.
Sample and data usage has to be in accordance with the separate biobanking ICF.
The BI-internal facilities storing biological samples from clinical trial participants as well 
as the external banking facility are qualified for the storage of biological samples collected 
in clinical trials 
An appropriate sample and data management system, incl. audit trail for clinical data and 
samples to identify and destroy such samples according to ICF is in place 


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A fit for the purpose documentation (biomarker proposal, analysis plan and report) ensures 
compliant usage 
A fit for purpose approach will be used for assay/equipment validation depending on the 
intended use of the biomarker data
Samples and/or data may be transferred to third parties and other countries as specified in 
the biobanking ICF
Methods and timing of sample collection
5.5.1.1
Sampling will be performed at the time points specified in the Flow chart.
DNA banking
Approx.  8.5 mL blood will be drawn into a PAXgene Blood DNA Tube, preferably at Visit 
2.
Plasma banking
Approx. 10 mL blood will be drawn into an EDTA blood collection tube.
Serum banking
Approx. 8.5mL blood will be drawn into a serum separation tube.
Urine banking
Approx. 10 mL urine (preferably morning mid-stream urine) will be collected.
For all biological samples collected, detailed instructions on sampling, preparation, 
processing, shipment and storage are provided in the laboratory manual. Plasma, serum and 
urine samples will be stored at an external biobanking facility contracted by the Sponsor; 
DNA, extracted from the original whole blood sample, will be stored at the Sponsor.
5.6
OTHER ASSESSMENTS
5.6.1
EQ-5D
Health related quality of life will be assessed using the EQ-5D-5L version (refer Appendix 
10.2.1) according to the Flow Chart. EQ-5D is a standardised instrument for use as a measure 
of health outcome. It is designed for self-completion by patients. 
The EQ-5D self-report questionnaire (EQ-5D) essentially consists of 2 pages comprising:

the descriptive system (five dimensions of health; namely mobility, self-care, usual 
activities, pain/discomfort, anxiety/depression). Each dimension comprises five levels (no 
problems, slight problems, moderate problems, severe problems, extreme 
problems/unable to perform activity). 

the EQ-VAS (visual analogue scale) which records the patient’s self-rated health status on 
a vertical graduated (0 – 100) VAS. 
For further description on completing the questionnaire refer to the last part of Section 5.2.1.


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5.6.2
Health Care Resource Utilisation (HCRU)
HCRU data will be used for health economic analysis (i.e. cost-effectiveness analysis) 
required for reimbursement decisions. Resource use will be captured via interview with the 
patient and entered in the eCRF at all on-site visits during the complete trial period, and will 
allow calculation of direct and indirect costs. Main components to be collected are 
unscheduled outpatient visits and hospitalisations.
5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor safety aspects, and to determine empagliflozin efficacy and 
safety in an appropriate way.
The scheduled measurements are appropriate to see drug induced changes in vital signs, 
standard laboratory values, biomarkers specific to efficacy of treatment of HF, and ECG. The 
primary and secondary endpoints are accepted for evaluation of efficacy, safety and 
tolerability on an oral HF drug and they are widely used in respective pivotal phase III 
studies.
Health related quality of life questionnaires are a necessary part for this phase III trial in order 
to collect data for a health economic evaluation. 
Therefore, the appropriateness of all measurements applied in this trial is given.


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6
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
All trial visits, except for screening visit and telephone visits should preferably take place 
before noon. The patient should be fasting (no food or liquid except water the last 10 – 16 
hours) at Visit 2 (Randomisation), EOT Visit and Follow Up Visit. 
If a patient mistakenly takes trial medication on the morning of Visit 4 before attending the 
clinic the visit should be rescheduled for another day as soon as possible, reminding the 
patients about expected time of dosing. The rescheduled visit must take place in a short 
enough time-frame so that the patient has sufficient trial medication available.
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.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
The Flow Chart summarises the investigational procedures to be done at each visit, and trial 
procedures should be performed before intake of any trial medication. The procedures are 
further described below.
6.2.1
Screening
No trial procedures should be done unless the patient has consented to taking part in the trial. 
Preferably the patient should also be informed about biobanking (including DNA) sampling 
already at this visit.
Once the patient has consented to the trial participation, she/he is considered to be enrolled in 
the trial and have started screening. The patient should be registered in the enrolment log and 
be registered in the IRT as a screened patient. Patients will continue to take background 
medication for heart failure and treatment for their concomitant disorders if applicable. 
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, the site may make a phone contact to inform the patient that he/she is no longer 
required to return to the clinic for Visit 2.
Patients who fail screening (fail to meet one or more of the inclusion criteria, and/or meet one 
or more of the exclusion criteria) following Visit 1 procedures should be registered as a 
screen failure in IRT.
6.2.2
Treatment period
Randomisation will occur at Visit 2 using IRT. The patients will return to the clinic for 
regularly scheduled visits 4, 12, 32 and 52 weeks after randomisation during the first year of 
trial participation, and every 24 weeks thereafter for the duration of the trial, 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.


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Telephone follow-up calls will be scheduled 10-12 weeks after every on-site visit starting 
after Visit 4 and continuing throughout the trial (see Flow chart). The telephone contacts will 
focus on safety (e.g. hospitalisations or occurrence of AEs), changes in concomitant therapy 
and trial medication compliance.
The patients should be fasting at the Randomisation Visit.
The optional blood sample for DNA will preferably be collected at the Randomisation Visit
for all patients eligible for randomisation, but could also be taken at any later visit after the 
separate consent is signed.
At any time during the treatment period the Investigator is allowed to adjust and optimise HF 
background therapy 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).
For sites selected to participate in collection of samples for PK analysis, please refer to 
Section 5.4 and the Lab Manual for details.
Patients will be dispensed medication at each on-site visit and allocation of new kit number(s)
will be managed through the IRT. Trial medication administration should be done after 
physical and laboratory assessments.
This is an event driven trial. Patients will remain in the treatment period until the necessary 
number of events is reached.
Permanent trial medication discontinuation is only justified when clear persistent 
contraindications arise, or when the patient requests to stop trial medication. See Section 
6.2.4 for details on how to handle trial medication discontinuations, and Section 3.3.4 for 
when discontinuation from trial is justified.
6.2.3
End of Treatment, Follow Up Period and Trial Completion
Patients on treatment at the time when required number of outcome events are reached (ref. 
Section 7.7), will be asked to return to the clinic for the EOT visit, with the proposed time 
schedule communicated via an investigator letter, followed by the Follow Up Visit 30 days 
later. 
During the EOT visit all trial medication will be collected and compliance calculated, 
occurrence of safety and efficacy endpoints will be assessed and complete physical 
examination, laboratory assessments and ECG will be performed (ref. Flow Chart).  
The Follow Up Visit should also be a clinic visit for all patients, and the following 
examinations should be performed (ref. Flow Chart):
-Concomitant Therapy 
-Vital signs and body weight
-NYHA classification


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-Documentation of any adverse events and endpoints
-Vital status
-Blood and urinary sampling
-KCCQ and EQ-5D
-Modified Rankin Scale (only in case of suspected stroke within last 90 days)
The patients should be fasting at the EOT and Follow Up Visit.
6.2.4
Early discontinuation of trial medication and trial termination
The EOT activities will be performed when a patient discontinues trial medication treatment 
permanently. 
Note. The EOT activities should not be used for temporary interruptions of trial medication. 
All patients will have a follow up visit 30 days following discontinuation of trial medication, 
irrespective whether they complete the treatment period or prematurely discontinue trial 
medication. 
Patients who discontinue trial medication prematurely should thereafter continue to follow 
scheduled visits until trial end. For patients reluctant to attend the scheduled visits after 
prematurely discontinuing trial medication, some trial assessments may be negotiated with 
exception of collection of adverse events, outcome events and concomitant therapy.
Please refer to Section 3.3.4.1 for detailed procedures to be followed in case a patient wants 
to stop trial medication.
In case of early trial termination (e.g. based on recommendation by the DMC, a reasonable 
timeframe to stop the trial (perform last patient visits) will be defined and communicated to 
the Investigators. 


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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, stratified by geographical region, status of DM (DM, pre-DM, no DM) , LVEF 
(<50%, ≥50%) and eGFR (CKD-EPI)cr (<60 mL/min/1.73 m², >=60 mL/min/1.73 m²) at 
screening visit. 
To ensure the trial population consist of a reasonable combination of non-, pre- and DM 
patients, and to aim for approximately 35% to 50% of the population or more with an LVEF 
>50% capping will be used on trial level (see also Section 3.3). Capping on regional level 
may be applied to achieve a contribution of each region to each category of diabetes status.
The composite primary endpoint is the time to first event of adjudicated CV death or 
adjudicated HHF. The statistical model for the primary analysis is the Cox proportional 
hazards model. The hazard ratio and its confidence limits will be determined for evaluating 
the superiority of empagliflozin to placebo for the primary endpoint.
The key secondary endpoints, which are part of the testing strategy, are

occurrence of adjudicated HHF (first and recurrent), and

eGFR (CKD-EPI)cr slope of change from baseline
7.2
NULL AND ALTERNATIVE HYPOTHESES
A hierarchical testing procedure will be followed for the assessment of the primary and the 
key secondary endpoints. For all endpoints, superiority of empagliflozin vs. placebo will be 
evaluated with a two-sided test in the following structure:
Null hypothesis: There is no difference between the effect of placebo and the effect of 
empagliflozin in terms of the endpoint in question. 
Alternative hypothesis: There is a difference between the effect of placebo and the effect of 
empagliflozin in terms of the endpoint in question. The tests will be performed in the 
following hierarchical order:
1. Time to first event of adjudicated CV death or adjudicated HHF
2. Occurrence of adjudicated HHF (first and recurrent)
3. eGFR (CKD-EPI)cr slope of change from baseline
Starting from step 1, if the null hypothesis is rejected, and the result is more favourable for 
empagliflozin, superiority is concluded in the tested endpoint, and the overall type I error is 
preserved for the test in the next step.  If at any step the null hypothesis is not rejected, 
subsequent tests are conducted in an exploratory fashion.
The overall type one error rate will be preserved at a level of 0.05 (2-sided). The type one 
error rate used at the final analysis will be influenced by the pre-planned interim analysis –
see Section 7.4. 


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In the final analysis after the evaluation of recurrent HHF, alpha will be split into 0.001 to be 
used for the analysis of eGFR slope, and the rest will be transferred to the meta-analyses. 
In case the trial is finished early at the time of interim analysis, using αinterim for the primary 
and key-secondary endpoints in the testing hierarchy according to the α-spending function in 
Section 7.4, the following α-split will be used for eGFR slope analysis and the meta-analyses:
0.1 * αinterim will be used for the eGFR slope analysis and
0.9 * αinterim will be transferred to the meta-analyses
In both the interim and final analyses, if the slope analysis is successful, the alpha of this 
branch will then be transferred to the meta-analyses.
The testing hierarchy is summarised in Figure 7.2: 1 showing the alpha-spending at the final 
analysis. 
Figure 7.2: 1
Hierarchical analysis of trial in HFpEF (1245.110) and the parallel 
trial in HFrEF (1245.121) showing the alpha-spending at the final 
analysis.
The other secondary endpoints will be evaluated in an exploratory manner. 
Time to 1st event of CV death 
or HHF
Recurrent HHF
Meta-analyses
HFrEF (1245.121)
αr2 = αr_final - αr1
αr1=0.001
eGFR Slope 
αr3=0.001
Time to 1st event of CV 
death or HHF 
Recurrent HHF
HFpEF (1245.110)
αp1=0.001
eGFR Slope 
αp3=0.001
αp2 = αp_final - αp1
αp_final
αr_final


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7.3
PLANNED ANALYSES
The primary 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.
Baseline status of DM is defined as:

DM: any pre-treatment HbA1c above 6.5 or history of DM as entered in the eCRF on 
the medical history page

Pre-DM: no history of DM and no HbA1c >=6.5 before treatment and a pre-treatment 
HbA1c value of >= 5.7 and <6.5  

Non-DM: not meeting criteria of DM or pre-DM above
For all other endpoints, baseline will be defined as the last available measurement before start 
of randomised trial medication.
7.3.1
Primary endpoint analyses
The primary endpoint will be evaluated on the randomised set using a Cox proportional 
hazards model with treatment, age (continuous), gender, geographical region, baseline status 
of DM (DM, pre-DM, no DM), LVEF (continuous) and eGFR (CKD-EPI)cr at baseline 
(continuous) as covariates.
The time to the event of interest will be computed as (event date −randomisation date) +1. 
All events observed after randomisation until trial termination will be included in the 
analysis.  Patients who do not have an event during the trial period will be censored at the 
individual day of trial completion or the last day that the patient was known to be free of the 
event, whichever is earlier. The time to censoring will be computed as (individual day of trial 
completion or the last day known to be free of the event – randomisation date) + 1. For 
patients who have more than one primary endpoint event during the trial, the time to the first 
occurrence of the primary endpoint event will be considered for the primary analysis. Only 
the adjudicated and confirmed events will be used for the primary analysis. 
To detect any heterogeneity in the treatment effect among diabetic patients, pre-diabetic 
patients and non-diabetic patients, a subgroup analysis will be performed by including the 
diabetic status by treatment interaction term into the Cox model. 


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Standard subgroup analyses of the primary endpoint include geographical region, sex, BMI, 
LVEF, renal function, prognostic factors, age, ethnicity, race and different background 
therapies etc. More details will be specified in the TSAP. 
A sensitivity analysis will be provided based on the treated set only including any events up 
to 30 days after treatment discontinuation. 
7.3.2
Secondary endpoint analyses
The key secondary endpoints occurrence of adjudicated HHF (first and recurrent) will be 
modelled using a joint frailty model together with adjudicated CV death in order to take into 
account the dependence between the endpoints. The joint frailty model will be adjusted for 
the same covariates as the primary analysis. 
The joint frailty model therefore models the hazards in the following way:
ri (t | ωi , Zi) = ωi exp {β’1 Zi}r0(t)
λi (t | ωi ,Zi) = ωi
α exp {β’2 Zi}λ0(t)
where ri(t) is the hazard of the recurrent HHF for the ith patient, proportional to the baseline 
intensity function r0. The hazard function of CV death for the ith patient is λi proportional to 
the baseline hazard λ0. β1 and β2 are vectors of the regression coefficients of the covariate
vectors Zi including treatment, age (continuous), gender, history of DM, geographical region, 
LVEF (continuous) and eGFR (CKD-EPI)cr at baseline (continuous). Patient specific 
independent random effects are denoted by ωi, with α giving the relation between HHF and 
CV death.
Patient specific independent random effects denoted by i and are assumed to follow a 
gamma distribution with mean 1.
The resulting likelihood function can be solved assuming piecewise constant hazards.  
Slope in change from baseline of eGFR (CKD-EPI)cr will be analysed by a random 
coefficient model allowing for random intercept and random slope per patient. The model 
will include the factors treatment, gender, geographical region, and status of DM as fixed 
effects and eGFR (CKD-EPI)cr at baseline (continuous), LVEF (continuous), age 
(continuous), time and interaction of treatment by time as linear covariates and allow for 
randomly varying slope and intercept between patients. The model will include all on-
treatment change from baseline data. 
Since the slope is run on the change from baseline data, the intercept will model the acute 
drop, whereas the long-term effect is modelled by the slope. 
Change from baseline in clinical summary score for HF symptoms and physical limitations 
domains of the KCCQ at week 52 will be evaluated by a mixed model repeated measures 
model including baseline score, LVEF (continuous), age (continuous) and eGFR (CKD-
EPI)cr at baseline (continuous) as linear covariates and treatment, visit, baseline score by 


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visit, visit by treatment, gender, geographical region and status of DM and as fixed effects. 
All on-treatment data up to week 52 will be included. 
Occurrence of all-cause hospitalisation (first and recurrent) will be evaluated by a similar
joint frailty as adjudicated HHF and will be evaluated with a joint model together with all-
cause mortality. 
The other time-to-event type of secondary endpoints will be analysed using the same Cox 
proportional hazards model as the primary analysis. 
This also applies for time to adjudicated CV death and all-cause mortality, rather than using 
the joint frailty model described above.  
7.3.3
Further endpoint analyses
Further time-to-event endpoints will be analysed in the same Cox proportional hazards model 
as the primary analysis.
Change from baseline to 30 days after treatment stop of eGFR (CKD-EPI)cr will be evaluated 
by an ANCOVA model, including treatment group, gender, geographical region and history 
of DM as fixed effect and baseline eGFR (CKD-EPI)cr (continuous), age (continuous), LVEF 
(continuous) as linear covariates.
An unmatched win ratio considering adjudicated CV death and adjudicated HHF will be 
analysed based on unmatched pairs. All patients randomised to empagliflozin will be 
compared to all patients randomised to placebo. Only common follow-up time will be 
considered for the comparison. Patients on empagliflozin are considered to have “won” the 
comparison if either the other patient has died while the patient on empagliflozin was still 
alive, or if both patients did not die, then if the other patient had more occurrences of HHF. 
The number of comparisons won is noted as NW. Patients on empagliflozin are considered to 
have “lost” the comparison if the empagliflozin patient died while the patient on placebo was 
still alive, or if both patients did not die, then if the patient on empagliflozin had more 
occurrences of HHF. The number of comparisons lost is noted as NL. The win ratio is NW/
NL. 
The rules for winning and losing follow Rogers 2014 [R16-4909] and analysis of the 
unmatched win ratio will be conducted as described in Pocock 2012 [R16-4813]. 
Further longitudinal continuous endpoints will be analysed in a mixed model with repeated 
measures (MMRM), including baseline value, age, LVEF and eGFR (CKD-EPI)cr at baseline 
as linear covariates and treatment group, visit, visit by treatment interaction, baseline by visit 
interaction, geographical region, gender and baseline history of DM as fixed effects.
The details of analyses will be defined in the TSAP prior to unblinding.
7.3.4
Safety analyses
In general, safety analyses will be descriptive in nature and will be based on BI standards. 
Standard BI summary tables and listings will be produced. No hypothesis testing is planned. 


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Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events. To this end, all adverse events occurring between start of treatment and end 
of the residual effect period REP of 7 days will be considered ‘treatment-emergent’. 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).
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 highlighted in the 
listings. Treatment groups will be compared descriptively with regard to distribution 
parameters as well as with regard to frequency and percentage of patients with abnormal 
values or clinically relevant abnormal values. 
Vital signs (blood pressure, pulse rate), physical examinations or other safety-relevant data 
observed at screening, baseline, during the course of the trial and at the end-of-trial 
evaluation will be assessed with regard to possible changes compared to findings before start 
of treatment.
Reasons for discontinuation and use of post-baseline concomitant medications will be 
tabulated.
The details of the analysis will be specified in the TSAP.
7.3.5
Pharmacokinetic analyses
Individual concentration-time data with descriptive statistics for empagliflozin trough 
concentrations will be presented in the clinical trial report.
7.3.6
Prespecified meta-analysis
On project level, meta-analyses are pre-specified. Data from this trial and a parallel trial in 
HFrEF patients, 1245.121, will be pooled. 
The statistical model will include trial as a covariate. More details are specified in the meta-
analysis plans.
7.4
INTERIM ANALYSES
The safety and conduct of the trial will be monitored by an independent DMC. Details on this 
process are outlined in the DMC charter. 
There will be one unblinded interim analysis to be conducted by the DMC. At time of interim 
analysis, the ExSC, the SEC, Sponsor, CRO, and all trial personnel will stay blinded to the 
interim results. For blinding please also refer to Section 4.1.5.1. 
After approximately 500 primary adjudicated outcome events have been accrued 
(approximately 60% of information is available) an interim analysis will be performed. 


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The following Hwang, Shih and De Cani α-spending function for the analysis at information 
fraction tk (planned to be approximately 60%) with parameter γ = -8 will be used:
∗(	, ) = min ,
 1 −
1 −  = min 0.025,
0.025 1 −
1 − 
For an interim analysis at the timepoint of approximately 60% of information, the chosen
alpha-spending function gives an alpha-level of 0.001 at time of interim. 
If the p-value for the primary endpoint and the p-value for CV-death (from the primary Cox 
proportional hazards model) are lower than the cutoff to be evaluated from the alpha-
spending function (planned at 0.001 one-sided), then the trial will be stopped for 
overwhelming efficacy. In this case, the hierarchy will be tested as specified in Section 7.2.
Otherwise the trial will be continued.
The final alpha-level is therefore planned at a one-sided alpha-level of 0.0248 which 
translates in a two-sided alpha of 0.0496. 
The event rate will be assessed by the trial team in a blinded manner only during trial 
recruitment and before the unblinded interim analysis (see Section 7.7).
7.5
HANDLING OF MISSING DATA
There will be no imputation of data for safety data or for time-to event endpoints. For patients 
who discontinue the trial treatment prematurely, all efforts will be made to follow patients for 
survival and for any other endpoints including the primary and key secondary endpoints until 
the end of the trial.
For the slope analysis of eGFR (CKD-EPI)cr, all available on-treatment change from baseline 
data will be used. Patients without on-treatment data after randomisation will not be included 
in this analysis. 
For the analysis of change from baseline to 30 days after treatment stop, only available data 
will be used. Only patients with post-treatment data will be used in this analysis. 
For other longitudinal endpoints such as KCCQ scores, MMRM methodology will be used. 
Models will be run on both all observed data and all observed on-treatment data. Details of 
the imputation rule will be given in the statistical analysis plan.
An eGFR (CDK-EPI)cr reduction is considered sustained, if it is determined by two or more 
consecutive post-baseline central laboratory measurements separated by at least 30 days (first 
to last of the consecutive eGFR values). If there is no additional measurement after the eGFR 
reduction is observed and the patient dies within 60 days of this measurement without second 
measurement >= 30 days after the first, then the eGFR reduction is also considered sustained.


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7.6
RANDOMISATION
The trial will be performed as a double-blind design with respect to placebo and 
empagliflozin. Subjects will be randomised to the trial treatments in a 1:1 ratio. The 
randomisation will be stratified by the following factors:

Geographical region (North America, Latin America, Europe, Asia, Other)

Status of DM at screening:
o
no DM (HbA1c < 5.7% without the intake of antidiabetic medication, unless 
taken for a non-DM indication, and no history of DM), or 
o
pre-DM (HbA1c >=5.7% and <6.5% without the intake of antidiabetic 
medication unless taken for a non-DM indication, and no history of DM), or
o
DM (HbA1c >= 6.5% or intake of antidiabetic medication for a DM 
indication, or a history of DM)

eGFR (CKD-EPI)cr at screening 
o
<60 mL/min/1.73 m² 
o
≥60 mL/min/1.73 m²

LVEF
o
LVEF < 50%
o
LVEF ≥50%
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 (CTR). Access to 
the codes will be controlled and documented.
7.7
DETERMINATION OF SAMPLE SIZE
For the sample size calculation, a yearly event rate in the placebo group of 10% is assumed.
The assumption is based on the CHARM-Preserved study and part of the TOPCAT study
from the Americas [R07-4374, R16-1458]. The annual event rates in CHARM-Preserved 
were 8.1% in the candesartan group and 9.1% in the placebo group. The annual rates from the 
Americas in the TOPCAT study were 10.4 in the spironolactone group and 12.6 in the 
placebo group.
The trial is designed to achieve a power of 90% for a two sided test at level α = 0.05.
The following table presents the number of required events together with the number of to be 
randomised and treated patients assuming an accrual period of 18 months and a follow-up 
period of 20 months for different assumed true hazard ratios. However, the follow-up period 
is not fixed but the trial will continue until the necessary number of events has been observed, 
which are confirmed by the adjudication committee. 


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The drop-out rate from the trial is assumed to be low (< 1% per year) and is therefore not 
further considered for the determination of sample size. 
Table 7.7: 1
Sample size calculation – not including interim analyses:
Yearly event rate
for HHF+CV 
Death (Placebo)
Hazard 
ratio
Number of events for 90% 
power for HHF+CV 
Death
Number of patients
for 18 months accrual 
and 20 months follow up
10%/Year
0.70
331
1710
10%/Year
0.75
509
2562
10%/Year
0.80
841
4126
10%/Year
0.85
1601
7656
10%/Year
0.90
3814
17814
A hazard ratio of 0.8 was chosen as a conservative estimate based on the results of the 
EMPA-REG OUTCOME trial described in Section 1.2.3
Therefore, at least 841 confirmed primary events should be observed and at least 4126
patients should be randomised and treated in order to achieve a power of 90% assuming a 
true hazard ratio of 0.8.
Including interim analysis with Hwang-Shih-deCani alphaspending with gamma=-8 at 60% 
of information will diminish the power only slightly to 89.98%. 
The event rate will be assessed in a blinded manner during recruitment before any interim
unblinding. If the accumulated blinded data suggests a lower event rate based on an assumed 
hazard ratio of 0.8 between the groups, then the number of randomised patients may be 
increased to a maximum of 6000 patients. The number of confirmed primary outcome events 
will not be affected by this consideration and will remain 841 events. 
Calculations were performed using ADDPLAN6.1.1 by ADDPLAN Inc.
Based on the abovementioned assumptions, and considering that HHF (first and recurrent) 
will only be tested if the primary endpoint is successful, the chance of showing significance 
for HHF (first and recurrent) in a positive trial is at least 70%.
For the integration of a Japanese population in this global phase III trial, and in order to
comply with the regulatory requirements for bridging the trial results to this population, the
Japanese patients to be randomised will be followed and controlled if necessary. 
Approximately 145 patients are expected to be randomised to each treatment arm for the 
Japanese population.


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8
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY
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 GCP, relevant BI SOPs and CRO SOPs, the EU regulation 536/2014, the Japanese GCP 
regulations (Ministry of Health and Welfare Ordinance No. 28, March 27, 1997) and other 
relevant regulations. 
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient.
The Investigator will inform the Sponsor or delegate immediately of any urgent safety 
measures taken to protect the trial subjects against any immediate hazard, and also of any 
serious breaches of the protocol or of ICH GCP.
The BI transparency and publication policy can be found on the following web page: 
trials.boehringer-ingelheim.com. The rights of the Investigator and of the Sponsor with 
regard to publication of the results of this trial are described in the Investigator contract. As a 
rule, no trial results should be published prior to finalisation of the Clinical Trial Report.
For Japan only: The rights of the investigator / trial site and of the Sponsor or delegate with 
regard to publication of the results of this trial are described in the investigator contract / trial 
site’s contract. As a general rule, no trial results should be published prior to finalisation of 
the Clinical Trial Report.
The certificate of insurance cover is made available to the Investigator and the patients, and is 
stored in the ISF (Investigator Site File).
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 ICF and any additional patient-information form 
retained by the Investigator as part of the trial records. A signed copy of the ICF and any 
additional patient information must be given to each patient or the patient’s legally accepted 
representative.
The Investigator must give a full explanation to trial patients based on the patient information 
form. A language understandable to the patient should be chosen, technical terms and 
expressions avoided, if possible. 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 ICF after confirming that the patient understands the contents. The Investigator 


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must sign (or place a seal on) and date the ICF. If a trial collaborator has given a 
supplementary explanation, the trial collaborator also signs (or places a seal on) and dates the 
ICF.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the Sponsor's or delegate’s instructions.
The respective procedure for illiterate patients is described in the Appendix 10.1.
The consent and re-consenting process should be properly documented in the source 
documentation.
The patient must be informed that his/her personal trial-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of 
disclosure must also be explained to the patient.
The patient must be informed that his / her medical records may be examined by authorised 
monitors (CML/CL/ Clinical Research Associate (CRA)) or Clinical Quality Assurance 
auditors appointed by BI, by appropriate IRB / IEC members, and by inspectors from 
regulatory authorities.
8.2
DATA QUALITY ASSURANCE
In order to achieve a high level of standardised processes, data collection of efficacy and 
safety endpoints is coordinated centrally:

central lab analysis of efficacy endpoints, biomarkers and safety lab

central ECG collection (for clinically relevant ECG changes documented as an AE or 
suspected clinically relevant ECG changes)

central IRT for stratification, randomisation and kit allocation at each visit

central adjudication of HHF and cardiovascular events, and hepatic adjudication.
The data management procedures to ensure the quality of the data are described in detail in 
the trial data management and analysis plan available in eTMF.
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
ECRF for individual patients will be provided by the Sponsor or delegate. 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 


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other data pertinent to the investigation on each trial subject. 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 eCRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the subject may not be sufficient to confirm eligibility for the 
trial and the Investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case the Investigator must make three documented attempts to retrieve 
previous medical records. If this fails, a verbal history from the patient, documented in their 
medical records, would be acceptable.
Before providing any copy of patients’ source documents to the Sponsor or delegate 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 to ensure 
patient confidentiality.
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 eCRF, data must be derived from source documents, for example:

Patient identification: gender, date or year of birth (in accordance with local laws and 
regulations)

Patient participation in the trial (substance, trial number, patient number, date patient was 
informed)

Dates of Patient’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

Adverse events and outcome events (onset date (mandatory), and end date (if available))

Serious adverse events (onset date (mandatory), and end date (if available))

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available)

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.


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8.3.2
Direct access to source data and documents
The Sponsor or delegate will monitor the conduct of the trial by regular on-site monitoring 
visits and in-house data quality review. The frequency of on-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 permit trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the eCRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector (e.g. 
FDA). The CRA and auditor may review all eCRFs and ICFs. The accuracy of the data will 
be verified by direct comparison with the source documents described in Section 8.3.1. The 
Sponsor or delegate will also monitor compliance with the protocol and ICH GCP.
An adaptive approach to clinical trial monitoring will be utilised. This is initiated by an 
assessment of the risk associated with the trial combined with an assessment of critical data 
and processes. A Risk Assessment Mitigation Plan and Integrated Project Management Plan 
collectively document the strategies involved with the implementation of onsite, remote and 
central monitoring activities in order to direct focus to the areas of greatest risk which have 
the most potential impact to safety patient and data quality. Trial oversight is achieved by 
regular review of a report of risk which then influences any required changes to the 
monitoring strategy.
The Investigator /institution will allow on-site trial-related monitoring, audits, IRB/IEC
review and regulatory inspections. Direct access should be granted to all source documents
(paper and e-records) including progress notes, copies of laboratory and medical test results
The CRA and auditor may review all CRFs and ICFs. The accuracy of the data will be 
verified by direct comparison with the source documents described in Section 8.3.1.
The Sponsor/CRO will also monitor compliance with the protocol and ICH GCP.
8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source documents and essential documents (including ISF) 
according to the national or local requirements (whatever is longer) valid at the time of the 
end of the trial.
Sponsor:
The Sponsor or delegate 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 regulatory reporting obligation and in accordance to the 
regulatory requirements. As this trial is primarily intended to evaluate the cardiovascular 
impact of empagliflozin in patients with chronic heart failure, the Sponsor will not report the 
SAEs included in the protocol exempted events list of the eCRF as described in 


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Section 5.3.7.2. Events will be recorded and reported regularly to the DMC. The Sponsor will 
ensure that all appropriate regulatory agencies confirm that this approach is acceptable to 
them.
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 and in Section 5.5.1.
Patient privacy will be ensured by using patient identification code numbers. 
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook. Treatment data may be given to the patient’s personal physician or to other 
appropriate medical personnel responsible for the patient’s welfare. Data generated as a result 
of the trial need to be available for inspection on request by the participating physicians, the 
Sponsor’s representatives or delegates, by the IRB / IEC and the regulatory authorities.
8.6
TRIAL MILESTONES
The start of the trial is defined as the date of the enrolment of the first patient in the whole 
trial.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial
“Last Patient Out”).
The “Last Patient Drug Discontinuation” (LPDD) date is defined as the date on which the last 
patient at an individual trial site ends trial medication (as scheduled per protocol or 
prematurely). Individual Investigators will be notified of SUSARs occurring with the trial 
medication until 30 days after LPDD at their site.
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the Sponsor 
with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the respective laws.
A final report of the clinical trial data will be written only after all patients have completed 
the trial in all countries (EU or non-EU) to incorporate and consider all data in the report.
The Sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient 
(EU or non-EU).


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For Japan only: When the trial is completed, the Investigator should inform the head of the 
trial site of the completion in writing, and the head of the trial site should promptly inform the 
IRB and Sponsor of the completion in writing.
8.7
PROTOCOL VIOLATIONS
For Japan only: The investigator should document any deviation from the protocol regardless 
of their reasons. Only when the protocol was not followed in order to avoid an immediate 
hazard to trial subjects or for other medically compelling reason, the principal investigator 
should prepare and submit the records explaining the reasons thereof to the Sponsor or 
delegate, and retain a copy of the records.
8.8
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
TRIAL RELATED INJURY
For Japan only: In the event of health injury associated with this trial, the Sponsor is 
responsible for compensation based on the contract signed by the trial site


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9
REFERENCES
9.1
PUBLISHED REFERENCES
P13-04190
Seman L, Macha S, Nehmiz G, Simons G, Ren B, Pinnetti S, Woerle HJ, 
Dugi K
Empagliflozin (BI 10773), a potent and selective SGLT2 inhibitor, 
induces dose dependent glucosuria in healthy subjects.
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Barnett AH, Mithal A, Manassie J, Jones R, Rattunde H, Woerle HJ, 
Broedl UC, EMPA-REG RENAL Trial Investigators
Efficacy and safety of empagliflozinadded to existing antidiabetes 
treatment in patients with type 2 diabetes and chronic kidney disease: a 
randomised, double-blind, placebo-controlled trial.
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P15-00589
Inzucchi SE, Zinman B, Wanner C, Ferrari R, Fitchett D, Hantel S, 
Espadero RM, Woerle HJ, Broedl UC, Johansen OE
SGLT-2 inhibitors and cardiovascular risk: proposed pathways and 
review of ongoing outcome trials.
Diabetes Vasc Dis Res, (2015)
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Chilton R, Tikkanen I, Cannon CP, Crowe S, Woerle HJ, Broedl UC, 
Johansen OE
Effects of empagliflozin on blood pressure and markers of arterial 
stiffness and vascular resistance in patients with type 2 diabetes.
Diabetes Obes Metab 17 (12), 1180 - 1193 (2015)
P15-09840
Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, 
Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi
SE, EMPA-REG OUTCOME Investigators
Empagliflozin, cardiovascular outcomes, and mortality in type 2 
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N Engl J Med 373 (22), 2117 - 2128 (2015)
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P15-10667 Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ,
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ER, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol 
G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Sorlie PD, 
Stein J, Towfighi A, Turan TN, Virani SS, Willey JZ, Woo D, Yeh 
RW, Turner MB, On behalf of the American Heart Association Statistics 
Committee and Stroke Statistics Subcommittee Heart disease and stroke 
statistics - 2015 update: a report from the American Heart Association.


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Circulation 131 (4), e29 - e322 (2015)
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Fitchett D, Zinman B, Wanner C, Lachin JM, Hantel S, Salsali A, 
Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE, EMPA-REG 
OUTCOME Trial Investigators
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OUTCOME trial.
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Ferrannini E, Baldi S, Frascerra S, Astiarraga B, Heise T, Bizzotto R, 
Mari A, Pieber TR, Muscelli E
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cotransporter 2 inhibition in subjects without diabetes and patients with 
type 2 diabetes. 
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Clyde W. Yancy, Mariell Jessup, Biykem Bozkurt, Javed Butler, Donald
E. Casey, Mark H. Drazner, Gregg C. Fonarow, Stephen A. Geraci, 
Tamara Horwich, James L. Januzzi, Maryl R. Johnson, Edward K. 
Kasper, Wayne C. Levy, Frederick A. Masoudi, Patrick E. McBride,
John J.V. McMurray, Judith E. Mitchell, Pamela N. Peterson, Barbara
Riegel, Flora Sam, Lynne W. Stevenson, W.H. Wilson Tang, Emily J.
Tsai, Bruce L. Wilkoff
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of the American College of Cardiology Foundation/ American Heart 
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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 
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et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and 
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Mattheus M, et al, EMPA-REG OUTCOME Investigators
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Levey AS, Stevens LA, Schmid CH, Zhang Y, Castro AF, Feldman HI, 
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Disease Epidemiology Collaboration (CKD-EPI)
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Investigators
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Ambrosy AP, Fonarow GC, Butler J, Chioncel O, Greene SJ, 
Vaduganathan M, Nodari S, Lam CSP, Sato N, Shah AN, 
Gheorghiade M


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Clark AL, Cleland JG
Elevated glycated haemoglobin is a strong predictor of mortality in 
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Packer M, PARADIGM-HF Investigators, PARADIGM-HF Committees
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ARNI with ACEI to Determine Impact on Global Mortality and 
Morbidity in Heart Failure trial. Circ Heart Fail 9, e002560 (2016)
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with congestive heart failure, Eur Heart J, 2000 Aug;21(16):1368-75
R16-4813
Pocock SJ, Ariti CA, Collier TJ, Wang D
The win ratio: a new approach to the analysis of composite endpoints in 
clinical trials based on clinical priorities.
Eur Heart J 33, 176 - 182 (2012)
R16-4909
Rogers JK, Pocock SJ, McMurray JJV, Granger CB, Michaelson EL, 
Ostergren J, et al
Analysing recurrent hospitalizations in heart failure: a review of 
statistical methodology, with application to CHARM-Preserved.
Eur J Heart Fail 16, 33 - 40 (2014)
9.2
UNPUBLISHED REFERENCES
c01678844-06
Empagliflozin Investigator’s Brochure, Current Version
c09670340 
Empa_EMA responses to RSI_1245.25_stats-outputs-ru0765
c11764168
Empa_EMA responses to RSI_1245.25_stats-outputs-ru1045


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10 APPENDICES
10.1 INCLUSION OF ILLITERATE PATIENTS
10.1.1 Patient reported outcome forms 
In the event of recruiting an illiterate patient, the following process should be followed with 
respect to completion of the EQ-5D self-report questionnaire and the KCCQ:

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 questions will be read 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 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 EQ-5D questionnaire and the 
KCCQ should be performed in a quiet area where the patient can consider his/her responses 
to both the descriptive system and VAS.
10.1.2 Patient information and informed consent (including biobanking)
In the event of recruiting an illiterate patient, the following process should be followed with
respect to patient information and informed consent:

The designated site personnel performing the informed consent process will read the
trial approved patient information sheet and ICFs to the patient, and explain the
details of the trial, all in the presence of an impartial witness.

This impartial witness must be literate, and can be the patient’s relative or caregiver,
or a member of staff employed by the clinic but not part of the immediate trial team.
In addition, if there are any further local regulations with respect to the consent of
illiterate patients, these should also be followed.

The requirements of the trial will be explained thoroughly and the patient will be
given ample time to ask questions and consider his/her participation. If he/she wishes,
the patient can take the patient information sheet and ICFs home for further
consideration.

If patient agrees to take part in the trial, he/she would then return to the clinic for the
consent process to be completed. The site designated personnel responsible for this
process will confirm that the patient has no further questions in the presence of the


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same impartial witness (if the patient returns on another day). If a different impartial 
witness is present, the entire informed consent process must be repeated.

Participating patients will provide a thumb impression or make a mark (or signature if 
the patient is able to sign him/herself) on the signature section of the ICFs.

The date of the patient’s signature will be left blank as the patient is illiterate.
However, if the patient is able, he/she will date the mark/signature personally.

The impartial witness or the site designated personnel may write the name of the 
patient on the ICFs.

The impartial witness should enter his/her name, sign and personally date the witness 
section of the ICFs. In countries where local data protection regulation permits it, the 
address or identification number of the impartial witness should also be entered. The 
signature then attests that the content of the patient information sheet and ICFs was 
accurately explained to the patient, who apparently understood and freely gave 
consent to participate in the trial.

The designated site personnel also signs and personally dates the ICFs.

The same process as outlined above will be followed for obtaining consent for the 
optional sampling for biobanking (including DNA).


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10.2 PATIENT REPORTED OUTCOMES
10.2.1 EQ-5D 


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10.2.2 KCCQ 


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10.3 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
10.4 MODIFIED RANKIN SCALE
Scale
Description
0
No symptoms at all
1
No significant disability despite symptoms; able to carry out all usual duties and 
activities
2
Slight disability; unable to carry out all previous activities, but able to look after 
own affairs without assistance
3
Moderate disability; requiring some help, but able to walk without assistance
4
Moderately severe disability; unable to walk without assistance and unable to 
attend to own bodily needs without assistance
5
Severe disability; bedridden, incontinent and requiring constant nursing care and 
attention
6
Dead
10.5 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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10.6 BLOOD PRESSURE MEASURMENT 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, blood pressure should be taken 3 times in both arms. If the pressures differ by 
more than 10 mmHg (as in the presence of a subclavian steal syndrome), the arm with the 
higher pressure (systolic or diastolic) should be used for subsequent measurements.
After the patient has rested quietly, in the seated position for five minutes, three blood 
pressure measurements will be taken approximately two minutes apart and all three results 
must be entered in the eCRF. The seated HR will be taken during one of the two-minute 
intervals.
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 calculation of mean values, 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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11 DESCRIPTION OF GLOBAL AMENDMENT(S)
This is the original protocol.
Number of global amendment
Date of CTP revision
EudraCT 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
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 
 
 
 
 
 
 
c03946327
1.0
clinical-trial-protocol-version-1
A phase III randomised, double-blind trial to evaluate efficacy and safety of once
daily empagliflozin 10 mg compared to placebo, in patients with chronic Heart
Failure with preserved Ejection Fraction (HFpEF).
Author-Trial Clinical Monitor
09 Nov 2016 19:33 CET
Approval-Team Member Medicine
09 Nov 2016 20:37 CET
Author-Trial Statistician
10 Nov 2016 09:17 CET
Approval-Therapeutic Area Head
10 Nov 2016 10:57 CET
Author-Trial Clinical
Pharmacokineticist
10 Nov 2016 13:15 CET
Verification-Paper Signature
Completion
15 Nov 2016 17:43 CET


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Document Number: 
Technical Version Number:
 
(Continued) Signatures (obtained electronically) 
Meaning of Signature  
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CLINICAL TRIAL PROTOCOL
Document Number:
c03946327-04
EudraCT No.:
2016-002278-11
BI Trial No.:
1245.110
BI 
Investigational 
Product(s):
Empagliflozin
Title:
A phase III randomised, double-blind trial to evaluate efficacy and safety 
of once daily empagliflozin 10 mg compared to placebo, in patients with 
chronic Heart Failure with preserved Ejection Fraction (HFpEF).
Lay title:
EMPagliflozin outcomE tRial in patients with chrOnic heaRt failure
EMPEROR-Preserved
Clinical Phase:
III
Trial Clinical 
Monitor:
Coordinating 
Investigators
Status
Final Protocol (based on Global Amendment 03)
Version and 
Date:
Version: 4.0
Date: 20 Nov 2019
Page 1 of 130
Proprietary confidential information
2019 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
Name of company:
Boehringer Ingelheim 
Name of finished product:
Jardiance
Name of active ingredient:
Empagliflozin
Protocol date
09 NOV 2016
Trial number:
1245.110
Revision date:  
20 Nov 2019
Title of trial:
A phase III randomised, double-blind trial to evaluate efficacy and safety of once 
daily empagliflozin 10 mg compared to placebo, in patients with chronic Heart 
Failure with preserved Ejection Fraction (HFpEF)
Coordinating 
Investigator:
Trial site(s):
Multicentre trial in approximately 22 countries.
Clinical phase:
III
Objective(s):
The objective of this event-driven trial is to demonstrate superiority of 
empagliflozin 10 mg versus placebo in patients with symptomatic, chronic HF and 
preserved ejection fraction (LVEF > 40%) under stable treatment of HF symptoms
Methodology:
Randomised, double blind, placebo controlled, parallel group trial.  
No. of patients:
total entered:
Approximately 4126 randomised
If the accumulated blinded data suggests a slower accrual of primary outcome 
events over calendar time than was originally projected, then the number of patients 
randomised may be increased up to 6000. Operationally, the recruitment period 
would be extended and could continue up to 6 months before the target number of 
events is expected to be achieved.  Such a decision would be made during 
recruitment and before any interim unblinding. The number of primary outcome 


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Jardiance
Name of active ingredient:
Empagliflozin
Protocol date
09 NOV 2016
Trial number:
1245.110
Revision date:  
20 Nov 2019
events required is not affected by this consideration.
each treatment:
Approximately 2063 (2 treatment groups) This may be increased up to 
approximately 3000 per treatment group.
Diagnosis :
Heart failure (HF) with preserved ejection fraction (EF).
Main criteria
for inclusion:

Patients with chronic HF diagnosed for at least 3 months before Visit 1 and
currently in NYHA HF class II-IV

Chronic HF with preserved EF defined as LVEF > 40 % per local reading
(obtained by echocardiography, radionuclide ventriculography, invasive
angiography, MRI or CT), and no prior measurement of LVEF ≤ 40% under
stable conditions. A historical LVEF may be used if it was measured within 6
months prior to visit 1, and more than 90 days after any myocardial infarction
(as defined in exclusion criterion No.1) or the LVEF may be measured after
study consent has been obtained. The LVEF must be documented in an official
report prior to randomization.

Elevated NT-proBNP > 300 pg/ml for patients without AF, OR > 900 pg/ml for
patients with AF, analysed at the Central laboratory at Visit 1

Patients must have at least one of the following evidence of HF:
a) Structural heart disease (left atrial enlargement and/or left
ventricular hypertrophy) documented by echocardiogram at Visit 1, OR
b) Documented hospitalisation for HF (HHF) within 12 months prior to Visit 1

Oral diuretics, if prescribed to patient according to local guideline and
discretion of the Investigator, should be stable for at least 1 week prior to Visit
2 (Randomisation)

eGFR (CKD-EPI)cr ≥ 20 mL/min/1.73m2 at Visit 1
Test product(s):
Empagliflozin
dose:
10 mg q.d.
mode of 
administration:
p.o.
Comparator products:
Placebo


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Jardiance
Name of active ingredient:
Empagliflozin
Protocol date
09 NOV 2016
Trial number:
1245.110
Revision date:  
20 Nov 2019
dose:
NA
mode of 
administration:
p.o.
Duration of treatment:
•
4-28 days screening period
•
The study was designed based on an assumption of 18 months recruitment
and an event rate of 10%.  The actual length of the recruitment period may
be extended beyond 18 months and the follow-up period may be adjusted
to achieve the 841 confirmed primary outcome events.  The estimated total
trial duration and length of the double-blind treatment for each patient will
vary accordingly.
•
Follow-up visit 30 days after end of treatment
The trial will continue until the required number of adjudicated primary endpoint 
events have occurred to be able to comply with the objective of the trial.
Endpoints
Primary endpoint;
The composite primary endpoint for this trial is the time to first event of adjudicated 
CV death or adjudicated HHF in patients with HFpEF.
Key secondary endpoints; 
The key secondary endpoints which are part of the testing strategy, are the 
following: 
-
Occurrence of adjudicated HHF (first and recurrent)
-
eGFR (CKD-EPI)cr slope of change from baseline
Other secondary endpoints are:
-
Time to first occurrence of chronic dialysis or renal transplant or sustained
reduction of ≥40% eGFR (CKD-EPI)cr or
o
sustained eGFR (CKD-EPI)cr <15 mL/min/1.73 m2 for patients with
baseline eGFR ≥30 mL/min/1.73 m2
o
sustained eGFR (CKD-EPI)cr <10 mL/min/1.73 m2 for patients with
baseline eGFR <30 mL/min/1.73 m2

Time to first adjudicated HHF

Time to adjudicated CV death

Time to all-cause mortality

Time to onset of diabetes mellitus (DM) in patients with pre-DM

Change from baseline in clinical summary score (HF symptoms and physical
limitations domains) of the KCCQ at week 52


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Jardiance
Name of active ingredient:
Empagliflozin
Protocol date
09 NOV 2016
Trial number:
1245.110
Revision date:  
20 Nov 2019

Occurrence of all-cause hospitalisation (first and recurrent)
Safety criteria:

Adverse events (AE)

AE of special interest (AESI)

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

Assessment of vital status
Statistical methods:
The overall type one error rate will be preserved at a level of 0.05 (2-sided). The 
primary and the key secondary endpoints will be analysed in the following testing 
hierarchy:
1.
Time to first event of adjudicated CV death or adjudicated HHF
2.
Occurrence of adjudicated HHF (first and recurrent)
3.
eGFR (CKD-EPI)cr slope of change from baseline
At the final analysis, after the evaluation of recurrent HHF, alpha will be split into 
0.001 to be used for the analysis of eGFR slope analysis, and the rest will be 
transferred to the meta-analyses which will include this trial and the trial conducted 
in parallel in patients with HFrEF (1245.121). 
For the primary analysis of the primary endpoint a Cox proportional hazards 
regression model of time to first event of adjudicated CV death or adjudicated HHF
with covariates of age (continuous), gender treatment, geographical regions, history 
of DM (DM, Pre-DM, No DM), LVEF (continuous) and eGFR (CKD-EPI)cr at 
baseline (continuous) will be used. The primary analysis will be performed on the 
randomised (intention to treat) set.
Approximately 4126 patients will be randomised to accumulate approximately 841 
confirmed primary events within 18 months accrual and approximately 20 
additional months follow-up period to achieve a power of ~90%. If the accumulated 
blinded data suggests a slower accrual of primary outcome events over calendar 
time than originally projected, then the number of patients randomised may be 
increased up to 6000 patients. Operationally, the recruitment period would be 
extended and could continue up to 6 months before the target number of events is 
expected to be achieved. Such a decision would be made during recruitment before 
any interim unblinding. The number of 841 confirmed primary outcome events is 
not affected by this consideration. 


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Jardiance
Name of active ingredient:
Empagliflozin
Protocol date
09 NOV 2016
Trial number:
1245.110
Revision date:  
20 Nov 2019
One interim analysis is planned after approximately 500 primary adjudicated events 
have been accrued. If the pre-specified criteria for stopping for success at the 
interim analysis has been reached, the Executive Steering Committee (ExSC) and 
the Sponsor will be informed. The final decision on whether to stop the trial will be 
made by the Sponsor. 
Safety will be evaluated descriptively on the treated set. 


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FLOW CHART
Trial Period
Scree
ning1
Randomised Treatment Period2
Follow Up
Period 3
Relevant CTP section
Visit
1
2
3
4
5
Phone
call
6
7
Phone
call
8
9
Phone 
call
10
11
Phone 
call
12
13
Phone 
call
14
15
Phone 
call
16
EOT 
Visit
FU 
Visit3
Trial week
-3
1
4
12
22
32
42
52
64
76
88
100
112
124
136
148
EOT 
Visit
EOT + 
30 
days
Days from 
Randomisation Visit 
window4
-28
to -4
1
29±7
85
±7
155 ±7
225
±7
295 ±7
365 
±7
449
±7
533
±7
617
±7
701
±7
785
±7
869
±7
953
±7
1037
±7
---
---
±7
Fasting status5
NF
F
NF
NF
-
NF
NF
-
NF
-
NF
-
NF
-
NF
F
F
Informed Consent 6
X
3, 8
In-/exclusion criteria
X
X
3.3
Medical History/ 
Concomitant 
diagnoses
X
8.3.1
Screening (register in 
IRT)
X
6.2.1
Randomisation (via 
IRT)
X
6.2.2
Demographics7
X
-
NYHA classification
X
X
X
X
X
X
X
X
X
X
X
X
5.2.2
10.3
Physical exam
X
X
X
X
X
X
X
X
5.3.1
Clinical routine exam8
X
X
X
X
X
X
X
X
X
X
5.3.2
Vital signs 9
X
X
X
X
X
X
X
X
X
X
X
X
5.3.3
Height 
X
-


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Trial Period
Screen
ing1
Randomised Treatment Period2
Follow Up
Period 3
Relevant CTP section
Visit
1
2
3
4
5
Phone
call
6
7
Phone
call
8
9
Phone 
call
10 
11
Phone 
call
12
13
Phone 
call
14
15 
Phone 
call
16
EOT 
Visit
FU 
Visit3
Trial week
-3
1
4
12
22
32
42
52
64
76
88
100
112
124
136
148
EOT 
Visit
EOT + 
30 
days
Days from 
Randomisation 
Visit window4
-28 to -
4
1
29±7
85
±7
155 ±7
225
±7
295 ±7
365 
±7
449
±7
533
±7
617
±7
701
±7
785
±7
869
±7
953
±7
1037
±7
---
---
±7
Fasting status5
NF
F
NF
NF
-
NF
NF
-
NF
-
NF
-
NF
-
NF
F
F
Weight
X
X
X
X
X
X
X
X
X
X
X
X
5.2.4
Concomitant 
Therapy 
X
X
X
X
X
X
X
X
X
X
X
X
4.2
Assessment of 
Endpoints10, 11
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
5.2, 5.3
12-lead-ECG 12
X
X
5.3.5
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
5.3.7
KCCQ
X
X
X
X
X
X
5.2.1
EQ-5D
X
X
X
X
X
X
X
X
5.6.1
HCRU 
X
X
X
X
X
X
X
X
X
X
5.6.2
Urine Pregnancy 
Test 13
X
X
X
X
X
X
X
X
X
X
X
5.3.4.2
Safety lab Tests
X14
X
X
X
X
X
X
X
X
X
X
X
5.3.4
NT-proBNP
X
X
X
X
X
X
X
X
5.5
High-sensitivity 
TroponinT
X
5.5
HbA1c 15
X
X
X
X
X
X
X
X
X
X
-


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Trial Period
Screen
ing1
Randomised Treatment Period2
Follow Up
Period 3
Relevant CTP section
Visit
1
2
3
4
5
Phone
call
6
7
Phone
call
8
9
Phone 
call
10 
11
Phone 
call
12
13
Phone 
call
14
15 
Phone 
call
16
EOT 
Visit
FU 
Visit3
Trial week
-3
1
4
12
22
32
42
52
64
76
88
100
112
124
136
148
EOT 
Visit
EOT + 
30 
days
Days from 
Randomisation 
Visit window4
-28 to -
4
1
29±7
85
±7
155 ±7
225
±7
295 ±7
365 
±7
449
±7
533
±7
617
±7
701
±7
785
±7
869
±7
953
±7
1037
±7
---
---
±7
Fasting status5
NF
F
NF
NF
-
NF
NF
-
NF
-
NF
-
NF
-
NF
F
F
Lipid profile panel 
X
X
X
X
X
5.3.4
eGFR (CKD-EPIcr
formula)
X
X
X
X
X
X
X
X
X
X
X
X
5.3.4.1
UACR
X
X
X
X
X
X
X
X
X
X
X
X
5.3.4
PK sampling 
(substudy)16
X
5.4.1
Sampling for 
biobanking of 
serum/plasma/urine/
DNA (optional, 
requires  separate 
informed consent)17
X18
X
X
5.5.1
Dispense trial 
medication19
X
X
X
X
X
X
X
X
X
4.1.4
6.2.2
Return Medication/ 
medication 
compliance check
X
X
X
X
X
X
X
X
X
4.3


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1.
The screening procedures can be done on different days within the time window.
2.
From Visit 8 and onwards, on-site visits will be scheduled every 24 weeks until end of trial. 
Patients who prematurely discontinue trial medication will perform EOT visit and Follow Up visit, and then continue with scheduled visits until the trial is stopped. 
For patients not willing to attend scheduled visits, telephone calls must be made regularly (ref. Section 3.3.4.1) to document any occurrence of outcome events and vital 
status. 
If the trial continues beyond 148 weeks, visits are to be repeated with same intervals as from week 64 and onwards.
3.
Timepoint for the EOT will be communicated via an Investigator letter when the Sponsor is confident that required number of events will be reached within a reasonable 
timeframe (ref. Section 3.1 and 6.2.3). All patients will have a follow up visit 30 days following regular or premature completion of the treatment period. 
4.
Visit dates are determined per the date of randomisation.  If a visit is missed, the patient should be returned to the original visit schedule at the next visit.
5.
NF = non fasting, F=fasting. Fasting means no food or liquid intake except for water the last 10-16 hours
6.
All visit 1 procedures should be performed within 28 days of signing the informed consent form (ICF).
7.
If accepted by local authorities or ethic committees, demographics to be collected in this trial are gender, year of birth, ethnicity and race. 
8.
The Investigator will be asked to record results from clinical routine examinations like ECG, echocardiography or similar procedures (MRI, CT-scan, etc.), and if 
applicable information gathered from interrogations of the ICD in the eCRF.
9.
Vital signs measurements in this trial are blood pressure and pulse rate. 
10. Protocol specified outcome events should be collected on the appropriate eCRF page. Exemptions from reporting on the SAE form are specified in Section 5.3.7.
11. For patients with non-fatal stroke the Modified Rankin Scale (MRS) should be scored by the investigator based on an interview at the next regular on-site visit after the 
onset of the stroke. In those cases where MRS assessment occurred within 90 days after the stroke, a repeat MRS-assessment should be performed at the next on-site 
visit.  For patients who experience a non-fatal stroke less than 90 days prior to the study closure date, the final MRS assessment will occur at the final study visit for that 
patient.
12. For the 12-lead ECG done at screening and EOT visit, the interpretation of the tracing must be made locally by a qualified physician or appropriately qualified designee
and documented on the ECG section of the eCRF. In case of any cardiac symptoms (indicating rhythm disorders or cardiac ischaemia), additional 12-lead ECG(s) should 
be done to document a potential outcome event.
13. For female patients of child-bearing potential, local urine pregnancy test should be performed according to the Flow Chart. More frequent testing should be performed if 
required by local regulations/authorities.
14. For the screening Visit 1, the safety laboratory is limited to liver transaminases, alkaline phosphatase, serum creatinine and haematology panel. Patients do not have to be 
fasting.
15. HbA1c to be analysed in all patients, e.g. diabetics and non-diabetics.
16. For PK analysis, one blood sample will be collected prior to the next scheduled dose of trial medication at Visit 4 and between 22 to 26 h after the most recent drug 
intake. 
17. Collection of biobanking samples (plasma, serum, urine, DNA) is optional. Participating patients are required to give informed consent specifically for biobanking. 
Samples will be stored at a biobanking facility for future research. 
18. DNA biobanking requires only one blood sample to be taken, preferably at Visit 2 (Randomisation). However, collection at later visits is permitted as long as the 
informed consent for biobanking remains valid. 
19. At all visits; the respective kit number has to be allocated to the patient via IRT. Trial medication should be taken after all trial related procedures are completed at an on-
site visit.


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TABLE OF CONTENTS
CLINICAL TRIAL PROTOCOL.....................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................7
TABLE OF CONTENTS .................................................................................11
ABBREVIATIONS...........................................................................................15
1
INTRODUCTION................................................................................18
1.1
MEDICAL BACKGROUND............................................................................18
1.2
DRUG PROFILE ...............................................................................................19
1.2.1
Non-clinical assessment of safety .................................................................19
1.2.2
Clinical pharmacokinetics ............................................................................19
1.2.3
Clinical efficacy and safety...........................................................................19
2
RATIONALE, OBJECTIVES, AND BENEFIT-RISK 
ASSESSMENT .....................................................................................23
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................23
2.2
TRIAL OBJECTIVES.......................................................................................24
2.3
BENEFIT-RISK ASSESSMENT......................................................................24
3
DESCRIPTION OF DESIGN AND TRIAL POPULATION..........28
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................28
3.1.1
Administrative structure of the trial ...........................................................29
Clinical Event Committee ..........................................................................30
3.1.1.1
Hepatic external adjudication.....................................................................30
3.1.1.2
Adjudication of ketoacidosis ......................................................................30
3.1.1.3
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S) .....................................................................................31
3.3
SELECTION OF TRIAL POPULATION ......................................................31
3.3.1
Main diagnosis for trial entry.......................................................................33
3.3.2
Inclusion criteria............................................................................................33
3.3.3
Exclusion criteria...........................................................................................34
3.3.4
Removal of patients from therapy or assessments .....................................36
Removal of individual patients...................................................................36
3.3.4.1
Discontinuation of the trial by the Sponsor................................................38
3.3.4.2
4
TREATMENTS....................................................................................39
4.1
INVESTIGATIONAL TREATMENTS ..........................................................39
4.1.1
Identity of the investigational Medicinal product and comparator..........39
4.1.2
Selection of doses in the trial ........................................................................39
4.1.3
Method of assigning patients to treatment groups.....................................40
4.1.4
Drug assignment and administration of doses for each patient................40
4.1.5
Blinding and procedures for unblinding.....................................................41
Blinding ......................................................................................................41
4.1.5.1
Unblinding and breaking the code..............................................................41
4.1.5.2
4.1.6
Packaging, labelling and re-supply..............................................................41
4.1.7
Storage conditions .........................................................................................42
4.1.8
Drug accountability.......................................................................................42


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4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................42
4.2.1
Other treatments and emergency procedures ............................................42
4.2.2
Restrictions.....................................................................................................43
4.3
TREATMENT COMPLIANCE .......................................................................44
5
VARIABLES AND THEIR ASSESSMENT.....................................45
5.1
TRIAL EFFICACY ENDPOINTS...................................................................45
5.1.1
Primary endpoint(s) ......................................................................................45
5.1.2
Secondary endpoint(s)...................................................................................45
5.1.3
Further endpoints..........................................................................................45
5.2
ASSESSMENT OF EFFICACY.......................................................................47
5.2.1
KCCQ.............................................................................................................47
5.2.2
New York Heart Association classification.................................................48
5.2.3
NT-proBNP....................................................................................................48
5.2.4
Body weight....................................................................................................48
5.2.5
Blood pressure ...............................................................................................48
5.3
ASSESSMENT OF SAFETY............................................................................49
5.3.1
Physical examination.....................................................................................49
5.3.2
Clinical routine examination........................................................................49
5.3.3
Vital signs.......................................................................................................49
5.3.4
Safety laboratory parameters.......................................................................49
Renal function.............................................................................................50
5.3.4.1
Pregnancy testing........................................................................................51
5.3.4.2
Criteria for hypoglycaemic events..............................................................51
5.3.4.3
Urinary tract infections and genital infections ...........................................51
5.3.4.4
Ketone monitoring in patients with type 1 diabetes (T1DM) only.............52
5.3.4.5
5.3.5
Electrocardiogram.........................................................................................52
5.3.6
Other safety assessments...............................................................................53
Outcome of non-fatal stroke.......................................................................53
5.3.6.1
Hepatic events.............................................................................................53
5.3.6.2
5.3.7
Assessment of adverse events .......................................................................53
Definitions of AEs......................................................................................53
5.3.7.1
Adverse event collection and reporting......................................................57
5.3.7.2
5.4
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS (SUBSTUDY).........................................................61
5.4.1
Pharmacokinetic endpoints ..........................................................................61
5.4.2
Methods of sample collection........................................................................61
5.4.3
Analytical determinations.............................................................................61
5.5
ASSESSMENT OF BIOMARKERS................................................................61
5.5.1
Biobanking (optional)....................................................................................61
Methods and timing of sample collection...................................................62
5.5.1.1
5.6
OTHER ASSESSMENTS..................................................................................63
5.6.1
EQ-5D.............................................................................................................63
5.6.2
Health Care Resource Utilisation (HCRU).................................................63
5.7
APPROPRIATENESS OF MEASUREMENTS.............................................63
6
INVESTIGATIONAL PLAN .............................................................64


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6.1
VISIT SCHEDULE............................................................................................64
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................64
6.2.1
Screening........................................................................................................64
6.2.2
Treatment period...........................................................................................65
6.2.3
End of Treatment, Follow Up Period and Trial Completion ....................66
6.2.4
The patients should be fasting at the EOT and Follow Up Visit. Early 
discontinuation of trial medication and trial termination.........................66
7
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE.....................................................................................68
7.1
STATISTICAL DESIGN – MODEL ...............................................................68
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................68
7.3
PLANNED ANALYSES....................................................................................70
7.3.1
Primary endpoint analyses ...........................................................................70
7.3.2
Secondary endpoint analyses........................................................................71
7.3.3
Further endpoint analyses............................................................................72
7.3.4
Safety analyses...............................................................................................73
7.3.5
Pharmacokinetic analyses.............................................................................73
7.3.6
Prespecified meta-analysis............................................................................73
7.4
INTERIM ANALYSES .....................................................................................73
7.5
HANDLING OF MISSING DATA ..................................................................74
7.6
RANDOMISATION ..........................................................................................75
7.7
DETERMINATION OF SAMPLE SIZE ........................................................75
8
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY......................................77
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ..........................................................................................................77
8.2
DATA QUALITY ASSURANCE .....................................................................78
8.3
RECORDS ..........................................................................................................79
8.3.1
Source documents..........................................................................................79
8.3.2
Direct access to source data and documents...............................................80
8.3.3
Storage period of records..............................................................................80
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................81
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY.......81
8.6
TRIAL MILESTONES......................................................................................81
8.7
PROTOCOL VIOLATIONS ............................................................................82
8.8
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
TRIAL RELATED INJURY.............................................................................82
9
REFERENCES.....................................................................................83
9.1
PUBLISHED REFERENCES...........................................................................83
9.2
UNPUBLISHED REFERENCES.....................................................................87
10
APPENDICES......................................................................................88
10.1
INCLUSION OF ILLITERATE PATIENTS..................................................88
10.1.1
Patient reported outcome forms ..................................................................88
10.1.2
Patient information and informed consent (including biobanking) .........88
10.2
PATIENT REPORTED OUTCOMES ............................................................90


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10.2.1
EQ-5D.............................................................................................................90
10.2.2
KCCQ.............................................................................................................93
10.3
NYHA FUNCTIONAL CLASSIFICATION...................................................95
10.4
MODIFIED RANKIN SCALE .........................................................................95
10.5
STRUCTURAL HEART DISEASE.................................................................95
11
DESCRIPTION OF GLOBAL AMENDMENT(S)..........................96
11.1
GLOBAL AMENDMENT 1 .............................................................................96
11.2
GLOBAL AMENDMENT 2 ...........................................................................120
11.3
GLOBAL AMENDMENT 3 ...........................................................................126


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ABBREVIATIONS 
ACE
Angiotensin Converting Enzyme
AE
Adverse Event
AESI
Adverse Event of Special Interest
AF
Atrial fibrillation or Atrial flutter
ALT
Alanine-Aminotransferase
ARB
Angiotensin Receptor Blocker
ARNI
Angiotensin Receptor blocker-Neprilysin Inhibitor
AST
Aspertate-Aminotransaminase
BI
Boehringer Ingelheim
BMI
Body Mass Index
CA
Competent Authority
CEC
Clinical Event Committee
CI
Confidence Interval
CK
Creatine Kinase
CKD
Chronic Kidney Disease
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration Equation
CL
Clinical Lead (title refers to CRO’s Project Leader on national/regional 
level)
CML
Local Clinical Monitor (title refers to Sponsor’s Project Leader on 
national/regional level)
CRA
Clinical Research Associate
CRO
Clinical Research Organisation
CRT
Cardiac Resynchronisation 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
DNA
Deoxyribonucleic acid
ExSC
Executive Steering Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EF
Ejection Fraction
eGFR
Estimated Glomerular Filtration Rate
EOT
End of treatment
EQ5D
EuroQol 5 dimensions
eTMF
Electronic Trial Master File
EudraCT
European Clinical Trials Database
GCP
Good Clinical Practice
GI
Gastrointestinal


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HbA1c
Glycated Haemoglobin
HCRU
Health Care Resource Utilisation
HDL
High Density Lipoprotein
HF
Chronic Heart Failure
HHF
Hospitalisation for Heart Failure
HFpEF
Heart Failure with Preserved Ejection Fraction
HFrEF
Heart Failure with Reduced Ejection Fraction
HR
Heart Rate
HRQOL
Health-related quality of life
IB
Investigator’s Brochure
ICD
Implantable Cardioverter Defibrillator
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
i.v.
Intravenous
KA
Ketoacidosis
KCCQ
Kansas City Cardiomyopathy Questionnaire
LA
Left Atrial
LDL
Low Density Lipoprotein
LPDD
Last Patient Drug Discontinuation
LVEF
Left Ventricular Ejection Fraction
MACE
Major Adverse Cardiovascular Event
MedDRA
Medical Dictionary for Drug Regulatory Activities
MI
Myocardial Infarction
MMRM
Mixed Model Repeated Measures
MRA
Mineralocorticoid Receptor Antagonist
MRI
Magnetic Resonance Imaging
MRS
Modified Rankin Scale
NCC
National Coordinator Committee
NT-proBNP
N-terminal of the prohormone brain natriuretic peptide
NYHA
New York Heart Association 
PK
Pharmacokinetics
p.o.
per os (oral)
PSA
Prostate-Specific Antigen
q.d.
quaque die (once a day)
RBC
Red Blood Cells
REP
Residual Effect Period, after the last dose of medication with measureable 
drug levels or pharmacodynamic effects still likely to be present
RI
Renal Impairment
RS
Randomisation Set
SAE
Serious Adverse Event
SBP
Systolic blood Pressure
SEC
Scientific Excellence Committee
SGLT-1
Sodium-glucose co-transporter 1


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SGLT-2
Sodium-glucose co-transporter 2
SMQ
Standardised MedDRA Query
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
T1DM
Type 1 diabetes mellitus
T2DM
Type 2 diabetes mellitus
TIA
Transient Ischaemic Attack
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
UACR
Urine Albumin Creatinine Ratio
ULN
Upper limit of normal
UTI
Urinary Tract Infection
VAS
Visual Analogue Scale
WBC
White Blood Cells
WOCBP
Women of childbearing potential


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1
INTRODUCTION
1.1
MEDICAL BACKGROUND
Chronic heart failure (HF) is a progressive syndrome characterised by the inability of the 
heart to provide adequate blood supply to meet the metabolic demand of different tissues or 
to be able to do so only at the expense of elevated left ventricle filling pressure. HF is a 
prevalent disease affecting an estimated 26 million people worldwide. In the United States 
alone the prevalence is 5.7 million, and there are 670,000 new cases per year [R16-1527]. HF 
is associated with premature mortality and frequent hospitalisation. Approximately 50% of 
patients who develop HF die within 5 years after diagnosis [P16-03952]. Annually, more than 
1 million patients are hospitalised with a primary diagnosis of HF. HF is the most common 
cause of hospitalisation among individuals above 65 years of age in the western countries
[P16-03760]. Two types of HF have been defined mainly based on the LV ejection fraction 
(EF) and also other structural changes in heart muscle. They consist of heart failure with 
reduced EF (HFrEF) <40% and heart failure with preserved EF (HFpEF) ≥40%. Relative 
prevalence of HFpEF among HF patients is approximately 50% [R16-1528]. 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 rate of rehospitalisation 
among patients with HFrEF is close to 29% within 60-90 days of hospitalisation discharge 
which is equal to HFpEF [R16-1527].
Despite advances in therapy and management, HF remains a deadly clinical syndrome. After 
HHF, the one year mortality rate is high and not different between patients with preserved or 
reduced left ventricular ejection fraction (LVEF) [R16-2217], underscoring a high unmet 
medical need in this population. 
About 25 to 45% of patients with HF have concomitant type 2 diabetes mellitus (T2DM), and 
nearly 15-25% have borderline DM (pre-diabetes), indicating a potential link between the HF 
syndromes and glucometabolic disturbances [R16-2382, R16-2384]. 
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 mortality and morbidity remains 
high. For HFpEF, however, control of congestive symptoms during acute episodes is the 
mainstay of management of these patients and no class of drugs have shown to increase 
survival or reduce HHF [P16-03760, P16-05920]. 
Empagliflozin is an orally available inhibitor of the renal dependent glucose co-transporter 2 
(SGLT-2) indicated for, reduction of blood glucose in patients with T2DM by promoting 
urinary glucose excretion. It also reduces blood pressure, arterial stiffness and measures of 
the myocardial workload, likely through various mechanisms, as well as improving other CV 
risk factors (uric acid, visceral fat mass, albuminuria) [P15-00589, P15-09541].  


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In 2010 Boehringer Ingelheim (BI) initiated the EMPA-REG OUTCOME trial to explore CV 
benefit of the drug as well as to establish the safety profile of empagliflozin [P15-09840]. 
This trial completed in 2015 and showed 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” and HHF by 34%.
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 significant reduction in CV death, HHF, and composite of “HHF or CV death” [P16-
01253]. 
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 the urinary sodium excretion returns 
to normal within few days of empagliflozin administration, the effect on urinary glucose 
continues.
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) [c01678844-06] and local prescribing information for empagliflozin.
1.2.1
Non-clinical assessment of safety
For further information regarding pre-clinical evaluation, please refer to the current version 
of the IB for empagliflozin.
1.2.2
Clinical pharmacokinetics
In humans, empagliflozin predominantly showed linear pharmacokinetic (PK). Empagliflozin 
reaches peak levels at approximately 1.5 hours and showed a biphasic decline with the 
terminal elimination half-life of 12.4 hours ranging from 10 to 19 hours.
Empagliflozin exposure increases with renal or hepatic impairment; however, no dose 
adjustment is recommended as the observed changes in exposure were not clinically 
meaningful. No clinically relevant PK interactions were observed with other oral
antidiabetics, warfarin, verapamil, ramipril, simvastatin, digoxin, hydrochlorothiazide, 
torasemide, emfibrozil, rifampicin, probenecid and oral contraceptives (Microgynon®). 
For further details refer to the current version of the IB for empagliflozin.
1.2.3
Clinical efficacy and safety
Approximately 550 healthy volunteers were exposed to empagliflozin (up to 800 mg single 
dose and up to 50 mg multiple dosing). Approximately 8500 patients with T2DM have been 
treated with empagliflozin in research studies, of which approximately 4400 have been 


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treated for more than 52 weeks. Also, empagliflozin was tested in over 4600 patients with 
T2DM and high CV risk for median treatment duration of 2.6 years.
The EMPA-REG OUTCOME trial was a randomised, placebo-controlled trial of 
empagliflozin 10 and 25 mg in 7020 patients with T2DM and high CV risk. It ended in 2015 
after accruing the minimum prespecified 691 major adverse CV events. Empagliflozin was 
associated with significant risk reduction of all-cause mortality by 32% (HR 0.68; 95% CI 
0.57, 0.82 p<0.0001) and CV death by 38% (HR 0.62; 95% CI 0.49, 0.77, p value <0.0001). 
In addition, the EMPA-REG OUTCOME trial showed reduction in the prespecified and 
adjudicated composite outcome of “CV death or HHF” by 34% (HR 0.66; 95% CI 0.55, 0.79, 
p value <0.0001). This result was consistent across various predefined sensitivity analysis and 
internal consistency was confirmed by showing overall homogeneity over a wide range of 
subgroups, including patients with and without history of HF at baseline. There was no 
significant difference in improving CV outcomes between the 10 and 25 mg dose.
The Phase III studies in T2DM showed that treatment with empagliflozin 10 mg or 25 mg 
once daily for up to 24 weeks results in a reduction of Glycated Haemoglobin (HbA1c) up to 
1%, body weight reduction between 2-3 kg, and a decrease in systolic blood pressure (SBP) 
between 3-5 mmHg compared with placebo. This was consistently observed with 
empagliflozin as monotherapy, add on to metformin, metformin and sulphonylurea, 
pioglitazone with or without metformin, and to basal insulin with metformin and/or 
sulphonylurea. Phase III studies up to 104 weeks in T2DM support the sustained effect of 
empagliflozin.
In clinical studies, empagliflozin was well tolerated in both healthy volunteers and patients 
with T2DM including patients with high CV risk up to a median duration of 2.6 years. The 
frequency of overall Adverse Events (AEs), AEs leading to discontinuation and Serious AE 
(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. In general there was a small increase in frequency of 
urinary tract infection (UTI) compared to placebo. There was an increase in frequency of 
genital infections with the use of empagliflozin. There was a small increase in total 
cholesterol, low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) 
cholesterol and no significant changes in triglycerides. No changes in electrolytes were 
observed with empagliflozin. 
In the EMPA-REG OUTCOME trial renal function over time, as measured by the eGFR, is 
shown in Figure 1.2.3:1 [P16-06807].  After the initial decrease, eGFR remained steady in the 
empagliflozin group and was reversed after the cessation of the trial medication (Figure 
1.2.3:2). At the follow-up visit, the adjusted mean difference from placebo in the change from 
baseline in the eGFR with each of the two doses of empagliflozin was 4.7 ml per minute per 
1.73 m2 (95% confidence interval, 4.0 to 5.5; P<0.001 for both comparisons) (Figure 
1.2.3:2). The data indicated that the initial drop in eGFR after administration of empagliflozin 
is reversible and most likely due to hemodynamic carnages. This is very similar to what have 
been observed with ACEi and ARBs. The EMPA-REG OUTCOME trial also generated the 
hypothesis that the expected deterioration in renal function in patients with T2DM slowed 


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down after using empagliflozin, and this will be further tested in the HF trials using the eGFR 
slope analysis and composite renal endpoints (see Section 5.1.2 and 5.1.3).


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Figure 1.2.3:1
Change in eGFR over192 weeks in the EMPA-REG OUTCOME 
trial.
Figure 1.2.3:2
Change in eGFR from baseline to last measurement during treatment 
and follow-up in the EMPA-REG OUTCOME trial.


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In a dedicated trial in patients with moderate and severe RI (eGFR between 15-60 
mL/min/1.73 m2 [Chronic Kidney Disease (CKD3 and CKD4)]) treatment with empagliflozin 
was well tolerated and in patients with CKD3 led to statistically significant reduction of 
HbA1c and clinically meaningful improvement in body weight and BP compared to placebo 
at Week 24, these results were sustained for up to 52 weeks [P14-01211]. In patients with 
CKD4 renal impairment (RI), while there was not change in the glycaemic response, the 
reduction in BP and renal hemodynamic changes (similar to what was observed in the 
EMPA-REG OUTCOME trial) were preserved. In the EMPA-REG OUTCOME trial a
similar reduction in CV risk was observed in the subgroup of patients with different degree of 
RI, including patients with eGFR between >45-60 and >30-45 mL/min/1.73 m2.
2
RATIONALE, OBJECTIVES, AND BENEFIT-RISK ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
Heart failure is an important public health problem, and one of the leading causes of 
hospitalisation in the Western countries. With the increasingly aging population and 
increasing incidence of obesity, the scope and cost to society associated with this condition 
will progressively rise. There is an unmet medical need in treatment of patients with HFpEF.  
Despite advances in the management of HF, no new therapies have been found to improve 
outcomes by reducing mortality or morbidity (i.e. CV death or HHF) in these patients [P16-
03760]. HF also significantly decreases health-related quality of life (HRQOL) and 
pharmacological therapies have not shown consistent improvement in HRQOL.
Empagliflozin improves survival in patients with high cardiovascular risk by mechanisms 
which go beyond the blood glucose lowering effect. There was no heterogeneity by baseline 
HbA1c categories in HHF or “CV death and HHF” risk reduction in the EMPA-REG 
OUTCOME trial. Empagliflozin exerts its glucose lowering effect by preventing sodium and 
glucose reabsorption. The initial natriuresis will be compensated within days of drug 
administration through changes in tubulo-glomerular feedback. However, the glucosuria lasts 
as long as the medication is used.  This leads to consequent hemodynamic changes associated 
with a modest osmotic diuresis, blood pressure lowering effect, improvement in arterial 
stiffness, reduction in oxidative stress, and decrease in heart rate (HR) x Pressure product, a 
measure of myocardial oxygen consumption, with no increase in HR and no effect on 
sympathetic nerve activity [P15-00589, P15-09541]. Of note, the effect of empagliflozin on 
improving CV outcomes is evident even at low urinary glucose excretion demonstrated in 
those with low HbA1c as well as in those with reduced renal function (i.e. eGFR < 60
mL/min/1.73 m2). Subgroup analysis of the EMPA-REG OUTCOME trial showed no 
difference in patients with baseline HbA1c <7%, 7% to 8%, 8% to 9%, or >9% for CV death 
or HHF risk reduction. In addition, patients who had no HbA1c change or only modest 
change up to 0.2% throughout the trial have shown to have a similar risk reduction of HHF as 
the patients with at least 0.3% or higher reduction in HbA1c. Also as noted changes in BP 
reduction and hemodynamic changes were preserved in patients with CKD4, despite loss of 
glycaemic efficacy. Lack of correlation between CV outcome improvement and blood 
glucose levels provides supporting evidence that the benefit of empagliflozin in HHF or CV 
death risk reduction should also be expected in patients without DM [P16-01253, c09670340, 
c11764168]. The beneficial CV effects of empagliflozin cannot be explained by the modest 


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glucose control achieved in the EMPA-REG OUTCOME trial. Other outcome trials with the 
goal of tight glycaemic control (ADVANCE, ACCORD, and VADT) have failed to show 
significant CV benefit [R16-1560] and decrease in incident HF or mortality [R16-0736]. 
It should be noted that in a mechanistic study, non-DM subjects showed metabolic changes 
such as, increase in endogenous glucose production, and substrate shift from glucose to lipid 
oxidation similar to those observed in patients with T2DM after one dose and up to 4 weeks 
of daily administration of empagliflozin [P16-01830]. Furthermore, in a trial of healthy 
volunteers, empagliflozin 10 mg resulted in approximately 50 g glucosuria per day [P13-
04190]. This amount of glucose excretion is similar to what had been observed in patients 
with eGFR between 30-60 mL/min 1.73 m2 (CKD3) which was close to 55 g glucosuria per 
day. In the EMPA-REG OUTCOME trial patients with CKD3 showed a trend for the CV 
death or HHF risk reduction very similar to the risk reduction in the main cohort and in 
patients with CKD2 and 1. While the higher level of glucosuria is associated with a higher 
HbA1c reduction and better glycaemic control, this correlation is lacking for the CV benefits 
associated with empagliflozin, and in fact a lower glucose excretion similar to what has been 
observed in patients with CKD3 or in healthy volunteers seems to be sufficient to improve 
the CV outcomes. Therefore, the expected benefit of empagliflozin such as BP reduction, 
weight loss, improvement in arterial stiffness, and hemodynamic changes, as well as CV 
benefits seen in patients with T2DM is also speculated to be seen in HF patients without DM
and in patients with CKD3 and 4. These findings further support the rationale of exploring 
the effect of empagliflozin beyond DM. Although the type of HF was not assessed entering 
the EMPA-REG OUTCOME trial, it is highly likely in this trial both patients with preserved 
and reduced ejection fraction were included, considering the high prevalence of both HFrEF 
and HFpEF in patients with DM [R16-1529].
The modes of action described above, and beneficial effect in patients with history of HF in 
the EMPA-REG OUTCOME trial, further supports the scientific rationale of performing this 
trial to explore the effect of empagliflozin in patients with HFpEF.
2.2
TRIAL OBJECTIVES
The objective of this event-driven trial is to demonstrate superiority of empagliflozin 10 mg 
versus placebo in patients with symptomatic, chronic HF and preserved ejection fraction 
(LVEF > 40%) under stable treatment of HF symptoms.
For further description of trial endpoints and statistical analysis, please refer to Section 5 and 
7.
This trial is part of an investigational clinical trial program of empagliflozin in patients with
chronic HF. A trial to investigate the efficacy and safety in patients with reduced EF (LVEF 
≤40%) is ongoing in parallel.
2.3
BENEFIT-RISK ASSESSMENT
The overall benefits and safe 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. 
The overall tolerability and safety profile outlined in Section 1.2, and the current IB, supports 
chronic administration of empagliflozin 10 mg in human studies. 


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In this trial, the effect of empagliflozin will be evaluated in HF patients.  DM is known to be 
a frequent and clinically important co-morbidity in HF patients.  To evaluate this important 
co-morbidity, HF patients across the DM spectrum (i.e., T1DM, T2DM, pre-diabetes) as well 
as HF patients who do not have DM, will be included in this trial.    
Special safety considerations are required for patients with T1DM, and several safety 
monitoring strategies will be employed, including training of investigators and education of 
patients on the risk and prevention strategies for ketoacidosis (KA) and diabetic ketoacidosis 
(DKA).  Since an SGLT-2 inhibitor may alter the typical presentation of this condition, 
patients will receive a home monitoring device to measure blood ketones and a diary for
patients to record their blood glucose, ketone values, and insulin intake.  Patients with T1DM 
will also be required to carry  a trial information card which includes information about the 
possible altered presentation of KA to be presented to health care professionals should the 
patient be seen in an urgent care setting.  For further details refer to Section 4.2.1.
As outlined above, inclusion of patients who do not have diabetes is also allowed in this trial.
It has been shown that 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 RI. Because in the EMPA REG 
Outcome study no difference in CV benefit was detected for patients with RI vs the overall 
population, it is it is hypothesized that this amount of glucosuria is not the main factor to 
obtain 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 occurrences of 
symptomatic hypoglycemia were detected [U12-2707-01]. It is noted that in patients with 
T2DM the risk of hypoglycemia was only increased with empagliflozin compared to the 
placebo group in patients who were concomitantly treated with insulin or a sulfonylurea.  
Further, in a mechanistic study [c11963611-01], subjects without DM were shown to increase 
endogenous glucose production in response to glucosuria after administration of 
empagliflozin.  As a result, blood glucose levels remained in the normal range for these 
individuals [P16-01830]. Therefore, it is scientifically reasonable to hypothesize that in non-
diabetic patients, with no medical indication for insulin or sulfonylurea treatment that the risk 
of hypoglycemia associated with empagliflozin treatment would be lower than in patients 
with T2DM.  
Because the mode of action, blockade of the SGLT2 with consequent glucosuria, is the same 
in patients with and without diabetes, although to different degrees, it is considered likely that 
the tolerability of empagliflozin may be no less favourable in patients without DM compared 
to patients with T2DM. 
There is also currently limited therapeutic experience with empagliflozin in patients aged 85 
years and older.  The prevalence of HF increases with age and the therapeutic options in the 


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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.  Special 
caution should be used in these patients, who may be at increased risk of adverse 
consequences attributable to empagliflozin-related volume depletion.
Many patients with chronic HF have RI, and to ensure that the trial results reflect this 
population, patients with eGFR ≥20 ml/min/1.73m2 can be included.  In the EMPA-REG 
OUTCOME trial, the cardiovascular benefits of empagliflozin were not driven by its 
pharmacological effect of lowering blood glucose and were consistently noted in patients 
with different degrees of RI, including patients with eGFR between > 30 and < 45
ml/min/1.37m2.  In previous trials in patients with T2DM the safety profile in moderate and 
severe RI were comparable to the overall trial population [P17-10453].  Renal safety will be 
closely monitored throughout the trial.  Refer to section 5.3.4.1. and 5.3.7.1.
Investigators will be encouraged to treat participants to best standard of care in compliance 
with the local guidelines and recommendations for HF, and DM if present.
Based on the putative mechanism of actions (reviewed in Section 2.1) and the result of the 
EMPA-REG OUTCOME trial, it is assumed that patients with HFpEF should benefit from 
empagliflozin treatment on top of guideline-directed therapies. The safety profile of 
empagliflozin in these patients should follow a similar trend which was previously observed 
in over 10000 patients with T2DM treated with empagliflozin, including patients with high 
CV risk.  Safety will be ensured by close monitoring of the subjects for AEs both clinically 
and by laboratory testing. 
To continue the assessment of the long-term safety of empagliflozin, adjudication of 
cardiovascular events, certain hepatic events, and KA 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). For further details please refer to Section 3.1.1.
One interim analysis is planned after approximately 500 primary events have been accrued. If 
the prespecified criteria for stopping for success at the interim analysis has been reached, the 
Executive Steering Committee (ExSC) and the Sponsor will be informed. The final decision 
whether to stop the trial will be made by Sponsor. For further details refer to Section 7.4.
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.
Empagliflozin causes intravascular volume contraction. In patients with volume depletion, 
correcting this condition prior to initiation of empagliflozin is recommended. 
Although rare, a potential for drug induced liver injury (DILI) is under constant surveillance 
by the Sponsor 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 5.3.6.1.


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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, WOCBP must agree to the requirements for
pregnancy testing and contraceptive methods described in this protocol.


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3
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This randomised, double-blind, multi-national, parallel group trial compares empagliflozin 10 
mg once daily to placebo as add-on to standard of care treatment in patients with HFpEF.
Figure 3.1: 1 
Trial design
Patients are included in the trial once they have signed the informed consent form (ICF). All 
patients suitable after screening and who still meet the inclusion/exclusion criteria when 
returning for Visit 2 approximately 1-3 weeks later will be randomised into one of the 
treatment groups in a 1:1 manner.
Randomisation will be stratified with respect to geographical region (North America, Latin 
America, Europe, Asia and “Other”, history of DM (DM, pre-DM, no DM), LVEF (<50%, 
≥50%) and eGFR (CKD-EPI)cr (<60 mL/min/1.73 m², ≥60mL/min/1.73 m²) at screening.
The trial is event-driven and all randomised patients will remain in the trial until the defined 
number of adjudicated primary endpoint events has been reached. Estimated trial duration is 
38 months with a recruitment period of approximately 18 months. The actual length of the 
recruitment period may be extended beyond 18 months and the follow-up period may be 
adjusted to achieve to achieve the 841 confirmed primary outcome events.  The estimated 
total trial duration and length of the double-blind treatment for each patient will vary 
accordingly. The total number of randomised patients may be adapted based on assessment of 
the blinded event rate. If the accumulated blinded data suggests a slower accrual of primary 
outcome events over calendar time than originally projected, then the number of patients 
randomised may be increased up to 6000. Operationally, the recruitment period would be 
extended and could continue up to 6 months before the target number of events is expected to 
be achieved. The number of primary outcome events required is not affected by this 
consideration.  For further details refer to Section 7.7.
The number of confirmed adjudicated primary endpoint events will be continuously 
monitored during the trial. As soon as the available data reliably suggests that the total 
number of patients with an adjudication confirmed primary endpoint event will be reached 
Screening
N= 4854
Placebo
N=2063
Empagliflozin 10 mg
N= 2063
F-U
R
N=4126
1-3 weeks                                              ~20-38 months*                      30 days 


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within a given timeframe, the trial team will initiate required actions to stop the trial. From 
this time point on, all patients are expected to perform their last visit (EOT visit) with the 
proposed time schedule communicated via an investigator letter. See also Section 6.2.3.
* based on an 18 months recruitment and event rate as outlined as Section 7.7.
3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim (BI). The operational aspects (trial 
management and monitoring) of the trial and Data Management will be outsourced globally 
to a Contract Research Organisation (CRO).
A Coordinating Investigator is responsible to coordinate Investigators at different centres 
participating in this multicentre and multinational trial. Tasks and responsibilities are defined 
in a contract stored in the electronic Trial Master File (eTMF) at the CRO.
An ExSC and a Scientific Excellence Committee (SEC) consisting of independent experts 
and Sponsor representatives will be established to support Sponsor in designing the trials and 
successful execution. The ExSC and SEC will have a scientific and advisory function in the 
trial. The ExSC will be involved with the detailed trial design discussions and decision 
making while the SEC has wide representation of different scientific disciplines and will be 
consulted on the topics requiring broader consensus. The composition of the ExSC and the 
SEC will be documented in the eTMF. The tasks and responsibilities will be agreed in 
contracts between the ExSC and the SEC and the Sponsor, and also summarised in an ExSC-
and SEC-charter filed in the eTMF.
A National Coordinators Committee (NCC) will be established and will consist of leading 
expert(s) in each participating country.  The national coordinators will support the Sponsor in 
the successful execution of the trial.  The NCC will have an advisory function in the trial.  
The tasks and responsibilities will be agreed in contracts between the NCC member and the 
Sponsor.  
A data-monitoring committee (DMC), independent of the Sponsor and CRO will assess the 
progress of the trial, including an unblinded safety and efficacy assessment at specified 
intervals, and to recommend to the Sponsor whether to continue, modify, or stop the trial. 
Measures are in place to ensure blinding of the Sponsor, ExSC, SEC, NCC, CRO and all 
other trial participants. The tasks and responsibilities of the DMC will be specified in a 
charter. The DMC will maintain written records of all its meetings.
Relevant documentation on the participating (Principal) Investigators and other important 
participants, including their curricula vitae, will be filed in the Investigator Site File (ISF).
BI has appointed a Trial Clinical Monitor, responsible for coordinating all required activities, 
in order to

manage the trial in accordance with applicable regulations and applicable BI and CRO 
Standard Operating Procedures (SOPs),

direct the clinical trial team in the preparation, conduct, and reporting of the trial,

ensure appropriate oversight of vendors.


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Statistical Evaluation will be done by BI according to BI SOPs, and Data Management will 
be done by the CRO in accordance with CRO SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial will be 
defined according to BI and CRO SOPs, and the applicable SOPs will be listed in the contract 
with the CRO. A list of responsible persons and relevant local information can be found in 
the ISF.
A central laboratory service and an Interactive Voice/Web-based Response System (IRT) -
vendor will be used in this trial. Details will be provided in the IRT Manual and Central 
Laboratory Manual, available in ISF.
Clinical Event Committee
3.1.1.1
An independent external committee (Clinical Event Committee, [CEC]) will be established to 
adjudicate centrally and in a blinded fashion whether pre-specified criteria for adjudication 
endpoints are met.
For any events that qualify for adjudication, trial sites will be required to provide in a timely 
manner clinical documentation such as (but not limited to) electrocardiograms (ECGs), 
laboratory values, angiography reports, echocardiography reports, CT and/or Magnetic 
Resonance Imaging (MRI) reports, discharge summaries, and autopsy reports to support the 
external event adjudication. If the CEC requests more data, all efforts must be made by the 
site to collect all available data to support adjudication. 
For reporting of events and exemption from expedited reporting refer to Section 5.3.7.2.
The tasks and responsibilities of the CEC, and the pre-specified criteria for adjudication will 
be specified in a charter. The CEC will maintain the adjudication results in writing.
Hepatic external adjudication
3.1.1.2
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 laboratory values, histological analysis, reports from
ultrasound, CT, MRI, scintigraphy, hospital discharge letters, and medical reports from other 
physicians. All evaluations will be performed in a blinded fashion. The assessments will be 
analysed based on empagliflozin data combined from multiple trials (i.e. on project level).
Adjudication of ketoacidosis
3.1.1.3
Events suspected to be metabolic acidosis, KA and DKA will be adjudicated by independent 
external experts in a blinded fashion.


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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 and mortality. The aim of this trial is to recruit patients with HFpEF on various HF 
background therapies to evaluate the long term effect of empagliflozin on CV death and HHF 
in a real life clinical setting.
Due to its mode of action empagliflozin should be efficacious in treating patients with HF 
and could provide additional efficacy in combination with any given background therapy. 
The placebo-controlled design is considered ethically acceptable on the basis of appropriate 
criteria for patient discontinuation, ability to change background therapy to maintain, or 
obtain, sufficient level of hemodynamic control as defined in relevant local and regional 
guidelines for optimised standard of care.
The double-blind treatment period is planned until the necessary number of events is 
observed to evaluate efficacy of empagliflozin compared to standard of care. The 30 days
follow-up period is considered to be sufficient for assessment of adverse events and efficacy 
outcomes after stopping trial medication.
Patients should be receiving appropriate care as defined by their physician or practitioner for 
all cardiovascular conditions according to the prevailing guidelines. This should be conducted 
in the context of local or regional guidance for primary or secondary CV prevention.
The rationale for dose and dose-interval selection is described in Section 4.1.2.
3.3
SELECTION OF TRIAL POPULATION
An appropriate number of patients will be screened for the trial in approximately 22
countries. Approximately 560 trial centres will participate to ensure that the estimated 4126
patients are randomised to trial medication and complete the trial. Investigators who fail to 
randomise at least one patient in the first 12 weeks from centre initiation may be excluded 
from further participation. If enrolment is delayed, additional centres may be initiated. The 
total number of randomised patients may be adapted based on assessment of the blinded 
event rate. If the accumulated blinded data suggests a slower accrual of primary outcome 
events over calendar time than originally projected, then the number of patients randomised 
may be increased up to 6000. Operationally, the recruitment period would be extended and 
could continue up to 6 months before the target number of events is expected to be achieved. 
The number of primary outcome events required is not affected by this consideration.  For 
further details refer to Section 7.7.
Clinical trials contribute toward reducing health disparities through improved knowledge 
about treatment among diverse populations. Greater diversity in clinical trial samples allows 
for broader generalisation of trial results, increased minority access to trials, improved
standards of care, decreased disparities in disease treatment and outcomes, and improved 
external validity supported by a more representative sample. Greater number of African-
Americans as an example, suffer from HF and all efforts must be made to have adequate 
representation of this minority population from the USA [P15-10667]. Each Investigator


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should develop a recruitment strategy that ensures the recruitment of a representative patient 
population and takes into consideration gender, race and ethnicity.
According to previous heart failure trials and registries the prevalence of DM amongst 
patients with HF varies from 25% to 40%. Prevalence of pre-DM is not clearly understood 
but it is estimated to vary from 15% to 50% [R16-2382, R16-2384]. In a recent large HF 
outcome trial, 35% of the patients reported to have DM, another 15% found to have 
undiagnosed DM and around 27% had pre-DM [R16-2383]. 
Since there is a chance that empagliflozin, as a diabetes drug, when used in CV outcome 
trials recruits more patients with T2DM, capping on trial level will be used to aim for a 
similar distribution of patients with DM, pre-DM or no DM as it is expected in the population 
of patients with the HF in real life. 
Via IRT it will be ensured that approximately a minimum of 35 % of the trial population will 
be patients with DM, a minimum of 15 % will be patients with pre -DM and a minimum of 
20 % will be non-diabetic patients. 
Additionally recruitment to the three categories of DM, pre-DM or no DM will be monitored 
on regional level. Capping on regional level may be applied to achieve a contribution of each 
region to each category of diabetes status. DM in this context is defined as active treatment 
with antidiabetic medication (for indication of DM) or screening HbA1c ≥6.5% or history of 
DM. Pre-DM is defined as screening HbA1c ≥5.7% and <6.5% without the intake of 
antidiabetic medication (unless taken for a non-DM indication) and no history of DM, and 
patients with no DM is defined as screening HbA1c < 5.7 % without any intake of 
antidiabetic medication (unless taken for a non-DM indication) and no history of DM [R16-
2261].
IRT will be used to aim for a trial population consisting of approximately 35% to 50% with 
an LVEF >50%. To ensure adequate enrolment of patients the final decision on capping will 
be based on the recommendation from the ExSC during the recruitment period.
Screening of patients for this trial is competitive, i.e. screening for the trial will stop at all 
centres when a sufficient number of patients have been randomised to trial treatment. 
Investigators will be notified when screening is complete and will not be allowed to recruit 
additional patients thereafter. Patients who have completed visit 1 procedures prior to 
notification of the termination of recruitment will be allowed to be randomised in the trial, if 
they meet all eligibility criteria. Patient eligibility will be based upon a complete medical 
history including a physical examination and clinical laboratory tests. Judgment of the 
clinical relevance of a concomitant disease is at the discretion of the Investigator.
Re-screening and/or re-testing (of assessments) is permitted if approved by Local Clinical 
Monitor (CML)/Clinical Lead (CL) or delegate. 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:


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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 result 
based on previously available laboratory results. The re test should be carried out as soon as 
possible so the laboratory test results will be received within the next planned visit windows 
in order to avoid protocol window violations. 
Re-screening:
-
Re-screening of the same patient is only allowed once.
-
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.
A log of all patients enrolled into the trial (i.e. who have signed ICF) will be maintained in 
the ISF at the investigational site irrespective of whether they have been treated with 
investigational drug or not.
3.3.1
Main diagnosis for trial entry
The trial will be performed in patients with HF with an ejection fraction >40 %. 
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
1. Age ≥18 years at screening. For Japan only: Age ≥20 years at screening
2. Male or female patients. WOCBP a must be ready and able to use highly effective 
methods of birth control per ICH M3 (R2) [R09-1400] 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
3. Patients with chronic HF diagnosed for at least 3 months before Visit 1, and currently 
in HF NYHA class II-IV
4. Chronic HF with preserved EF defined as LVEF > 40 % per local reading (obtained 
by echocardiography, radionuclide ventriculography, invasive angiography, MRI or
CT), and no prior measurement of LVEF ≤ 40% under stable conditionsb. A historical 
LVEF may be used if it was measured within 6 months prior to visit 1, and more than 
90 days after any myocardial infarction (as defined in exclusion criterion No.1) or the 
LVEF may be measured after study consent has been obtained. The LVEF must be 
documented in an official report prior to randomization.
________________________________
aWomen of childbearing potential are defined as:
-
having experienced menarche and
-
not postmenopausal (12 months with no menses without an alternative medical cause) and 
-
not permanently sterilised (e.g., hysterectomy, bilateral oophorectomy or bilateral salpingectomy).
b In the Investigator’s opinion


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5. Elevated N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) > 300 
pg/ml for patients without AF, OR > 900 pg/ml for patients with AF, analysed at the 
Central laboratory at Visit 1
6. Patients must have at least one of the following evidence of HF: 
a.
Structural heart diseasec (left atrial enlargement and/or left ventricular 
hypertrophy) documented by echocardiogram at Visit 1 or within 6 months 
prior to Visit 1, OR
b. Documented HHFd within 12 months prior to Visit 1
7. Oral diuretics, if prescribed to patient according to local guidelines and discretion of 
the Investigator, should be stable for at least 1 week prior to Visit 2 (Randomisation)
8. Body Mass Index (BMI) < 45 kg/m2 at Visit 1
9. Signed and dated written ICF in accordance with GCP and local legislation prior to 
admission to the trial
3.3.3
Exclusion criteria
1. MI (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 ischaemic attack (TIA) in past 90 
days prior to Visit 1
2. Heart transplant recipient or listed for heart transplant
3. Implantation of cardioverter defibrillator (ICD) within 3 months prior to Visit 1
4. Implanted cardiac resynchronisation therapy (CRT)
5. 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
6. Any severe (obstructive or regurgitant) valvular heart disease expected to lead to 
surgery during the trial in the Investigator’s opinion
7. Acute decompensated HF (exacerbation of chronic HF) requiring intravenous (i.v.)
diuretics, i.v. inotropes or i.v. vasodilators, or left ventricular assist device within 1 
week from discharge to Visit 1, and during screening period until Visit 2 
(Randomisation)
8. Atrial fibrillation (AF) or atrial flutter with a resting heart rate > 110 bpm documented 
by ECG at Visit 1 (screening)
9. Systolic blood pressure (SBP) ≥ 180 mmHg at Visit 2. If SBP >150 mmHg and <180 
mmHg at Visit 2, the patient should be receiving at least 3 antihypertensive drugs
10. Symptomatic hypotension and/or a SBP < 100 mmHg at Visit 1 or Visit 2
________________________________
c Structural heart disease is further defined in Appendix 10.5
d The main reason for HHF must be HF. Documentation for HHF must be provided in the source documents


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11. Chronic pulmonary disease requiring home oxygen, 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
12. 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
13. Impaired renal function, defined as eGFR < 20 mL/min/1.73 m2 (CKD-EPI)cr or 
requiring dialysis, as determined at Visit 1
14. Haemoglobin < 9 g/dl at Visit 1
15. History of ketoacidosis
16. 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 replacement ) within 
90 days after visit 1
17. Gastrointestinal (GI) surgery or GI disorder that could interfere with absorption of 
trial medication in the investigator’s opinion 
18. Any documented active or suspected malignancy or history of malignancy within 2
years prior to screening, except appropriately treated basal cell carcinoma of the skin, 
in situ carcinoma of uterine cervix or low risk prostate cancer (patients with pre-
treatment PSA < 10 ng/mL and biopsy Gleason score of ≤ 6  and clinical stage T1c or 
T2a)
19. Presence of any other disease than heart failure with a life expectancy of <1 year in the 
investigator’s opinion
20. 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
21. 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.
22. 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
23. Known allergy or hypersensitivity to empagliflozin or other SGLT-2 inhibitors
24. Chronic alcohol or drug abuse or any condition that, in the investigator’s opinion, 
makes them an unreliable trial subject or unlikely to complete the trial
25. Women who are pregnant, nursing, or who plan to become pregnant while in the trial
26. 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 


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3.3.4
Removal of patients from therapy or assessments
Removal of individual patients
3.3.4.1
This is a long-term outcome trial and every effort should be made by the site staff to 
encourage patients to remain in the trial and on trial medication unless medical condition 
substantially changes to alter the safety profile. If a patient is withdrawn from the trial the 
ExSC and the Sponsor should be informed immediately about each individual case.
Prematurely discontinuation of trial medication
For patients who prematurely discontinue trial medication all efforts should be made to 
observe these patients and ask them to continue to attend the scheduled visits until the end of 
trial. It is expected that all efforts are made to follow up on the collection of all adverse 
events, outcome events and concomitant therapy, and to have a complete dataset without 
missing data.
If a patient who prematurely discontinued trial medication is not willing to return to the 
predefined trial visits, at minimum a telephone call every 24 weeks (preferably every 12
weeks) and a telephone call at trial end will be required, to document the occurrence of 
outcome events and vital status. If possible, other AE’s and concomitant therapy changes 
since last visit must be recorded. 
Every attempt must be made by the Investigator to ensure patients continue participating in 
the trial during trial medication interruptions and after discontinuation of trial medication.
Patients who prematurely discontinue trial medication are allowed to restart treatment, at any 
time if appropriate in the opinion of the Investigator. At every visit following trial medication 
discontinuation Investigators must consider if trial medication can be re-started.
Patients that are not actively taking trial medication may be less motivated to adhere to the 
scheduled trial visits. Investigators and site staff should work to detect early signs of losing 
interest and readily present such patients (not actively taking trial medication) with the 
following options to encourage continued participation:
Option 1 
Continue to attend regularly scheduled trial visits at the centre until the trial 
ends
Option 2 
Conduct all remaining trial visits over the phone
Option 3
Discontinue participation in remaining trial activities but permit collection of 
vital status and CV outcome events at the end of the trial through the patient or 
alternative person designated by the patient (e.g., family, spouse, partner, legal 
representative, or physician) even if only by telephone. If possible, other AE’s 
and concomitant therapy changes to be recorded. Sites should encourage the 
patient to return to the clinic for the final study visit.
Option 4 
Discontinue participation in remaining trial activities but permit collection of 
vital status at the end of the trial through the patient, alternative person 
designated by the patient, or through review of patient’s medical information 
from alternative sources (e.g., doctor’s notes, hospital records, etc.)


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Patients will be asked to choose the most rigorous form of follow-up that they are willing to 
comply with.
A patient could be instructed to permanently stop the trial medication only after discussion 
with Investigator, if eligibility criteria are being violated, or if the patient fails to comply with 
the protocol (e.g. non-attendance at trial assessments).
Withdrawal of informed consent
A patient has the right to withdraw informed consent for participation at any time for any 
reason. However, withdrawal of consent from trial participation should be very rare and 
unusual. Because of this, the Investigator must be involved in the discussions with the patient 
regarding a withdrawal of consent. Additionally, the Investigator must discuss the withdrawal 
of consent with the Sponsor’s/CRO’s representative prior to stopping trial participation.
Early discontinuation of trial medication is not a criterion for withdrawal of consent for 
participation in the trial.
The right to withdraw informed consent at any time for any reason also applies to the optional 
informed consent to biobanking (including deoxyribonucleic acid (DNA) sampling), which is 
separate from the consent for trial participation.
If the patient withdraws informed consent for participation in the trial, the trial will end for 
that patient. The patient should stop taking trial medication and should be asked to complete 
the end of treatment (EOT) visit and follow-up procedures as described in the Flow Chart. 
Completing these procedures is strongly recommended for the patient’s safety. Patients that 
withdraw informed consent will not be replaced.
Vital status must be collected at the end of trial for patients that withdraw consent from trial 
participation, if allowed by local regulations.
Patients lost to follow-up
If a patient is lost, every effort will be made by the Investigator and site staff to contact and 
locate the patient before the patient is declared lost to follow-up. Investigators and site staff 
must use every possible allowable means, according to local regulations, to locate patients 
who have missed visits. Efforts to contact the patient may include but are not limited to:
•
Calling all numbers for patient and listed contacts (including in the evening and on
weekends).
•
Calling primary care physician, referring specialist and/or other listed physicians for
more recent information, date of last office visit or to determine vital status.
•
Sending an email and follow up with mailing certified letters (return receipt requested) 
to all known patient addresses and all listed contacts (e.g., relatives, friends, 
neighbours) that were provided by the patient.
•
Reviewing patient’s records and medical notes for any details of a hospitalisation,
doctor’s visit or other procedure that may indicate location or status of subject.
•
Use Internet to search for possible contact information for the patient.
•
Try reverse directory for phone numbers to get possible addresses and/or new contact


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details.
•
Utilise social networking sites.
•
Check local, regional, and national public records to locate the patient or search for 
vital status in accordance with local law.
•
Consider home visit.
•
Contact patient finder service.
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 5.3.4.2).
An excessive withdrawal rate can have a severe negative impact on the scientific value of the 
trial. The Intention To Treat analysis requires that all randomised patients be followed until 
trial end even if the trial medication was temporarily interrupted, discontinued or never 
started. Every effort should be made to keep the patients in the trial as scheduled. This 
includes careful patient selection and appropriate explanation of the trial requirements and 
procedures prior to enrolment as well as an explanation of the consequences of premature 
withdrawal.
Discontinuation of the trial by the Sponsor
3.3.4.2
BI reserves the right to discontinue the trial overall or at a particular trial centre at any time 
for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial centre
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial (see also 
Section 3.1.1).
3. Violation of GCP, the Clinical Trial Protocol (CTP), or the contract disturbing the 
appropriate conduct of the trial
The Investigator / the trial centre 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 BI.
4.1.1
Identity of the investigational Medicinal product and comparator
The characteristics of test products are below:
Substance:
empagliflozin
Pharmaceutical formulation:
film-coated tablet
Source:
Boehringer Ingelheim
Unit strength:
10 mg
Posology:
1 tablet once daily
Rout of administration:
oral
Substance:
placebo matching empagliflozin
Pharmaceutical formulation:
film-coated tablet
Source:
Boehringer Ingelheim
Unit strength:
-
Posology:
1 tablet once daily
Rout of administration:
oral
4.1.2
Selection of doses in the trial
Empagliflozin 10 mg and 25 mg are approved for the treatment of T2DM.
Empagliflozin exerts its effect by promoting glucosuria and consequent hemodynamic 
changes associated with diuresis, improvement in arterial stiffness, blood pressure lowering 
effect with no increase in HR and reduction in HR x Pressure product, an index of myocardial 
oxygen consumption. These modes of actions support the scientific rationale of using 
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 


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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 about 50g glucosuria. 
Given the lower exposure with 10 mg empagliflozin similar general safety, and CV effects 
similar for both doses, empagliflozin 10 mg once daily has been selected in this trial.
For further details see current version of the IB.
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 the randomisation plan. The assignment will 
occur in a blinded fashion via Interactive Response Technology (IRT).
To facilitate the use of the IRT, the Investigator will receive a manual including all necessary 
instructions for using the system. A copy of the manual will be available in the ISF.
Patient assignment to the treatment group will be determined by a computer generated 
random sequence. Access to the randomisation code will be controlled and documented - for 
further details please refer to Section 4.1.5.1. and 4.1.5.2.
Using this procedure, relevant parties will be blinded to the treatment group assignment.
For information on stratification and capping please refer to Section 3.3.
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 in a double-blind and single-dummy manner. 
Dispensing of kits for the double-blind treatment period will begin at Visit 2 and continue at 
every visit until end of trial.  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.  On days before the next 
visit, the dose should be taken 22-26 hours before the planned dose at the visit. No double 
doses should be taken.
Patients should be instructed not to take their medication on the morning of trial visits as they 
will be dosed whilst in the clinic. 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.


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4.1.5
Blinding and procedures for unblinding
Blinding
4.1.5.1
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 randomisation code will be kept secret by Clinical Trial Support up to database lock.
Unblinding and breaking the code
4.1.5.2
Emergency unblinding will be available to the Investigator via the IRT. It must only be used 
in an emergency situation when the identity of the trial medication must be known to the 
Investigator in order to provide appropriate medical treatment or otherwise assure safety of 
trial participants. Whenever possible and if time allows, the need for unblinding will be 
discussed with the medical representative from the Sponsor or delegate before the unblinding 
of trial medication takes place. The reason for unblinding must be documented in the source 
documents and/or appropriate eCRF page along with the date and the initials of the person 
who broke the code.
The patient could continue with trial medication after unblinding.
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 to be shared 
further.
For Japan only: In this blinded trial, an emergency code break will be available to the 
Investigator / the sub-Investigators via the IRT. This code break may only be accessed in 
emergency situations when the identity of the trial medication must be known to the 
Investigator /the sub-Investigators in order to provide appropriate medical treatment or if 
required to assure the safety of trial participants. Each site receives a manual from the IRT 
provider that contains instructions on how to unblind the treatment of a patient via the IRT 
(via 24-hour Emergency helpline). If the code break for a patient is accessed, the Sponsor or 
delegate must be informed immediately. The reason for accessing the code break, together 
with the date, must be documented on the appropriate eCRF page. In case third party needs to 
break the code, however, when the Investigator cannot be reached, the code can be opened by 
calling emergency code manager.
4.1.6
Packaging, labelling and re-supply
The investigational products will be provided by BI or a designated CRO. They will be 
packaged and labelled in accordance with the principles of Good Manufacturing Practice 


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(GMP). Re-supply to the sites will be managed via the IRT, which will also monitor expiry 
dates of supplies available at the sites.
For details of packaging and the description of the label, please refer to the ISF.
4.1.7
Storage conditions
Trial medication must be stored under the recommended storage conditions indicated on the 
label. A temperature log must be maintained by the investigator / pharmacist / investigational 
drug storage manager to make certain that the drug supplies are stored at the correct 
temperature. 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 or delegate when the following 
requirements are fulfilled:

Approval of the trial protocol by the Institutional Review Board (IRB) / ethics committee 

Availability of a signed and dated clinical trial contract between the Sponsor or delegate 
and the head of the investigational site,

Approval/notification of the regulatory authority, e.g. competent authority (CA),

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 

For USA; Availability of Form 1572
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, CRO or warehouse / drug distribution centre or 
alternative disposal of unused products. If applicable, the Sponsor, CRO 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 CTP and 
reconcile all investigational products received from the Sponsor or delegate. At the time of 
return to the Sponsor/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
The use of medication for the treatment of HF will be at the discretion of the Investigator and 
should be in accordance with local/international guidelines. 


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All concomitant (additional) medications and other therapies should be recorded on the 
appropriate pages of the eCRF. 
Concomitant antidiabetic medications should be adjusted individually as clinically indicated 
by the patient’s usual diabetes care provider. Restrictions of antidiabetic background therapy 
are described in Section 4.2.2. 
Patients without a diagnosis of DM experiencing repeated or severe symptoms such as 
nervousness, sweating, intense hunger, trembling, weakness and palpitations should contact 
the Investigator or other healthcare professional, as these symptoms might be suggestive of 
hypoglycaemia. In the case of hypoglycaemia, in patients with or without DM, that may put 
the patient at risk (e.g. repeated symptomatic hypoglycaemia or severe hypoglycaemia), 
appropriate care should be provided at the discretion of the Investigator.
Special attention must be paid to the prevention of KA. 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, KA and DKA. Cases of DKA have been reported 
in patients treated with empagliflozin, including fatal cases. In a number of reported cases, 
the presentation of the condition was atypical with only moderately increased blood glucose 
values; below 14 mmol/l (250 mg/dl).
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 KA immediately according to local guidelines if 
these symptoms occur, regardless of blood glucose level. If KA 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 KA while taking empagliflozin include patients on a 
very low carbohydrate diet (as the combination may further increase ketone body production), 
patients with an acute illness, pancreatic disorders suggesting insulin deficiency (e.g. Type 1 
diabetes mellitus (T1DM), history of pancreatitis or pancreatic surgery), insulin dose 
reduction (including insulin pump failure), alcohol abuse, severe dehydration, and patients 
with a history of KA. 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 KA (e.g. prolonged fasting due to acute illness 
or surgery), the Investigator should consider monitoring for KA and temporarily discontinue 
the trial medication. 
There are no trial specific emergency procedures to be followed.
4.2.2
Restrictions
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 does not include the 30 days 


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period between the EOT and the Follow Up Visit occurring at study close-out (see section 
6.2.3) .
If any restricted treatment is given during the conduct of the trial, the trial medication can be 
discontinued temporarily, or if needed permanently.
If the patient is in need of any additional treatment during this period, this may be given at 
the discretion of the Investigator. The patient can still remain on trial medication.
WOCBP must use the contraception methods as described in the patient information.
4.3
TREATMENT COMPLIANCE
Patients are requested to bring all remaining trial medication including empty package 
material with them when attending visits.
The Investigator or his/her designate will count the number of the returned tablets and 
calculate the compliance based on the number of tablets taken, divided by the number of 
tablets that should have been taken since last visit, multiplied by 100. See formula below.
Compliance (%) = 
Compliance should be between 80% and 120%. Compliance should be emphasised with a
goal of at least 80% compliance rate. 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.
Number of tablets actually taken since last tablet count x 100
Number of tablets which should have been taken in the same period


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5
VARIABLES AND THEIR ASSESSMENT
5.1
TRIAL EFFICACY ENDPOINTS
5.1.1
Primary endpoint(s)
The composite primary endpoint for this trial is the time to first event of adjudicated CV 
death or adjudicated HHF in patients with Heart Failure with preserved Ejection Fraction 
(HFpEF).
5.1.2
Secondary endpoint(s)
The key secondary endpoints which are part of the testing strategy, are the following: 
1. Occurrence of adjudicated HHF (first and recurrent),
2. eGFR (CKD-EPI)cr slope of change from baseline
Other secondary endpoints (not part of confirmatory testing hierarchy on trial level) are the 
following:

Time to first occurrence of chronic dialysis or renal transplant or sustained* reduction 
of ≥40% eGFR (CKD-EPI)cr or
o
sustained eGFR (CKD-EPI)cr <15 mL/min/1.73 m2 for patients with baseline 
eGFR ≥30 mL/min/1.73 m2
o
sustained eGFR (CKD-EPI)cr <10 mL/min/1.73 m2 for patients with baseline 
eGFR <30 mL/min/1.73 m2
*An eGFR (CDK-EPI)cr reduction is considered sustained, if it is determined by two or more 
consecutive post-baseline central laboratory measurements separated by at least 30 days (first 
to last of the consecutive eGFR values).
Chronic dialysis is defined as dialysis with a frequency of twice per week or more often for at 
least 90 days.

Time to first adjudicated HHF

Time to adjudicated CV death

Time to all-cause mortality

Time to onset of DM (defined as HbA1c ≥6.5% or as diagnosed by the Investigator)
in patients with pre-DM defined as no history of DM and no HbA1c ≥6.5 before 
treatment, and a pre-treatment HbA1c value of ≥5.7 and <6.5

Change from baseline in clinical summary score (HF symptoms and physical 
limitations domains) of the Kansas City Cardiomyopathy Questionnaire (KCCQ) at 
week 52

Occurrence of  all-cause hospitalisation (first and recurrent)
5.1.3
Further endpoints
-
Time from first to second adjudicated HHF


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-
Time to first all-cause hospitalisation
-
Occurrence of adjudicated HHF within 30 days after first adjudicated HHF
-
Occurrence of adjudicated HHF and CV death. This endpoint will account for clinical 
hierarchies in composite outcomes, i.e. CV death is ascribed greater importance than 
HHF (see win ratio in Section 7.3.3)
-
New onset of atrial fibrillation
-
Adjudicated MI (fatal or non-fatal)
-
Adjudicated stroke (fatal or non-fatal)
-
Adjudicated TIA
-
Composite of time to first event of all-cause mortality and all cause hospitalisation
-
Composite of adjudicated CV death or adjudicated non-fatal MI
-
Composite of adjudicated CV death or adjudicated non-fatal stroke
-
Adjudicated CV death, adjudicated non-fatal MI, adjudicated non-fatal stroke (3-point 
MACE)
-
Progression to macro albuminuria (defined as UACR >300 mg/g) from baseline for 
patients with baseline UACR ≤ 300 mg/g 
-
Time to first new onset of sustained normo− or micro albuminuria (UACR ≤300 
mg/g) in patients with macro albuminuria at baseline
-
Time to first new onset of sustained normo albuminuria (UACR < 30 mg/g) in 
patients with micro- or macro albuminuria at baseline
-
eGFR (CKD-EPI)cr change from baseline to 30 days after treatment stop
-
Composite of sustained reduction of ≥40% eGFR (CKD-EPI)cr or sustained eGFR
(CKD-EPI)cr <15 mL/min/1.73 m2 (< 10 mL/min/1.73 m2 for patients with eGFR 
(CKD-EPI)cr < 30mL/min/1.73 m2 at baseline), or adjudicated CV death
-
Composite of sustained reduction of ≥40% eGFR (CKD-EPI)cr or sustained eGFR
(CKD-EPI)cr <15 mL/min/1.73 m2 (< 10 mL/min/1.73 m2 for patients with eGFR 
(CKD-EPI)cr < 30mL/min/1.73 m2 at baseline), or all-cause mortality
-
Composite of sustained reduction of ≥40% eGFR (CKD-EPI)cr or sustained eGFR 
(CKD-EPI)cr <15 mL/min/1.73 m2 (< 10 mL/min/1.73 m2 for patients with eGFR 
(CKD-EPI)cr < 30mL/min/1.73 m2 at baseline), adjudicated CV death, or adjudicated 
HHF


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-
Change from baseline in KCCQ overall summary score at week 52
-
Change from baseline in KCCQ total symptom score at week 52
-
Change from baseline in KCCQ individual domains at week 52
-
Change from baseline in KCCQ based on patient-preferred outcome at week 52
-
Change in NYHA class from baseline at week 52
-
Change from baseline in Health-related quality of life measured by EQ-5D
-
Health economic analysis by Health Care Resource Utilisation 
-
Changes in NT-proBNP from baseline over time 
-
Change in albuminuria from baseline over time
-
Change in albuminuria from baseline over time by baseline UACR) categories (<30 
mg/g, ≥30mg/g to ≤300mg/g, >300 mg/g)
-
Incidence of acute renal failure (based on narrow SMQ)
-
Time to first acute kidney injury (based on the preferred term)
-
Change from baseline in body weight over time
-
Change from baseline in Systolic Blood Pressure (SBP) over time
-
Change from baseline in Diastolic Blood Pressure (DBP) over time
-
Change from baseline in pulse rate over time
-
Change from baseline in HbA1c over time in the overall population and in 3 
subgroups (non-DM, pre-DM, and DM)
Refer to the trial statistical analysis plan (TSAP) for the complete set of further endpoints. 
5.2
ASSESSMENT OF EFFICACY
The CEC is responsible for the adjudication of all relevant CV events, which could 
potentially fulfil the criteria for the primary, secondary and further endpoints. The CEC 
charter is available in the ISF for details regarding adjudication. Please also refer to Section 
3.1.1.1 for information on the CEC. 
5.2.1
KCCQ
KCCQ is a 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. 


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The paper-and-pen version in the required native language of the patient will be used. If the 
required language is not available then the patient is not required to complete the 
questionnaire. 
The questionnaire takes about 5-8 minutes to complete and will be distributed according to 
the Flow Chart. 
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 10.1.
To assess the further endpoint of change from baseline in KCCQ based on patient-preferred 
outcome at week 52, the investigator or designee will be required to ask the patient one 
additional question about which domain is the most difficult for the patient to cope with.  The 
response to this question will be recorded in the eCRF.
5.2.2
New York Heart Association classification
The New York Heart Association (NYHA) functional classification will be used to classify 
the severity of the patients’ heart failure (ref. Appendix 10.3). 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 until end of the trial. If a visit is designated as an on-site visit but is conducted by 
phone, the NYHA functional classification must be performed.
5.2.3
NT-proBNP
Refer to Section 5.5 Assessment of biomarkers
5.2.4
Body weight
BMI (kg/m2) will be calculated for determination of eligibility at Visit 1.
Body weight will be measured at all on-site visits:

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.).
5.2.5
Blood pressure
SBP and DBP as well as pulse rate (electronically or by palpation, count for 1 minute) will be 
measured after 5 minutes of rest in the seated position according to the Flow Chart. At visit 1, 
after the patient has rested quietly, in the seated position for five minutes, three blood 
pressure measurements will be taken and recorded in the eCRF. The mean of these 3 blood 
pressure values will be used to determine eligibility.  At subsequent visits, blood pressure 


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recordings should be measured using a similar type of and validated certified blood pressure 
recording instrument on the same arm, when possible. 
5.3
ASSESSMENT OF SAFETY
5.3.1
Physical examination
A complete physical examination will be performed by the Investigator according to the Flow 
Chart. Documentation of, and findings from the physical examination, must be part of the 
source documents available at the site.
5.3.2
Clinical routine examination
During the course of the trial the patient may undergo examinations that are not trial specific 
but a part of the clinical routine such as:
-
ECG
-
Echocardiography, radionuclide ventriculography, invasive angiography, MRI or CT.
In order to capture arrhythmias and significant changes in ECG, and LVEF measurements in 
echocardiography (or similar), the Investigator will be asked to enter the results from these 
examinations in the eCRF.
If the patient has an ICD the Investigator will be asked to enter information gathered from 
interrogations of the ICD in the eCRF.
5.3.3
Vital signs
Vital signs to be measured are SBP, DBP and pulse rate. 
5.3.4
Safety laboratory parameters
All safety laboratory samples will be collected as described in the Flow Chart. 
All parameters that will be determined during the trial conduct are listed in Table 5.3.4: 1.
The analysis will be performed by a central laboratory. The respective reference range and 
details about sample handling and shipment will be provided in the ISF (Lab Manual).


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Table 5.3.4: 1
Safety laboratory parameters – whole blood, serum or plasma
Haematology
Hematocrit
Haemoglobin
- Reticulocyte Count (reflex test if Hb 
outside normal range)
Red Blood Cells (RBC) / Erythrocytes
White Blood Cells / 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
Calcium
Chloride
Creatinine
Creatine kinase (CK)
Hs Troponin I (reflex tests if CK is elevated)
Glucose
Magnesium
Phosphate 
Potassium
Protein total
Sodium
Urea (BUN)
Uric acid
Lipids
Cholesterol (total)
HDL cholesterol
Calculated LDL cholesterol
Triglycerides (reflex test for direct measurement of LDL cholesterol triggered if 
triglycerides are > 400 mg/dl or 4.52 mmol/l)
Renal function
5.3.4.1
Urine albumin/creatinine ratio (UACR) in spot urine will be determined and calculated at the 
central laboratory.
The estimated glomerular filtration rate (eGFR) will be derived from serum creatinine values, 
age, sex and race based on the CKD-EPI equation [R12-1392]:
GFR = 141 × min (Scr /κ, 1)α × max(Scr /κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 1.159 
[if black]
where:
Scr is serum creatinine in mg/dL,
κ is 0.7 for females and 0.9 for males,
α is -0.329 for females and -0.411 for males,
min indicates the minimum of Scr /κ or 1, and
max indicates the maximum of Scr /κ or 1.


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The race of the patient will be entered because of potential differences due to race.  The 
CKD-EPI equation considers the race as an adjustment factor, therefore the race must be 
known for accurate estimation.
In case of an eGFR loss of ≥ 40% since baseline, or when the eGFR drops to < 15 
mL/min/1.73 m2 for patients with an eGFR ≥ 30 mL/min/1.73 m2 at baseline (<10 
mL/min/1.73 m2 for patients with an eGFR < 30 mL/min/1.73 m2 at baseline); an additional 
visit between 30 days to preferably 60 days after detection should be scheduled (unless 
detected at the EOT visit at trial end) to collect a blood sample for repeat central analysis of 
creatinine for calculation of the eGFR. If a signal of abnormal creatinine or eGFR is reported 
to the site by others (e.g. treating physicians from local labs), an additional sample should be 
sent to central lab, and if it is still abnormal, another sample should be sent to central lab 
between 30 days and preferably 60 days.
Kidney function will be classified as described in the table below (Table 5.3.4.1:1):
Table 5.3.4.1: 1
Classification of kidney function
CKD stage
eGFR
1
≥ 90
2
60-89
3a
45-59
3b
30-44
4
15-29
5
< 15
Pregnancy testing
5.3.4.2
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 5.3.7.2.
Criteria for hypoglycaemic events
5.3.4.3
In DM patients, 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.
Urinary tract infections and genital infections
5.3.4.4
Patients having a history of chronic/recurrent urinary tract infections (UTI) or genital 
infections or an acute episode of UTI or genital infection at screening will be identified, and 


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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.
Ketone monitoring in patients with type 1 diabetes (T1DM) only
5.3.4.5
Patients with T1DM will be provided an electronic device to determine their ketone 
concentration (i.e. a blood glucose monitoring device/meter that is also capable of measuring 
blood ketones).  
Patients should be advised to measure their ketones at least one daily, ideally after fasting for 
at least 6 hours, throughout the treatment period and for 5 days after empagliflozin / placebo 
treatment has been stopped.  Patients should be reminded to test their ketones in case of any 
symptoms of KA, e.g. nausea, vomiting, and abdominal pain.  Patients must be reminded 
about the signs and symptoms of KA, on the interpretation of ketone values measured via the 
meter, and on appropriate action to take in the event of increased ketone levels (see below).  
In the same way as during routine clinical care, patients should also be reminded to test for 
ketones in case of repeatedly elevated blood glucose levels (e.g. >11.1 mmol/L (> 200 
mg/dL)) which cannot be explained.  
Patients will be instructed that in the event of increased ketones, they are to either follow the 
rules given by their treating physician (e.g. increased fluid intake and/or insulin bolus) or 
contact their trial site.  Blood glucose and ketone levels should be checked every 1-2 hours 
until they are back in a range considered to be normal.  Patients are to be instructed to 
immediately refer themselves to hospital and/or the Investigator, or to contact an emergency 
physician in case of a blood ketone concentration > 1.5 mmol/L (as indicated in the meter 
manual).  In case of a suspected KA a blood gas test (pH, bicarbonate) should be performed 
locally at the earliest opportunity and the patient treated according to local medical 
judgement.  The results of the blood gas test will be collected on the relevant page of the 
eCRF.
Patients not adhering to the instructions given by the Investigator should be retrained at the 
earliest possible opportunity.  The risk benefit for the patient continuing on study treatment 
should be considered.
5.3.5
Electrocardiogram
ECGs will be performed at visits as indicated in the Flow Chart. Printed paper traces from 
12-lead ECGs (I, II, III, aVR, aVL, aVF, V1-V6) will be collected. They should be evaluated, 
signed, dated and commented upon by the treating physician/Investigator or appropriately 
qualified designee and stored locally. The diagnosis and results from the ECG reports should
be collected in the eCRF.
In the event of any cardiac symptoms (i.e. suspicion of heart rhythm disorders or cardiac 
ischaemia) during the course of the trial, if an additional ECG is recorded at time of event, or 
later at the next regular visit, they will be evaluated, signed, dated and commented upon by 
the treating physician/Investigator and stored locally. Any clinically relevant new changes in 


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the ECG (regardless of patients’ symptoms) should be reported as AEs and followed up 
and/or treated locally until normal or stable condition. ECG associated with cardiovascular 
endpoints must be submitted to the adjudication committee together with the baseline ECG.
Each ECG tracing stored locally should be labelled with trial and patient number, patient 
initials and date. 
5.3.6
Other safety assessments
Outcome of non-fatal stroke
5.3.6.1
For patients experiencing a non-fatal stroke the Modified Rankin Scale (MRS) should be 
used to assess stroke outcome (Appendix 10.4). The scale is widely used in clinical practice 
and consists of grades, from 0 to 6, with 0 corresponding to no symptoms and 6 
corresponding to dead. Investigators will measure and score the MRS based on an interview 
with the patient at the next regular on-site visit after the onset of the stroke. In those cases 
where MRS assessment occurred within 90 days after the stroke, a repeat MRS-assessment 
should be performed at the next on-site visit. For patients who experience a non-fatal stroke 
less than 90 days prior to the study closure date, the final MRS assessment will occur at the 
final study visit for that patient.  Detailed information on the stroke (date and time of onset, 
type, symptoms, method of detection, outcome) will be collected in the eCRF.
Hepatic events
5.3.6.2
For assessment of hepatic events please refer to Section 3.1.1.2.
5.3.7
Assessment of adverse events
Definitions of AEs
5.3.7.1
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.
Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility. Adverse reactions may arise 
from use of the product within or outside the terms of the marketing authorisation or from 
occupational exposure. Conditions of use outside the marketing authorisation include off-
label use, overdose, misuse, abuse and medication errors.
Serious adverse event


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A serious adverse event (SAE) is defined as any AE which:

results in death,

is life-threatening, this refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe.

requires inpatient hospitalisation or prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity,

is a congenital anomaly/birth defect,
or

is to be deemed serious for any other reason if it is an important medical event when 
based upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation or development of dependency or 
abuse. 
For Japan only: The following events will be handled as “deemed serious for any other 
reason”: AEs which possibly lead to disability will be reported as SAEs.
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
BI has set up a list of AEs, which by their nature, can always be considered to be “serious” 
even though they may not have met the criteria of an SAE as given above.
The latest list of “Always Serious AEs” can be found in the ISF. These events should always 
be reported as SAEs as described above.
Note: Cancers of new histology and exacerbations of existing cancer must be reported as a 
serious event regardless of the duration between discontinuation of the drug and the 
occurrence of the cancer.
Adverse events of Special Interest (AESIs)
The term AESI relates to any specific AE that has been identified at the substance 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/CRO’s Pharmacovigilance Department 
within the same timeframe that applies to SAE, see Section 5.3.7.2.
The following are considered as AESIs:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 


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
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

Marked peak 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.
For the AESI “decreased renal function” the patient needs to be followed-up appropriately 
based on local clinical guidance. 
The Investigator should refer to follow-up schedule for renal endpoint events described in 
Section 5.3.4.1.
Ketoacidosis
If metabolic acidosis, KA 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 KA which may occur at lower plasma glucose levels in patients with DM and 
potentially also in non-diabetic patient population. The diagnosis of KA in these patients can 
be based on arterial pH≤7.30, serum bicarbonate levels <15 and measurement of serum beta-
hydroxybutrate levels. Other diagnostic criteria which can support the diagnosis of KA are 
urine ketones and anion gap >10. 
Investigators should note that not all criteria mentioned above need to apply for the diagnosis 
of KA, and clinical judgment should also be taken into consideration.
Events leading to lower limb amputation
Any event leading to a lower limb procedure of amputation, auto-amputation or 
disarticulation as defined below is considered as an AESI.  
“Amputation is a resection of a limb through a bone. Disarticulation is a resection of a limb 
through a joint. Auto-amputation is a spontaneous separation of non-viable portion of the 
lower limb.


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Not included in this definition are debridement (removal of callus or dead tissue), procedures 
on a stump (like stump revision, drainage of an abscess, wound revision etc.) and other 
procedures (e.g., nail resection or removal) without a concomitant resection of a limb 
(amputation or disarticulation).” (International Working Group of Diabetic Foot, 2015).
Each lower limb amputation, disarticulation, or auto-amputation should be reported 
separately. The SAE report should include the date of the procedure, the level of amputation 
or disarticulation, the medical condition(s) leading to the procedure and if the patient had 
some of the known risk factor(s) for lower limb amputation.
Intensity of AEs
The intensity of the AE should be judged based on the following:
Mild: 
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate: 
Enough discomfort to cause interference with usual activity
Severe: 
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
The definition of an adverse reaction implies at least a reasonable possibility of a causal
relationship between a suspected medicinal product and an adverse event. An adverse
reaction, in contrast to an adverse event, is characterised by the fact that a causal relationship
between a medicinal product and an occurrence is suspected.
Medical judgment should be used to determine the relationship, considering all relevant
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge,
confounding factors such as concomitant medication, concomitant diseases and relevant
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship
could be:
•
The event is consistent with the known pharmacology of the drug
•
The event is known to be caused by or attributed to the drug class.
•
A plausible time to onset of the event relative to the time of drug exposure.
•
Evidence that the event is reproducible when the drug is re-introduced
•
No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).
•
The event is typically drug-related and infrequent in the general population not
exposed to drugs (e.g. Stevens-Johnson syndrome).
•
An indication of dose-response (i.e. greater effect size if the dose is increased, smaller
effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship
could be:


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•
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 medication continues or remains 
unchanged.
For Japan only: The reason for the decision on causal relationship for unlisted AEs needs to 
be provided in the eCRF.
Adverse event collection and reporting
5.3.7.2
AE Collection
The Investigator shall maintain and keep detailed records of all AEs in their patient files. The 
following must be collected and documented on the appropriate eCRF(s) by the Investigator:

From signing the ICF onwards through the Residual Effect Period (REP), until 
individual patient's end of trial:
o
all AEs (serious and non-serious), Outcome events and all AESIs.

After the individual patient’s end of trial:
The Investigator does not need to actively monitor the patient for AEs, but must
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 on the eCRF.
The rules for Adverse Event Reporting exemptions still apply.


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REP (7days)
Report all AEs and all AESIs
Screening/Treatment phase
Remaining F-U
End of treatment Visit
F-U visit /
End of Study
Signed 
ICF
Related SAEs and related
AESIs of which the investigator 
may subsequently become 
aware of
Figure 5.3.7.2: 1
Timelines for adverse event collection
The REP (timeframe after last dose of trial medication when measurable drug levels or 
pharmacodynamic effects are still likely to be present) is defined as 7 days after the last trial 
medication application. All AEs which occurred through the treatment phase and throughout 
the REP will be considered as on treatment. Please also refer to Section 7.3.4.
Events which occurred after the REP will be considered as post treatment events.
AE reporting to the Sponsor/CRO and timelines
The Investigator must report all non-exempted SAEs, AESIs and non-serious AEs which are
relevant for the reported SAE or AESI, on the BI SAE form immediately (within 24 hours) to 
the specified unique entry point (contact details provided in the ISF). The same timeline 
applies if follow-up information becomes available. In specific occasions the Investigator 
could inform the Sponsor/CRO 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, appropriate follow-up forms have 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 paper 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 SAE form (if applicable):
Worsening of the underlying disease or of other pre-existing conditions. Exemptions 
are specified in “Exemptions to SAE reporting” and must be adhered to as described 
in that chapter.
Patient considered “on-
treatment” until end of REP


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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 trial inclusion they will be considered as baseline conditions.
All (S)AEs, including those persisting after individual patient’s end of trial must be followed 
up until they have resolved, have been sufficiently characterised, or no further information 
can be obtained.
For some types of AEs additional information will be collected in the CRF due to the nature 
of the event and mechanisms of action of the trial medication. These listed AEs are distinct 
from AESI:
-
Hypoglycaemic event
-
Genital infection
-
Acute pyelonephritis
-
Sepsis
-
Urinary tract infection
-
Bone fracture
Pregnancy
In rare cases pregnancy may occur in a clinical trial. Once a patient has been enrolled into 
this clinical trial and has taken trial medication, the Investigator must report any drug 
exposure during pregnancy (DEDP) immediately (within 24 hours) to the Sponsor’s/CRO’s
unique entry point (country-specific contact details will be provided in the ISF). The 
Pregnancy Monitoring Form for Clinical Trials (Part A) should be used. 
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the Sponsor’s/CRO’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.
Exemptions to SAE reporting
A list of adverse events that commonly occur in the trial population or which are components 
of trial endpoints are exempted from reporting on the SAE form, if the event onset is after 
randomization and the event does not qualify as AESI. These events are known consequences 
of the underlying disease and it is not possible, based on a single case, to conclude that there 
is a reasonable possibility that the investigational drug caused these events. Pulmonary 
complications of heart failure are added to the exemption list, since patients with HF 
commonly experience such complications. Thus these events could be reported as pulmonary 
events, although the underlying aetiology was attributed to HF.


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Regardless of relationship to trial medication, these events will not be reported by the 
Sponsor to regulatory agencies or ethics committees in an expedited manner unless they 
qualify as an AESI (for definition of AESI, see above) with fulfilment of expedited 
regulatory safety reporting requirements.
These events include: 
Cardiovascular (CV) related death. The CV related death also includes death due to 
undetermined cause, and death due to pulmonary events that may be secondary to 
complications of heart failure such as pulmonary oedema, pulmonary vascular disease 
secondary to heart disease.
HF hospitalisation
Non-fatal MI
Non-fatal stroke and TIA
CV hospitalisation events
Pneumonia (fatal and non-fatal)
New or exacerbated COPD (fatal and non-fatal)
Based on the same conclusion that it is not possible to perform a causality assessment on 
these events based on a single case, the trial investigators are exempted from performing a 
causality assessment and reporting these adverse events on the SAE form to the Sponsor, if 
event onset is after randomization and the event does not qualify as AESI.
All exempted events must be collected systematically on the eCRF (within 24 hours). The 
investigator is also required to provide all defined supporting documentation (ref to ISF). 
If the events specified above occur before randomization, they are not exempted from 
immediate reporting on the SAE form.  In addition, whenever such events meet the definition 
of an AESI, then no exemption applies, regardless of occurrence before or after 
randomization.
An independent Data Monitoring Committee (DMC) will monitor the safety data in the trial 
on an ongoing basis. Reported SAEs occurring after randomisation that are protocol 
exempted events will be collected in the eCRFs and evaluated by the DMC. These events will 
not be collected on SAE forms for expedited review or reporting.
Aggregate analysis of endpoint data to determine any potential benefit or risk and to ensure 
patient safety during the clinical trial will be performed on a regular basis by the DMC.
If any exempted event or any other adverse event (serious or non-serious) occurs, the 
investigator or attending physician has the responsibility and will take direction and 


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appropriate action to provide care for the patient and to decide whether or not the trial 
medication should be discontinued.
This reporting policy assumes global regulatory agency approval.
5.4
DRUG CONCENTRATION MEASUREMENTS AND PHARMACOKINETICS
(SUBSTUDY)
5.4.1
Pharmacokinetic endpoints
The PK sampling will be done from a limited number of randomised patients (approximately 
1650 patients) and at sites in pre-selected countries only. The pre-dose blood samples will be 
collected at visit 4 to determine plasma empagliflozin trough concentrations. These samples 
will serve to determine steady state trough concentrations of empagliflozin.
The date and exact clock time of trial medication intake the day before this visit will be 
recorded together with the date and exact clock time of drawing the trough PK sample.
5.4.2
Methods of sample collection
The time interval for blood sample collection relative to the most recent intake of trial
medication should be between 22 and 26 h. For quantification of empagliflozin trough plasma 
concentrations, 3 mL of blood will be drawn from a forearm vein in an EDTA-anticoagulant 
blood drawing tube at each time-point. Details of sample handling and sample logistics can 
be found in the ISF (Central lab manual).
5.4.3
Analytical determinations
Empagliflozin concentrations in plasma samples will be determined by a validated HPLC
MS/MS assay (high performance liquid chromatography, tandem mass spectrometry). In 
order to identify samples from patients taking placebo, the bioanalyst will be un-blinded so 
that samples from patients receiving placebo will not be analysed for empagliflozin.
5.5
ASSESSMENT OF BIOMARKERS
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. 
Samples for the determination of high-sensitivity cardiac troponin T will be collected at Visit 
2 (Randomisation) and analysed at the Central Laboratory.
5.5.1
Biobanking (optional)
Participation in sampling for biobanking (including DNA) is voluntary and not a prerequisite 
for participation in the trial. Biobanking samples will be taken only after separate informed 
consent has been given in accordance with local ethical and regulatory requirements. Banked 
samples may be analysed in the future for scientific evaluations or to further, for example, the 
mechanistic understanding of drug effects and/or to identify genetic or other factors 
associated with response to therapy or the risk of adverse drug reactions. 


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Measures are in place to comply with the applicable rules for the collection, biobanking and 
future use of biological samples and clinical data, in particular.
Sample and data usage has to be in accordance with the separate biobanking ICF.
The BI-internal facilities storing biological samples from clinical trial participants as well 
as the external banking facility are qualified for the storage of biological samples collected 
in clinical trials 
An appropriate sample and data management system, incl. audit trail for clinical data and 
samples to identify and destroy such samples according to ICF is in place 
A fit for the purpose documentation (biomarker proposal, analysis plan and report) ensures 
compliant usage 
A fit for purpose approach will be used for assay/equipment validation depending on the 
intended use of the biomarker data
Samples and/or data may be transferred to third parties and other countries as specified in 
the biobanking ICF
Methods and timing of sample collection
5.5.1.1
Sampling will be performed at the time points specified in the Flow chart.
DNA banking
Approx.  8.5 mL blood will be drawn into a PAXgene Blood DNA Tube, preferably at Visit 
2.  In Korea, a 6 mL K2 EDTA tube will be used.
Plasma banking
Approx. 10 mL blood will be drawn into an EDTA blood collection tube.
Serum banking
Approx. 8.5mL blood will be drawn into a serum separation tube.
Urine banking
Approx. 10 mL urine (preferably morning mid-stream urine) will be collected.
For all biological samples collected, detailed instructions on sampling, preparation, 
processing, shipment and storage are provided in the laboratory manual. Plasma, serum and 
urine samples will be stored at an external biobanking facility contracted by the Sponsor; 
DNA, extracted from the original whole blood sample, will be stored at the Sponsor except 
for samples collected in China. These samples will be stored at an external biobanking 
facility contracted by the Sponsor.


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5.6
OTHER ASSESSMENTS
5.6.1
EQ-5D
Health related quality of life will be assessed using the EQ-5D-5L version (refer Appendix 
10.2.1) according to the Flow Chart. EQ-5D is a standardised instrument for use as a measure 
of health outcome. It is designed for self-completion by patients. 
The EQ-5D self-report questionnaire (EQ-5D) essentially consists of 2 pages comprising:

the descriptive system (five dimensions of health; namely mobility, self-care, usual 
activities, pain/discomfort, anxiety/depression). Each dimension comprises five levels (no 
problems, slight problems, moderate problems, severe problems, extreme 
problems/unable to perform activity). 

the EQ-VAS (visual analogue scale) which records the patient’s self-rated health status on 
a vertical graduated (0 – 100) VAS. 
For further description on completing the questionnaire refer to the last part of Section 5.2.1.
5.6.2
Health Care Resource Utilisation (HCRU)
HCRU data will be used for health economic analysis (i.e. cost-effectiveness analysis) 
required for reimbursement decisions. Resource use will be captured via interview with the 
patient and entered in the eCRF at all on-site visits during the complete trial period, and will 
allow calculation of direct and indirect costs. Main components to be collected are 
unscheduled outpatient visits and hospitalisations.
5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor safety aspects, and to determine empagliflozin efficacy and 
safety in an appropriate way.
The scheduled measurements are appropriate to see drug induced changes in vital signs, 
standard laboratory values, biomarkers specific to efficacy of treatment of HF, and ECG. The 
primary and secondary endpoints are accepted for evaluation of efficacy, safety and 
tolerability on an oral HF drug and they are widely used in respective pivotal phase III 
studies.
Health related quality of life questionnaires are a necessary part for this phase III trial in order 
to collect data for a health economic evaluation. 
Therefore, the appropriateness of all measurements applied in this trial is given.


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6
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
All trial visits, except for screening visit and telephone visits should preferably take place 
before noon. The patient should be fasting (no food or liquid except water the last 10 – 16 
hours) at Visit 2 (Randomisation), EOT Visit and Follow Up Visit. 
If a patient mistakenly takes trial medication on the morning of Visit 4 before attending the 
clinic or comes in non-fasted where a fasting condition is required (refer to the Flow Chart),
the visit should be rescheduled for another day as soon as possible, reminding the patients 
about expected time of dosing. The rescheduled visit must take place in a short enough time-
frame so that the patient has sufficient trial medication available.
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.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
The Flow Chart summarises the investigational procedures to be done at each visit, and trial 
procedures should be performed before intake of any trial medication. The procedures are 
further described below.
6.2.1
Screening
No trial procedures should be done unless the patient has consented to taking part in the trial. 
Preferably the patient should also be informed about biobanking (including DNA) sampling 
already at this visit.  
Patients who have been diagnosed with T1DM are to be provided with the consent form that 
contains information relevant for patients with T1DM.    
Once the patient has consented to the trial participation, she/he is considered to be enrolled in 
the trial and have started screening. The patient should be registered in the enrolment log and 
be registered in the IRT as a screened patient. Patients will continue to take background 
medication for heart failure and treatment for their concomitant disorders if applicable. The 
screening visit may be conducted over multiple days, at the discretion of the investigator, as 
long as all screening procedures are performed and resulted within the allowable visit 
window in the flow chart.  For example, a site may obtain written informed consent followed 
by collection of samples for the safety lab analysis and ECG. Remaining procedures may be 
performed on a separate day, once it is confirmed that the patient’s laboratory values, 
including NTproBNP value, are not exclusionary.
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, the site may make a phone contact to inform the patient that he/she is no longer 
required to return to the clinic for Visit 2.


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Patients who fail screening (fail to meet one or more of the inclusion criteria, and/or meet one 
or more of the exclusion criteria) following Visit 1 procedures should be registered as a 
screen failure in IRT.
6.2.2
Treatment period
Randomisation will occur at Visit 2 using IRT. The patients will return to the clinic for 
regularly scheduled visits 4, 12, 32 and 52 weeks after randomisation during the first year of 
trial participation, and every 24 weeks thereafter for the duration of the trial, 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.
Telephone follow-up calls will be scheduled 10-12 weeks after every on-site visit starting 
after Visit 4 and continuing throughout the trial (see Flow chart). The telephone contacts will 
focus on safety (e.g. hospitalisations or occurrence of AEs), changes in concomitant therapy 
and trial medication compliance.
The patients should be fasting at the Randomisation Visit.
Consenting patients with T1DM are to be provided with the ketone monitoring device, the 
patient diary and Trial information card.  The site staff are to provide instruction to the 
patient on how to properly use the ketone monitoring device and the importance of recording 
their glucose, ketone and insulin intake throughout the trial.  At all subsequent visits, site staff 
are required to review the patient’s diary with the patient to ensure that the diary is properly 
completed.  Patients with T1DM should be provided with ketone monitoring supplies as 
necessary.  
The optional blood sample for DNA will preferably be collected at the Randomisation Visit
for all patients eligible for randomisation, but could also be taken at any later visit after the 
separate consent is signed.
At any time during the treatment period the Investigator is allowed to adjust and optimise HF 
background therapy 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).
For sites selected to participate in collection of samples for PK analysis, please refer to 
Section 5.4 and the Lab Manual for details.
Patients will be dispensed medication at each on-site visit and allocation of new kit number(s)
will be managed through the IRT. Trial medication administration should be done after 
physical and laboratory assessments.
This is an event driven trial. Patients will remain in the treatment period until the necessary 
number of events is reached.


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Permanent trial medication discontinuation is only justified when clear persistent 
contraindications arise, or when the patient requests to stop trial medication. See Section 
6.2.4 for details on how to handle trial medication discontinuations, and Section 3.3.4 for 
when discontinuation from trial is justified.
6.2.3
End of Treatment, Follow Up Period and Trial Completion
Patients on treatment at the time when required number of outcome events are reached (ref. 
Section 7.7), will be asked to return to the clinic for the EOT visit, with the proposed time 
schedule communicated via an investigator letter, followed by the Follow Up Visit 30 days 
later. If a patient has prematurely discontinued trial medication is not willing to return to the 
clinic for predefined trial visits, a telephone call at trial end will be required, to document the 
occurrence of outcome events and vital status.  Other AEs and concomitant therapy changes 
since the last visit should be recorded in the eCRF. Sites should encourage the patient to 
return to the clinic for the final study visit (ref. Section 3.3.4.1).
During the EOT visit all trial medication will be collected and compliance calculated, 
occurrence of safety and efficacy endpoints will be assessed and complete physical 
examination, laboratory assessments and ECG will be performed (ref. Flow Chart).  
The Follow Up Visit should also be a clinic visit for all patients, and the following 
examinations should be performed (ref. Flow Chart):
-Concomitant Therapy 
-Vital signs and body weight
-NYHA classification
-Documentation of any adverse events and endpoints
-Vital status
-Blood and urinary sampling
-KCCQ and EQ-5D
-Modified Rankin Scale (only in case of suspected stroke within last 90 days)
6.2.4
The patients should be fasting at the EOT and Follow Up Visit. Early 
discontinuation of trial medication and trial termination
The EOT activities will be performed when a patient discontinues trial medication treatment 
permanently. 
Note. The EOT activities should not be used for temporary interruptions of trial medication. 
All patients will have a follow up visit 30 days following discontinuation of trial medication, 
irrespective whether they complete the treatment period or prematurely discontinue trial 
medication. 
Patients who discontinue trial medication prematurely should thereafter continue to follow 
scheduled visits until trial end. For patients reluctant to attend the scheduled visits after 
prematurely discontinuing trial medication, some trial assessments may be negotiated with 
exception of collection of adverse events, outcome events and concomitant therapy.


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Please refer to Section 3.3.4.1 for detailed procedures to be followed in case a patient wants 
to stop trial medication.
In case of early trial termination (e.g. based on recommendation by the DMC, a reasonable 
timeframe to stop the trial (perform last patient visits) will be defined and communicated to 
the Investigators. 


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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, stratified by geographical region, status of DM (DM, pre-DM, no DM) , LVEF 
(<50%, ≥50%) and eGFR (CKD-EPI)cr (<60 mL/min/1.73 m², >=60 mL/min/1.73 m²) at 
screening visit. 
To ensure the trial population consist of a reasonable combination of non-, pre- and DM 
patients, and to aim for approximately 35% to 50% of the population or more with an LVEF 
>50% capping will be used on trial level (see also Section 3.3). Capping on regional level 
may be applied to achieve a contribution of each region to each category of diabetes status.
The composite primary endpoint is the time to first event of adjudicated CV death or 
adjudicated HHF. The statistical model for the primary analysis is the Cox proportional 
hazards model. The hazard ratio and its confidence limits will be determined for evaluating 
the superiority of empagliflozin to placebo for the primary endpoint.
The key secondary endpoints, which are part of the testing strategy, are

occurrence of adjudicated HHF (first and recurrent), and

eGFR (CKD-EPI)cr slope of change from baseline
7.2
NULL AND ALTERNATIVE HYPOTHESES
A hierarchical testing procedure will be followed for the assessment of the primary and the 
key secondary endpoints. For all endpoints, superiority of empagliflozin vs. placebo will be 
evaluated with a two-sided test in the following structure:
Null hypothesis: There is no difference between the effect of placebo and the effect of 
empagliflozin in terms of the endpoint in question. 
Alternative hypothesis: There is a difference between the effect of placebo and the effect of 
empagliflozin in terms of the endpoint in question. The tests will be performed in the 
following hierarchical order:
1. Time to first event of adjudicated CV death or adjudicated HHF
2. Occurrence of adjudicated HHF (first and recurrent)
3. eGFR (CKD-EPI)cr slope of change from baseline
Starting from step 1, if the null hypothesis is rejected, and the result is more favourable for 
empagliflozin, superiority is concluded in the tested endpoint, and the overall type I error is 
preserved for the test in the next step.  If at any step the null hypothesis is not rejected, 
subsequent tests are conducted in an exploratory fashion.


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The overall type one error rate will be preserved at a level of 0.05 (2-sided). The type one 
error rate used at the final analysis will be influenced by the pre-planned interim analysis –
see Section 7.4. 
In the final analysis after the evaluation of recurrent HHF, alpha will be split into 0.001 to be 
used for the analysis of eGFR slope, and the rest will be transferred to the meta-analyses. 
In case the trial is finished early at the time of interim analysis, using αinterim for the primary 
and key-secondary endpoints in the testing hierarchy according to the α-spending function in 
Section 7.4, the following α-split will be used for eGFR slope analysis and the meta-analyses:
0.1 * αinterim will be used for the eGFR slope analysis and
0.9 * αinterim will be transferred to the meta-analyses
In both the interim and final analyses, if the slope analysis is successful, the alpha of this 
branch will then be transferred to the meta-analyses.
The testing hierarchy is summarised in Figure 7.2: 1 showing the alpha-spending at the final 
analysis. 
Figure 7.2: 1
Hierarchical analysis of trial in HFpEF (1245.110) and the parallel 
trial in HFrEF (1245.121) showing the alpha-spending at the final 
analysis.
Time to 1st event of CV death 
or HHF
Recurrent HHF
Meta-analyses
HFrEF (1245.121)
αr2 = αr_final - αr1
αr1=0.001
eGFR Slope 
αr3=0.001
Time to 1st event of CV 
death or HHF 
Recurrent HHF
HFpEF (1245.110)
αp1=0.001
eGFR Slope 
αp3=0.001
αp2 = αp_final - αp1
αp_final
αr_final


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The other secondary endpoints will be evaluated in an exploratory manner. 
7.3
PLANNED ANALYSES
The primary 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.
Baseline status of DM is defined as:

DM: any pre-treatment HbA1c above 6.5 or history of DM as entered in the eCRF on 
the medical history page

Pre-DM: no history of DM and no HbA1c >=6.5 before treatment and a pre-treatment 
HbA1c value of >= 5.7 and <6.5  

Non-DM: not meeting criteria of DM or pre-DM above
For all other endpoints, baseline will be defined as the last available measurement before start 
of randomised trial medication.
7.3.1
Primary endpoint analyses
The primary endpoint will be evaluated on the randomised set using a Cox proportional 
hazards model with treatment, age (continuous), gender, geographical region, baseline status 
of DM (DM, pre-DM, no DM), LVEF (continuous) and eGFR (CKD-EPI)cr at baseline 
(continuous) as covariates.
The time to the event of interest will be computed as (event date −randomisation date) +1. 
All events observed after randomisation until completion of the planned treatment phase will 
be included in the analysis.  Patients who do not have an event will be censored at the 
individual end of the planned treatment phase or the last day that the patient was known to be 
free of the event, whichever is earlier. The time to censoring will be computed as (individual 
end of the planned treatment phase or the last day known to be free of the event –
randomisation date) + 1. For patients who have more than one primary endpoint event during 
the trial, the time to the first occurrence of the primary endpoint event will be considered for 
the primary analysis. Only the adjudicated and confirmed events will be used for the primary 
analysis. 


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To detect any heterogeneity in the treatment effect among diabetic patients, pre-diabetic 
patients and non-diabetic patients, a subgroup analysis will be performed by including the 
diabetic status by treatment interaction term into the Cox model. 
Standard subgroup analyses of the primary endpoint include geographical region, sex, BMI, 
LVEF, renal function, prognostic factors, age, ethnicity, race and different background 
therapies etc. More details will be specified in the TSAP. 
A sensitivity analysis will be provided based on the TS only including any events up to 30
days after treatment discontinuation. 
7.3.2
Secondary endpoint analyses
The key secondary endpoints occurrence of adjudicated HHF (first and recurrent) will be 
modelled using a joint frailty model together with adjudicated CV death in order to take into 
account the dependence between the endpoints. The joint frailty model will be adjusted for 
the same covariates as the primary analysis. 
The joint frailty model therefore models the hazards in the following way:
ri (t | ωi , Zi) = ωi exp {β’1 Zi}r0(t)
λi (t | ωi ,Zi) = ωi
α exp {β’2 Zi}λ0(t)
where ri(t) is the hazard of the recurrent HHF for the ith patient, proportional to the baseline 
intensity function r0. The hazard function of CV death for the ith patient is λi proportional to 
the baseline hazard λ0. β1 and β2 are vectors of the regression coefficients of the covariate
vectors Zi including treatment, age (continuous), gender, history of DM, geographical region, 
LVEF (continuous) and eGFR (CKD-EPI)cr at baseline (continuous). Patient specific 
independent random effects are denoted by ωi, with α giving the relation between HHF and 
CV death.
Patient specific independent random effects denoted by i and are assumed to follow a 
gamma distribution with mean 1.
The resulting likelihood function can be solved assuming piecewise constant hazards.  
Slope in change from baseline of eGFR (CKD-EPI)cr will be analysed by a random 
coefficient model allowing for random intercept and random slope per patient. The model 
will include the factors treatment, gender, geographical region, and status of DM as fixed 
effects and eGFR (CKD-EPI)cr at baseline (continuous), LVEF (continuous), age 
(continuous), time, interaction of treatment by time and interaction of eGFR (CKD-EPI)cr  at 
baseline (continuous) by time as linear covariates and allow for randomly varying slope and 
intercept between patients. The model will include all on-treatment change from baseline 
data. 
Since the slope is run on the change from baseline data, the intercept will model the acute 
drop, whereas the long-term effect is modelled by the slope. 


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Change from baseline in clinical summary score for HF symptoms and physical limitations 
domains of the KCCQ at week 52 will be evaluated by a mixed model repeated measures
(MMRM) model including LVEF (continuous), age (continuous) and eGFR (CKD-EPI)cr at 
baseline (continuous) as linear covariates and baseline score by visit, visit by treatment, 
gender, geographical region and status of DM and as fixed effects. All on-treatment data up 
to week 52 will be included. 
Occurrence of all-cause hospitalisation (first and recurrent) will be evaluated by a similar
joint frailty as adjudicated HHF and will be evaluated with a joint model together with all-
cause mortality. 
The other time-to-event type of secondary endpoints will be analysed using the same Cox 
proportional hazards model as the primary analysis. 
This also applies for time to adjudicated CV death and all-cause mortality, rather than using 
the joint frailty model described above.  
7.3.3
Further endpoint analyses
Further time-to-event endpoints will be analysed in the same Cox proportional hazards model 
as the primary analysis.
Change from baseline to 30 days after treatment stop of eGFR (CKD-EPI)cr will be evaluated 
by an ANCOVA model, including treatment group, gender, geographical region and history 
of DM as fixed effect and baseline eGFR (CKD-EPI)cr (continuous), age (continuous), LVEF 
(continuous) as linear covariates.
An unmatched win ratio considering adjudicated CV death and adjudicated HHF will be 
analysed based on unmatched pairs. All patients randomised to empagliflozin will be 
compared to all patients randomised to placebo. Only common follow-up time will be 
considered for the comparison. Patients on empagliflozin are considered to have “won” the 
comparison if either the other patient has died while the patient on empagliflozin was still 
alive, or if both patients did not die, then if the other patient had more occurrences of HHF, or 
if the number of occurrences of HHF is the same but the time to the first occurrence of HHF 
is longer. The number of comparisons won is noted as NW. Patients on empagliflozin are 
considered to have “lost” the comparison if the empagliflozin patient died while the patient 
on placebo was still alive, or if both patients did not die, then if the patient on empagliflozin 
had more occurrences of HHF, or if the number of occurrences of HHF is the same but the
time to the first occurrence of HHF is shorter. The number of comparisons lost is noted as NL. 
The win ratio is NW/ NL. 
The rules for winning and losing follow a modified Rogers 2014 [R16-4909] approach also
considering the time to the first HHF event in case of a tie on the number of HHF events. The 
analysis of the unmatched win ratio will be conducted as described in Pocock 2012 [R16-
4813]. 
Further longitudinal continuous endpoints will be analysed in a MMRM, including age, 
LVEF and eGFR (CKD-EPI)cr at baseline as linear covariates and visit by treatment 


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interaction, baseline by visit interaction, geographical region, gender and baseline history of 
DM as fixed effects.
The details of analyses will be defined in the TSAP prior to unblinding.
7.3.4
Safety analyses
In general, safety analyses will be descriptive in nature and will be based on BI standards. 
Standard BI summary tables and listings will be produced. No hypothesis testing is planned. 
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events. To this end, all adverse events occurring between start of treatment and end 
of the REP of 7 days will be considered ‘treatment-emergent’. 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).
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 highlighted in the 
listings. Treatment groups will be compared descriptively with regard to distribution 
parameters as well as with regard to frequency and percentage of patients with abnormal 
values or clinically relevant abnormal values. 
Vital signs (blood pressure, pulse rate), physical examinations or other safety-relevant data 
observed at screening, baseline, during the course of the trial and at the end-of-trial 
evaluation will be assessed with regard to possible changes compared to findings before start 
of treatment.
Reasons for discontinuation and use of post-baseline concomitant medications will be 
tabulated.
The details of the analysis will be specified in the TSAP.
7.3.5
Pharmacokinetic analyses
Individual concentration-time data with descriptive statistics for empagliflozin trough 
concentrations will be presented in the Clinical Trial Report (CTR).
7.3.6
Prespecified meta-analysis
On project level, meta-analyses are pre-specified. Data from this trial and a parallel trial in 
HFrEF patients, 1245.121, will be pooled. 
The statistical model will include trial as a covariate. More details are specified in the meta-
analysis plans.
7.4
INTERIM ANALYSES
The safety and conduct of the trial will be monitored by an independent DMC. Details on this 
process are outlined in the DMC charter. 


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There will be one unblinded interim analysis to be conducted by the DMC. At time of interim 
analysis, the ExSC, the SEC, Sponsor, CRO, and all trial personnel will stay blinded to the 
interim results. For blinding please also refer to Section 4.1.5.1. 
After approximately 500 primary adjudicated outcome events have been accrued 
(approximately 60% of information is available) an interim analysis will be performed. 
The following Hwang, Shih and De Cani α-spending function for the analysis at information 
fraction tk (planned to be approximately 60%) with parameter γ = -8 will be used:
∗(	, ) = min ,
 1 −
1 −  = min 0.025,
0.025 1 −
1 − 
For an interim analysis at the timepoint of approximately 60% of information, the chosen
alpha-spending function gives an alpha-level of 0.001 at time of interim. 
If the p-value for the primary endpoint and the p-value for CV-death (from the primary Cox 
proportional hazards model) are lower than the cutoff to be evaluated from the alpha-
spending function (planned at 0.001 one-sided), then the trial will be stopped for 
overwhelming efficacy. In this case, the hierarchy will be tested as specified in Section 7.2.
Otherwise the trial will be continued.
The final alpha-level is therefore planned at a one-sided alpha-level of 0.0248 which 
translates in a two-sided alpha of 0.0496. 
The event rate will be assessed by the trial team in a blinded manner only during trial 
recruitment and before the unblinded interim analysis (see Section 7.7).
7.5
HANDLING OF MISSING DATA
There will be no imputation of data for safety data or for time-to event endpoints. For patients 
who discontinue the trial treatment prematurely, all efforts will be made to follow patients for 
survival and for any other endpoints including the primary and key secondary endpoints until 
the end of the trial.
For the slope analysis of eGFR (CKD-EPI)cr, all available on-treatment change from baseline 
data will be used. Patients without on-treatment data after randomisation will not be included 
in this analysis. 
For the analysis of change from baseline to 30 days after treatment stop, only available data 
will be used. Only patients with post-treatment data will be used in this analysis. 
For other longitudinal endpoints such as KCCQ scores, MMRM methodology will be used. 
Models will be run on both all observed data and all observed on-treatment data. Details of 
the imputation rule will be given in the statistical analysis plan.


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An eGFR (CDK-EPI)cr reduction is considered sustained, if it is determined by two or more 
consecutive post-baseline central laboratory measurements separated by at least 30 days (first 
to last of the consecutive eGFR values). If there is no additional measurement after the eGFR 
reduction is observed and the patient dies within 60 days of this measurement without second 
measurement >= 30 days after the first, then the eGFR reduction is also considered sustained.
7.6
RANDOMISATION
The trial will be performed as a double-blind design with respect to placebo and 
empagliflozin. Subjects will be randomised to the trial treatments in a 1:1 ratio. The 
randomisation will be stratified by the following factors:

Geographical region (North America, Latin America, Europe, Asia, Other)

Status of DM at screening:
o
no DM (HbA1c < 5.7% without the intake of antidiabetic medication, unless 
taken for a non-DM indication, and no history of DM), or 
o
pre-DM (HbA1c >=5.7% and <6.5% without the intake of antidiabetic 
medication unless taken for a non-DM indication, and no history of DM), or
o
DM (HbA1c >= 6.5% or intake of antidiabetic medication for a DM 
indication, or a history of DM)

eGFR (CKD-EPI)cr at screening 
o
<60 mL/min/1.73 m² 
o
≥60 mL/min/1.73 m²

LVEF
o
LVEF < 50%
o
LVEF ≥50%
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 CTR. Access to the codes will be 
controlled and documented.
7.7
DETERMINATION OF SAMPLE SIZE
For the sample size calculation, a yearly event rate in the placebo group of 10% is assumed.
The assumption is based on the CHARM-Preserved study and part of the TOPCAT study
from the Americas [R07-4374, R16-1458]. The annual event rates in CHARM-Preserved 
were 8.1% in the candesartan group and 9.1% in the placebo group. The annual rates from the 
Americas in the TOPCAT study were 10.4 in the spironolactone group and 12.6 in the 
placebo group.
The trial is designed to achieve a power of 90% for a two sided test at level α = 0.05.


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The following table presents the number of required events together with the number of to be 
randomised and treated patients assuming an accrual period of 18 months and a follow-up 
period of 20 months for different assumed true hazard ratios. However, the follow-up period 
is not fixed but the trial will continue until the necessary number of events has been observed, 
which are confirmed by the adjudication committee. 
The drop-out rate from the trial is assumed to be low (< 1% per year) and is therefore not 
further considered for the determination of sample size. 
Table 7.7: 1
Sample size calculation – not including interim analyses:
Yearly event rate
for HHF+CV 
Death (Placebo)
Hazard 
ratio
Number of events for 90% 
power for HHF+CV 
Death
Number of patients
for 18 months accrual 
and 20 months follow up
10%/Year
0.70
331
1710
10%/Year
0.75
509
2562
10%/Year
0.80
841
4126
10%/Year
0.85
1601
7656
10%/Year
0.90
3814
17814
A hazard ratio of 0.8 was chosen as a conservative estimate based on the results of the 
EMPA-REG OUTCOME trial described in Section 1.2.3
Therefore, at least 841 confirmed primary events should be observed and at least 4126
patients should be randomised and treated in order to achieve a power of 90% assuming a 
true hazard ratio of 0.8.
Including interim analysis with Hwang-Shih-deCani alphaspending with gamma=-8 at 60% 
of information will diminish the power only slightly to 89.98%. 
The event rate and recruitment progress will be assessed in a blinded manner during 
recruitment before any interim unblinding. If the accumulated blinded data suggests a slower 
accrual of primary outcome events over calendar time than originally projected, then the 
number of randomised patients may be increased to a maximum of 6000 patients. 
Operationally, the recruitment period would be extended and could continue up to 6 months 
before the target number of events is expected to be achieved.  The number of confirmed 
primary outcome events will not be affected by this consideration and will remain 841 events. 
Calculations were performed using ADDPLAN6.1.1 by ADDPLAN Inc.


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Based on the abovementioned assumptions, and considering that HHF (first and recurrent) 
will only be tested if the primary endpoint is successful, the chance of showing significance 
for HHF (first and recurrent) in a positive trial is at least 70%.
For the integration of a Japanese population in this global phase III trial, and in order to
comply with the regulatory requirements for bridging the trial results to this population, the
Japanese patients to be randomised will be followed and controlled if necessary. 
Approximately 145 patients are expected to be randomised to each treatment arm for the 
Japanese population.
8
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY
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 SOPs and CRO SOPs, the EU regulation 
536/2014, the Japanese GCP regulations (Ministry of Health and Welfare Ordinance No. 28, 
March 27, 1997) and other relevant regulations. 
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient.
The Investigator will inform the Sponsor or delegate immediately of any urgent safety 
measures taken to protect the trial subjects against any immediate hazard, and also of any 
serious breaches of the protocol or of ICH GCP.
The BI transparency and publication policy can be found on the following web page: 
trials.boehringer-ingelheim.com. The rights of the Investigator and of the Sponsor with 
regard to publication of the results of this trial are described in the Investigator contract. As a 
rule, no trial results should be published prior to finalisation of the CTR.
For Japan only: The rights of the investigator / trial site and of the Sponsor or delegate with 
regard to publication of the results of this trial are described in the investigator contract / trial 
site’s contract. As a general rule, no trial results should be published prior to finalisation of 
the CTR.
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 IRB / Independent Ethics Committee (IEC) and 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 


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regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory, and the ICF and any additional patient-information form 
retained by the Investigator as part of the trial records. A signed copy of the ICF and any 
additional patient information must be given to each patient or the patient’s legally accepted 
representative.
The Investigator must give a full explanation to trial patients based on the patient information 
form. A language understandable to the patient should be chosen, technical terms and 
expressions avoided, if possible. 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 ICF after confirming that the patient understands the contents. The Investigator 
must sign (or place a seal on) and date the ICF. If a trial collaborator has given a 
supplementary explanation, the trial collaborator also signs (or places a seal on) and dates the 
ICF.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the Sponsor's or delegate’s instructions.
The respective procedure for illiterate patients is described in the Appendix 10.1.
The consent and re-consenting process should be properly documented in the source 
documentation.
The patient must be informed that his/her personal trial-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of 
disclosure must also be explained to the patient.
The patient must be informed that his / her medical records may be examined by authorised 
monitors (CML/CL/ Clinical Research Associate (CRA)) or Clinical Quality Assurance 
auditors appointed by BI, by appropriate IRB / IEC members, and by inspectors from 
regulatory authorities.
8.2
DATA QUALITY ASSURANCE
In order to achieve a high level of standardised processes, data collection of efficacy and 
safety endpoints is coordinated centrally:

central lab analysis of efficacy endpoints, biomarkers and safety lab

central IRT for stratification, randomisation and kit allocation at each visit

central adjudication of HHF and cardiovascular events, and hepatic adjudication.
The data management procedures to ensure the quality of the data are described in detail in 
the trial data management and analysis plan available in eTMF.
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.


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8.3
RECORDS
ECRF for individual patients will be provided by the Sponsor or delegate. 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 subject. 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 eCRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the subject may not be sufficient to confirm eligibility for the 
trial and the Investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case the Investigator must make three documented attempts to retrieve 
previous medical records. If this fails, a verbal history from the patient, documented in their 
medical records, would be acceptable.
Before providing any copy of patients’ source documents to the Sponsor or delegate 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 to ensure 
patient confidentiality.
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 eCRF, data must be derived from source documents, for example:

Patient identification: gender, date or year of birth (in accordance with local laws and 
regulations)

Patient participation in the trial (substance, trial number, patient number, date patient was 
informed)

Dates of Patient’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

Adverse events and outcome events (onset date (mandatory), and end date (if available))

SAEs (onset date (mandatory), and end date (if available))

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available)

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 


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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 or delegate will monitor the conduct of the trial by regular on-site monitoring 
visits and in-house data quality review. The frequency of on-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 permit trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the eCRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector (e.g. 
FDA). The CRA and auditor may review all eCRFs and ICFs. The accuracy of the data will 
be verified by direct comparison with the source documents described in Section 8.3.1. The 
Sponsor or delegate will also monitor compliance with the protocol and ICH GCP.
An adaptive approach to clinical trial monitoring will be utilised. This is initiated by an 
assessment of the risk associated with the trial combined with an assessment of critical data 
and processes. A Risk Assessment Mitigation Plan and Integrated Project Management Plan 
collectively document the strategies involved with the implementation of onsite, remote and 
central monitoring activities in order to direct focus to the areas of greatest risk which have 
the most potential impact to safety patient and data quality. Trial oversight is achieved by 
regular review of a report of risk which then influences any required changes to the 
monitoring strategy.
The Investigator /institution will allow on-site trial-related monitoring, audits, IRB/IEC
review and regulatory inspections. Direct access should be granted to all source documents
(paper and e-records) including progress notes, copies of laboratory and medical test results
The CRA and auditor may review all CRFs and ICFs. The accuracy of the data will be 
verified by direct comparison with the source documents described in Section 8.3.1.
The Sponsor/CRO will also monitor compliance with the protocol and ICH GCP.
8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source documents and essential documents (including ISF) 
according to the national or local requirements (whatever is longer) valid at the time of the 
end of the trial.
Sponsor:
The Sponsor or delegate must retain the essential documents according to the Sponsor’s 
SOPs.


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8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal regulatory reporting obligation in accordance with
regulatory requirements. Exemptions from expedited reporting are described in Section 
5.3.7.2.  
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 and in Section 5.5.1.
Patient privacy will be ensured by using patient identification code numbers. 
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook. Treatment data may be given to the patient’s personal physician or to other 
appropriate medical personnel responsible for the patient’s welfare. Data generated as a result 
of the trial need to be available for inspection on request by the participating physicians, the 
Sponsor’s representatives or delegates, by the IRB / IEC and the regulatory authorities.
8.6
TRIAL MILESTONES
The start of the trial is defined as the date of the enrolment of the first patient in the whole 
trial.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial
“Last Patient Out”).
The “Last Patient Drug Discontinuation” (LPDD) date is defined as the date on which the last 
patient at an individual trial site ends trial medication (as scheduled per protocol or 
prematurely). Individual Investigators will be notified of SUSARs occurring with the trial 
medication until 30 days after LPDD at their site.
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the Sponsor 
with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / CA in each participating EU member state will be notified about the trial 
milestones according to the respective laws.
A final report of the clinical trial data will be written only after all patients have completed 
the trial in all countries (EU or non-EU) to incorporate and consider all data in the report.
The Sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient 
(EU or non-EU).


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For Japan only: When the trial is completed, the Investigator should inform the head of the 
trial site of the completion in writing, and the head of the trial site should promptly inform the 
IRB and Sponsor of the completion in writing.
8.7
PROTOCOL VIOLATIONS
For Japan only: The investigator should document any deviation from the protocol regardless 
of their reasons. Only when the protocol was not followed in order to avoid an immediate 
hazard to trial subjects or for other medically compelling reason, the principal investigator 
should prepare and submit the records explaining the reasons thereof to the Sponsor or 
delegate, and retain a copy of the records.
8.8
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
TRIAL RELATED INJURY
For Japan only: In the event of health injury associated with this trial, the Sponsor is 
responsible for compensation based on the contract signed by the trial site


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9
REFERENCES
9.1
PUBLISHED REFERENCES
P13-04190
Seman L, Macha S, Nehmiz G, Simons G, Ren B, Pinnetti S, Woerle HJ, 
Dugi K
Empagliflozin (BI 10773), a potent and selective SGLT2 inhibitor, 
induces dose dependent glucosuria in healthy subjects.
Clin Pharmacol Drug Dev 2 (2), 152 - 161 (2013)
P14-01211
Barnett AH, Mithal A, Manassie J, Jones R, Rattunde H, Woerle HJ, 
Broedl UC, EMPA-REG RENAL Trial Investigators
Efficacy and safety of empagliflozinadded to existing antidiabetes 
treatment in patients with type 2 diabetes and chronic kidney disease: a 
randomised, double-blind, placebo-controlled trial.
Lancet Diabetes Endocrinol 2 (5), 369 - 384 (2014)
P15-00589
Inzucchi SE, Zinman B, Wanner C, Ferrari R, Fitchett D, Hantel S, 
Espadero RM, Woerle HJ, Broedl UC, Johansen OE
SGLT-2 inhibitors and cardiovascular risk: proposed pathways and 
review of ongoing outcome trials.
Diabetes Vasc Dis Res, 12(2), 90-100 (2015)
P15-09541
Chilton R, Tikkanen I, Cannon CP, Crowe S, Woerle HJ, Broedl UC, 
Johansen OE
Effects of empagliflozin on blood pressure and markers of arterial 
stiffness and vascular resistance in patients with type 2 diabetes.
Diabetes Obes Metab 17 (12), 1180 - 1193 (2015)
P15-09840
Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, 
Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi 
SE, EMPA-REG OUTCOME Investigators
Empagliflozin, cardiovascular outcomes, and mortality in type 2 
diabetes.
N Engl J Med 373 (22), 2117 - 2128 (2015)
P15-10667
Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ,
Cushman M, De Ferranti S, Després JP, Fullerton HJ, Howard VJ, 
Huffman MD, Judd SE, Kissela BM, Lackland DT, Lichtman JH, 
Lisabeth LD, Liu S, Mackey RH, Matchar DB, McGuire DK, Mohler III 
ER, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol 
G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Sorlie PD, 
Stein J, Towfighi A, Turan TN, Virani SS, Willey JZ, Woo D, Yeh 
RW, Turner MB, On behalf of the American Heart Association Statistics 
Committee and Stroke Statistics Subcommittee Heart disease and stroke 
statistics - 2015 update: a report from the American Heart Association.


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Circulation 131 (4), e29 - e322 (2015)
P16-01253
Fitchett D, Zinman B, Wanner C, Lachin JM, Hantel S, Salsali A, 
Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE, EMPA-REG 
OUTCOME Trial Investigators
Heart failure outcomes with empagliflozin in patients with type 2 
diabetes at high cardiovascular risk: results of the EMPA-REG 
OUTCOME trial.
Eur Heart J, 37(19), 1526-1534 (2016)
P16-01830
Ferrannini E, Baldi S, Frascerra S, Astiarraga B, Heise T, Bizzotto R, 
Mari A, Pieber TR, Muscelli E
Shift to fatty substrate utilization in response to sodium.glucose 
cotransporter 2 inhibition in subjects without diabetes and patients with 
type 2 diabetes. 
Diabetes 65 (5), 1190 - 1195 (2016)
P16-03760
Clyde W. Yancy, Mariell Jessup, Biykem Bozkurt, Javed Butler, Donald
E. Casey, Mark H. Drazner, Gregg C. Fonarow, Stephen A. Geraci, 
Tamara Horwich, James L. Januzzi, Maryl R. Johnson, Edward K. 
Kasper, Wayne C. Levy, Frederick A. Masoudi, Patrick E. McBride,
John J.V. McMurray, Judith E. Mitchell, Pamela N. Peterson, Barbara
Riegel, Flora Sam, Lynne W. Stevenson, W.H. Wilson Tang, Emily J.
Tsai, Bruce L. Wilkoff
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 (2016)
P16-05920
Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, 
et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and 
chronic heart failure: the Task Force for the Diagnosis and Treatment of 
Acute and Chronic Heart Failure of the European Society of Cardiology 
(ESC), developed with the special contribution of the Heart Failure 
Association (HFA) of the ESC. Eur Heart J, 37, 2129-2200 (2016)


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P16-06807
Wanner C, Inzucchi SE, Lachin JM, Fitchett D, Eynatten M von, 
Mattheus M, et al, EMPA-REG OUTCOME Investigators
Empagliflozin and progression of kidney disease in type 2 diabetes.
N Engl J Med 375 (4), 323 - 334 (2016)
R07-4374
Yusuf S, Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJV, 
Michelson EL, Olofsson B, Ostergren J, CHARM Investigators
Effects of candesartan in patients with chronic heart failure and 
preserved left-ventricular ejection fraction: the CHARM-Preserved trial.
Lancet 362, 777 - 781 (2003)
R09-1400
European Medicines Agency (EMEA). ICH topic M3 (R2) non-clinical 
safety studies for the conduct of human clinical trials and marketing 
authorization for pharmaceuticals: step 4: note for guidance on non-
clinical safety studies for the conduct of human clinical trials and 
marketing authorization for pharmaceuticals (June 2009, 
CPMP/ICH/286/95). http://www.emea.europa.eu 2009
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)
A new equation to estimate glomerular filtration rate.
Ann Intern Med 150 (9), 604 - 612 (2009)
R16-0736
Turnbull FM, Abraira C, Anderson RJ, Byington RP, Chalmers JP, 
Duckworth WC, Evans GW, Gerstein HC, Holman RR, Moritz TE, Neal 
BC, Ninimiya T, Patel AA, Paul SK, Travert F, Woodward M
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Diabetologia 52, 2288 - 2298 (2009)
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Bertram Pitt, M.D., Marc A. Pfeffer, M.D., Ph.D., Susan F. Assmann, 
Ph.D., Robin Boineau, M.D., Inder S. Anand, M.D., Brian Claggett, 
Ph.D., Nadine Clausell, M.D., Ph.D., Akshay S. Desai, M.D., M.P.H., 
Rafael Diaz, M.D., Jerome L. Fleg, M.D., Ivan Gordeev, M.D., Ph.D., 
Brian Harty, M.A., John F. Heitner, M.D., Christopher T. Kenwood, 
M.S., Eldrin F. Lewis, M.D., M.P.H., Eileen O'Meara, M.D., Jeffrey L. 
Probstfield, M.D., Tamaz Shaburishvili, M.D., Ph.D., Sanjiv J. Shah, 
M.D., Scott D. Solomon, M.D., Nancy K. Sweitzer, M.D., Ph.D., Song 
Yang, Ph.D., and Sonja M. McKinlay, Ph.D., for the TOPCAT
Investigators
Spironolactone for heart failure with preserved ejection fraction.
N Engl J Med 370 (15), 1383 - 1392 (2014)
R16-1527
Ambrosy AP, Fonarow GC, Butler J, Chioncel O, Greene SJ, 
Vaduganathan M, Nodari S, Lam CSP, Sato N, Shah AN, 
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The global health and economic burden of hospitalizations for heart
failure: lessons learned from hospitalized heart failure registries.              
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R16-1528
Owan TE, Redfield MM
Epidemiology of diastolic heart failure.
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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
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ventricular ejection fraction: prevalence, therapies, and outcomes.
Circulation 126 (1), 65 - 75 (2012)
R16-1560
Bergenstal RM, Bailey CJ, Kendall DM. Type 2 diabetes: assessing the 
relative risks and benefits of glucose-lowering medications. Am J Med 
2010. 123(4):374.e9-374.e18
R16-2217
Cheng RK, Cox M, Neely ML, Heidenreich PA, Bhatt DL, Eapen ZJ,
Hernandez AF, Butler J, Yancy CW, Fonarow GC
Outcomes in patients with heart failure with preserved, borderline, and
reduced ejection fraction in the Medicare population.
Am Heart J 168 (5), 721 - 730.e3 (2014)
R16-2261
American Diabetes Association. Standards of medical care in diabetes -
2016. Diabetes Care 2016. 39(Suppl 1):S1-S112
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)
R16-2383
Kristensen SL, Preiss D, Jhund S, Squire I, Silva Cardoso J, Merkely 
B, Martinez F, Starling RC, Desai AS, Lefkowitz MP, Rizkala AR, 
Roueau JL, Shi VC, Solomon SD, Swedberg K, Zile MR, McMurray JJ, 
Packer M, PARADIGM-HF Investigators, PARADIGM-HF Committees
Risk related to pre-diabetes mellitus and diabetes mellitus in heart failure 
with reduced ejection fraction: insights from Prospective Comparison of 
ARNI with ACEI to Determine Impact on Global Mortality and 
Morbidity in Heart Failure trial. Circ Heart Fail 9, e002560 (2016)
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 


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with congestive heart failure, Eur Heart J, 2000 Aug;21(16):1368-75
R16-4813
Pocock SJ, Ariti CA, Collier TJ, Wang D
The win ratio: a new approach to the analysis of composite endpoints in 
clinical trials based on clinical priorities.
Eur Heart J 33, 176 - 182 (2012)
R16-4909
Rogers JK, Pocock SJ, McMurray JJV, Granger CB, Michaelson EL, 
Ostergren J, et al
Analysing recurrent hospitalizations in heart failure: a review of 
statistical methodology, with application to CHARM-Preserved.
Eur J Heart Fail 16, 33 - 40 (2014)
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Wanner C, Lachin JM, Inzucchi SE, Fitchett D, Mattheus M, George J, 
Woerle HJ, Broedl UC, von Eynatten M, Zimman B.  Empagliflozin and 
clinical outcomes in patients with type 2 diabetes, established 
cardiovascular disease and chronic kidney disease.  Circ. (2017) 
9.2
UNPUBLISHED REFERENCES
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Empagliflozin Investigator’s Brochure, Current Version
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Empa_EMA responses to RSI_1245.25_stats-outputs-ru0765
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Lewis-D’Agostino D, Fagan N, Wu J, Stanley J.  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.  1245.66 Clinical Trial Report, 28 
Mar 2017
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10 APPENDICES
10.1 INCLUSION OF ILLITERATE PATIENTS
10.1.1 Patient reported outcome forms 
In the event of recruiting an illiterate patient, the following process should be followed with 
respect to completion of the EQ-5D self-report questionnaire and the KCCQ:

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 questions will be read 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 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 EQ-5D questionnaire and the 
KCCQ should be performed in a quiet area where the patient can consider his/her responses 
to both the descriptive system and VAS.
10.1.2 Patient information and informed consent (including biobanking)
In the event of recruiting an illiterate patient, the following process should be followed with
respect to patient information and informed consent:

The designated site personnel performing the informed consent process will read the 
trial approved patient information sheet and ICFs to the patient, and explain the 
details of the trial, all in the presence of an impartial witness.

This impartial witness must be literate, and can be the patient’s relative or caregiver, 
or a member of staff employed by the clinic but not part of the immediate trial team. 
In addition, if there are any further local regulations with respect to the consent of
illiterate patients, these should also be followed.

The requirements of the trial will be explained thoroughly and the patient will be 
given ample time to ask questions and consider his/her participation. If he/she wishes, 
the patient can take the patient information sheet and ICFs home for further 
consideration.

If patient agrees to take part in the trial, he/she would then return to the clinic for the 
consent process to be completed. The site designated personnel responsible for this 
process will confirm that the patient has no further questions in the presence of the 


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same impartial witness (if the patient returns on another day). If a different impartial 
witness is present, the entire informed consent process must be repeated.

Participating patients will provide a thumb impression or make a mark (or signature if 
the patient is able to sign him/herself) on the signature section of the ICFs.

The date of the patient’s signature will be left blank as the patient is illiterate.
However, if the patient is able, he/she will date the mark/signature personally.

The impartial witness or the site designated personnel may write the name of the 
patient on the ICFs.

The impartial witness should enter his/her name, sign and personally date the witness 
section of the ICFs. In countries where local data protection regulation permits it, the 
address or identification number of the impartial witness should also be entered. The 
signature then attests that the content of the patient information sheet and ICFs was 
accurately explained to the patient, who apparently understood and freely gave 
consent to participate in the trial.

The designated site personnel also signs and personally dates the ICFs.

The same process as outlined above will be followed for obtaining consent for the 
optional sampling for biobanking (including DNA).


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10.2 PATIENT REPORTED OUTCOMES
10.2.1 EQ-5D 


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10.2.2 KCCQ 


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10.3 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
10.4 MODIFIED RANKIN SCALE
Scale
Description
0
No symptoms at all
1
No significant disability despite symptoms; able to carry out all usual duties and 
activities
2
Slight disability; unable to carry out all previous activities, but able to look after 
own affairs without assistance
3
Moderate disability; requiring some help, but able to walk without assistance
4
Moderately severe disability; unable to walk without assistance and unable to 
attend to own bodily needs without assistance
5
Severe disability; bedridden, incontinent and requiring constant nursing care and 
attention
6
Dead
10.5 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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11 DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1 GLOBAL AMENDMENT 1
Date of CTP revision
23 Nov 2017
EudraCT number
2016-002278-11
BI Trial number
1245.110
BI Investigational Product(s)
Empagliflozin
Title of protocol
A phase III randomised, double-blind trial to 
evaluate efficacy and safety of once daily 
empagliflozin 10 mg compared to placebo, in 
patients with chronic Heart Failure with preserved 
Ejection Fraction (HFpEF).
Section to be changed
Clinical Trial Protocol Synopsis:  Main criteria
for inclusion
Description of change
Patients with chronic HF diagnosed for at least 3 
months before Visit 1 and currently in HF NYHA 
class II-IV
Was changed to:
Patients with chronic HF diagnosed for at least 3 
months before Visit 1 and currently in HF NYHA
HF class II-IV
Rationale for change
Editorial correction
Section to be changed
Clinical Trial Protocol Synopsis:  Main criteria for 
inclusion
Description of change

Chronic HF with preserved EF defined as 
LVEF > 40 % per local reading (obtained 
by echocardiography, radionuclide 
ventriculography, invasive angiography, 
MRI or CT), and no prior measurement of 
LVEF ≤ 40% under stable conditions. The 
EF must have been obtained and 
documented at visit 1or within 6 months 
prior to Visit 1 and more than 90 days after 
any MI (as defined in exclusion criterion 
No. 1)
Was changed to:

Chronic HF with preserved EF defined as 
LVEF > 40 % per local reading (obtained 
by echocardiography, radionuclide 


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ventriculography, invasive angiography, 
MRI or CT), and no prior measurement of 
LVEF ≤ 40% under stable conditions. A 
historical LVEF may be used if it was 
measured within 6 months prior to visit 
1, and more than 90 days after any 
myocardial infarction (as defined in 
exclusion criterion No.1) or the LVEF 
may be measured after study consent has 
been obtained. The LVEF must be 
documented in an official report prior to 
randomization. The EF must have been 
obtained and documented at visit 1or within 
6 months prior to Visit 1 and more than 90 
days after any MI (as defined in exclusion 
criterion No. 1)
Rationale for change
To clarify that the LVEF must be documented in an 
official report prior to randomization and that a 
historical LVEF may be used as long as the LVEF 
was measured within 6 months prior to visit 1.
Section to be changed
Clinical Trial Protocol Synopsis:  Duration of 
treatment
Description of change
•
4-21 days screening period 
Was changed to:
•
4-21 28 days screening period 
Rationale for change
To provide sites with additional time to complete 
all screening procedures.
Section to be changed
Clinical Trial Protocol Synopsis:  Duration of 
treatment
Description of change
Approximately 20-38 months double-blind 
treatment until the required number of primary 
events is reached with empagliflozin or placebo.
Was changed to:
Approximately 20-38 months double-blind 
treatment until the required number of primary 
events is reached with empagliflozin or placebo.
The study was designed based on an assumption 
of 18 months recruitment and an event rate of 
10%.  The actual length of the recruitment 
period may be extended beyond 18 months and 
the follow-up period may be adjusted to achieve 
the 841 confirmed primary outcome events.  The 
estimated total trial duration and length of the 
double-blind treatment for each patient will 
vary accordingly.


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Rationale for change
To clarify that the overall recruitment and follow-
up period will vary depending on the observed 
event rate.
Section to be changed
Clinical Trial Protocol Synopsis:  Duration of 
treatment
Description of change
The trial will continue until required number of 
adjudicated primary endpoint events have occurred 
to be able to comply with the objective of the trial.
Was changed to:
The trial will continue until the required number of 
adjudicated primary endpoint events have occurred 
to be able to comply with the objective of the trial.
Rationale for change
Editorial correction
Section to be changed
Clinical Trial Protocol Synopsis: Endpoints
Description of change
Other secondary endpoints are:
Time to first occurrence of sustained reduction of 
≥40% eGFR (CKD-EPI)cr or
Was changed to:
Time to first occurrence of chronic dialysis or
renal transplant or sustained reduction of ≥40% 
eGFR (CKD-EPI)cr or
Rationale for change
The requirement to initiate chronic dialysis or a 
renal transplant is considered to indicate a 
sustained reduction in renal function compared to 
baseline.  Dialysis at baseline is considered 
exclusionary for study entry.
Section to be changed
Flow Chart
Description of change
Visit 1 window was revised from -21 to -4 days to -
28 days to -4 days
Rationale for change
To provide sites with additional time to complete 
all screening procedures.
Section to be changed
Flow Chart
Description of change
ECG to be collected at visit 1 instead of at visit 2.
Rationale for change
To allow the investigator to determine if patient is 
in AF at time of screening.
Section to be changed
Flow Chart Footnote #6
Description of change
Informed consent may be obtained prior to visit 1 
in order to give time to collect medical records. 
Visit 1 should be performed within 30 days of 
signing the informed consent form (ICF).
Was changed to: 
Informed consent may be obtained prior to visit 
1 in order to give time to collect medical 


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records. All visit 1 procedures should be 
performed within 30 28 days of signing the 
informed consent form (ICF).
Rationale for change
Footnote was revised to ensure consistency with 
flow chart visit window.
Section to be changed
Flow Chart Footnote #10
Description of change
Protocol specified outcome events should be 
collected on the appropriate eCRF page only. The 
outcome events which are exempted from SAE 
reporting are listed in Section 5.3.6.
Was changed to:
Protocol specified outcome events should be 
collected on the appropriate eCRF page only. The 
outcome events which are exempted Exemptions
from SAE reporting on the SAE form are listed
specified in Section 5.3.7.
Rationale for change
Process clarification for reporting of outcome 
events.  Correction to the section number 
referenced.
Section to be changed
Flow Chart Footnote # 12
Description of change
For the 12-lead ECG done at the baseline and EOT 
visit, the interpretation of the tracing must be made 
locally by a qualified physician and documented on 
the ECG section of the eCRF. 
Was changed to:
For the 12-lead ECG done at the baseline
screening and EOT visit, the interpretation of the 
tracing must be made locally by a qualified 
physician or appropriately qualified designee 
and documented on the ECG section of the eCRF.
Rationale for change
Footnote was updated to reflect ECG collection at 
visit 1 versus visit 2.  ECGs can be interpreted by 
appropriate qualified site staff.
Section to be changed
Flow Chart Footnote #14
Description of change
For the screening Visit 1, the safety laboratory is 
limited to liver transaminases, alkaline 
phosphatase, serum creatinine and urinalysis. 
Patients do not have to be fasting.
Was changed to:
For the screening Visit 1, the safety laboratory is 
limited to liver transaminases, alkaline 
phosphatase, serum creatinine and urinalysis 
haematology panel. Patients do not have to be 
fasting.


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Rationale for change
Routine urinalysis is not required to assess 
eligibility however haematology panel is required 
to assess exclusion criteria #14. 
Section to be changed
Abbreviations
Description of change
The following abbreviations were added:
AF:  Atrial fibrillation or Atrial flutter
HRQOL:  Health-related quality of life
KA:  Ketoacidosis
NCC:  National Coordinator Committee
NYHA definition was revised from New York 
Heart Association Classification to:
New York Heart Association Classification
The following abbreviations were removed as they 
are not used in the protocol.
ACR:  Albumin creatinine ratio
BNP: B-type Natriuretic Peptide
CHF:  chronic heart failure
EDC:  electronic data capture
TDMAP:  trial data management and analysis plan
UGE:  urinary glucose excretion
Rationale for change
Administrative corrections
Section to be changed
1.1 Medical Background
Description of change
Chronic heart failure (HF) is a progressive 
syndrome characterised by the inability of the heart 
to provide adequate blood supply to meet the 
metabolic demand of different tissues or do it at the 
expense of elevated left ventricle filling pressure.
Was changed to:
Chronic heart failure (HF) is a progressive 
syndrome characterised by the inability of the heart 
to provide adequate blood supply to meet the 
metabolic demand of different tissues or to be able 
to do it so only at the expense of elevated left 
ventricle filling pressure.
Rationale for change
Editorial correction.
Section to be changed
1.2 Drug Profile
Description of change
Empagliflozin has been developed for the treatment 
of T2DM, and has received marketing approval in 
various regions including the European Union, 
Latin America, USA and Japan where it is 
marketed under the brand name Jardiance®.
Was changed to:
Empagliflozin has been developed for the treatment 
of T2DM, and has received marketing approval in 


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various regions including, for example, the 
European Union, Latin American countries, USA 
and Japan where it is marketed under the brand 
name Jardiance®.
Rationale for change
Editorial correction.
Section to be changed
2.3 Benefit Risk Assessment
Description of change
The following information was added:
In this trial, the effect of empagliflozin will be 
evaluated in HF patients.  DM is known to be a 
frequent and clinically important co-morbidity in 
HF patients.  To evaluate this important co-
morbidity, HF patients across the DM spectrum 
(i.e., T1DM, T2DM, pre-diabetes) as well as HF 
patients who do not have DM, will be included in 
this trial.    
Special safety considerations are required for 
patients with T1DM, and several safety monitoring 
strategies will be employed, including training of 
investigators and education of patients on the risk 
and prevention strategies for  ketoacidosis (KA) 
and diabetic ketoacidosis (DKA).  Since an SGLT-
2 inhibitor may alter the typical presentation of this 
condition, patients will receive a home monitoring 
device to measure blood ketones and a diary for 
patients to record their blood glucose, ketone 
values, and insulin intake.  Patients with T1DM 
will also be required to carry  a trial information 
card which includes information about the possible 
altered presentation of KA to be presented to health 
care professionals should the patient be seen in an 
urgent care setting.  For further details refer to 
Section 4.2.1.
As outlined above, inclusion of patients who do not 
have diabetes is also allowed in this trial. It has 
been shown that 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 RI. Because 
in the EMPA REG Outcome study no difference in 
CV benefit was detected for patients with RI vs the 
overall population, it is it is hypothesized that this 
amount of glucosuria is not the main factor to 
obtain CV effects with empagliflozin.
There are no long-term safety data for 


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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 
occurrences of symptomatic hypoglycemia were 
detected [U12-2707-01]. It is noted that in patients 
with T2DM the risk of hypoglycemia was only 
increased with empagliflozin compared to the
placebo group in patients who were concomitantly 
treated with insulin or a sulfonylurea.  Further, in a 
mechanistic study [c11963611-01], subjects 
without DM were shown to increase endogenous 
glucose production in response to glucosuria after 
administration of empagliflozin.  As a result, blood 
glucose levels remained in the normal range for 
these individuals [P16-01830] Therefore, it is 
scientifically reasonable to hypothesize that in non-
diabetic patients, with no medical indication for 
insulin or sulfonylurea treatment that the risk of 
hypoglycemia associated with empagliflozin 
treatment would be lower than in patients with 
T2DM.  
Because the mode of action, blockade of the 
SGLT2 with consequent glucosuria, is the same in 
patients with and without diabetes, although to 
different degrees, it is considered likely that the 
tolerability of empagliflozin may be no less 
favourable in patients without DM compared to 
patients with T2DM. 
There is also currently limited therapeutic 
experience with empagliflozin in patients aged 85 
years and older.  The prevalence of HF 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.  Special caution 
should be used in these patients, who may be at 
increased risk of adverse consequences attributable 
to empagliflozin-related volume depletion.


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Many patients with chronicHF have RI, and to 
ensure that the trial results reflect this population, 
patients with eGFR ≥ 20 ml/min/1.73m2 can be 
included.  In the EMPA-REG OUTCOME trial, the 
cardiovascular benefits of empagliflozin were not 
driven by its pharmacological effect of lowering 
blood glucose and were consistently noted  in 
patients with different degrees of RI, including 
patients with eGFR between > 30 and < 45 
ml/min/1.37m2.  In previous trials in patients with 
T2DM the safety profile in moderate and severe RI 
were comparable to the overall trial population 
[P17-10453].  Renal safety will be closely 
monitored throughout the trial.  Refer to section 
5.3.4.1. and 5.3.7.1.
Rationale for change
Information was added to provide the risk benefit 
assessment for inclusion of patients who are 
elderly, have T1DM or may not have DM or with 
reduced renal function.
Section to be changed
2.3 Benefit Risk
Description of change
The following was deleted.
Special attention will be paid to prevent metabolic 
acidosis, KA and diabetic ketoacidosis (DKA). For 
further details refer to Section 4.2.1.
Rationale for change
Information was included in the 3rd paragraph in 
section 2.3.  
Section to be changed
Figure 3.1:1
Description of change
An asterisk was added to: “20-38 months” in 
Figure 3.1:1
Rationale for change
To clarify that the overall recruitment and follow-
up period will vary depending on the observed 
event rate.
Section to be changed
3.1 Overall trial design and plan
Description of change
The estimated length of the double-blind treatment 
will vary from approximately 20 to 38 months for 
each patient.  The trial duration may be prolonged 
in case the number of patients and/or primary 
endpoint events is not reached within the planned 
timelines.
Was changed to:
The actual estimated length of the double-blind 
treatment will vary from approximately 20 to 38 
months for each patient recruitment period may 
be extended beyond 18 months and the follow-


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up period may be adjusted to achieve to achieve 
the 841 confirmed primary outcome events.  The 
estimated total trial duration and length of the 
double-blind treatment for each patient will 
vary accordingly. The trial duration may be 
prolonged in case the number of patients and/or 
primary endpoint events is not reached within the 
planned timelines.
Rationale for change
To clarify that the overall recruitment and follow-
up period will vary depending on the observed 
event rate.
Section to be changed
3.1 Overall trial design and plan
Description of change
A footnote was added for Figure 3.1:1
* based on an 18 months recruitment and event rate 
as outlined as Section 7.7.
Rationale for change
To clarify that the overall recruitment and follow-
up period will vary depending on the observed 
event rate.
Section to be changed
3.1.1 Administrative structure of the trial
Description of change
The following paragraph was added: 
A National Coordinators Committee (NCC) will be 
established and will consist of leading expert(s) in 
each participating country.  The national 
coordinators will support the Sponsor in the 
successful execution of the trial.  The NCC will 
have an advisory function in the trial.  The tasks 
and responsibilities will be agreed in contracts 
between the NCC member and the Sponsor.
Rationale for change
A national coordinator committee was set up to 
advise on the trial.
Section to be changed
3.1.1 Administrative structure of the trial
Description of change
Measures are in place to ensure blinding of the 
Sponsor, ExSC, SEC, CRO and all other trial 
participants.
Was changed to:
Measures are in place to ensure blinding of the 
Sponsor, ExSC, SEC, NCC, CRO and all other 
trial participants.
Rationale for change
The NCC will also be blinded in a similar manner 
to other committees, sponsor and CRO.
Section to be changed
3.3 Selection of trial population


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Description of change
Approximately 500 trial centres will participate to 
ensure that the estimated 4126 patients are 
randomised to trial medication and complete the 
trial.
Was changed to:
Approximately 500 560 trial centres will 
participate to ensure that the estimated 4126 
patients are randomised to trial medication and 
complete the trial.
Rationale for change
Additional sites will participate in the trial.
Section to be changed
3.3.2 Inclusion Criteria #4
Description of change
The EF must have been obtained and documented 
at Visit 1 or within 6 months prior to Visit 1, and 
more than 90 days after any myocardial infarction 
(as defined in exclusion criterion No. 1)
Was changed to: 
A historical LVEF may be used if it was 
measured within 6 months prior to visit 1, and 
more than 90 days after any myocardial 
infarction (as defined in exclusion criterion 
No.1) or the LVEF may be measured after study 
consent has been obtained. The LVEF must be 
documented in an official report prior to 
randomization.The EF must have been obtained 
and documented at Visit 1 or within 6 months prior 
to Visit 1, and more than 90 days after any 
myocardial infarction (as defined in exclusion 
criterion No. 1)
Rationale for change
To clarify that the LVEF must be documented in an 
official report prior to randomization and that a 
historical LVEF may be used as long as the LVEF 
was measured within 6 months prior to visit 1.
Section to be changed
3.3.2 Inclusion Criteria footnote a
Description of change
-
not permanently sterilised (e.g., tubal 
occlusion, hysterectomy, bilateral 
oophorectomy or bilateral salpingectomy).
Was changed to:
-
not permanently sterilised (e.g., tubal 
occlusion, hysterectomy, bilateral 
oophorectomy or bilateral salpingectomy).
Rationale for change
Tubal occlusion is considered to be a highly 
effective method of contraception but is not 
considered to be permanent sterilisation.
Section to be changed
3.3.3 Exclusion Criteria #8


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Description of change
Atrial fibrillation or atrial flutter with a resting 
heart rate > 110 bpm documented by ECG at Visit 
2 (Randomisation)
Was changed to:
Atrial fibrillation or atrial flutter with a resting 
heart rate > 110 bpm documented by ECG at Visit 
2 1 (Randomisation Screening)
Rationale for change
ECG to be performed at visit 1 instead of visit 2.  
Therefore exclusion criterion is updated 
accordingly.
Section to be changed
3.3.3 Exclusion Criteria # 21
Description of change
Treatment with any SGLT-2 inhibitor or combined 
SGLT-1 and 2 inhibitor within 1 week prior to 
Visit 1 or during screening period until Visit 2 
(Randomisation)
Was changed to:
Current use or prior use of a Treatment with any
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.
Rationale for change
Patients should not have standard of care therapy 
withheld or changed for the purposes of study 
enrolment.  
Section to be changed
3.3.4.1 Removal of individual patients
Description of change
The following was added to option 3.
If possible, other AE’s and concomitant therapy 
changes to be recorded. Sites should encourage 
the patient to return to the clinic for the final 
study visit.
Rationale for change
To encourage complete reporting of all relevant 
information for patients who have discontinued 
study drug.
Section to be changed
5.1.2 Secondary endpoint(s)
Description of change
Time to first occurrence of sustained* reduction of 
≥40% eGFR (CKD-EPI)cr or
Was changed to:
Time to first occurrence of chronic dialysis or
renal transplant or sustained* reduction of ≥40% 
eGFR (CKD-EPI)cr or


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Rationale for change
The requirement to initiate chronic dialysis or renal 
transplant is considered to indicate a sustained 
reduction in renal function compared to baseline.  
Dialysis at baseline is considered exclusionary for 
study entry.
Section to be changed
5.1.2 Secondary endpoint(s)
Description of change
Added to this section: 
Chronic dialysis is defined as dialysis with a 
frequency of twice per week or more often for at 
least 90 days.
Rationale for change
The requirement to initiate chronic dialysis is 
considered to indicate a sustained reduction in 
renal function compared to baseline.
Section to be changed
5.2.1 KCCQ
Description of change
Added to this section: 
To assess the further endpoint of change from 
baseline in KCCQ based on patient-preferred 
outcome at week 52, the investigator or designee 
will be required to ask the patient one additional 
question about which domain is the most 
difficult for the patient to cope with.  The 
response to this question will be recorded in the 
eCRF.
Rationale for change
To clarify the evaluation of the further endpoint of: 
Change from baseline in KCCQ based on patient-
preferred outcome at week 52
Section to be changed
5.2.2 New York Heart Association classification
Description of change
The classification of patient’s physical activity 
according to NYHA will be performed at all on-site 
and telephone visits until end of the trial. 
Was changed to:
The classification of patient’s physical activity 
according to NYHA will be performed at all on-site 
and telephone visits until end of the trial. If a visit 
is designated as an on-site visit but is conducted 
by phone, the NYHA functional classification 
must be performed.
Rationale for change
To clarify when NYHA function classification 
should be performed.
Section to be changed
5.2.5 Blood Pressure
Description of change
SBP and DBP as well as pulse rate (electronically 
or by palpation, count for 1 minute) will be 
measured after 5 minutes of rest in the seated 
position according to the Flow Chart. All 


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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 in Appendix 10.6.
Was changed to:
SBP and DBP as well as pulse rate (electronically 
or by palpation, count for 1 minute) will be 
measured after 5 minutes of rest in the seated 
position according to the Flow Chart. At visit 1, 
after the patient has rested quietly, in the seated 
position for five minutes, three blood pressure 
measurements will be taken and recorded in the 
eCRF. The mean of these 3 blood pressure 
values will be used to determine eligibility.  At 
subsequent visits, All blood pressure recordings 
should be made measured using a similar type of 
and validated certified blood pressure recording 
instrument on the same arm, when possible. 
Further details on blood pressure measurement 
procedure are provided in Appendix 10.6.
Rationale for change
Detailed procedure for measurement of blood 
pressure is not required as changes in SBP and 
DBP will be analysed descriptively.
Section to be changed
5.3.4.5 Ketone monitoring in patients with type 1 
diabetes (T1DM) only
Description of change
New section added:
5.3.4.5 Ketone monitoring in patients with type 1 
diabetes (T1DM) only
Patients with T1DM will be provided an electronic 
device to determine their ketone concentration (i.e. 
a blood glucose monitoring device/meter that is 
also capable of measuring blood ketones).  
Patients should be advised to measure their ketones 
at least one daily, ideally after fasting for at least 6 
hours, throughout the treatment period and for 5 
days after empagliflozin / placebo treatment has 
been stopped.  Patients should be reminded to test 
their ketones in case of any symptoms of KA, e.g. 
nausea, vomiting, and abdominal pain.  Patients 
must be reminded about the signs and symptoms of 
KA, on the interpretation of ketone values 
measured via the meter, and on appropriate action 
to take in the event of increased ketone levels (see 
below).  In the same way as during routine clinical 
care, patients should also be reminded to test for 


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ketones in case of repeatedly elevated blood 
glucose levels (e.g. >11.1 mmol/L (> 200 mg/dL)) 
which cannot be explained.  
Patients will be instructed that in the event of 
increased ketones, they are to either follow the 
rules given by their treating physician (e.g. 
increased fluid intake and/or insulin bolus) or 
contact their trial site.  Blood glucose and ketone 
levels should be checked every 1-2 hours until they 
are back in a range considered to be normal.  
Patients are to be instructed to immediately refer 
themselves to hospital and/or the Investigator, or to 
contact an emergency physician in case of a blood 
ketone concentration > 1.5 mmol/L (as indicated in 
the meter manual).  In case of a suspected KA a 
blood gas test (pH, bicarbonate) should be 
performed locally at the earliest opportunity and 
the patient treated according to local medical 
judgement.  The results of the blood gas test will be 
collected on the relevant page of the eCRF.
Patients not adhering to the instructions given by 
the Investigator should be retrained at the earliest 
possible opportunity.  The risk benefit for the 
patient continuing on study treatment should be
considered.
Rationale for change
To include, in the protocol, the ketone monitoring 
strategy for patients with T1DM.  Information is 
currently contained in the ISF.
Section to be changed
5.3.5 Electrocardiogram
Description of change
ECGs will be performed at Visit 2, and at the EOT 
Visit as indicated in the Flow Chart. Printed paper 
traces from 12-lead ECGs (I, II, III, aVR, aVL, 
aVF, V1-V6) will be collected. They should be 
evaluated, signed, dated and commented upon by 
the treating physician/Investigator and stored 
locally.
Was changed to:
ECGs will be performed at Visit 2, and at the EOT 
Visit visits as indicated in the Flow Chart. Printed 
paper traces from 12-lead ECGs (I, II, III, aVR, 
aVL, aVF, V1-V6) will be collected. They should 
be evaluated, signed, dated and commented upon 
by the treating physician/Investigator or 
appropriately qualified designee and stored 
locally.


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Rationale for change
ECG to be measured at visit 1 instead of at visit 2.  
ECGs can be interpreted by appropriate qualified 
site staff.
Section to be changed
5.3.7.1 Definitions of AEs
Description of change
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. Any suspected 
transmission via a medicinal product of an 
infectious agent is considered a serious adverse 
reaction.
Was changed to:
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. Any suspected 
transmission via a medicinal product of an 
infectious agent is considered a serious adverse 
reaction.
Rationale for change
Editorial correction.
Section to be changed
5.3.7.1 Definitions of AEs
Description of change
AESIs need to be reported to the Sponsor’s/CRO’s 
Pharmacovigilance Department within the same 
timeframe that applies to SAE, see below
Was changed to:
AESIs need to be reported to the Sponsor’s/CRO’s 
Pharmacovigilance Department within the same 
timeframe that applies to SAE, see below Section 
5.3.7.2
Rationale for change
Editorial clarification.
Section to be changed
5.3.7.2 Adverse event collection and reporting
Description of change
From signing the ICF onwards through the 
Residual Effect Period (REP), until individual 
patient's end of trial participation:
Was changed to:
From signing the ICF onwards through the 
Residual Effect Period (REP), until individual 
patient's end of trial participation:
Rationale for change
Editorial clarification.
Section to be changed
5.3.7.2 Adverse event collection and reporting


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Description of change

After the individual patient’s end of trial:
The Investigator does not need to actively monitor 
the patient for AEs, but must report relevant SAEs 
and relevant AESIs of which the Investigator may 
become aware of.
Was changed to:

After the individual patient’s end of trial:
The Investigator does not need to actively 
monitor the patient for AEs, but must report 
relevant related SAEs and relevant 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 on 
the eCRF.
The rules for Adverse Event Reporting 
exemptions still apply.
Rationale for change
Clarification that related SAEs and AESIs are to be 
reported and that exemptions to AE reporting will 
apply.
Section to be changed
5.3.7.2:1  Timelines for adverse event collection
Description of change
Remaining F-U (~23days)
Was changed to:
Remaining F-U (~23days)
And:
Relevant SAEs and AESIs of which the 
investigator may subsequently become aware of
Was changed to:
Relevant Related SAEs and related AESIs of 
which the investigator may subsequently become 
aware of
Rationale for change
To clarify the requirement to report related SAEs 
and AESIs at the end of the trial and to clarify that 
the follow-up period is not contained to 23 days.
Section to be changed
5.3.7.2 Adverse event collection and reporting
Description of change
The following text was moved from above Figure 
5.3.7.2:1 to below.
The REP (timeframe after last dose of trial 
medication when measurable drug levels or 
pharmacodynamic effects are still likely to be 
present) is defined as 7 days after the last trial 


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medication application. All AEs which occurred 
through the treatment phase and throughout the 
REP will be considered as on treatment. Please also 
refer to Section 7.3.4.
Events which occurred after the REP will be 
considered as post treatment events.
Rationale for change
Editorial correction
Section to be changed
5.3.7.2 Adverse event collection and reporting
Description of change
The Investigator must report all non-exempted 
SAEs, AESI and any non-serious AE relevant for 
the reported SAE, immediately (within 24 hours) 
on the BI SAE form. The same timeline applies if 
follow-up information becomes available.
Was changed to:
The Investigator must report all non-exempted 
SAEs, AESIs and any non-serious AEs which are
relevant for the reported SAE or AESI, on the BI 
SAE form immediately (within 24 hours) on the BI 
SAE form to the specified unique entry point 
(contact details provided in the ISF). The same 
timeline applies if follow-up information becomes 
available. In specific occasions the Investigator 
could inform the Sponsor/CRO 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, appropriate follow-up forms have to be 
provided.  For follow-up information the same 
rules and timeline apply as for initial 
information.
Rationale for change
Editorial clarifications.
Section to be changed
5.3.7.2 Adverse event collection and reporting
Description of change
The following text was removed:
For Japan only: All SAEs must be reported 
immediately to the head of the trial site. 
Any protocol exempted event that occurs prior to 
randomisation and fulfils the criteria of an SAE 
will be reported immediately (within 24 hours) by 
the Investigator on the BI SAE form via fax 
immediately (within 24 hours) to the 
Sponsor's/CRO’s unique entry point (country 
specific contact details will be provided in the ISF); 


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however, if the patient has been randomised, the 
exempted events will not be reported as SAEs to 
the sponsor and no causality assessment will be 
performed. These events will be entered only on 
the AE eCRF pages (within 24 hours). The 
investigator is also required to provide all 
defined supporting documentation.
In specific occasions the Investigator could inform 
the Sponsor/CRO upfront via telephone. This does 
not replace the requirement to complete and fax the 
BI SAE form.
If any exempted event or any other adverse event 
(serious or non-serious) occurs, the investigator or 
attending physician has the responsibility and will 
take direct and appropriate action to provide care 
for the patient and to decide whether or not the trial 
medication should be discontinued.
An independent Data Monitoring Committee 
(DMC) will monitor the safety data in the trial on 
an ongoing basis. Reported SAEs occurring after 
randomisation that are protocol exempted events 
will be collected in the eCRFs and evaluated by the 
DMC. These events will not be collected on SAE 
forms for expedited review or reporting.
Aggregate analysis of endpoint data to determine 
any potential benefit or risk and to ensure patient 
safety during the clinical trial will be performed on 
a regular basis by the DMC.
With receipt of any further information to these 
events, appropriate follow-up forms have to be 
provided. For follow-up information the same rules 
and timeline apply as for initial information.
Rationale for change
Editorial clarification.  Information is found 
elsewhere in Section 5.3.7.2.
Section to be changed
5.3.7.2 Adverse event collection and reporting
Description of change
For each AE, the Investigator should provide the 
information requested on the appropriate eCRF 
pages and the paper SAE form.
Was changed to:
For each AE, the Investigator should provide the 
information requested on the appropriate eCRF 
pages and the paper SAE form, if applicable.
Rationale for change
To clarify that not all AEs will need to be reported 
on the SAE form.


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Section to be changed
5.3.7.2 Adverse event collection and reporting
Description of change
Once a patient has been enrolled into this clinical 
trial and has taken trial medication, the Investigator 
must report immediately (within 24 hours) a 
potential drug exposure during pregnancy (DEDP) 
to the Sponsor’s/CRO’s unique entry point 
(country-specific contact details will be provided in 
the ISF).
Was changed to:
Once a patient has been enrolled into this clinical 
trial and has taken trial medication, the Investigator 
must report any drug exposure during pregnancy 
(DEDP) immediately (within 24 hours) to the 
Sponsor’s/CRO’s unique entry point (country-
specific contact details will be provided in the ISF).
Rationale for change
Editorial clarification.
Section to be changed
5.3.7.2 Adverse event collection and reporting
Description of change
A list of serious adverse events that commonly 
occur in the trial population or which are 
components of trial endpoints are exempted from 
expedited reporting.
Was changed to:
A list of serious adverse events that commonly 
occur in the trial population or which are 
components of trial endpoints are exempted from 
expedited reporting on the SAE form, if the event 
onset is after randomization and the event does 
not qualify as AESI.
Rationale for change
Clarification on handling of exempted events.
Section to be changed
5.3.7.2 Adverse event collection and reporting
Description of change
Regardless of relationship to trial medication, 
these events will not be reported by the Sponsor 
to regulatory agencies or ethics committees in 
an expedited manner.
Was changed to:
Regardless of relationship to trial medication, 
these events will not be reported by the Sponsor 
to regulatory agencies or ethics committees in 
an expedited manner unless they qualify as an 
AESI (for definition of AESI, see above) with 
fulfilment of expedited regulatory safety 
reporting requirements.
Rationale for change
To clarify handling of AESIs and exempted 
reporting.


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Section to be changed
5.3.7.2 Adverse event collection and reporting
Description of change
Based on the same conclusion that it is not possible 
to perform a causality assessment on these events 
based on a single case, the trial investigators are 
exempted from performing a causality assessment 
and reporting these adverse events on the SAE 
form to the Sponsor.
All exempted events will be collected 
systematically on the eCRF (within 24 hours) from 
the time of randomisation throughout follow up.
Was changed to:
Based on the same conclusion that it is not possible 
to perform a causality assessment on these events 
based on a single case, the trial investigators are 
exempted from performing a causality assessment 
and reporting these serious adverse events on the 
SAE form to the Sponsor, if event onset is after 
randomization and the event does not qualify as 
AESI.
All such exempted events will must be collected 
systematically on the eCRF (within 24 hours) from 
the time of randomisation throughout follow up.
The investigator is also required to provide all 
defined supporting documentation (ref to ISF). 
If the events specified above occur before 
randomization, they are not exempted from 
immediate reporting on the SAE form.  In 
addition, whenever such events meet the 
definition of an AESI, then no exemption 
applies, regardless of occurrence before or after 
randomization.
An independent Data Monitoring Committee 
(DMC) will monitor the safety data in the trial 
on an ongoing basis. Reported SAEs occurring 
after randomisation that are protocol exempted 
events will be collected in the eCRFs and 
evaluated by the DMC. These events will not be 
collected on SAE forms for expedited review or 
reporting.
Aggregate analysis of endpoint data to 
determine any potential benefit or risk and to 
ensure patient safety during the clinical trial 
will be performed on a regular basis by the 
DMC.


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If any exempted event or any other adverse 
event (serious or non-serious) occurs, the 
investigator or attending physician has the 
responsibility and will take direction and 
appropriate action to provide care for the 
patient and to decide whether or not the trial 
medication should be discontinued.
Rationale for change
Additional clarification on handling of exempted 
events.
Section to be changed
5.4.1 Pharmacokinetic Endpoints
Description of change
The PK sampling will be done from a limited 
number of randomised patients (approximately 
1650 patients) and at pre-selected sites only.
Was changed to: 
The PK sampling will be done from a limited 
number of randomised patients (approximately 
1650 patients) and at sites in pre-selected sites
countries only.
Rationale for change
To clarify that PK samples will be collected from 
all sites within a country selected for PK collection.
Section to be changed
5.5.1.1. Methods and timing of sample collection
Description of change
Approx.  8.5 mL blood will be drawn into a 
PAXgene Blood DNA Tube, preferably at Visit 2.
Was changed to:
Approx.  8.5 mL blood will be drawn into a 
PAXgene Blood DNA Tube, preferably at Visit 2.  
In Korea, a 6 mL K2 EDTA tube will be used.
Rationale for change
In Korea a different tube type must be used due to 
local regulations.
Section to be changed
5.5.1.1. Methods and timing of sample collection
Description of change
Plasma, serum and urine samples will be stored at 
an external biobanking facility contracted by the 
Sponsor; DNA, extracted from the original whole 
blood sample, will be stored at the Sponsor.
Was changed to:
Plasma, serum and urine samples will be stored at 
an external biobanking facility contracted by the 
Sponsor; DNA, extracted from the original whole 
blood sample, will be stored at the Sponsor except 
for samples collected in China. These samples 
will be stored at an external biobanking facility 
contracted by the Sponsor.
Rationale for change
DNA samples collected from patients in China will 
not be exported out of the country.


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Section to be changed
6.1 Visit schedule
Description of change
If a patient mistakenly takes trial medication on the 
morning of Visit 4 before attending the clinic the 
visit should be rescheduled for another day as soon 
as possible, reminding the patients about expected 
time of dosing.
Was changed to:
If a patient mistakenly takes trial medication on the 
morning of Visit 4 before attending the clinic or 
comes in non-fasted where a fasting condition is 
required (refer to the Flow Chart), the visit 
should be rescheduled for another day as soon as 
possible, reminding the patients about expected 
time of dosing.
Rationale for change
Editorial clarification.
Section to be changed
6.2.1 Screening
Description of change
The following paragraph was added after the first 
paragraph in this section.
Patients who have been diagnosed with T1DM 
are to be provided with the consent form that 
contains information relevant for patients with 
T1DM.  
Rationale for change
To include in the protocol, the guidance to site on 
the consent process for patients with T1DM. This 
information is currently included in the ISF.
Section to be changed
6.2.1 Screening
Description of change
The following was added to this section.
The screening visit may be conducted over 
multiple days, at the discretion of the 
investigator, as long as all screening procedures 
are performed and resulted within the allowable 
visit window in the flow chart.  For example, a 
site may obtain written informed consent 
followed by collection of samples for the safety 
lab analysis and ECG. Remaining procedures 
may be performed on a separate day, once it is 
confirmed that the patient’s laboratory values, 
including NTproBNP value, are not 
exclusionary.
Rationale for change
To clarify that screening procedures may be 
performed on different days.
Section to be changed
6.2.2. Treatment period
Description of change
The following paragraph was added to this section.
Consenting patients with T1DM are to be 


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provided with the ketone monitoring device, the 
patient diary and Trial information card.  The 
site staff are to provide instruction to the patient 
on how to properly use the ketone monitoring 
device and the importance of recording their 
glucose, ketone and insulin intake throughout 
the trial.  At all subsequent visits, site staff are 
required to review the patient’s diary with the 
patient to ensure that the diary is properly 
completed.  Patients with T1DM should be 
provided with ketone monitoring supplies as 
necessary.
Rationale for change
To provide guidance on ketone monitoring for 
patients with T1DM.  This information is currently 
provided in the ISF.
Section to be changed
6.2.3 End of Treatment, Follow Up Period and 
Trial Completion
Description of change
The following paragraph was added to this section.
If a patient has prematurely discontinued trial 
medication is not willing to return to the clinic 
for predefined trial visits, a telephone call at 
trial end will be required, to document the 
occurrence of outcome events and vital status.  
Other AEs and concomitant therapy changes 
since the last visit should be recorded in the 
eCRF.  Sites should encourage the patient to 
return to the clinic for the final study visit (ref. 
Section 3.3.4.1).
Rationale for change
To encourage complete reporting of all relevant 
information for patients who have discontinued 
study drug.
Section to be changed
8.2 Data Quality Assurance
Description of change
The following was removed from this section:
central ECG collection (for clinically relevant ECG 
changes documented as an AE or suspected 
clinically relevant ECG changes)
Rationale for change
ECGs will not be collected for and submitted for 
central reading. However, they will be collected as 
part of the source documentation submitted for 
adjudication of endpoints for which they are 
clinically relevant
Section to be changed
8.4 Expedited reporting of adverse events
Description of change
BI is responsible to fulfil their legal regulatory 
reporting obligation and in accordance to the 
regulatory requirements. As this trial is primarily 


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intended to evaluate the cardiovascular impact of 
empagliflozin in patients with HF, the Sponsor will 
not report the SAEs included in the protocol 
exempted events list of the eCRF as described in 
Section 5.3.7.2. Events will be recorded and 
reported regularly to the DMC. The Sponsor will 
ensure that all appropriate regulatory agencies 
confirm that this approach is acceptable to them.
Was changed to:
BI is responsible to fulfil their legal regulatory 
reporting obligation and in accordance to thewith 
regulatory requirements. Exemptions from 
expedited reporting are described in Section 
5.3.7.2.  As this trial is primarily intended to 
evaluate the cardiovascular impact of empagliflozin 
in patients with chronic heart failure, the Sponsor 
will not report the SAEs included in the protocol 
exempted events list of the eCRF as described in 
Section 5.3.7.2. Events will be recorded and 
reported regularly to the DMC. The Sponsor will 
ensure that all appropriate regulatory agencies 
confirm that this approach is acceptable to them.
Rationale for change
Aligned section 8.4 with section 5.3.7.2 and 
removed redundancy.
Section to be changed
9.1 Publish references
Description of change
Updated reference information was provided for 
the following references:
P15-00589
P16-01253
P16-05920
R16-2382
The following new references were added:
P17-10453
P16-01830
Rationale for change
To provide complete reference information.
Section to be changed
9.2 Unpublished references
Description of change
The following new reference was provided:
c11963611-01
U12-2707-01
Rationale for change
To provide complete reference information.
Section to be changed
10.6 Blood pressure measurement procedure
Description of change
The following appendix was deleted.
10.6 BLOOD PRESSURE MEASUREMENT 


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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, blood pressure should be taken 3 times 
in both arms. If the pressures differ by more than 
10 mmHg (as in the presence of a subclavian steal 
syndrome), the arm with the higher pressure 
(systolic or diastolic) should be used for 
subsequent measurements.
After the patient has rested quietly, in the seated 
position for five minutes, three blood pressure 
measurements will be taken approximately two 
minutes apart and all three results must be entered 
in the eCRF. The seated HR will be taken during 
one of the two-minute intervals.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 calculation of mean values, 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).
Rationale for change
Blood pressure procedure was simplified and 
included in Section 5.2.5.
11.2 GLOBAL AMENDMENT 2
Date of CTP revision
19 Jul 2018
EudraCT number
2016-002278-11
BI Trial number
1245.110
BI Investigational Product(s)
Empagliflozin


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Title of protocol
A phase III randomised, double-blind trial to 
evaluate efficacy and safety of once daily 
empagliflozin 10 mg compared to placebo, in 
patients with chronic Heart Failure with preserved 
Ejection Fraction (HFpEF).
Section to be changed
Cover Page and Clinical trial protocol synopsis
Description of change
Change in address of Coordinating investigators 
was change from:
Professor Stefan Anker, MD
Universitaetsmedizin Goettingen
Robert-Koch-Strasse 40
D-37075 Göttingen, Germany
Phone: +49-551-39-20911, Fax: +49-551-39-20918
Professor Javed Butler, MD
Cardiology Division, Health Sciences Center
Stony Brook University Hospital
NY 11794, USA
Phone: +1 631-444-1066, Fax: +1 631-444-1054
to: 
Professor Stefan Anker, MD 
Berlin-Brandenburg Center for Regenerative 
Therapies (BCRT)
Charité - Universitätsmedizin Berlin
Division of Cardiology and Metabolism – Heart 
Failure, Cachexia & Sarcopenia, Augustenbuger 
Platz 1
13353 Berlin, Germany
Phone:  +49-30-450-553025 Fax:  +49-30-450-
553951
Professor Javed Butler, MD
Prof. and Chairman of the Department of 
Medicine, 
The University of Mississippi Medical Center,
2500 North State Street
Jackson, Mississippi, USA 39216
Phone: +1 601-984-5600 Fax: +1 601-984-5608
Rationale for change
Both Coordinating Investigators had moved to new 
institutions.


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Section to be changed
Clinical trial protocol synopsis (number of patients 
and statistical methods)
3.1 Overall trial design and plan
3.3 Selection of the trial population
7.7  Determination of sample size
Description of change
Clinical trial protocol synopsis: number of 
patients
Based on blinded assessment of the event rate of 
the primary endpoint, which is performed during 
recruitment before any interim unblinding, the 
number of patients randomised may be increased 
up to 6000. The number of primary outcome events 
required is not affected by this consideration.
Was changed to:
Based on If the accumulated blinded assessment
data suggests a slower accrual of primary 
outcome events over calendar time, than was 
originally projected, then of the event rate of the 
primary endpoint, which is performed during 
recruitment before any interim unblinding, the 
number of patients randomised may be increased 
up to 6000. Operationally, the recruitment 
period would be extended and could continue up 
to 6 months before the target number of events 
is expected to be achieved.  Such a decision 
would be made during recruitment and before
any interim unblinding. The number of primary 
outcome events required is not affected by this 
consideration.
Clinical trial protocol synopsis: statistical 
methods
The number of patients randomised may be 
increased up to 6000 patients based on the 
recruitment progress and a blinded assessment of 
the event rate, which is performed during 
recruitment before any interim unblinding. The 
number of 841 confirmed primary outcome events 
is not affected by this consideration. 
Was changed to: 
If the accumulated blinded data suggests a 
slower accrual of primary outcome events over 
calendar time than originally projected, then
Tthe number of patients randomised may be 
increased up to 6000 patients. Operationally, the 
recruitment period would be extended and 


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could continue up to 6 months before the target 
number of events is expected to be achieved. 
Such a decision would be made based on the 
recruitment progress and a blinded assessment of 
the event rate, which is performed during 
recruitment before any interim unblinding. The 
number of 841 confirmed primary outcome events 
is not affected by this consideration.
Overall trial design and plan: 
The total number of randomised patients may be 
adapted based on assessment of the blinded event 
rate. For further details refer to Section 7.7.
Was changed to:  
The total number of randomised patients may be 
adapted based on assessment of the blinded event 
rate.  If the accumulated blinded data suggests a 
slower accrual of primary outcome events over 
calendar time than originally projected, then the 
number of patients randomised may be 
increased up to 6000. Operationally, the 
recruitment period would be extended and 
could continue up to 6 months before the target 
number of events is expected to be achieved. 
The number of primary outcome events 
required is not affected by this consideration. 
For further details refer to Section 7.7.
Selection of the trial population
The total number of randomised patients may be 
adapted based on assessment of the blinded event 
rate. For further details refer to Section 7.7.
Was changed to: 
The total number of randomised patients may be 
adapted based on assessment of the blinded event 
rate.  If the accumulated blinded data suggests a 
slower accrual of primary outcome events over 
calendar time than originally projected, then the 
number of patients randomised may be 
increased up to 6000. Operationally, the 
recruitment period would be extended and 
could continue up to 6 months before the target 
number of events is expected to be achieved. 
The number of primary outcome events 
required is not affected by this consideration.  
For further details refer to Section 7.7.


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Determination of sample size:
The event rate will be assessed in a blinded manner
during recruitment before any interim unblinding. 
If the accumulated blinded data suggests a lower 
event rate based on an assumed hazard ratio of 0.8 
between the groups, then the number of 
randomised patients may be increased to a 
maximum of 6000 patients. The number of 
confirmed primary outcome events will not be 
affected by this consideration and will remain 841 
events.
Was changed to: 
The event rate and recruitment progress will be 
assessed in a blinded manner during recruitment 
before any interim unblinding. If the accumulated 
blinded data suggests a slower accrual of primary 
outcome events over calendar time than 
originally projected, then rate based on an 
assumed hazard ratio of 0.8 between the groups, 
then the number of randomised patients may be 
increased to a maximum of 6000 patients.  
Operationally, the recruitment period would be 
extended and could continue up to 6 months 
before the target number of events is expected to 
be achieved. The number of confirmed primary 
outcome events will not be affected by this 
consideration and will remain 841 events.
Rationale for change
Allows an increase in the number of patients to 
safeguard the overall duration of the study whether 
a slower accrual of primary outcome events is due 
to initial slower recruitment or lower event rate or 
both, compared to that projected in planning.
Section to be changed
Clinical trial protocol synopsis (number of patients 
and sample size)
Description of change
Approximately 2063 (2 treatment groups).
Was changed to:  
Approximately 2063 (2 treatment groups) This 
may be increased up to approximately 3000 per 
treatment group.
Rationale for change
To clarify that the number of patients that are 
randomized per treatment group may be increased.
Section to be changed
Flow Chart (footnote 11)
5.3.6.1  Outcome of non-fatal stroke
Description of change
Flow Chart footnote 11:


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For patients with non-fatal stroke the Modified 
Rankin Scale (MRS) should be scored by the 
investigator based on an interview at the next 
regular on-site visit after the onset of the stroke. In 
those cases where MRS assessment occurred 
within 90 days after the stroke, a repeat MRS-
assessment should be performed at the next on-site 
visit.
Was changed to:
For patients with non-fatal stroke the Modified 
Rankin Scale (MRS) should be scored by the 
investigator based on an interview at the next 
regular on-site visit after the onset of the stroke. In 
those cases where MRS assessment occurred 
within 90 days after the stroke, a repeat MRS-
assessment should be performed at the next on-site 
visit.  For patients who experience a non-fatal 
stroke less than 90 days prior to the study 
closure date, the final MRS assessment will 
occur at the final study visit for that patient.
Outcome of non-fatal stroke:
Investigators will measure and score the MRS 
based on an interview with the patient at the next 
regular on-site visit after the onset of the stroke. In 
those cases where MRS assessment occurred 
within 90 days after the stroke, a repeat MRS-
assessment should be performed at the next on-site 
visit. Detailed information on the stroke (date and 
time of onset, type, symptoms, method of 
detection, outcome) will be collected in the eCRF.
Was changed to:  
Investigators will measure and score the MRS 
based on an interview with the patient at the next 
regular on-site visit after the onset of the stroke. In 
those cases where MRS assessment occurred 
within 90 days after the stroke, a repeat MRS-
assessment should be performed at the next on-site 
visit.  For patients who experience a non-fatal 
stroke less than 90 days prior to the study 
closure date, the final MRS assessment will 
occur at the final study visit for that patient. 
Detailed information on the stroke (date and time 
of onset, type, symptoms, method of detection, 
outcome) will be collected in the eCRF.


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Rationale for change
To clarify that the collection of the MRS 
assessment for a stroke that occurs within the last 
90 days before the end of the trial will be done at 
the final study visit for that individual patient. As 
severity of non-fatal stroke is not part of the 
primary, secondary, or other endpoints of this study 
the last MRS assessment in these patients will be 
less than 90 days after their stroke in order not to 
delay the end of the trial.
11.3 GLOBAL AMENDMENT 3
Date of amendment
20 Nov 2019
EudraCT number
EU number
2016-002278-11
BI Trial number
1245.110
BI Investigational Product(s)
Empagliflozin
Title of protocol
A phase III randomised, double-blind trial to 
evaluate efficacy and safety of once daily 
empagliflozin 10 mg compared to placebo, in 
patients with chronic Heart Failure with preserved 
Ejection Fraction (HFpEF).
Global Amendment due to urgent safety reasons
Global Amendment
Section to be changed
4.2.2 Restrictions
Description of change
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 30 days period between 
the EOT and the Follow Up Visit.
Was changed to:
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 does not include the 30 days period 
between the EOT and the Follow Up Visit
occurring at study close-out (see section 6.2.3).
Rationale for change
The use of SGLT-2 inhibitors or combined SGLT-
1 and 2 inhibitors does not need to be prohibited 


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during the follow-up period as the patient is no 
longer taking the study medication, and because 
events which occur during the follow-up period at 
study close out are not to be included in the 
primary analysis. Furthermore investigators are 
encouraged to treat patients to the best standard of 
care in compliance with local guidelines and 
recommendations for HF and diabetes if present 
(see section 2.3).
Section to be changed
7.3.1 Primary endpoint analyses
Description of change
All events observed after randomisation until trial 
termination will be included in the analysis.  
Patients who do not have an event during the trial 
period will be censored at the individual day of 
trial completion or the last day that the patient was 
known to be free of the event, whichever is earlier. 
The time to censoring will be computed as 
(individual day of trial completion or the last day 
known to be free of the event – randomisation date) 
+ 1.
Was changed to:
All events observed after randomisation until 
completion of the planned treatment phase will 
be included in the analysis.  Patients who do not 
have an event will be censored at the individual
end of the planned treatment phase or the last 
day that the patient was known to be free of the 
event, whichever is earlier. The time to censoring 
will be computed as (individual end of the 
planned treatment phase or the last day known to 
be free of the event – randomisation date) + 1. 
Rationale for change
The intention-to-treat analysis approach was
chosen to as closely as possible reflect real-life 
conditions, disregarding any occurrences of 
treatment stop or restart of treatment, that may 
happen in clinical practice. 
The study defined treatment discontinuation in the 
close-out period is administrative and does not 
resemble clinical practice. Therefore, its inclusion 
does not reflect the objective of the primary 
analysis.
Consequently, only events up to the completion of 
the planned treatment phase will be included in the 


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primary analysis.
Section to be changed
7.3.2 Secondary endpoint analyses
Description of change
The model will include the factors treatment, 
gender, geographical region, and status of DM as 
fixed effects and eGFR (CKD-EPI)cr at baseline 
(continuous), LVEF (continuous), age 
(continuous), time and interaction of treatment by 
time as linear covariates and allow for randomly 
varying slope and intercept between patients.
Was changed to:
The model will include the factors treatment, 
gender, geographical region, and status of DM as 
fixed effects and eGFR (CKD-EPI)cr at baseline 
(continuous), LVEF (continuous), age 
(continuous), time, and interaction of treatment by 
time and interaction of eGFR (CKD-EPI)cr  at 
baseline (continuous) by time as linear covariates 
and allow for randomly varying slope and intercept 
between patients.
Rationale for change
Implemented to allow for slope varying with 
baseline eGFR since this is a medically more 
reasonable model.
Section to be changed
7.3.2 Secondary endpoint analyses
7.3.3 Further endpoint analyses
Description of change
Secondary endpoint analyses
Change from baseline in clinical summary score 
for HF symptoms and physical limitations domains 
of the KCCQ at week 52 will be evaluated by a 
mixed model repeated measures (MMRM) model 
including baseline score, LVEF (continuous), age 
(continuous) and eGFR (CKD-EPI)cr at baseline 
(continuous) as linear covariates and treatment, 
visit, baseline score by visit, visit by treatment, 
gender, geographical region and status of DM and 
as fixed effects. All on-treatment data up to week 
52 will be included. 
Was changed to:


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Change from baseline in clinical summary score 
for HF symptoms and physical limitations domains 
of the KCCQ at week 52 will be evaluated by a 
mixed model repeated measures (MMRM) model 
including baseline score, LVEF (continuous), age 
(continuous) and eGFR (CKD-EPI)cr at baseline 
(continuous) as linear covariates and treatment, 
visit, baseline score by visit, visit by treatment, 
gender, geographical region and status of DM and 
as fixed effects. All on-treatment data up to week 
52 will be included.
Further endpoint analyses
Further longitudinal continuous endpoints will be 
analysed in a MMRM, including baseline value, 
age, LVEF and eGFR (CKD-EPI)cr at baseline as 
linear covariates and treatment group, visit, visit by 
treatment interaction, baseline by visit interaction, 
geographical region, gender and baseline history of 
DM as fixed effects.
Was changed to:
Further longitudinal continuous endpoints will be 
analysed in a MMRM, including baseline value,
age, LVEF and eGFR (CKD-EPI)cr at baseline as 
linear covariates and treatment group, visit, visit 
by treatment interaction, baseline by visit 
interaction, geographical region, gender and 
baseline history of DM as fixed effects.
Rationale for change
Individual model terms were removed from the 
MMRM if already included as interaction term 
with treatment or visit to specify MMRMs in 
condensed form. This simplifies the model and 
reduces the chance of convergence issues.
Section to be changed
7.3.3 Further endpoint analyses
Description of change
Patients on empagliflozin are considered to have 
“won” the comparison if either the other patient has 
died while the patient on empagliflozin was still 
alive, or if both patients did not die, then if the 
other patient had more occurrences of HHF. The 
number of comparisons won is noted as NW. 
Patients on empagliflozin are considered to have 
“lost” the comparison if the empagliflozin patient 


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died while the patient on placebo was still alive, or 
if both patients did not die, then if the patient on 
empagliflozin had more occurrences of HHF. The 
number of comparisons lost is noted as NL. The 
win ratio is NW/ NL. 
The rules for winning and losing follow Rogers 
2014 [R16-4909] and analysis of the unmatched 
win ratio will be conducted as described in Pocock 
2012 [R16-4813]. 
Was changed to:
Patients on empagliflozin are considered to have 
“won” the comparison if either the other patient has 
died while the patient on empagliflozin was still 
alive, or if both patients did not die, then if the 
other patient had more occurrences of HHF, or if 
the number of occurrences of HHF is the same 
but the time to the first occurrence of HHF is 
longer. The number of comparisons won is noted 
as NW. Patients on empagliflozin are considered to 
have “lost” the comparison if the empagliflozin 
patient died while the patient on placebo was still 
alive, or if both patients did not die, then if the 
patient on empagliflozin had more occurrences of 
HHF, or if the number of occurrences of HHF is 
the same but the time to the first occurrence of 
HHF is shorter. The number of comparisons lost 
is noted as NL. The win ratio is NW/ NL. 
The rules for winning and losing follow a modified
Rogers 2014 [R16-4909] approach also
considering the time to the first HHF event in 
case of a tie on the number of HHF events. and
The analysis of the unmatched win ratio will be 
conducted as described in Pocock 2012 [R16-
4813]. 
Rationale for change
Time to first HHF event is also considered relevant 
information to avoid ties in case the number of 
HHF events is identical.


APPROVAL / SIGNATURE PAGE 
Document Number: 
 
Technical Version Number:
Document Name: 
Title: 
Signatures (obtained electronically) 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
c03946327
4.0
clinical-trial-protocol-version-04
A phase III randomised, double-blind trial to evaluate efficacy and safety of once
daily empagliflozin 10 mg compared to placebo, in patients with chronic Heart
Failure with preserved Ejection Fraction (HFpEF).
Author-Clinical Trial Leader
21 Nov 2019 20:13 CET
Approval-Team Member Medicine
21 Nov 2019 20:19 CET
Approval-Therapeutic Area Head
21 Nov 2019 20:48 CET
Author-Trial Clinical
Pharmacokineticist
21 Nov 2019 20:58 CET
Author-Trial Statistician
22 Nov 2019 09:01 CET
Verification-Paper Signature
Completion
25 Nov 2019 22:21 CET


Boehringer Ingelheim 
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Document Number: 
Technical Version Number:
 
(Continued) Signatures (obtained electronically) 
Meaning of Signature  
Signed by 
Date Signed 
c03946327
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SAP_001.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c14526274-02
BI Trial No.:
1245.110
Title:
A phase III randomised, double-blind trial to evaluate efficacy and 
safety of once daily empagliflozin 10 mg compared to placebo, in 
patients with chronic Heart Failure with preserved Ejection Fraction 
(HFpEF).
EMPEROR-Preserved
Investigational
Product:
Empagliflozin, BI 10773
Responsible trial 
statistician:
Date of statistical 
analysis plan:
21 FEB 2017 SIGNED
Version:
Final
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE............................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES ...................................................................................................................4
2.
LIST OF ABBREVIATIONS...............................................................................5
3.
INTRODUCTION.................................................................................................9
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ....................10
5.
ENDPOINTS........................................................................................................11
5.1
PRIMARY ENDPOINT......................................................................................11
5.2
SECONDARY ENDPOINTS .............................................................................11
5.2.1
Key secondary endpoints ....................................................................................11
5.2.2
Other Secondary endpoints................................................................................11
5.3
FURTHER ENDPOINTS...................................................................................11
5.4
OTHER VARIABLES ........................................................................................11
5.4.1
Kansas City Cardiomyopathy Questionnaire (KCCQ) scores........................11
6.
GENERAL ANALYSIS DEFINITIONS...........................................................17
6.1
TREATMENTS...................................................................................................17
6.2
IMPORTANT PROTOCOL VIOLATIONS (IPVS).......................................18
6.3
PATIENT SETS ANALYSED ...........................................................................20
6.4
SUBGROUPS.......................................................................................................20
6.5
POOLING OF CENTRES..................................................................................24
6.6
HANDLING OF MISSING DATA AND OUTLIERS ....................................24
6.6.1
Imputation methods ............................................................................................24
6.6.2
Missing data.........................................................................................................24
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS....................27
6.8 
CALCULATION OF TIME TO EVENT .........................................................29
6.8.1
Start date..............................................................................................................29
6.8.2
Date of event.........................................................................................................29
6.8.3
Censoring .............................................................................................................30
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..................................................................................................33
7.4.2
Sensitivity analyses..............................................................................................34
7.4.3 
Proportional hazards assumption violated .......................................................34
7.4.4
Subgroup analyses...............................................................................................35
7.5
SECONDARY ENDPOINTS .............................................................................35
7.5.1
Key secondary endpoints ....................................................................................35
7.5.2
Other Secondary endpoints................................................................................38
7.6
FURTHER ENDPOINTS...................................................................................39
7.7
EXTENT OF EXPOSURE .................................................................................42
7.8
SAFETY ANALYSIS..........................................................................................43


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7.8.1
Adverse events .....................................................................................................43
7.8.1.1
Assignment of AEs to treatment ...........................................................................43
7.8.1.2
Analysis of other significant AEs..........................................................................44
7.8.1.3
AE summaries .......................................................................................................44
7.8.1.4
Adverse events of special interest (AESIs) ...........................................................45
7.8.1.5
Specific AEs..........................................................................................................46
7.8.1.6
Events qualifying for external adjudication by the CEC and Hepatic External 
Adjudication and Adjudication of ketoacidosis ....................................................50
7.8.1.7
AEs while patients taking wrong medication........................................................50
7.8.1.8
Adverse event incidence rates ...............................................................................51
7.8.2
Laboratory data...................................................................................................51
7.8.3
Vital signs.............................................................................................................53
7.8.4
Electrocardiogram (ECG) ..................................................................................53
7.8.5
Others ...................................................................................................................53
8.
REFERENCES ....................................................................................................54
9.
ADDITIONAL SECTIONS................................................................................55
9.1
REGIONS AND COUNTRIES..........................................................................55
9.2
CONCOMITANT MEDICATION....................................................................55
9.3
ADDITIONAL SUB-GROUP ANALYSIS FOR REGIONAL 
SUBMISSIONS....................................................................................................56
9.4
INTERIM ANALYSES.......................................................................................56
10.
HISTORY TABLE..............................................................................................57


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LIST OF TABLES
Table 6.1: 1
Treatment regimens / study intervals................................................................17
Table 6.1: 2
Endpoint specific follow-up period for the assignment to active treatment.....18
Table 6.2: 1
Important protocol violations ...........................................................................18
Table 6.4: 1
Categories of covariates for displays of baseline characteristics and 
subgroup analyses.............................................................................................21
Table 6.7: 1
Time windows for post-baseline efficacy measurements scheduled for each 
on-treatment visit for the first 3 years ..............................................................28
Table 7.6: 1
CKD staging .....................................................................................................41
Table 9.1: 1
Regions and countries.......................................................................................55
Table 10: 1
History table .....................................................................................................57


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ACE 
Angiotensin Converting Enzyme
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine transaminase
ANCOVA
Analysis of covariance
ARB 
Angiotensin Receptor Blocker
ARNI 
Angiotensin Receptor blocker-Neprelysin Inhibitor
ASA
Acetylsalicylic acid
AST
Aspartate transaminase
ATC
Anatomical-Therapeutic-Chemical
BI
Boehringer Ingelheim
BicMQ
Boehringer Ingelheim customized MedDRA Query
BMI
Body mass index
BP
Blood pressure
CCB
Calcium channel blocker
CEC
Clinical Event Committee
CI
Confidence interval
CIF
Cumulative Incidence Function
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CRF
Case report form
CRT 
Cardiac resynchronisation therapy
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Cardiovascular
DBL
Data base lock
DBP
Diastolic Blood Pressure
DKA
Diabetic ketoacidosis
DM 
Diabetes mellitus
DM&SM
Data Management and Statistics Manual
ECG
Electrocardiogram
eCRF
Electronic Case Report Form


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Term
Definition / description
eGFR
Estimated glomerular filtration rate
EMA
European Medicines Agency 
EoT
End-Of-Text
EOT
End of treatment
EQ5D
EuroQoL 5 dimensions
EudraCT
European Clinical Trials Database
FPG
Fasting plasma glucose
FU
Follow-up
GI
Gastrointestinal
HbA1c
Glycosylated haemoglobin
HCRU
Health Care Resource Utilisation
HDL-C
High density lipoprotein cholesterol
HF
Chronic Heart Failure
HHF
Hospitalisation for heart failure
HLT
High level term
hsTnT
high-sensitivity troponin T
HR
Hazard ratio
ICD 
Implantable Cardioverter Defibrillator
ICH
International Conference on Harmonisation
IPV
Important protocol violation
IRT
Interactive Response Technology
ITT
Intention-to-treat
IVRS
Interactive voice response system
JFM
Joint frailty model
KCCQ
Kansas City Cardiomyopathy Questionnaire
LAVD
Left ventricular assist device
LDL-C
Low density lipoprotein cholesterol
LLT
Low level term
LVEF
Left ventricular ejection fraction
LVOT
Last value on treatment
LTFU
Lost to follow-up


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Term
Definition / description
Max
Maximum
MedDRA
Medical Dictionary for Regulatory Activities
MI
Myocardial infarction
Min
Minimum
MMRM
Mixed models repeated measures
MRA 
Mineralocorticoid Receptor Antagonist
Non-CV
Non-cardiovascular
NT pro-BNP
N-terminal pro b-type natriuretic peptide
NYHA
New York Heart Association Classification
OC-AD
Observed Case including data after discontinuation
OC-OT
Observed Case on-treatment
PK
Pharmacokinetic
PAOD
Peripheral Arterial Occlusive Disease
PT
Preferred term
Q1
Lower quartile
Q3
Upper quartile
PDMAP
Project data management and analysis plan
RS
Randomized set
SAE
Serious adverse event
SAS
Statistical Analysis System
SBP
Systolic blood pressure
SCR
Screened set
SD
Standard deviation
SE
Standard error
SGLT-1
Sodium-glucose co-transporter 1
SGLT-2
SGLT-2 Sodium-glucose co-transporter 2
SI
Système international d'unités
SMQ
Standardized MedDRA query
SOC
System organ class
TBILI
Total bilirubin
TS
Treated set
TS-FU
Treated set – Follow-up


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Term
Definition / description
TSAP
Trial statistical analysis plan
UACR
Urine Albumin Creatinine Ratio
ULN
Upper limit of normal
UTI
Urinary tract infection
WHO DD
World Health Organization Drug Dictionary


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


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
N/A


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
The primary endpoint is defined in the CTP Section 5.2.1.  
For further clarification: Adjudicated CV death always includes death adjudicated as death 
due to undetermined cause. This is applicable throughout all analyses wherever adjudicated 
CV death is mentioned. 
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
Secondary endpoints are specified in the CTP Sections 5.1.2.
5.2.2
Other Secondary endpoints
Other secondary endpoints are specified in the CTP Sections 5.1.2 and 5.2.
5.3
FURTHER ENDPOINTS
Further endpoints are listed in the CTP Section 5.1.3. The definition and assessment can be 
found in Section 5.2.
Further endpoints added include:

Time to non-cardiovascular (non-CV) death

Fasting plasma glucose (FPG) change from baseline to last value on treatment
(LVOT) and follow-up (FU), overall and by status of diabetes mellitus (DM)
5.4
OTHER VARIABLES
5.4.1
Kansas City Cardiomyopathy Questionnaire (KCCQ) scores
There are 10 summary scores within the KCCQ, which are calculated as follows:
1. Physical Limitation
Code responses to each of Questions 1a-f as follows:

Extremely limited = 1

Quite a bit limited = 2

Moderately limited = 3

Slightly limited = 4

Not at all limited = 5


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
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

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


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
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

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


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If at least one of Questions 4, 6 and 8 is not missing, then the Symptom Burder 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
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


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
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:
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


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
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
(sum of the responses to those n-i questions) / n


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
There will be 4 basic treatment phases in this trial: screening, study treatment phase (with 
either empagliflozin 10mg or matching placebo), post-treatment and post-study.  However, 
during the study treatment phase, patients are allowed to go off-treatment and subsequently 
re-start treatment.  This may happen not at all or repeatedly for a given patient.
The purpose of the definitions below is to describe all the different study/treatment intervals, 
in which a patient can lie during the course of the trial. Note that the term "treatment regimen" 
also covers the “off-treatment” time periods.
Table 6.1: 1
Treatment regimens / study intervals
Label
Interval
Start date 
Screening
Screening
Date of informed consent
Placebo/
Empagliflozin 10mg
Treatment
Date of first administration of double-
blind study treatment
Off-treatment (if applicable)
During Treatment 
interval, but not on 
treatment
Date of last administration of the 
study medication before temporarily 
discontinuation + 1 day
Placebo/
Empagliflozin 10mg 
(if applicable)
During Treatment 
interval, after restart 
of study medication
Date study medication re-started
Post-treatment
Post-treatment
Date of last administration of study 
drug + 1 day
Post-study
Post-study
Date of trial completion +1 day
Details on the definition of on-treatment period for different endpoints are listed in 
Table 6.1:2. The efficacy analyses will follow the intention-to-treat (ITT) principle in 
assigning patients to treatment groups, i.e. patients will be analysed as randomised. 
Safety analyses will also assign patients to the treatment group as randomized.
If a patient erroneously receives the wrong trial drug, the patient will be analysed as per the 
randomized treatment for all analyses, since patients are to be brought back to the site and 
dispensed correct drug as soon as possible. Additionally, the AEs with an onset during the 
time of the incorrect study treatment will be listed separately. 


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Table 6.1: 2
Endpoint specific follow-up period for the assignment to active treatment 
Endpoint
Last day of assignment to treatment 
phase
(days after study drug stop date)
Adverse events
7
Safety laboratory measurements
3
Heart rate
1
Glycosylated haemoglobin (HbA1c)
7
FPG
1
Body weight
1
Creatinine and estimated glomerular filtration rate
(eGFR)
1
N-terminal pro b-type natriuretic peptide (NT pro-
BNP)
1
Blood pressure
1
6.2
IMPORTANT PROTOCOL VIOLATIONS (IPVS)
A protocol violation (PV) 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.
The IPVs 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 violations
Category / 
Code
Description
Requirements
Excluded 
from
A
Entrance criteria not met
A1
Target indication not met
A1.06
No chronic HF NYHA class II-IV
Inclusion criterion #3 violated
None
A1.07
Conditions on ejection fraction (EF) 
violated
Inclusion criterion #4 violated
None
A1.08
Conditions on NT-proBNP violated
Inclusion criterion #5 violated
None
A1.09
Conditions on HF violated
Inclusion criterion #6 violated
None
A2
Inclusion criteria not met
A2.02
Age out of range
Inclusion criterion #1 violated
None
A2.08
Specific inclusion criterion for women 
of child-bearing potential violated
Inclusion criterion #2 violated
None
A3
Exclusion criteria not met
A3.27
Patient with unstable conditions
Exclusion criteria #1, #2, #7, #11, or #16 
violated
None


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Table 6.2: 1
Important protocol violations (cont.)
Category / 
Code
Description
Requirements
Excluded 
from
A3.42
Recently implanted ICD
Exclusion criterion #3 violated
None
A3.43
Implanted CRT
Exclusion criterion #4 violated
None
A3.29
Cardiomyopathy infiltrative diseases 
(e.g. amyloidosis), accumulation 
diseases (e.g. hemochromatosis, 
Morbus Fabry ), muscular dystrophies, 
with reversible causes (e.g. stress 
cardiomyopathy), hypertrophic 
obstructive cardiomyopathy or known 
pericardial constriction
Exclusion criterion #5 violated
None
A3.30
Any severe (obstructive or regurgitant) 
valvular heart disease, obstructive or 
regurgitant, or any valvular disease 
expected to lead to surgery during the 
trial in the opinion of the investigator
Exclusion criterion #6 violated
None
A3.31
Atrial fibrillation or atrial flutter with a 
resting heart rate >110bpm
Exclusion criterion #8 violated
None
A3.32
Systolic blood pressure at visit 1 or 2 
out of range
Exclusion criterion #9 or #10 violated
None
A3.06
Indication of liver disease
Exclusion criterion #12 violated
None
A3.09
Renal insufficiency or renal impairment 
(assessed by eGFR)
Exclusion criterion #13 violated
None
A3.34
Haemoglobin at visit 1 below cut-off
Exclusion criterion #14 violated
None
A3.35
History of Ketoacidosis
Exclusion criterion #15violated
None
A3.36
Gastrointestinal (GI) surgery or GI 
disorder that could interfere with study 
medication absorption in the 
investigator’s opinion
Exclusion criterion #17 violated
None
A3.37
Documented or active malignancy
Exclusion criterion #18
None
A3.38
Life expectancy of <1 years in the 
opinion of the investigator
Exclusion criterion #19 violated
None
A3.39
Intake of restricted medications or any 
drug considered likely to interfere with 
the safe conduct of the trial
Exclusion criterion #20 violated
None
A3.40
Treatment with any SGLT-2 inhibitor 
or SGLT-1 and 2 inhibitor
Exclusion criterion #21 violated
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 #22 violated
None
A3.41
Known allergy or hypersensitivity to 
empagliflozin
Exclusion criterion #23 violated
None
A3.13
Relevant alcohol or drug abuse and
condition affected study compliance
Exclusion criterion #24 violated
None
A3.12
Specific exclusion criterion for 
premenopausal women violated
Exclusion criterion #25 violated
None
A3.14
Any other clinical condition unsafe for 
participation
Exclusion criterion #26 violated
None
B
Informed consent
B1
Informed consent not available/not 
done
Informed consent date missing or 
inclusion criterion #9 violated
All
B2
Informed consent too late
Informed consent date was after Visit 1
None


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Table 6.2: 1
Important protocol violations (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
D
Concomitant medication
D2.02
Use of prohibited medication 
Use of SGLT-2 or combined SGLT-1 and 
2 – inhibitors after randomization before 
trial termination 
None
6.3
PATIENT SETS ANALYSED
The following patient sets are defined

Screened Set (SCR)
Consists of all patients screened for the trial, with informed consent given and who
completed at least one screening procedure at Visit 1.

Randomised set (RS)
This patient set includes all randomised patients, whether treated or not.

Treated set (TS)
This patient set includes all patients who were dispensed study medication and were
documented to have taken at least one dose of investigational treatment.

Treated Set-Follow-up (TS-FU)
All patients in the TS, for whom a follow-up visit was performed between 23 and 45
days after last intake of study medication.
6.4
SUBGROUPS
Subgroups to be considered in the analyses are provided below in Table 6.4: 1. Missing 
categories for subgroup variables will not be considered in the respective analysis.
If there is missing information directly from central laboratory for any of the subgroups of 
parameters, where data is also collected in the IRT system, then the information as transferred 
from IRT will be used to assign a patient to a certain category. 


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Table 6.4: 1
Categories of covariates for displays of baseline characteristics and subgroup 
analyses
Variable
Categorization
Demo-
graphics*
Subgroups for 
Efficacy 
endpoints**
Safety
Age (years)
<50
50 to <65
65 to <75
75 to <85
>= 85
X
<50
50 to <65
65 to <75
>= 75 
X
X§
X
< 65
≥65
X
X
Gender
male
female
X
X
X
Region
NA, LA, Europe, Asia, 
Other+
X
X
X
Ethnicity
Hispanic/ Latino
Not Hispanic/ Latino
X
X
X
Race
White
Black/ African-American
Asian
Other including mixed race
X
X
X
BMI (kg/m2)
<30
≥30
X
X
eGFR at baseline
>=90
60 to <90
45 to <60
30 to <45
15 to <30
<15 
X
>=90
60 to <90
45 to <60
30 to <45
<30
X
X§
X
>=60
<60
X
X
UACR
UACR (in mg/g):
<30 
>=30 to <=300 
>300
X
X§


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Table 6.4: 1
Categories of covariates for displays of baseline characteristics and 
subgroup analyses (cont.)
Variable
Categorization
Demo-
graphics*
Subgroups for 
Efficacy 
endpoints**
Safety
Diabetes at baseline
DM, no-DM
X
X
X
DM, pre-DM, non-DM
X
X
History of hypertension
Yes / No
X
X
Baseline SBP
< / >= median
X
X
Baseline BP
SBP<140 and DBP<90 vs. 
SBP>= 140 or DBP>=90
X
X
X (volume 
depletion 
AEs)
Atrial Fibrillation at 
baseline
Yes/ No
X
X
Baseline LVEF
</>=50
X
X
< / >= median
X
History of HHF
Yes / No
X
X
Cause of HF
Ischemic /
Non-ischemic
X
X
Time since diagnosis of HF
<= 1 year, 1-5 years, > 5 
years
X
X§
NYHA at baseline
I/II vs. III/IV
X
X
NT-proBNP at baseline
< / >= median
X
X
Baseline use of ACE-
inibitor, ARB or ARNi
Yes / No
X#
X
X (renal 
AEs and 
volume 
depletion 
AEs)
Baseline use of ACE-
inhibitor or ARB but no 
ARNi
Yes / No
X#
X
Baseline use of ARNi
Yes / No
X#
X
Baseline use of MRA 
Yes / No
X#
X
Baseline use of diuretics
Yes / No
X#
X
X (renal 
AEs and 
volume 
depletion 
AEs)
Baseline use of loop or 
high-ceiling diuretics
Yes / No
X#
X
X (renal 
AEs  and 
volume 
depletion)
Baseline use of thiazides
Yes / No
X#
X


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Table 6.4: 1
Categories of covariates for displays of baseline characteristics and 
subgroup analyses (cont.)
Variable
Categorization
Demo-
graphics*
Subgroups for 
Efficacy 
endpoints**
Safety
Baseline use of diuretics 
low-ceiling excluding 
thiazides
Yes / No
X#
X
Baseline use of beta-
blockers
Yes / No
X#
X
Baseline use of Ivabradine
Yes / No
X#
X
Baseline use of CCB 
dihydropyridines
Yes / No
X#
X
Baseline use of CCB non-
dihydropyridines
Yes / No
X#
X
Baseline use of digitalis
Yes / No
X#
X
baseline hemoglobin 
< / >= median
X
hsTnT at baseline
< / >= median
X
* The column demographics shows categories shown in the overall demographics.
Demographics are not planned by subgroup.
** Subgroups planned for the primary endpoint, time to cardiovascular (CV) death, time to
first HHF, HHF (first and recurrent), renal slope.
+ Region categorization: see Table 9.1.1.
# part of the presentation of baseline concomitant therapy as outlined in section Section 7.2
§The interaction tests for these subgroups will be trend tests taking into account ordering of
the subgroups.


6.5
POOLING OF CENTRES
This section is not applicable because centre/country is not included in the statistical model.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
6.6.1
Imputation methods
There will be no imputation of data for safety analyses. For patients who discontinue the trial 
treatment prematurely, all efforts will be made to follow patients for survival and for any 
other endpoints including the primary and key secondary endpoints until the end of the trial. 
There will be different methods of looking at 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 6.1:1)) are considered. 
Measurements are assigned to planned weeks according to Table 6.7: 1
Observed case including data after discontinuation (OC-AD):
All available data are considered, including values obtained on treatment or post-treatment.
Measurements are assigned to planned weeks according to Table 6.7: 1
KCCQ imputation
For endpoints of KCCQ scores, for patients who die, a worst score (score of 0) will be 
imputed for the score at all subsequent scheduled visits after the date of death where the score 
would have been assessed.
The following is used for longitudinal and time to event-data:
Multiple imputations:
A multiple imputations approach will be considered to impute missing data. Multiple 
imputation approaches taken are further specified in Section 7 with the planned sensitivity 
analyses. 
6.6.2
Missing data
Adverse event data 
Missing or partial date information for AEs will be replaced according to general Boehringer 
Ingelheim (BI) rules described in the BI guidance for handling of missing and incomplete AE 
dates (2).
Adverse event onset dates, including 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.


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Death date
For patients with a record of death captured on the electronic case report form (eCRF) with 
missing or only partial death date from all available sources, the death date will be derived 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, last day known to be alive + 1 day 
and date of trial completion.
Missing information on the date of first administration of trial drug
If the date of first drug administration is missing but the patient was randomised, the date of 
the first drug administration will be set to the date of randomisation. If the date of first 
administration is partially missing with the month and year present, the day will be set to the 
date of randomisation if randomisation was in the same month. If randomisation was in the 
month prior to the first drug administration the missing day will be imputed as the first day of 
the month. 
Missing date of last FU for non-fatal events. 
If the date of last FU for non-fatal events is missing, it will be imputed as the last of any of the 
following data:

visit dates

date if any assessment such as NYHA, blood pressure, EQ5D, KCCQ, pregnancy test,
central laboratory

adverse event/outcome event start and end dates except fatal events

onset dates of adjudicated (confirmed and non-confirmed) events except fatal events

drug administration dates, last drug stop date,

date of clinical routine exam

date of trial completion (if patient did not die)
Missing date of trial completion (=last contact or date of death)
If the date is completely missing the following rules will be applied:

If a patient has withdrawn informed consent, this date will be imputed by the date of
IC withdrawal.

If a patient died and has not withdrawn consent, this date will be imputed by the date
of death.

If the date is incomplete with only month and year reported, the date will be imputed
by the first day of the month.

If a patient did not die, the date of trial completion will be imputed by the last date the
patient was known to free of non-fatal events.
All other cases need to be assessed by the trial team on an individual basis, using the above 
points as guidance.
Missing information on the date of trial medication stop


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
If this date is missing and the end-of treatment visit date is available, date of trial
medication stop will be imputed by the date of the end-of-treatment visit.

If the date is incomplete with only month and year and the respective visit date is
missing, the date of last drug administration will be imputed by the last day of this
month. If this would be later than the date of trial completion, then the date of trial
completion will be used for imputation.

If a patient is lost-to-follow up, no date of last drug administration is reported and the
date of the end-of treatment visit is not available, the date of last drug administration is
set as the date of last FU for non-fatal events.

For a patient who dies in the treatment phase with no information on the date of last
drug administration, the date is set as the date of death, assuming that the patient took
the medication until the date of death.
If the imputed date based on the above rules is later than the longest treatment duration based 
on drug supply, then trial medication stop will be imputed based on the longest treatment 
duration based on drug supply.
If after imputation, the date of trial completion is before the date of last drug administration, 
the start of the post-study period is defined as the maximum of last drug administration +1 
day and the date of the trial completion +1 day.
All other cases need to be assessed by the trial team on an individual basis, trying to use the 
points above as guidance.  
Missing information on concomitant therapy dates
For incomplete date information always 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.  
Missing measurement to confirm “sustained” decrease
An eGFR (CDK-EPI)cr reduction is considered sustained, if it is determined by two or more 
consecutive post-baseline central laboratory measurements separated by at least 30 days (first 
to last of the consecutive eGFR values). If there is no additional measurement >= 30 days 
after the eGFR reduction is observed and the patient dies within 60 days of this measurement, 
then the eGFR reduction is also considered sustained.
Pharmacokinetic (PK) variables
Missing data and outliers of PK data are handled according to (3)


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6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
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. 
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 analysed as before any 
intake of randomised trial medication. 
For randomised patients without any treatment intake: 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 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. 
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 and 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. 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. 


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Table 6.7: 1
Time windows for post-baseline efficacy measurements scheduled for each on-
treatment visit for the first 3 years
Time window (actual days after 
baseline)
Visit number
Visit label
Planned days
Start
End
Endpoints assessed at each on-site visit (e.g. creatinine / eGFR)
2
Baseline
0
NA
1
3
Week 4
28
2
56
4
Week 12
84
57
154
6
Week 32
224
155
294
8
Week 52
364
295
448
10
Week 76
532
449
616
12
Week 100
700
617
784
14
Week 124
868
785
952
16
Week 148 
1036
953
1120
18
…
FU
FU
Trt stop + 30 days
Trt stop + 23 
days
Trt stop + 45 
days
KCCQ
2
Baseline
0
NA
1
3
Week 4
28
2
126
6
Week 32
224
127
294
8
Week 52
364
295
532
FU
FU
Trt stop + 30 days
Trt stop + 23 
days
Trt stop + 45 
days
A 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 KCCQ can be found in Table 6.7: 1
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. If there are two 
observations which have the same difference in days to the planned day or if there are two 
observations on the same day, the first value will be used.
Time windows for assignment of planned off-treatment measurement


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For evaluation of the off-treatment assessment ‘at 30 day follow-up’ only values obtained at 
>= 23 days to <= 45 days after last trial drug stop will be considered.
The value that is closest to the planned day of 30 days after last trial drug stop will be used. If 
there are 2 values equally close, the later value will be used.
6.8 
CALCULATION OF TIME TO EVENT
This section describes the calculation of the time to event and the time that patients without an 
event are in the study (under risk). 
Consistent with that approach, the respective time intervals determine the start and end for the 
derivation of occurrence of a specific event.
For those patients with an event, the time to event is calculated as: 
<date of event> - < start date> + 1
For those patients without an event, the time at risk is calculated as:
<date of censoring> - < start date > + 1
6.8.1
Start date
In general, the time to event will be derived from the date of randomisation. 
If study drug administration happened before calling IVRS, the date of first drug
administration will be used as start date.
For the following endpoints (analysed as occurrence or time to first event), the date of first 
drug intake will be used as start date:
•
AE analyses acc. to Section 7.8.1
•
Endpoints purely based on laboratory measurements, that include a relation to
baseline (such as change decrease from baseline >= 40%, doubling vs baseline,
etc. )
Please note, that for composite endpoints, that include component(s) using randomisation date 
and other component(s) using first drug intake date as start date, the time at risk for the 
composite will start with date of randomisation (which may be earlier). For the individual 
components, the component specific start date will be used.
6.8.2
Date of event
For adjudicated events, the date determined by the adjudication committee will be used; this 
can be different from the investigator reported date.
For the endpoints of time to CV death, time to all-cause mortality and time to non CV death 
the respective death date will be used rather than time to the first onset of the fatal AE.


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For composite outcomes, e.g. time to adjudicated HHF or adjudicated CV death, the earliest 
onset date of the corresponding components will be used. For the component of CV death or 
other death components, date of death will always be used rather than the onset date also for 
composite outcomes. 
For endpoints, where myocardial infarction (MI) and stroke are included as a fatal and non-
fatal component, the onset of the event is considered for the derivation of time to first 
occurrence, not the date of death. For time to CV death the date of death is used for a fatal MI 
or fatal stroke. 
The time to first occurrence type of endpoints based on laboratory data including endpoints
including the requirement a “sustained” measurement are determined by the date of the first 
measurement that fulfils this condition.
For events with multiple possible episodes, such as HHF or all-cause hospitalisation, the onset 
date of the first episode will be used unless noted otherwise. The same applies to time-to-AE 
analysis.
For analysis of recurrent events, time at risk for the next event will start at the day after the 
end date of an event. For HHF and all-cause hospitalization the end date will be the day of 
discharge. If date of discharge is missing then it will be assumed that the discharge was the
day after hospitalization unless the AE is marked as fatal, in which case date of death will be 
used. 
6.8.3
Censoring
The underlying principle is that the censoring date should be the last date a patient was known 
to be free of an endpoint event (e.g. free of each component of HHF + CV death).
Patients without occurrence of a specific endpoint (composite endpoint or individual 
components) will be considered censored at the last date, the patient was known to be free of 
the event. For non-fatal events this is the last date the patient could be followed up for all non-
fatal events as documented in the eCRF or imputed in as per Section 6.6.2.. 
Censoring is considered independent from study drug intake.
All-cause mortality
A patient, without the event will be censored at the latest of
•
Date of study completion
•
Last AE onset date or last AE end (if complete-imputed dates not used)
•
Last date known alive from the vital status page
Endpoints of any cause-specific death, e.g. CV death 
The same censoring rule as in all-cause mortality applies, and in addition, date of death if died 
from other causes than the one specified in the endpoint.


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Endpoints based on laboratory data only 
Patients who already fulfil the respective condition at baseline or without post-baseline 
laboratory measurements are not considered in the number of patients at risk for this endpoint. 
If a baseline laboratory measurement is not available for the parameter of interest, it is 
assumed that the patient did not experience the condition corresponding to the endpoint at 
baseline and the patient is included in the patients at risk for this endpoint. Patients without an 
event and available post-baseline laboratory measurements will be considered censored at the 
date of last laboratory sampling of the corresponding parameter. Patients with missing 
baseline laboratory required to derive a change from baseline and patients without laboratory 
data following the baseline measurement will be censored on the date of randomisation.
Composite endpoints 
Only patients that are included in the analyses for all components of the composite endpoint
will be included in the analysis of the composite.
Of those, a patient with at least one event in any of the components of the composite will be 
considered to have an event and the date of the first event will be used for the composite 
endpoint. A patient without an event will be considered censored at the earliest of all 
censoring dates of the component endpoints.
Censoring for analyses up to trt stop + x days
For any analyses until a certain number of x days after treatment discontinuation (e.g. 
sensitivity analyses until 30 days after treatment discontinuation), censoring time will be the 
minimum of the censoring time as described above and treatment discontinuation + x days. 
Patients with an event after treatment discontinuation + x days will be censored at treatment 
discontinuation + x days. 


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7.
PLANNED ANALYSIS
For End-Of-Text (EoT) tables, the set of summary statistics is: N / Mean / SD / SE / Min / Q1 
(lower quartile)/ Median / Q3 (upper quartile)/ Max. The 1st and 99th percentiles might be 
substituting minimum and maximum in tables with open-ended values to safeguard against 
implausible extremes.
Geometric means and ranges will be added to the presentation or replace the presentation of 
mean and standard deviation for parameters which rather follow a log-normal distribution 
than a normal distribution. 
Statistical parameters will be displayed to a defined number of decimal places as specified in 
the BI guideline “Reporting of Clinical Trials and Project Summaries” (4)
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 analyzed by treatment 
groups and presented in the clinical trial report as a frequency-distribution. The number of 
patients participating (screened, randomized, screened but not randomized, etc.) in the study 
by region, country and, for treated patients, centre, will also be analyzed 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 summarized by country and by age group for reporting in EudraCT. (see (13)). 
Number of patients lost to follow up (no information on vital status after start of study 
closure) and number of patients lost to follow up for the primary endpoint (no information on 
primary endpoint after start of study closure) will be summarised. 
The frequency of patients with IPVs will be presented by treatment group for the randomized 
set. The frequency of patients in different analysis sets will also be analyzed for each 
treatment group.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Demographics and baseline characteristics will be analyzed based on RS. Standard descriptive 
analysis and summary tables will be presented. These summary tables will include description 
of subgroup variables detailed in Section 6.4. Descriptive analysis of the following variables 
measured at baseline will be presented: Age, height, body mass index (BMI), time since 
diagnosis, HbA1c, systolic blood pressure (SBP), diastolic blood pressure (DBP), weight, 
eGFR, UACR, NT-pro BNP, low density lipoprotein cholesterol (LDL-C) and high density 
lipoprotein cholesterol (HDL-C). 
A summary of the number of patients in each randomisation stratum per treatment planned vs. 
actual will also be shown. The planned information will be based upon the data received from 


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the interactive voice response system (IVRS) provider.  Analyses will be based on actual 
information collected via the CRF / central laboratory, not via IVRS.
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 (ATC3) and preferred name. Summaries will be presented for 
concomitant therapies taken at randomisation and separately those taken at or after 
randomisation. Separate summaries of use of heart failure-related drugs (e.g. ARNi, beta-
blockers, ivabradine, diuretics, ACE-inhibitors, ARBs, MRAs, digitalis), anticoagulants,
acetylsalicylic acid (ASA), or lipid lowering drugs at randomisation will be presented. Use of 
devices at randomisation will also be summarized at randomisation. 
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.
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the report. The number and 
percentage of patients with overall compliance will be reported. Overall compliance will be 
calculated as a weighted average of reported compliance. The sum of all reported compliance 
over the planned visits will be divided by the total duration. The treated set of patients will be 
considered.
7.4
PRIMARY ENDPOINT
7.4.1
Primary analysis
As the primary endpoint, time to the first event of adjudicated HHF or adjudicated CV death 
will be reported in days. The primary analysis will be based on RS, using all data available 
until trial completion, including the data after end of treatment.
The primary endpoint will be displayed using cumulative incidence function (CIF) curves and 
expressed as the hazard ratio with associated  two-sided 95% confidence intervals (CIs) and 
two-sided CIs based available alpha-level for the analysis. The alpha levels for the interim 
analysis and final analysis will follow the Hwang, Shih and De Cani α-spending function as 
specified in Section 7.4 of the CTP, which are expected to be 0.001 and 0.0248 (one-sided) 
when the interim analysis occurs at the time of 60% information.
Estimator and corresponding confidence intervals will not be corrected for interim analysis. 
The primary endpoint will be analysed using Cox regression, with factors of treatment 
(empagliflozin, placebo), region (North America, Latin America, Europe, Asia and “other” 
including India, South Africa, Turkey and Australia), baseline status of diabetes (diabetes, 
prediabetes, no diabetes), age (continuous), gender, left ventricular ejection fraction (LVEF)
(continuous) and eGFR (CKD-EPI)cr at baseline (continuous).  Since the stratification factors 
are included in the model as covariates, no stratified Cox regression will be used.


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Breslow’s method will be used for dealing with ties.
The individual relevant components of the composite will be summarized descriptively. In 
this descriptive analysis of the relevant component for the composite, CV death after HHF 
will not be counted. In all other analyses of CV death alone defined in this document, all CV 
deaths will be counted, disregarding any earlier events. 
7.4.2
Sensitivity analyses
The following sensitivity analyses will be conducted:

A Cox model including only treatment as covariate, not adjusting for any other
variables.

The same Cox regression will be performed on the TS, including only any events up to
30 days after treatment discontinuation.

For patients who are without primary event and lost to follow up before trial
completion, the treatment specific incidence rates for empagliflozin and placebo will
be used to impute the primary events in a multiple imputations framework. The
primary model will be applied to the imputed datasets. It is planned to perform 100
imputations. Rubin’s rules will used to summarize the log hazard ratios and the result
will be back-transformed to show a hazard ratio with confidence interval.

The endpoint will be evaluated based on investigator reported events.

A competing risk model by Fine-Gray will be explored, including the same set of
covariates as in the primary analysis, sub-distribution hazard ratios will be provided
(5)
A Kaplan-Meier curve of time to censoring for primary endpoint will be presented in order to 
assess whether there was differential censoring. For this analysis an event will count as 
censoring and a censoring (including censoring due to the competing event of non-CV death)
will count as event. 
7.4.3
Proportional hazards assumption violated
The proportional hazards assumption will be explored by plotting log (-log (survival 
function)) against the log of time by treatment group and checked for parallelism. The 
interaction of treatment with log of time will be included in the model described above for an 
exploratory analysis. Further, Schoenfeld residuals for each covariate and treatment will be 
plotted against time and log (time).
In case the proportionality assumption is violated for treatment, an attempt will be undertaken 
to identify groups of patients for which the proportionality assumption holds and a stratified 
Cox regression will be performed. The HR and corresponding CIs will be obtained from the 
stratified Cox model.


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In addition a piecewise Cox model assuming proportional hazards in a series of consecutive 
time intervals as proposed by Collett (6) will be investigated.
7.4.4
Subgroup analyses
Subgroup variables will be explored as described in Section 6.4 for the primary endpoint. The
HR between the two treatments along with 95% CI and the p-value for test of treatment 
equality within each category of the subgroup as well as the p-value for the subgroup-by-
treatment interaction will be estimated by the Cox proportional hazard model including the 
same covariates as in the primary analysis of primary endpoint, the subgroup variable if not 
part of the covariates of the primary analysis model, and subgroup-by-treatment interaction. If 
the subgroup variable is a categorization of a continuous covariate, this covariate will be 
dropped from the subgroup model. A forest plot will be presented with the estimated HR and 
the two-sided 95% CI for each subgroup category. The CIF plots will also be presented for 
each subgroup category.
For those subgroups marked as § in Table 6.4.1. the interaction p-values will be conducted as 
trend tests, taking into account that the subgroup categorizations are ordered. 
If there are less than 14 patients with events in one subgroup, then this subgroup will not be 
included in the model. If this leaves only one subgroup, the subgroup analysis will not be 
conducted. 
For the continuous covariates LVEF, eGFR and age, the influence of the covariate will also be 
investigated on a continuous scale. For this purpose the continuous covariate will be added to 
the model if not already included and the interaction term of the continuous covariate and 
treatment will additionally be included into the model. The hazard ratio depending on the 
continuous covariate will be plotted and the interaction p-value will be reported. 
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
Occurrence of adjudicated HHF (first and recurrent)
Hospitalisation for heart failure will be analysed by a joint frailty model (JFM) that accounts 
for the dependence between recurrent HHF and CV death (7) The primary analysis will be
based on all data available until trial completion, including the data after end of treatment.
Define Ti0 = 0 and let Ti1, Ti2,…, TiNi be the recurrent event times for person i, where Ni is the 
number of recurrent HHF events before Xi =min(Ci,Di), the minimum of an independent 
censoring time Ci and a dependent CV death time Di. The JFM is defined through the hazard 
functions for the recurrent event process and CV death


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The recurrent heart failure hospitalisations hazard function for the i-th patient conditional on 
the patient specific random frailty, i, is given by ri and is proportional to the baseline 
intensity function, r0. The conditional hazard function for time to CV death for patient i is 
given by, i, with the baseline hazard given by 0, and 1, 2 are p x 1 vectors of regression 
coefficients associated with vectors of covariates zi. The same covariates as for the analysis of 
the primary endpoint will be used, e.g. ß.1=treatment (empagliflozin, placebo), ß.2=region
(North America, Latin America, Europe, Asia and “other” including India, South Africa, 
Turkey and Australia), ß.3=baseline status of diabetes (diabetes, prediabetes, no diabetes) etc.
Patient specific independent random effects are denoted by i and are assumed to follow a 
gamma distribution with mean 1 and variance . The correlation of the recurrent events is
quantified by , with higher values corresponding to greater within-patient correlation and 
also greater between-patient variability. The parameter  determines the relationship between 
the recurrent heart failure hospitalisations and time to CV death. When  < 0, higher frailty 
will result in a greater risk of recurrence and lower risk of terminal event (i.e. a negative 
correlation between the frailties), and when  > 0, higher frailty will result in a greater risk of 
recurrence and is associated with a higher risk of CV death (i.e. a positive correlation between 
the frailties). 
Let tij and xi be the observed recurrent event times and follow-up, respectively. Denote by 	ij
and Δi, the indicator of the recurrent event at time tij and the indicator of CV death at time xi, 
respectively. The likelihood for person i is then given by the following:
Adopting piecewise constant hazards for the recurrent events and CV death allows estimation 
of the likelihood by Gaussian quadrature. The implementation of Gaussian quadrature 
techniques is incorporated into Proc NLMIXED of SAS 9.4. SAS Code as given in (9) will be 
used.ESUG 2008
The joint model gives two distinct hazard ratios:
HRHHF = exp{11} is the hazard ratio associated with the effect of treatment on the recurrent 
event rate of HHF, and HRCVD = exp{21} is the CV death hazard ratio.
Estimates and 95%-CI for the hazard ratios and for  (relationship between the recurrent heart 
failure hospitalisations and CV death) will be given.
The following sensitivity analyses will be conducted 

Based on the TS, including only any events up to 30 days after treatment
discontinuation

Instead of CV-death, jointly model HHF with all-cause mortality as the terminal
events


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
The endpoint will be additionally evaluated based on investigator reported events for
HHF and CV death.

A parametric joint gamma-frailty model will model the recurrent event component
using a Poisson distribution and model the CV mortality component using a log-
logistic distribution, conditional on the frailty parameter. Individual frailties are again
assumed to follow a Gamma distribution. Thus HHF rates follow a negative binomial
distribution and times to CV death follow a Lomax distribution (see (8))
In case the semi-parametric joint modelling cannot converge numerically with the existing 
SAS procedures, the parametric joint gamma-frailty model as described above may be used 
instead for the confirmatory analysis.
The number of HHF events per patients will be summarized descriptively. Additionally a 
negative binomial model will be fitted to the data of recurrent HHF. This will be done once 
including only treatment as covariate and once including all covariates as the primary model. 
Rate ratio and confidence intervals of both models will be reported. 
The mean cumulative incidence will be displayed for adjudicated recurrent HHF.
Subgroup analyses will be explored as outlined in Section 6.4 for adjudicated recurrent HHF.
For subgroup analyses the term of subgroup (if not already part of the model) and subgroup 
by treatment will be added to the model of the recurrent event. If the subgroup variable is a 
categorization of a continuous covariate, this covariate will be dropped from the subgroup 
model. 
eGFR (CKD-EPI)cr slope of change from baseline
Slope in change from baseline of eGFR (CKD-EPI)cr will be analysed by a random coefficient 
model allowing for random intercept and random slope per patient. The model will include 
the factors treatment, gender, geographical region, and status of DM as fixed effects and 
eGFR (CKD-EPI)cr at baseline (continuous), LVEF (continuous), age (continuous), time and 
interaction of treatment by time as linear covariates and allow for randomly varying slope and 
intercept between patients. The model will include all on-treatment change from baseline 
data. 
Since the slope is run on the change from baseline data, the intercept will model the acute 
drop, whereas the long-term effect is modelled by the slope.
A plot of individual patient slopes and separately of individual patient intercepts will be 
provided per treatment.
Multiple imputation will be used to handle missing data as a sensitivity analysis. All variables 
included in the analysis model will be included in the imputation model. After exploring the 
missing data mechanism and observed measurements on the blinded data additional variables 
may also be included in the imputation model. If the data is monotone missing, a regression 
model will be used for imputation. In the case of non-monotone missing, a Markov chain 
Monte Carlo (MCMC) step will be used to create monotone missing data in multiple datasets. 
It is planned to perform 100 imputations. The regression method will then be used to 


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complete the imputation in each dataset. For each imputed complete dataset, the analysis 
model described above will be used for the analysis. The slope results will be summarized 
using Rubin’s rules.
Subgroup analyses as outlined in Section 6.4 will be explored for eGFR slope. The subgroup 
model will include additionally to the model described above, the subgroup if not already part 
of the model, subgroup by treatment and subgroup by treatment by time. If the subgroup 
variable is a categorization of a continuous covariate, this covariate will be dropped from the 
subgroup model. 
7.5.2
Other Secondary endpoints
No correction for multiple hypotheses testing will be made for other secondary endpoints.
Time to first event of sustained reduction of ≥40% eGFR (CKD-EPI)cr or 

(for patients with eGFR (CKD-EPI)cr ≥30 mL/min/1.73 m2 at baseline): sustained
eGFR <15 mL/min/1.73m2

(for patients with eGFR (CKD-EPI)cr <30 mL/min/1.73 m2 at baseline): sustained
eGFR < 10 mL/min/1.73 m2
Time to all-cause mortality
Time to first adjudicated HHF
Time to adjudicated CV death
Time to onset of DM in patients with baseline pre-DM
All time-to-event endpoints will be reported in days. 
The same model and data frame as used in the primary analysis of primary endpoint will be 
applied to all these time-to-event endpoints.
For time to first HHF and time to CV death, the analysis will be repeated based on 
investigator reported events. 
Change from baseline in clinical summary score (HF symptoms and physical limitations 
domains) of the Kansas City cardiomyopathy Questionnaire (KCCQ) at week 52
Change from baseline in clinical summary score for HF symptoms and physical limitations 
domains of the KCCQ at week 52 will be evaluated by a mixed model for repeated measures 
data including baseline score, LVEF (continuous), age (continuous) and eGFR (CKD-EPI)cr
at baseline (continuous) as linear covariates and treatment, visit, baseline score by visit, visit 
by treatment, gender, geographical region and status of diabetes at baseline as fixed effects. 
All on-treatment data up to week 52 will be included and the analysis will be conducted on 
the treated set. 


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A sensitivity analysis will be conducted including data after discontinuation (OC-AD) on the 
randomized set. 
Occurrence of all-cause hospitalisation (first and recurrent)
A similar joint frailty model as in the HHF will be analysed for all-cause hospitalization. 
Instead of CV death, all-cause mortality will be jointly modelled as the terminal events.
7.6
FURTHER ENDPOINTS
Time to event endpoints
Further time to event endpoints will generally be analysed in a Cox proportional hazards 
model similar to the primary analysis on RS. If the endpoint does not include any cause of 
death, a CIF plot with all-cause mortality as competing risk will be displayed; otherwise, a 
CIF plot with causes of death not included in the endpoint as competing risk will be 
displayed.
Continuous endpoints:
The following endpoints will be evaluated by mixed models repeated measures (MMRM) as 
defined in the protocol.
•
HbA1c change from baseline over time (OC-AD on the randomised set and OC-OT
on the treated set)
•
SBP, DBP change from baseline over time (OC-AD on the randomised set and
OC-OT on the treated set)
•
Weight change from baseline over time (OC-AD on the randomised set and OC-
OT on the treated set)
•
NT-pro BNP relative change from baseline over time (OC-AD on the randomised
set and OC-OT on the treated set) (value will be transformed to the log scale
before MMRM analysis. Estimates obtained from the model will then be back-
transformed and reported on the original scale.)
•
KCCQ overall summary score change from baseline at week 52 (OC-AD on the
randomised set and OC-OT on the treated set) (model will include all timepoints
up to week 52)
•
KCCQ individual domains change from baseline at week 52 (OC-AD on the
randomised set and OC-OT on the treated set) (model will include all timepoints
up to week 52)
•
KCCQ total symptom score change from baseline at week 52 (OC-AD on the
randomised set and OC-OT on the treated set) (model will include all timepoints
up to week 52)


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•
KCCQ based on patient-relevant outcome change from baseline at week 52 (OC-
AD on the randomised set and OC-OT on the treated set) (model will include all
timepoints up to week 52)
•
UACR relative change from baseline over time (OC-AD on the randomised set
and OC-OT on the treated set) (value will be transformed to the log scale before
MMRM analysis. Estimates obtained from the model will then be back-
transformed and reported on the original scale.)
•
eGFR (CKD-EPI)cr change from baseline over time (OC-AD on the randomised
set and OC-OT on the treated set)
As outlined in the protocol, the above endpoints will be analysed in a mixed model with 
repeated measures (MMRM), including baseline value, age, LVEF and eGFR (CKD-EPI)cr at 
baseline as linear covariates and treatment group, visit, visit by treatment interaction, baseline 
by visit interaction, geographical region, gender and baseline history of DM as fixed effects.
An additional factor of “week reachable” for the parameter in question, which for each patient 
is the theoretically reachable planned measurement based on the time of randomisation will 
adjust for the different planned study times. 
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 OC-OT on the treated set.
Additionally subgroup analyses will be performed as follows:
HbA1c change from baseline will be evaluated by status of diabetes (non-DM, pre-DM, DM). 
UACR will be evaluated by UACR at baseline (<30 mg/g, ≥30mg/g to ≤300mg/g, >300 
mg/g). 
In order to evaluate the mean effect on eGFR after approximately 3 years, the above described 
MMRM models will be used in the following way: a mean effect of the timepoints week 124, 
148 and 172 will be calculated. This will be done for the imputations of OC and OC-AD. 
For MMRM subgroup analyses, the model will additionally include the term for subgroup and 
the interaction terms for subgroup by visit, subgroup by treatment and subgroup by treatment 
by visit in addition. 
To support analysis of renal function, eGFR throughout the trial will be categorized according 
to the following CKD staging: All calculations for the staging of renal function will be based 
on the originally measured laboratory values and the upper limit of normals (ULNs) given by 
the laboratory, not on normalised values with BI standard reference ranges. 


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Table 7.6: 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 for eGFR (CKD-EPI)cr will be provided.
A summary will also be created representing the number of patients per treatment group who 
experienced a doubling in creatinine on treatment compared to baseline that was out of the 
normal range.
In cases where urine albumin values are reported to be below the quantification limits (e.g. <3 
mg/L) the albumin / creatinine ratio is determined as missing and will not be replaced by 
estimated values. 
Transitions from baseline to last value on-treatment based on the following UACR categories:
normal (<30mg/g), microalbuminuria (30-<=300 mg/g and macroalbuminuria (>300 mg/g) 
will be presented. 
For an evaluation of follow-up after discontinuation of trial medication an additional 
summary of the NT-proBNP, FPG, eGFR, UACR, creatinine and the KCCQ endpoints as 
above will be produced. This summary will include descriptive statistics for baseline, actual 
values and change from baseline to last on-treatment value and follow-up, and change from 
last on-treatment assessment to follow-up.  The TS-FU patient set will the basis for this 
summary, but only those patients with a valid baseline, last value on treatment and follow-up 
value will be included in all displays. Analyses will be repeated for patients with at least 52 
weeks of cumulative exposure. FPG analysis will also be conducted by DM status at baseline. 
Analyses of change from baseline to LVOT and FU as outlined above will be additionally 
modelled, separately for LVOT and FU. An analysis of covariance (ANCOVA) model 
including treatment group, gender, geographical region and history of DM as fixed effect and 
baseline eGFR (CKD-EPI)cr (continuous), age (continuous), LVEF (continuous) and baseline 
of the endpoint (if not already included) as linear covariates will be used.


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Descriptive statistics will be presented also for creatinine for the value at visit and change 
from baseline based on OC-AD on the randomised set and OC-OT on the treated set.
Win ratio:
An unmatched win ratio considering adjudicated CV death and adjudicated HHF will be 
analysed based on unmatched pairs. All patients randomised to empagliflozin will be 
compared to all patients randomised to placebo. Only common follow-up time will be 
considered for the comparison. Patients on empagliflozin are considered to have “won” the 
comparison if either the other patient has died due to CV causes while the patient on 
empagliflozin was still alive, or if both patients did not die due to CV causes, then if the other 
patient had more occurrences of HHF. The number of comparisons won is noted as NW. 
Patients on empagliflozin are considered to have “lost” the comparison if the empagliflozin 
patient died due to a CV cause while the patient on placebo was still alive, or if both patients 
did not die due to a CV cause, then if the patient on empagliflozin had more occurrences of 
HHF. The number of comparisons lost is noted as NL. The win ratio is NW/ NL. 
The rules for winning and losing follow Rogers 2014 (8) and analysis of the unmatched win 
ratio will be conducted as described in Pocock 2012 (10) . 
Other types of further endpoints
For other types of endpoints e.g. change in NYHA class at week 52, HCRU and EQ5D, 
descriptive statistics will be provided.
For NYHA class a shift table will also be provided for changes from baseline over time and 
for change from baseline to EOT and FU. 
Pharmacokinetic analysis
Descriptive statistics of trough concentrations of empagliflozin will be presented. 
7.7
EXTENT OF EXPOSURE
There will be three methods of calculating exposure:
a.
First intake to last intake of study drug, including off-treatment periods
b. First intake to last intake of study drug, excluding off-treatment periods
c.
Overall observational period (randomisation until end of follow-up for vital status, see
censoring for all-cause mortality in Section 6.8.3)
Descriptive statistics tables with mean, standard deviation (SD), median and range of the
number of days a patient was on treatment will be provided. These tables will also provide the 
sum-total of the time (in years) that all patients were on treatment.
Frequency tables of number and percentage of patients belonging to categorical ranges of 
exposure weeks will be provided as well. Following are the categories of exposure-ranges (in 
weeks): 0 to 12 weeks, >12 to 26 weeks, >26 to 52 weeks, >52 to 78 weeks, >78 to 104 


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weeks, >104 to 156 weeks, >156 weeks. Categorical ranges may be adapted based on the 
actual duration of the study. 
7.8
SAFETY ANALYSIS
The safety analysis will be based on the treated set (TS), treatment will be evaluated as 
randomised. 
The AE analysis will include all adverse events (including outcome events as reported by the 
investigator).
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 will be descriptive in nature and
will be based on the number of patients with AEs and not on the number of AEs.
AEs will be coded using the most recent version of the Medical Dictionary for Regulatory 
Activities (MedDRA) coding dictionary. 
Definitions of Boehringer Ingelheim customized MedDRA Queries (BIcMQs) for new 
MedDRA versions are maintained by the BI dictionary maintenance group. 
For analysis multiple AE occurrence data on the CRF will be collapsed into an AE provided 
that all of the following applies:
•
All AE attributes are identical (including LLT, intensity, action taken, therapy required,
seriousness, reason for seriousness, relationship, outcome, AE of special interest and also
additional information of specific AEs or AESIs such as source of sepsis (urinary tract or
not) 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 summarization of AE data, please refer to (2), (11).
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 
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 ‘post-treatment’. 
In Section 15.3 general AE analyses tables will present only on-treatment AEs (applying the 
rule of 7 days for assignment as on-treatment) for the treatments groups (exceptions for 
cancer events, hepatic events, lower limb amputations and bone fractures as well as 


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adjudicated events see below). When looking at BIcMQs or standardized MedDRA queries
(SMQs) and including all AEs up to termination of the trial, the time at risk will match the 
time at risk of non-fatal CV events (see section 6.8).  
Appendix 16.1.9.2 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.
The tables presenting frequency of AEs by SOC/PT and frequency of SAEs by SOC/PT will 
be repeated in Section 16.1.9.2 with treatment-specific post-treatment phase included, hereby 
also incidence rates for the post-treatment phase will be presented.
For listings, AEs will be assigned to one of the treatment phases of Screening, Placebo, Empa 
10, Placebo post-treat, Empa 10 post-treat, post-study. 
7.8.1.2 Analysis of other significant AEs
Other significant AEs will be reported and summarised according to ICH E3 (12) criterion. 
Thus, AEs classified as ‘other significant’ will include those non-serious adverse events with
‘action taken = study drug permanently / temporarily discontinued’.
7.8.1.3 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 7.8.1.8 will 
generally be included. AEs will also be reported by intensity (without incidence rates). 
Separate tables will be provided for patients with other significant adverse events, for patients 
with adverse events of special interest (AESIs), for patients with serious adverse events, for 
patients with AEs leading to discontinuation, and for patients with drug-related AEs.
Overall AE summaries, AEs by SOC and PT, SAEs and AEs leading to discontinuation will 
additionally be investigated by subgroups as outlined inTable 6.4: 1. 
AEs leading to death will be summarized up to end of the trial, also separately for those 
adjudicated as CV and those adjudicated non-CV cause. 
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 16.1.9.2 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


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
Serious Adverse Events for disclosure on EudraCT  by treatment
For further details, see also (13).
7.8.1.4 Adverse events of special interest (AESIs)
Hepatic injury
Adverse events reported as AEs of special interest relating to hepatic injury as specified in the 
protocol will be summarised. 
Additionally Hepatic AEs will be summarized based on an 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. This presentation will be repeated by DM status at baseline (DM vs no 
DM). Hepatic SAEs and hepatic AEs leading to disc based on the above SMQ definition will 
be presented.
In addition to the ‘7-day-on-treatment approach’, a ‘30-day-on-treatment approach’ will be 
presented for the overall hepatic adverse events based on the SMQ definition. 
Patients with hepatic injury will be listed.
For presentations on adjudicated hepatic events, refer to Section 7.8.1.6.
Decreased renal function
Adverse events reported as AEs of special interest relating to decreased renal function as 
specified in the protocol will be summarised. 
A frequency tables of patients with AEs related to decreased renal function by treatment, 
primary SOC and preferred term will additionally be provided based on the narrow 
standardized MedDRA query (SMQ) Acute renal failure (20000003). 
This presentation will be repeated by the subgroups as outlined in Table 6.4: 1. SAEs and AEs 
leading to disc based on the 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 decreased renal function will be listed.
Ketoacidosis


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A frequency tables of patients with AEs related to ketoacidosis will be presented by treatment, 
primary SOC and preferred term for investigator reported cases and for the broad and narrow 
BIcMQ definition of diabetic ketoacidosis. 
For the narrow BIcMQ diabetic ketoacidosis (DKA), SAEs and AEs leading to 
discontinuation will be presented. 
For presentations on adjudicated events, refer to Section 7.8.1.6
Patients with DKA based on the narrow and broad BIcMQ or investigator reported 
ketoacidosis will be listed. 
Events leading to lower limb amputation
A frequency table of patients with AEs leading to lower limb amputation as identified by the 
investigator by treatment, primary SOC and preferred term will be provided.
A separate tables for AEs leading to lower limb amputation which are leading to 
discontinuation will be presented. 
For events leading to lower limb amputations in addition to the ‘7-day-on-treatment approach’ 
all adverse events that occurred between first study drug intake up to study end will be 
presented (following censoring rules like non-fatal outcome events). For both approaches, 
SAEs will be presented. 
Lower limb amputations (up to study end) will additionally be summarised by level of 
amputation, reason for amputation, history of PAOD, previous amputation and status of DM 
at baseline (DM / no-DM). 
Patients with lower limb amputation will be listed.
7.8.1.5 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 will be categorised as follows:

asymptomatic hypoglycaemia: event not accompanied by typical symptoms of
hypoglycaemia but with a measured plasma glucose concentration ≤ 3.9 mmol/L (≤ 70
mg/dL)

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

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


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
severe hypoglycaemic episode: event requiring the assistance of another person to
actively administer carbohydrate, glucagon or other resuscitative actions

symptomatic hypoglycaemia and plasma glucose concentration > 3.9 mmol/L (70
mg/dL)

symptomatic hypoglycaemia and plasma glucose concentration not measured
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 asymptomatic or 
symptomatic 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 age category, renal function and 
diabetes background (no DM, patients with pre DM, patients with DM ) will be performed.
Time to the onset of the first confirmed hypoglycaemia will be displayed using a cumulative 
incidence function.
In addition the number of patients with hypoglycaemia according to BIcMQ will be 
presented.
Patients with hypoglycaemic events will be listed. 
UTI and genital infections
The following additional specific adverse events will also be assessed and be tabulated by 
treatment group:

Genital infections (narrow BIcMQ list and investigator assessment)

UTI (narrow BIcMQ 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),  time to onset of first episode 
(within the first 3 months of treatment or after), how the event was treated (no treatment, 
therapy assigned, hospitalisation), 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),  time to onset of first episode (within the first 3 months of treatment or 
after), anatomical location (upper UTI, lower UTI), how the event was treated (no treatment, 
therapy assigned, hospitalisation), whether leading to discontinuation of treatment, and the 
number of episodes per patient.
In the number of episodes analysis of UTI and genital infection AEs will be collapsed within 
each SSC regardless of preferred term with the collapsing following the description at the 
start of Section 7.8.1.


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For UTIs based on the narrow BIcMQ the subgroups as outlined in Table 6.4: 1 will be 
presented. The same will be done for genital infections based on the narrow BIcMQ. 
Complicated urinary tract infections defined as serious adverse events of narrow BIcMQ UTI, 
all events of sub-BIcMQ Pyelonephritis, all events of PT Urosepsis will be presented. 
Complicated genital infection: defined as all serious events using the narrow BIcMQ Genital 
infection will also be presented. 
UTIs leading to discontinuation based on the narrow BIcMQs will be presented, the same will 
be repeated for genital infections leading to discontinuation based on the narrow BIcMQ. 
Cumulative incidence functions will also be created for time to onset of the first UTI and for 
time to onset of the first genital infections, both based on the respective narrow BIcMQ. 
Patients will UTIs or genital infections will be listed. 
Pyelonephritis and sepsis 
The following specific adverse event will also be tabulated by treatment group:

Acute Pyelonephritis (based on investigator assessment): patient incidence overall and
by gender

Pyelonephritis (based on the narrow sub-SMQ): patient incidence overall and by
gender

Sepsis (based on investigator assessment): patient incidence overall and by source of
infection (UTI or not UTI)
Patients with pyelonephritis or sepsis 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 BIcMQ and investigator reporting).
Investigator reported fractures will be reported by type of fracture (traumatic vs. non-
traumatic).
For bone fractures based on the BIcMQ the subgroups as outlined in Table 6.4: 1 will be 
presented. Separate tables for bone fractures based on the BIcMQ, which are serious and 
those which are leading to discontinuation will be presented. 
For overall bone fracture based on the BIcMQ in addition to the ‘7-day-on-treatment 
approach’ all adverse events that occurred between first study drug intake up to study end will 
be presented (following censoring rules like non-fatal outcome events).
Patients with bone fractures will be listed.
Cancer events:


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Cancer will be based on the following Sub-SMQs of SMQ Malignancies (20000090):

Sub-SMQ Malignant or unspecified tumors (20000091)

Sub-SMQ Malignancy related conditions (20000092), excluding the PT "Acanthosis
nigricans".
Presentation will be done ordered by HLT. 
Frequency tables of patients with cancer by treatment, high level term and preferred term will 
be provided.  
For cancer in addition to the ‘7-day-on-treatment approach’ all adverse events that occurred 
between first study drug intake up to study end will be presented (following censoring rules 
like non-fatal outcome events). 
There will be an additional analysis including all patients who had a minimum cumulative 
study drug exposure of 6 months (excluding treatment gaps). All AEs starting from date when 
6 months cumulative exposure was reached up to individual day of trial completion will be 
shown (following censoring rules like non-fatal outcome events). 
Patients with cancer will be listed. 
Volume depletion
Volume depletion will be based on the BIcMQ. 
A frequency table of patients with volume depletion by treatment, primary SOC and preferred 
term will be provided. 
For volume depletion events the subgroups as outlined in Table 6.4: 1 will be presented. 
Separate tables for volume depletion events, which are serious and those which are leading to 
discontinuation will be presented. 
Patients with volume depletion will be listed.
A cumulative incidence function will be used to display the time to first volume depletion 
event.
For the analysis of laboratory data, refer to Section 7.8.2.
Venous embolic and thrombotic adverse events:
Venous embolic and thrombotic adverse events will be evaluated on the narrow SMQ. 
A frequency table of patients with venous embolic and thrombotic adverse events by 
treatment, primary SOC and preferred term will be provided. 


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The subgroups as outlined in Table 6.4: 1 will be presented. Separate tables for venous 
embolic and thrombotic adverse events, which are serious and those which are leading to 
discontinuation will be presented. 
Patients with venous embolic and thrombotic adverse events will be listed.
Increased urination
Frequency of increased urination will be summarised by primary SOC and preferred term
based on the project-defined PT list. 
7.8.1.6 Events qualifying for external adjudication by the CEC and Hepatic External 
Adjudication and Adjudication of ketoacidosis
An independent external CEC regularly reviews events and evaluates whether pre-specified 
criteria for these adjudication endpoints are met. Details on composition of the CEC, 
responsibilities and clinical event definitions are provided in the separate CEC Charter. 
Adjudication assessments will be incorporated into the database.
Details of the adjudication process are described in the CEC charter.
Cardiological/neurological adverse events:
Frequency tables will be provided based on SOC and preferred for events qualifying for 
adjudication.
The number of patients with confirmed events per event type and breakdown of event subtype 
will be presented. This will be done for all CEC confirmed events.
A frequency table contrasting local vs. central (adjudicated) assessments will also be 
generated.
A listing will be provided, that shows the trigger events and result of adjudication.
Hepatic adverse events:
Frequency tables summarizing 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 the end of the study. 
Ketoacidosis:
Frequency tables summarizing the adjudication results will be provided, including a listing 
showing the trigger events and adjudication results. This will include all adjudicated events up 
to the end of the study. 
7.8.1.7 AEs while patients taking wrong medication
A listing will be provided for AEs that occurred while a patient was taking the wrong 
medication.  Off-drug is not viewed as wrong medication.


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7.8.1.8 Adverse event incidence rates
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,
other significant AEs, serious AEs, and adverse events of special interest by SOC, 
respectively HLT, and PT.
The time at risk in patient years for 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
For ‘each row of a table’ (e.g. displaying an SOC), time at risk is calculated using start of first 
AE summarized 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 can 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.
7.8.2
Laboratory data
For continuous safety laboratory parameters standardized and normalized values will be 
derived as well as the differences to baseline. The process of standardization and 
normalization as well as standard analyses for safety laboratory data are described in the BI 
guidance for the Display and Analysis of Laboratory Data (14). All analyses considering 
multiple of times upper limit of normal (ULN) will be based on original and not normalized 
data.
Laboratory parameters will be shown in conventional units. Where conventional units differ 
from SI units, analyses will be repeated on SI units in the appendix. 


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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 (14)].
Baseline for safety laboratory parameters will be the last available measurement before the 
start of randomised trial medication. 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 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. 
Frequency tables will summarise the number of patients with potentially clinically significant 
abnormalities as defined for the current XLAB macro. 
Only patients with at least one available on-treatment value will be included in the analysis of 
an individual laboratory parameter. 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
Frequency tables of patients with elevated liver enzymes defined by ALT and/or AST, total 
bilirubin and AP combinations will be provided. A scatter plot of peak ALT against peak 
total bilirubin will be presented with reference lines for 3 x ULN ALT and 2 x ULN total 
bilirubin, including an indicator for treatment received.  Details on patients with elevated liver 
enzymes will be listed.
For the following parameters: total cholesterol, HDL-C, LDL-C, trigylcerides, haemoglobin 
and haematocrit the time course of changes will be assessed. The analysis will be performed 
by applying MMRM models to OC-AD data (on the randomised set) and respectively 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 normalization.


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The parameters LDL-C/HDL-C ratio and non-HDL cholesterol will be evaluated descriptively 
over time based on OC-AD data (on the randomised set) and OC-OT data (on the treated set). 
These analyses will be conducted on data before any normalization. 
For an evaluation of follow-up after discontinuation of trial medication an additional 
summary of haemoglobin, haematocrit, uric acid and lipid parameters will be produced. This 
summary will include descriptive statistics for baseline, actual values and change from 
baseline from last on-treatment value and follow-up, and change from last on-treatment 
assessment to follow-up.  The TS-FU patient set will the basis for this summary, but only 
those patients with a valid baseline, last value on treatment and follow-up value will be 
included in all displays. Analyses will be repeated for patients with at least 52 weeks of 
cumulative exposure. 
Analyses of change from baseline to LVOT and FU as outlined above will be additionally 
modelled, separately for LVOT and FU. An ANCOVA model including treatment group, 
gender, geographical region and history of DM as fixed effect and baseline eGFR (CKD-
EPI)cr (continuous), age (continuous), LVEF (continuous) and baseline of the endpoint as 
linear covariates will be used.
7.8.3
Vital signs
An MMRM analysis for heart rate over time will be provided based on OC-AD on the 
randomised set and OC-OT on the treated set imputations. The model will follow the MMRM 
analysis described in Section 7.6.
7.8.4
Electrocardiogram (ECG)
Clinically relevant abnormalities found at physical examination or ECG at Visit 2 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 summarized descriptively.. 
7.8.5
Others
Frequency of pregnancies and pregnancy outcomes will be listed by treatment.
Results of the Modified Rankin Scale will be summarized descriptively. 


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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
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current
version; IDEA for CON.
3
001-MCS 36-472: "Standards and processes for analyses performed within Clinical
Pharmacokinetics/Pharmacodynamics", current version; IDEA for CON.
4
001-MCG-159: "Reporting of Clinical Trials and Project Summaries", current
version; IDEA for CON.
5
R16-3839
Beyersmann J, Allignol A, Schumacher M
Competing risks and multistate models with R.
New York: Springer (2012)
6
R07-4680
Collett D
Modelling survival data in medical research
Chapman and Hall/CRC (2003)
7
R16-2229
Rogers JK, Yaroshinsky A, Pocock SJ, Stokar D, Pogoda J
Analysis of recurrent events with an associated informative dropout time: application 
of the joint frailty model.
Stat Med 35 (13), 2195 - 2205 (2016)
8
R16-4909
Rogers JK, Pocock SJ, McMurray JJV, Granger CB, Michaelson EL, Ostergren J, et 
al
Analysing recurrent hospitalizations in heart failure: a review of statistical 
methodology, with application to CHARM-Preserved.
Eur J Heart Fail 16, 33 - 40 (2014)
9
Li Lu, Chenwei Liu, Analysis of Correlated Recurrent and Terminal Events Data in 
SAS®, NESUG 2008
10
R16-4813
Pocock SJ, Ariti CA, Collier TJ, Wang D
The win ratio: a new approach to the analysis of composite endpoints in clinical trials 
based on clinical priorities.
Eur Heart J 33, 176 - 182 (2012)
11
001-MCG-156: "Handling and summarization of adverse event data for clinical trial
reports and integrated summaries", current version; IDEA for CON.
12
CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH 
Guideline Topic E3; Note For Guidance on Structure and Content of Clinical Study 
Reports, current version
13
001-MCG-159_RD-09: “Additional Analysis Requirements for Disclosing Data from
Clinical Trials - Display Templates", current version; IDEA for CON.
14
001-MCG-157: "Handling, Display and Analysis of Laboratory Data", current
version; IDEA for CON.
15
001-MCG-741: "Clinical subgroup analyses for local and regional Populations in Asia
- Clinical Bridging Study Waiver (BSW) and Descriptive Subgroup Analysis (SGA)
Reports” , current version; IDEA for CON.


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9.
ADDITIONAL SECTIONS
9.1
REGIONS AND COUNTRIES
Countries will be assigned to regions following the assignment of the IRT system, which is 
outlined in Table 9.1:1. Listed countries include currently planned backup countries. 
Table 9.1: 1
Regions and countries
Region
Country
Asia
China
Japan
Korea
Singapore
Europe
Belgium
Bulgaria
Czech Republic
Denmark
Germany
Hungary
Italy
Netherlands
Poland
Spain
Romania
Sweden
UK
Latin America
Argentina
Brazil
Colombia
Mexico
North America
Canada
US
Other
India
Australia
South Africa
Turkey
9.2
CONCOMITANT MEDICATION
Definitions of medication groups (such as ARBs, diuretics) will be based on World Health 
Organization Drug Dictionary (WHO DD) and will be stored in the PDMAP. 


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9.3
ADDITIONAL SUB-GROUP ANALYSIS FOR REGIONAL SUBMISSIONS
Disposition and demographics of the subpopulation for patients from USA and subgroup 
analyses for patient from the USA vs non-USA will be included in the appendix of the CTR. 
Efficacy endpoints evaluated will be primary endpoint, time to cardiovascular (CV) death, 
time to first HHF, HHF (first and recurrent) and renal slope. Safety will be summarized for 
patients from the USA.  
Additional country or region-specific analyses will be conducted for patients from Mexico, 
East-Asia (China, Japan and Korea), China, Japan, Korea and India to be included into the 
country-specific submission documents as also outlined in (15). Primary endpoint, time to 
cardiovascular (CV) death, time to first HHF, HHF (first and recurrent) and renal slope will 
be presented. Main adverse event overviews, disposition, demographics will be presented.
9.4
INTERIM ANALYSES
An interim analysis will be conducted by the DMC as outlined in the CTP. If based on the 
interim analysis it is decided to stop the trial for overwhelming efficacy, all analyses
belonging to the confirmatory testing strategy as described in this TSAP will be conducted on 
the snapshot as used for the interim analysis done by the DMC. All other analyses will be 
conducted on the final database lock. 


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Final
21-FEB-2017
None
This is the final TSAP without any 
modification


TITLE PAGE
Trial Statistical Analysis Plan
c14526274-04
BI Trial No.:
1245.110
Title:
A phase III randomised, double-blind trial to evaluate efficacy and 
safety of once daily empagliflozin 10 mg compared to placebo, in 
patients with chronic Heart Failure with preserved Ejection Fraction 
(HFpEF).
   Including Revised protocol # 03 [c03946327-04]
Investigational
Product:
Empagliflozin, BI 10773
Responsible trial 
statistician:
Date of statistical 
analysis plan:
12 FEB 2021 REVISED
Version:
Revised
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE............................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES ...................................................................................................................4
LIST OF FIGURES .................................................................................................................5
2.
LIST OF ABBREVIATIONS...............................................................................6
3.
INTRODUCTION...............................................................................................10
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ....................11
5.
ENDPOINTS........................................................................................................12
5.1
PRIMARY ENDPOINT......................................................................................12
5.2
SECONDARY ENDPOINTS .............................................................................12
5.2.1
Key secondary endpoints ....................................................................................12
5.2.2
Other secondary endpoints.................................................................................12
5.3
FURTHER ENDPOINTS...................................................................................12
5.4
OTHER VARIABLES ........................................................................................13
5.4.1
Kansas City Cardiomyopathy Questionnaire (KCCQ) scores........................13
5.4.2
LVEF ....................................................................................................................18
6.
GENERAL ANALYSIS DEFINITIONS...........................................................19
6.1
TREATMENTS...................................................................................................19
6.2
IMPORTANT PROTOCOL DEVIATIONS (IPDS) .......................................20
6.3
SUBJECT SETS ANALYSED ...........................................................................22
6.4
SUBGROUPS.......................................................................................................23
6.5
POOLING OF CENTRES..................................................................................26
6.6
HANDLING OF MISSING DATA AND OUTLIERS ....................................27
6.6.1
Imputation methods ............................................................................................27
6.6.2
Missing data.........................................................................................................28
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS....................30
6.8 
CALCULATION OF TIME TO EVENT .........................................................32
6.8.1
Start date..............................................................................................................32
6.8.2
Date of event.........................................................................................................33
6.8.3
Censoring .............................................................................................................33
7.
PLANNED ANALYSIS ......................................................................................36
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .........36
7.2
CONCOMITANT DISEASES AND MEDICATION......................................37
7.3
TREATMENT COMPLIANCE ........................................................................37
7.4
PRIMARY ENDPOINT......................................................................................37
7.4.1
Primary analysis of the primary endpoint(s)....................................................37
7.4.2
Sensitivity analyses..............................................................................................39
7.4.3 
Proportional hazards assumption violated .......................................................41
7.4.4
Subgroup analyses...............................................................................................41
7.5
SECONDARY ENDPOINTS .............................................................................42
7.5.1
Key secondary endpoints ....................................................................................42
7.5.2
Other Secondary endpoints................................................................................45
7.6
FURTHER ENDPOINTS...................................................................................47


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7.7
EXTENT OF EXPOSURE .................................................................................52
7.8
SAFETY ANALYSIS..........................................................................................52
7.8.1
Adverse events .....................................................................................................53
7.8.1.1
Assignment of AEs to treatment ...........................................................................53
7.8.1.2
AE summaries .......................................................................................................54
7.8.1.3
Adverse events of special interest (AESIs) ...........................................................54
7.8.1.4
Specific AEs..........................................................................................................56
7.8.1.5
Events qualifying for external adjudication by the CEC and Hepatic External 
Adjudication and Adjudication of ketoacidosis ....................................................60
7.8.1.6
AEs while patients taking wrong medication........................................................61
7.8.1.7
Adverse event incidence rates ...............................................................................61
7.8.1.8
COVID-19 related analyses...................................................................................62
7.8.2
Laboratory data...................................................................................................62
7.8.3
Vital signs.............................................................................................................64
7.8.4
ECG ......................................................................................................................64
7.8.5
Others ...................................................................................................................64
8.
REFERENCES ....................................................................................................65
9.
ADDITIONAL SECTIONS................................................................................66
9.1
REGIONS AND COUNTRIES..........................................................................66
9.2
CONCOMITANT MEDICATION....................................................................66
9.3
DEFINITION OF DM AT BASELINE.............................................................67
9.4
ADDITIONAL SUB-GROUP ANALYSIS FOR REGIONAL 
SUBMISSIONS....................................................................................................69
9.5
INTERIM ANALYSES.......................................................................................69
9.6
DETERMINATION OF SAMPLE SIZE..........................................................69
9.7
FURTHER SAFETY ANALYSES ....................................................................70
10.
HISTORY TABLE..............................................................................................72


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LIST OF TABLES
Table 6.1: 1
Treatment regimens / study intervals................................................................19
Table 6.1: 2
Endpoint specific assignment to the on-treatment phase..................................20
Table 6.2: 1
Important protocol deviations...........................................................................20
Table 6.4: 1
Categories of covariates for displays of baseline characteristics and 
subgroup analyses.............................................................................................24
Table 6.7: 1
Time windows for post-baseline efficacy measurements scheduled for each 
on-treatment visit for the first 3 years ..............................................................31
Table 7.6: 1
CKD staging .....................................................................................................50
Table 9.1: 1
Regions and countries.......................................................................................66
Table 9.3: 1
DM at baseline ..................................................................................................67
Table 10: 1
History table .....................................................................................................72


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LIST OF FIGURES
Figure 7.4.1: 1Hierarchical analysis of trial in HFpEF (1245.110) and the parallel trial in 
HFrEF (1245.121) showing the alpha-spending at the final analysis...............39


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ACE 
Angiotensin Converting Enzyme
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine transaminase
ANCOVA
Analysis of covariance
ARB 
Angiotensin Receptor Blocker
ARNI 
Angiotensin Receptor blocker-Neprilysin Inhibitor
ASA
Acetylsalicylic acid
AST
Aspartate transaminase
ATC
Anatomical-Therapeutic-Chemical
BI
Boehringer Ingelheim
BicMQ
Boehringer Ingelheim customized MedDRA Query
BMI
Body mass index
BP
Blood pressure
CCB
Calcium channel blocker
CEC
Clinical Event Committee
CI
Confidence interval
CIF
Cumulative Incidence Function
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CRF
Case report form
CRT 
Cardiac resynchronisation therapy
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Cardiovascular
DBL
Data base lock
DBP
Diastolic Blood Pressure
DKA
Diabetic ketoacidosis
DM 
Diabetes mellitus
DM&SM
Data Management and Statistics Manual
ECG
Electrocardiogram
eCRF
Electronic Case Report Form


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Term
Definition / description
eGFR
Estimated glomerular filtration rate
EMA
European Medicines Agency 
EoT
End-Of-Text
EOT
End of treatment
EQ-5D
EuroQoL 5 dimensions
EudraCT
European Clinical Trials Database
FG
Fasting glucose
FU
Follow-up
GI
Gastrointestinal
HbA1c
Glycosylated haemoglobin
HCRU
Health Care Resource Utilisation
HDL-C
High density lipoprotein cholesterol
HF
Chronic Heart Failure
HHF
Hospitalisation for heart failure
HLT
High level term
hsTnT
high-sensitivity troponin T
HR
Hazard ratio
ICD 
Implantable Cardioverter Defibrillator
ICH
International Conference on Harmonisation
IPD
Important protocol deviation
IRT
Interactive Response Technology
ITT
Intention-to-treat
IVRS
Interactive voice response system
JFM
Joint frailty model
KCCQ
Kansas City Cardiomyopathy Questionnaire
LVAD
Left ventricular assist device
LDL-C
Low density lipoprotein cholesterol
LLT
Low level term
LVEF
Left ventricular ejection fraction
LVOT
Last value on treatment
LTFU
Lost to follow-up
Max
Maximum


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Term
Definition / description
MedDRA
Medical Dictionary for Regulatory Activities
MI
Myocardial infarction
Min
Minimum
MMRM
Mixed models repeated measures
MRA 
Mineralocorticoid Receptor Antagonist
Non-CV
Non-cardiovascular
NT pro-BNP
N-terminal pro B-type natriuretic peptide
NYHA
New York Heart Association Classification
OC-AD
Observed Case including data after discontinuation
OC-OT
Observed Case on-treatment
PK
Pharmacokinetic
PAOD
Peripheral Arterial Occlusive Disease
PT
Preferred term
Q1
Lower quartile
Q3
Upper quartile
PDMAP
Project data management and analysis plan
RS
Randomized set
SAE
Serious adverse event
SAS
Statistical Analysis System
SBP
Systolic blood pressure
SCR
Screened set
SD
Standard deviation
SE
Standard error
SGLT-1
Sodium-glucose co-transporter 1
SGLT-2
Sodium-glucose co-transporter 2
SI
Système international d'unités
SMQ
Standardized MedDRA query
SOC
System organ class
TBILI
Total bilirubin
TS
Treated set
TS-FU
Treated set – Follow-up
TSAP
Trial statistical analysis plan


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Term
Definition / description
UACR
Urine Albumin Creatinine Ratio
ULN
Upper limit of normal
UTI
Urinary tract infection
WHO DD
World Health Organization Drug Dictionary


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


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
1. In the random coefficient model used to estimate slope in change from baseline of
eGFR (CKD-EPI)cr, an additional fixed effect term of interaction of eGFR (CKD-
EPI)cr  at baseline (continuous) by time is included.
2. As per protocol the objective of the trial is “to demonstrate superiority of
empagliflozin 10 mg versus placebo”.
The ITT analysis approach was chosen to as closely as possible reflect real-life
conditions, disregarding any occurrences of treatment stop or restart of treatment, that
may happen in clinical practice as well.
However, it is also recognized and recommended by the Executive Steering
Committee that the study-specific treatment discontinuation in the close-out period
does not resemble clinical practice.
Therefore for patients that complete the treatment period according to protocol after
close-out announcement the time at risk for efficacy endpoints ends at the
discontinuation of treatment and events occurring thereafter are not considered in the
efficacy analyses.
The primary estimand is now specified in Section 7.4.
An analysis including all events after randomization will be conducted as sensitivity
analysis for the primary endpoint and the key secondary endpoint of recurrent HHF. A
corresponding approach will be used for continuous endpoints.
3. Mixed model for repeated measures (MMRM) for KCCQ at week 52 as well as other
MMRMs were specified in condensed form to be in line with BI internal standards.
Therefore, individual model terms were removed from the MMRM if already included
as interaction term with treatment or visit. Additionally, the terms included in
MMRMs were aligned throughout the TSAP
4. The rules defining ‘win’ and ‘lose’ for the win ratio calculation were clarified and
adapted to also consider the time to first HHF event in case of a tie in the number of
HHF events. The adaption was made since time to first HHF event is also considered
relevant information to avoid ties in case the number of HHF events is identical. This
approach is a modification of the rules applied by Rogers 2014 (8).


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
The primary endpoint is the composite of time to first event of adjudicated CV death or 
adjudicated HHF.
For further clarification: Adjudicated CV death always includes death adjudicated as death 
due to undetermined cause. This is applicable throughout all analyses wherever adjudicated 
CV death is mentioned. 
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
Key secondary endpoints are: 

Occurrence of adjudicated HHF (first and recurrent)

eGFR (CKD-EPI)cr slope of change from baseline
5.2.2
Other secondary endpoints
Other secondary endpoints are specified in the CTP Sections 5.1.2 and 5.2, and in TSAP 
Section 7.5.2.
5.3
FURTHER ENDPOINTS
Further endpoints are listed in the CTP Section 5.1.3, and in TSAP Section 7.6. The definition 
and assessment can be found in Section 5.2.
Further endpoints added include:

Time to non-cardiovascular (non-CV) death (i.e. death cases not included in the
definition of adjudicated CV death)

Fasting glucose (FG) change from baseline to last value on treatment (LVOT) and
follow-up (FU), overall and by status of diabetes mellitus (DM)

Time to first investigator-defined CV hospitalization. Investigator-defined CV
hospitalization includes AEs ticked by the investigator as “CV hospitalization (due to
reasons other than heart failure, MI or stroke)” and AEs ticked as “Hospitalization for
Heart failure” as well as events ticked as “Cardiovascular (CV) Death other than CV
death attributed to myocardial infarction or stroke”, MI, stroke, non-fatal TIA that are
reported as requiring hospitalization.

Time to atrial fibrillation (defined as time to first reported ECG indicating atrial
fibrillation or to first AE with PT atrial fibrillation).


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5.4
OTHER VARIABLES
5.4.1
Kansas City Cardiomyopathy Questionnaire (KCCQ) scores
There are 10 summary scores within the KCCQ, which are calculated as follows:
1. Physical Limitation
Code responses to each of Questions 1a-f as follows:

Extremely limited = 1

Quite a bit limited = 2

Moderately limited = 3

Slightly limited = 4

Not at all limited = 5

Limited for other reasons or did not do = <missing value>
If at least three of Questions 1a-f are not missing, then the Physical Limitation Score is 
calculated as follows:
Physical Limitation Score = 100*[(mean of Questions 1a-f actually answered) – 1]/4
2. Symptom Stability
Code the response to Question 2 as follows:

Much worse = 1

Slightly worse = 2

Not changed = 3

Slightly better = 4

Much better = 5

I’ve had no symptoms over the last 2 weeks = 3
If Question 2 is not missing, then the Symptom Stability Score is calculated as follows:
Symptom Stability Score = 100*[(Question 2) – 1]/4
3. Symptom Frequency
Code responses to Questions 3, 5, 7 and 9 as follows:


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


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


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


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


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(sum of the responses to those n-i questions) / (n-i)
not
(sum of the responses to those n-i questions) / n
Patient-preferred outcome is derived from response to the question about which domain is the 
most difficult for the patient to cope with at baseline:

Loss of functional abilities: Physical Limitation Score

Symptoms due to your heart failure: Total Symptom Score

Your concern about how to manage your heart failure: Self-Efficacy Score

Suffering from depression, anxiety, emotional liability because you have heart 
failure: Quality of Life Score

Adapting your life to heart failure: Social Limitation Score
5.4.2
LVEF
Values of LVEF will be considered valid, when appropriate methodology was used. When 
methodology is missing, LVEF will be disregarded. 


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
There will be 4 basic treatment phases in this trial: screening, study treatment phase (with 
either empagliflozin 10mg or matching placebo), post-treatment and post-study.  However, 
during the study treatment phase, patients are allowed to go off-treatment and subsequently 
re-start treatment.  This may happen not at all or repeatedly for a given patient.
The purpose of the definitions below is to describe all the different study/treatment intervals, 
in which a patient can lie during the course of the trial. Note that the term "treatment regimen" 
also covers the “off-treatment” time periods.
Table 6.1: 1
Treatment regimens / study intervals
Label
Interval
Start date 
Screening
Screening
Date of informed consent
Placebo/
Empagliflozin 10mg
Treatment
Date of first administration of double-
blind study treatment
Off-treatment (if applicable)
During Treatment 
interval, but not on 
treatment
Date of last administration of the 
study medication before temporarily 
discontinuation + 1 day
Placebo/
Empagliflozin 10mg 
(if applicable)
During Treatment 
interval, after restart 
of study medication
Date study medication re-started
Post-treatment
Post-treatment
Date of last administration of study 
drug + 1 day
Post-study
Post-study
Date of trial completion +1 day
Details on the definition of on-treatment period for different endpoints are listed in 
Table 6.1:2. The efficacy analyses will follow the intention-to-treat (ITT) principle in 
assigning patients to treatment groups, i.e. patients will be analysed as randomised. 
Safety analyses will also assign patients to the treatment group as randomized.
If a patient erroneously receives the wrong trial drug, all subsequent medication packs 
dispensed to the patient will still be for the treatment group to which the patient was 
randomized. Therefore the adverse events will be analyzed as per randomized treatment, 
which is expected to reflect the prevailing treatment. 
In the exceptional case that a patient took the wrong treatment, adverse events may occur 
while being on the wrong treatment. Analyses of this data are described in Section 7.8.1.6. 


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Table 6.1: 2
Endpoint specific assignment to the on-treatment phase
Endpoint
Last day of assignment to the on-
treatment phase
(days after last intake of study 
medication)
Adverse events
7
Safety laboratory measurements, including Urine
Albumin Creatinine Ratio (UACR)
3
Heart rate
1
Glycosylated haemoglobin (HbA1c)
7
FG
1
Body weight
1
Creatinine and estimated glomerular filtration 
rate (eGFR)
1
N-terminal pro B-type natriuretic peptide (NT 
pro-BNP)
1
Blood pressure
1
Patient reported outcome
7
6.2
IMPORTANT PROTOCOL DEVIATIONS (IPDS)
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.
The 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 #3 not met
None
A1.07
Conditions on ejection fraction (EF) not 
met
Inclusion criterion #4 not met
None
A1.08
Conditions on NT-proBNP not met
Inclusion criterion #5 not met 
None
A1.09
Conditions on HF not met
Inclusion criterion #6 not met
None
A2
Inclusion criteria not met
A2.02
Age out of range
Inclusion criterion #1 not met
None


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Table 6.2: 1
Important protocol deviations (cont.)
Category / 
Code
Description
Requirements
Excluded 
from
A2.08
Specific inclusion criterion for women 
of child-bearing potential not met
Inclusion criterion #2 not met
None
A3
Exclusion criteria met
A3.44
Patient with unstable conditions
Exclusion criteria #1, #2, #7, #11 or #16 
met
None
A3.42
Recently implanted ICD
Exclusion criterion #3 met
None
A3.43
Implanted CRT
Exclusion criterion #4 met
None
A3.29
Patients with cardiomyopathies as 
defined in the protocol
Exclusion criterion #5 met
None
A3.30
Any severe (obstructive or regurgitant) 
valvular heart disease, obstructive or 
regurgitant, or any valvular disease 
expected to lead to surgery during the 
trial in the opinion of the investigator
Exclusion criterion #6 met
None
A3.31
Atrial fibrillation or atrial flutter with a 
resting heart rate >110bpm
Exclusion criterion #8 met
None
A3.33
Systolic blood pressure at visit 1 or 2 
out of range
Exclusion criterion #9. #10 met
None
A3.06
Indication of liver disease
Exclusion criterion #12 met
None
A3.09
Renal insufficiency or renal impairment 
(assessed by eGFR)
Exclusion criterion #13 met
None
A3.34
Haemoglobin at visit 1 below cut-off
Exclusion criterion #14 met
None
A3.35
History of Ketoacidosis
Exclusion criterion #15 met
None
A3.36
Gastrointestinal (GI) surgery or GI 
disorder that could interfere with study 
medication absorption in the 
investigator’s opinion
Exclusion criterion #17 met
None
A3.37
Documented or active malignancy
Exclusion criterion #18 met
None
A3.38
Life expectancy of <1 years in the 
opinion of the investigator
Exclusion criterion #19 met
None
A3.39
Intake of restricted medications or any 
drug considered likely to interfere with 
the safe conduct of the trial
Exclusion criterion #20 met
None
A3.40
Treatment with any SGLT-2 inhibitor 
or SGLT-1 and 2 inhibitor
Exclusion criterion #21 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 #22 met
None
A3.41
Known allergy or hypersensitivity to 
empagliflozin
Exclusion criterion #23 met
None
A3.13
Relevant alcohol or drug abuse and
condition affected study compliance
Exclusion criterion #24 met
None
A3.12
Specific exclusion criterion for 
premenopausal women not met
Exclusion criterion #25 met
None
A3.14
Any other clinical condition unsafe for 
participation
Exclusion criterion #26 met
None
B
Informed consent
B1
Informed consent not available/not 
done
Informed consent date missing or 
inclusion criterion #9 not met
All
B2
Informed consent too late
Informed consent date was after Visit 1
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
D
Concomitant medication
D2.02
Use of prohibited medication 
Use of SGLT-2 or combined SGLT-1 and 
2 inhibitors after randomization but before 
EOT visit occurring at study close out.
None
6.3
SUBJECT SETS ANALYSED
The following patient sets are defined

Screened Set (SCR)
Consists of all patients screened for the trial, with informed consent given and who 
completed at least one screening procedure at Visit 1.

Randomised set (RS)
This patient set includes all randomised patients, whether treated or not.

Treated set (TS)
This patient set includes all patients who were dispensed study medication and were 
documented to have taken at least one dose of investigational treatment.

Treated Set-Follow-up (TS-FU)
All patients in the TS, for whom a follow-up visit was performed (i.e. values of planned 
assessments- KCCQ, EQ-5D, vital signs or lab data reported) between 23 and 45 days 
after last intake of study medication.
The TS-FU does not include patients, where no planned measurements were taken, which 
may happen in case of telephone FU visits. Patients with intake of open label SGLT-2
inhibitor between their EOT and FU visit are also excluded from the TS-FU set.

Pharmacokinetic Set (PKS)
This patient set includes all evaluable patients of the treated set who provide at least 
one observation for at least one further PK endpoint of Cpre,ss,N for empagliflozin.


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6.4
SUBGROUPS
Subgroups to be considered in the analyses are provided below in Table 6.4: 1. Missing 
categories for subgroup variables will not be considered in the respective analysis.
If there is missing information for any of the subgroups, where data is also collected in the 
IRT system, then the information as transferred from IRT will be used to assign a patient to a 
certain category. 
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
Categorization
Demo-
graphics1
Subgroups 
for Efficacy 
endpoints2
Safety3
Diabetes at baseline
diabetic, non-diabetic
X
X
X (except 
ketoacidosis and 
hypoglycaemia)
non-diabetic (Pre-diabetes, 
normal (no pre-diabetes)),
diabetic (type 2 diabetes, type 
1 diabetes)
X
X (Ketoacidosis and 
hypoglycaemia)
Age (years)
<50
50 to <65
65 to <75
75 to <85
>= 85
X
X
< 70
≥70
X
X
Sex
male
female
X
X
X 
Region
NA, LA, Europe, Asia, 
Other+
X
X (overall4only)
Ethnicity
Hispanic/ Latino
Not Hispanic/ Latino
X
X (overall4 only)
Race$
White
Black/ African-American
Asian
Other including mixed race
X
X
X
BMI (kg/m2)
<30
≥30
X
X
eGFR at baseline
>=90
60 to <90
45 to <60
30 to <45
20 to <30
<20
X
>=90
60 to <90
45 to <60
30 to <45
<30
X
X
>=60
<60
X
X


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Table 6.4: 1
Categories of covariates for displays of baseline characteristics and subgroup 
analyses (cont.)
Variable
Categorization
Demo-
graphics1
Subgroups 
for Efficacy 
endpoints2
Safety3
UACR
UACR (in mg/g):
<30 
>=30 to <=300 
>300
X
Baseline SBP
< / >= median
X
Baseline BP
SBP<140 and DBP<90 
vs. SBP>= 140 or 
DBP>=90
X
X (volume 
depletion 
AEs and 
hypotension 
AEs)
History of Atrial 
Fibrillation or Atrial 
Flutter$$ 
Yes/ No
X
X
Baseline LVEF 
</>=50
X
<50, 50 to <60, >=60
X
X
History of HHF (in the last 
12 months)
Yes / No
X
X
Time since diagnosis of HF
<= 1 year, 1-5 years, > 5 -
10 years, >10 years
X
NYHA at baseline
I/II/III/IV
X
II vs. III/IV
X
NT-proBNP
< / >= median (calculated 
separately for patients 
with/without history of 
atrial fibrillation or atrial 
flutter$$)
X
Baseline uric acid 
Tertiles (calculated 
separately for males and 
females)
X
X
Baseline use of ACE-
inhibitor, ARB or ARNi
Yes / No
X#
X
X (renal 
AEs, 
volume 
depletion 
AEs and 
hypotension 
AEs
)
Baseline use of MRA 
Yes / No
X#
X


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Table 6.4: 1
Categories of covariates for displays of baseline characteristics and subgroup 
analyses (cont.)
Variable
Categorization
Demo-
graphics1
Subgroups
for Efficacy 
endpoints2
Safety3
Baseline use of diuretics
Yes / No
X#
X (renal 
AEs, 
volume 
depletion 
AEs and 
hypotension 
AEs)
Baseline use of  loop or 
high-ceiling diuretics
Yes / No
X#
X (renal 
AEs, 
volume 
depletion 
AEs and 
hypotension 
AEs)
1  The column demographics shows categories shown in the overall demographics. 
Demographics are not planned by subgroup. 
2 Subgroups planned for the primary endpoint, time to cardiovascular (CV) death, time to first 
HHF, HHF (first and recurrent), renal slope. 
3 X means subgroups planned for overall AE summaries, AEs by SOC and PT, SAEs, AEs 
leading to discontinuation, decreased renal function, UTI, genital infection, volume depletion, 
hypotension and bone fracture.
4 Overall means overall AE summaries, AEs by SOC and PT, SAEs and AEs leading to 
discontinuation
5 Median calculated separately for baseline atrial fibrillation or atrial flutter (determined by 
ECG) / no baseline atrial fibrillation and atrial flutter (determined by ECG)
+ Region categorization: see Table 9.1.1. 
# part of the presentation of baseline concomitant therapy as outlined in Section 7.2
$ Due to low number of patients in certain race categories, estimates for race subgroups may 
be unstable.
$$ history of atrial fibrillation or atrial flutter means atrial fibrillation or atrial flutter reported 
in any ECG before treatment intake or history of atrial fibrillation or atrial flutter reported as 
medical history.
Additional subgroup analyses for specific further endpoints are defined in Section 7.6
6.5
POOLING OF CENTRES
This section is not applicable because centre/country is not included in the statistical model.


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6.6
HANDLING OF MISSING DATA AND OUTLIERS
6.6.1
Imputation methods
There will be no imputation of data for safety analyses. For patients who discontinue the trial 
treatment prematurely, all efforts will be made to follow patients for survival and for any 
other endpoints including the primary and key secondary endpoints until the end of the trial. 
There will be different methods of looking at continuous longitudinal data. 
Observed case on-treatment (OC-OT):
Only the available data that were observed while patients were on study medication (defined 
as time from first drug intake until last permanent treatment stop date plus the endpoint 
specific follow-up time (as defined in Table 6.1:2) are considered. 
Measurements are assigned to planned weeks according to Table 6.7: 1
Observed case including data after treatment discontinuation (OC-AD):
All available data are considered, including values obtained on treatment or post-treatment.
Measurements are assigned to planned weeks according to Table 6.7: 1.
As described in Section 4, for patients that completed the treatment phase as planned (primary 
reason for end of treatment being completion of treatment period according to protocol), 
measurements after last study drug intake should not be considered. Therefore for those 
patients, any data after the endpoint specific follow-up time (as defined in Table 6.1:2) will 
not be included in the OC-AD analysis. 
KCCQ imputation
If not otherwise noted, for endpoints of KCCQ scores, for patients who die, a worst score 
(score of 0) will be imputed for the score at all subsequent scheduled visits after the date of 
death where the score would have been assessed.
Multiple imputations:
A multiple imputations approach will be considered to impute missing data. Multiple 
imputation approaches taken are further specified in Section 7 with the planned sensitivity 
analyses.  
Imputation of missing covariates in multivariate Cox regression models and for recurrent 
event analyses
To avoid excluding patients from Cox regression analyses due to missing covariates, the 
overall population median of the corresponding variable will be imputed for continuous 
covariates and the most frequent category will be imputed for categorical covariates.
No imputation will be done for covariates included in treatment by subgroup interaction 
terms.


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6.6.2
Missing data
Adverse event data 
Missing or partial date information for AEs will be replaced according to general Boehringer 
Ingelheim (BI) rules described in the BI guidance for handling of missing and incomplete AE 
dates (2).
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, last day known to be alive + 1 day, 
range of possible days based on partial death date and date of trial completion.
Missing information on the date of first administration of trial drug
If the date of first drug administration is missing but the patient was randomised, the date of 
the first drug administration will be set to the date of randomisation. If the date of first 
administration is partially missing with the month and year present, the day will be set to the 
date of randomisation if randomisation was in the same month. If randomisation was in the 
month prior to the first drug administration the missing day will be imputed as the first day of 
the month. 
Missing date of trial completion (=last contact or date of death)
If the date is completely missing the following rules will be applied:

If a patient has withdrawn informed consent, this date will be imputed by the date of 
IC withdrawal.

If a patient died and has not withdrawn consent and is not lost to follow-up, this date 
will be imputed by the date of death. 

If a patient did not die, the date of trial completion will be imputed by the last date the 
patient was known to free of non-fatal events. This is defined as the maximum of 
o
the last date the patient could be followed up for all non-fatal events as 
documented in the eCRF 
o
last onset or end date of an AE
o
Onset of an adjudicated event
o
End of treatment 
o
last visit date (NYHA class, EQ-5D, KCCQ, pregnancy test, vital signs, ECG,  
or central laboratory reported)  


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In case of a partially missing date, if the imputed date is before the first day (after the last day) 
of the month/year given as partial date, the first day (last 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

Trial completion (last contact date)

Longest extrapolated 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 patient basis, using the 
points above as guidance.  
Missing information on concomitant therapy dates
For incomplete date information generally the midpoint of the possible interval will be used.
If only the year is present the day and month will be imputed as 01 July, if year and month is
present the day will be imputed as 15. If the year is missing, the date will be considered
missing.
If this leads to contradictions for the start or end date of a concomitant therapy (e.g. imputed
end date before documented start date) a partial end date will be imputed as the end of the
interval or a partial start date will be imputed as the start of the interval in the database to
resolve this contradiction.
If the medication is reported as being taken at visit 2 (baseline) and the imputed start/end date 
contradicts this then the start/end date is imputed to the earliest/latest date respectively if this 
can resolve the contradiction.
Similarly if the medication is reported as not taken at visit 2 (baseline) and the imputed 
start/end date contradicts this then the start/end date is imputed to the baseline date/ 1 day 
prior to baseline respectively if this can resolve the contradiction.
All other cases or conflicting cases resulting from these imputation rules need to be assessed 
by the trial team on an individual patient basis.  
Missing measurement to confirm “sustained” decrease
An eGFR (CDK-EPI)cr reduction is considered sustained, if it is determined by two or more 
consecutive post-baseline central laboratory measurements separated by at least 30 days (first 
to last of the consecutive eGFR values). If there is no additional measurement >= 30 days 
after the eGFR reduction is observed and the patient dies within 60 days of this measurement, 
then the eGFR reduction is also considered sustained.
Pharmacokinetic (PK) variables
Missing data and outliers of PK data are handled according to (3)


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6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
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. 
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 assessments. 
For randomised patients without any treatment intake: 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 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. 
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. 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. 


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Table 6.7: 1
Time windows for post-baseline efficacy measurements scheduled for each on-
treatment visit for the first 3 years
Time window (actual days after 
baseline)
Visit number
Visit label
Planned days
Start
End
Endpoints assessed at each on-site visit (e.g. creatinine / eGFR)
2
Baseline A
1
NA
1
3
Week 4
29
2
57
4
Week 12
85
58
155
6
Week 32
225
156
295
8
Week 52
365
296
449
10
Week 76
533
450
617
12
Week 100 
701
618
785
14
Week 124
869
786
953
16
Week 148 
1037
954
1121
18
…
FU
FU
Trt stop + 30 days
Trt stop + 23 
days
Trt stop + 45 
days
KCCQ
2
Baseline A
1
NA
1
4
Week 12
85
2
154
6
Week 32
225
155
295
8
Week 52
365
296
435
EOT
EOT / Post 
week 52
NA
436
Trt stop
FU
FU
Trt stop + 30 days
Trt stop + 23 
days
Trt stop + 45 
days
A 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 KCCQ can be found in Table 6.7: 1
Only one observation per time window will be selected for analysis at an on-treatment visit –
the non-missing value will be selected which is closest to the protocol planned visit day. If 
there are two observations which have the same difference in days to the planned day or if 
there are two observations on the same day, the first value will be used. 


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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).
Time windows for assignment of planned off-treatment measurement
For evaluation of the off-treatment assessment ‘at 30 day follow-up’ only values obtained at 
>= 23 days to <= 45 days after last trial drug stop will be considered.
The value that is closest to the planned day of 30 days after last trial drug stop will be used. If 
there are 2 values equally close, the later value will be used.
6.8 
CALCULATION OF TIME TO EVENT
This section describes the calculation of the time to event and the time that patients without an 
event are in the study (under risk). 
Consistent with that approach, the respective time intervals determine the start and end for the 
derivation of occurrence of a specific event.
For those patients with an event, the time to event is calculated as: 
<date of event> - < start date> + 1
For those patients without an event, the time at risk is calculated as:
<date of censoring> - < start date > + 1
6.8.1
Start date
In general, the time to event will be derived from the date of randomisation. 
If study drug administration happened before calling IVRS, the date of first drug
administration will be used as start date.
For the following endpoints (analysed as occurrence or time to first event), the date of first 
drug intake will be used as start date:
•
AE analyses according to Section 7.8.1
•
Endpoints purely based on laboratory measurements, that include a relation to 
baseline (such as change decrease from baseline >= 40%, doubling vs baseline, 
etc. )


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Please note, that for composite endpoints, that include component(s) using randomisation date 
and other component(s) using first drug intake date as start date, the time at risk for the 
composite will start with date of randomisation (which may be earlier). For the individual 
components, the component specific start date will be used.
6.8.2
Date of event
For adjudicated events, the date determined by the adjudication committee will be used; this 
can be different from the investigator reported date.
For the endpoints of time to CV death, time to all-cause mortality and time to non CV death 
the respective death date will be used rather than time to the first onset of the fatal AE.
For composite outcomes, e.g. time to adjudicated HHF or adjudicated CV death, the earliest 
onset date of the corresponding components will be used. For the component of CV death or 
other death components, date of death will always be used rather than the onset date also for 
composite outcomes. 
For endpoints, where myocardial infarction (MI) and stroke are included as a fatal and non-
fatal component, the onset of the event is considered for the derivation of time to first 
occurrence, not the date of death. For time to CV death the date of death is used for a fatal MI 
or fatal stroke. 
The time to first occurrence type of endpoints based on laboratory data including endpoints 
including the requirement a “sustained” measurement are determined by the date of the first 
measurement that fulfils this condition.
For events with multiple possible episodes, such as HHF or all-cause hospitalisation, the onset 
date of the first episode will be used unless noted otherwise. The same applies to time-to-AE 
analysis.
For efficacy endpoint analyses (endpoints described in sections 7.4-7.6):
As described in Section 4, the follow-up period will not be included in the time at risk for 
efficacy endpoints. Therefore events later than the date of treatment discontinuation (if reason 
for discontinuation was completion) will not be counted.  
For the primary endpoint and the key secondary endpoint of recurrent HHF, additionally there 
will be sensitivity analysis including all events up to individual trial completion including the 
FU period. 
6.8.3
Censoring
The underlying principle is that the censoring date should be the last date a patient was known 
to be free of an endpoint event (e.g. free of each component of HHF + CV death).
For all endpoints except all-cause mortality and cause-specific death, patients without
occurrence of a specific endpoint (composite endpoint or individual components) will be 
considered censored at the individual day of trial completion. 


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The individual day of trial completion will be the latest of:

the last date the patient could be followed up for all non-fatal events as documented in 
the eCRF 

last onset of an AE or date of death

onset dates of adjudicated events

end of treatment

last visit date (NYHA class, EQ-5D, KCCQ, pregnancy test, vital signs, ECG,  or 
central laboratory- reported )
Censoring is considered independent from study drug intake.
All-cause mortality
A patient, without the event will be censored at the latest of
•
Individual day of trial completion (without the restrictions defined above for 
patients with withdrawn consent or lost to follow-up)
•
Last date known alive from the vital status page
Endpoints of any cause-specific death, e.g. CV death 
The same censoring rule as in all-cause mortality applies, and in addition, date of death if died 
from other causes than the one specified in the endpoint.
Endpoints based on laboratory data only 
Patients who already fulfil the respective condition at baseline are not considered in the 
number of patients at risk for this endpoint. 
If a baseline laboratory measurement is not available for the parameter of interest, it is 
assumed that the patient did not experience the condition corresponding to the endpoint at 
baseline and the patient is included in the patients at risk for this endpoint. Patients without an 
event and available post-baseline laboratory measurements will be considered censored at the 
date of last laboratory sampling of the corresponding parameter. Patients with missing 
baseline laboratory required to derive a change from baseline and patients without laboratory 
data following the baseline measurement will be censored on the date of randomisation. 
Composite endpoints 
Only patients that are included in the analyses for all components of the composite endpoint
will be included in the analysis of the composite.
Of those, a patient with at least one event in any of the components of the composite will be 
considered to have an event and the date of the first event will be used for the composite 


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endpoint. A patient without an event will be considered censored at the earliest of all 
censoring dates of the component endpoints.
For efficacy endpoint analyses (endpoints described in Section 7.4-7.6):
As described in Section 4, for patients that completed the treatment phase as planned (primary 
reason for end of treatment being completion of treatment period according to protocol)  the 
follow-up period will not be included in the time at risk for efficacy endpoints. Therefore for 
those patients, the minimum of the treatment discontinuation date and the above described 
dates will be used for censoring, except if specifically noted otherwise (for the sensitivity 
analysis). For patients that did not complete the treatment phase, the dates defined above will 
be used. 
For the primary endpoint and the key secondary endpoint of recurrent HHF, additionally there 
will be a sensitivity analysis considering all events up to individual trial completion including 
the FU period. 
Censoring for analyses up to trt stop + x days
For any analyses until a certain number of x days after treatment discontinuation (e.g. 
sensitivity analyses until 30 days after treatment discontinuation), censoring time will be the 
minimum of the censoring time as described above and treatment discontinuation + x days. 
Patients with an event after treatment discontinuation + x days will be censored at treatment 
discontinuation + x days. 


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7.
PLANNED ANALYSIS
For End-Of-Text (EoT) tables, the set of summary statistics is: N / Mean / SD / SE / Min / Q1 
(lower quartile)/ Median / Q3 (upper quartile)/ Max. The 1st and 99th percentiles might be 
substituting minimum and maximum in tables with open-ended values to safeguard against 
implausible extremes.
Geometric means and ranges will be added to the presentation or replace the presentation of 
mean and standard deviation for parameters which rather follow a log-normal distribution 
than a normal distribution. 
Statistical parameters will be displayed to a defined number of decimal places as specified in 
the BI guideline “Reporting of Clinical Trials and Project Summaries” (4)
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. 
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. (see (13)). 
Number of patients lost to follow up (no information on vital status after start of study 
closure) and number of patients lost to follow up for the primary endpoint (no information on 
primary endpoint after start of study closure) will be summarised. 
The reason for not randomising screened patients will be summarized descriptively. 
The frequency of patients with IPDs will be presented by treatment group for the randomised 
set. The frequency of patients in different analysis sets will also be analyzed for each 
treatment group.
Descriptive statistics on impact of COVID-19 on study visits as well as study medication 
intake will be provided.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Demographics and baseline characteristics will be analyzed based on RS. Demographics will 
be repeated on the TS if the analysis sets differ by more than 1%. Standard descriptive 
analysis and summary tables will be presented. These summary tables will include description 
of subgroup variables detailed in Section 6.4. Descriptive analysis of the following variables 
measured at baseline will be presented: Age, body mass index (BMI), time since diagnosis, 
systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate, weight, eGFR, 
UACR, NT-pro BNP, LVEF, hemoglobin and troponin T. HbA1c will be presented for 
patients with diabetes at baseline. NTproBNP will be shown for patients with or without atrial 
fibrillation/ atrial flutter at baseline.


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A summary of the number of patients in each randomisation stratum per treatment will also be 
shown. The information will be based upon the data received from the interactive voice 
response system (IVRS) provider.  Analyses will be based on actual information collected via 
the CRF / central laboratory, not via IVRS.
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 (ATC3) and preferred name. Summaries will be presented for 
concomitant therapies taken at baseline and separately those taken 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 newly introduced after baseline will be 
presented. Use of devices and other non-medication therapy at baseline and newly introduced 
after baseline will also be summarized. Changes of diuretic therapy over time will be 
summarized. 
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.
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the report. The number and 
percentage of patients with overall compliance will be reported. Overall compliance will be 
calculated as a weighted average of reported compliance. The sum of all reported compliance 
over the planned visits will be divided by the total duration. The treated set of patients will be 
considered.
7.4
PRIMARY ENDPOINT
The primary estimand of this trial is the hazard ratio of the time to first event of adjudicated 
HHF or adjudicated CV death between empagliflozin 10 mg and placebo in the population of 
patients with heart failure with preserved ejection fraction. The primary comparison will be 
made regardless of changes of treatment (including discontinuation of trial medication) until 
completion of the planned treatment phase. For clarification, this excludes events and time at 
risk after the protocol-specified treatment discontinuation for patients that complete the 
treatment period according to protocol. 
7.4.1
Primary analysis of the primary endpoint(s)
As the primary endpoint, time to the first event of adjudicated HHF or adjudicated CV death 
will be reported in days. The primary analysis will be based on RS, using all data available 
until completion of the planned treatment phase, including the data after end of treatment for 
patients not completing the treatment phase as planned.


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The primary endpoint will be displayed using cumulative incidence function (CIF) curves and 
expressed as the hazard ratio with associated  two-sided 95% confidence intervals (CIs) and 
two-sided CIs based available alpha-level for the analysis. 
For the interim analysis and final analysis, the following Hwang, Shih and De Cani α-
spending function at information fraction tk with parameter γ = -8 will be used:
The alpha levels are expected to be 0.001 and 0.0248 (one-sided) for the interim and final 
tests respectively, when the interim analysis occurs at the time of 60% information. 
Estimator and corresponding confidence intervals will not be corrected for interim analysis. 
The primary endpoint will be analysed using Cox regression, with factors of treatment 
(empagliflozin, placebo), region (North America, Latin America, Europe, Asia and “other” 
including India, South Africa and Australia), baseline status of diabetes (diabetes, prediabetes, 
no diabetes), age (continuous), sex, left ventricular ejection fraction (LVEF) (continuous) and 
eGFR (CKD-EPI)cr at baseline (continuous).  Since the stratification factors are included in 
the model as covariates, no stratified Cox regression will be used.
Breslow’s method will be used for dealing with ties.
The individual relevant components of the composite will be summarized descriptively. In 
this descriptive analysis of the relevant component for the composite, CV death after HHF 
will not be counted. In all other analyses of CV death alone defined in this document, all CV 
deaths will be counted, disregarding any earlier events. 
A hierarchical testing procedure will be followed for the assessment of the primary and key 
secondary endpoints.  For all endpoints, superiority of empagliflozin vs. placebo will be 
evaluated using a two-sided test.
The tests will be performed in the following hierarchical order:
1. Time to first event of adjudicated CV death or adjudicated HHF
2. Occurrence of adjudicated HHF (first and recurrent)
3. eGFR (CKD-EPI)cr slope of change from baseline
Starting from step 1, if the null hypothesis of no difference is rejected, and the result is more 
favourable for empagliflozin, superiority is concluded in the tested endpoint, and the overall 
type I error is preserved for the test in the next step.  If at any step the null hypothesis of no 
difference is not rejected, subsequent tests are conducted in an exploratory manner.
The overall type I error rate will be preserved at a level of 0.05 (2-sided).  The type I error 
rate used at the final analysis will be influenced by the pre-planned interim analysis.


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In the final analysis after the evaluation of recurrent HHF, alpha will be split into 0.001 to be 
used for the analysis of eGFR slope, and the rest will be transferred to the meta-analyses.
In case the trial is finished early at the time of interim analysis, using αinterim for the primary 
and key secondary endpoints in the testing hierarchy according to the α-spending function 
above, the following  α-split will be used for the eGFR slope analysis and the meta-analysis:
0.1 * αinterim will be used for the eGFR slope analysis and
0.9 * αinterim will be transferred to the meta-analyses
In both the interim and final analyses, if the slope analysis is successful, the alpha of this 
branch will then be transferred to the meta-analyses.
The testing hierarchy is summarized in Figure 7.4.1: 1.
Figure 7.4.1: 1
Hierarchical analysis of trial in HFpEF (1245.110) and the parallel trial 
in HFrEF (1245.121) showing the alpha-spending at the final analysis
7.4.2
Sensitivity analyses
The following sensitivity analyses will be conducted:

A Cox model including only treatment as covariate, not adjusting for any other 
variables. 


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
The same Cox regression as the primary analysis will be performed on the TS, with 
observation period up to 30 days after treatment discontinuation. Total number of
patients with primary events occurring during the 30 days after treatment 
discontinuation will also be tabulated.

For patients who are without primary event and lost to follow up before trial 
completion, the treatment specific incidence rates for empagliflozin and placebo for 
retrieved drop-outs will be used to impute the primary events in a multiple imputations 
framework.  The primary model will be applied to the imputed datasets. It is planned 
to perform 100 imputations. Rubin’s rules will be used to summarize the log hazard 
ratios and the result will be back-transformed to show a hazard ratio with confidence 
interval.

The endpoint will be evaluated based on investigator defined events (same model as 
the primary primary analysis). Investigator defined HHF includes AEs ticked by the 
investigator as “Hospitalisation due to heart failure”. Investigator defined CV death 
includes AEs ticked by the investigator as “CV death other than CV death attributed to 
myocardial infarction or stroke”, “Undetermined cause of death” as well as HHF, CV 
hospitalization, MI or stroke if the event was fatal.

A competing risk model by Fine-Gray will be explored, including the same set of 
covariates as in the primary analysis, sub-distribution hazard ratios will be provided
(5).

The primary analysis will be repeated to include all events up to individual trial 
completion including the follow-up period.

The primary analysis will be repeated to include only confirmed primary events which 
meet the CDISC guidance criteria for hospitalization for heart failure (i.e., confirmed 
by adjudication committee, but excluding those missing a physical sign or laboratory 
test, or both)

A Cox model including additional prognostic covariates, Log(NTProBNP), baseline 
atrial fibrillation/atrial flutter, and HHF in last 12 months, in addition to the covariates 
in the primary model.

COVID-19 sensitivity analyses will be conducted: 
o
The primary analysis will be repeated to include all events up to cutoff dates 
prior to COVID-19 outbreak – cutoff (censoring) dates are 30Nov2019 for 
China and 31Dec2019 for all other countries.
o
The same Cox regression model as for the primary endpoint will be fitted, 
however, adding an additional time dependent covariate for COVID-19 
outbreak (time dependent covariate being 0 before outbreak date defined above 
and 1 thereafter)


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o
The same Cox regression model as for the primary endpoint will be fitted, 
however, adding an additional time dependent covariate for COVID-19 
outbreak as well as a treatment by COVID-19 outbreak interaction term
o
The primary analysis will be repeated to include all events up to 7 days prior a 
reported SARS-CoV-2 infection (based on broad scope SARS-CoV-2 
infections)
A Kaplan-Meier curve of time to censoring for primary endpoint will be presented in order to 
assess whether there was differential censoring. For this analysis, a primary endpoint event 
will be counted as censoring and a censoring (including censoring due to the competing event 
of non-CV death) will be counted as an event. 
7.4.3
Proportional hazards assumption violated
The proportional hazards assumption will be explored by plotting log (-log (survival 
function)) against the log of time by treatment group and checked for parallelism. The 
interaction of treatment with log of time will be included in the model described above for an 
exploratory analysis. Further, Schoenfeld residuals for each covariate and treatment will be 
plotted against time and log (time).
In case the proportionality assumption is violated for treatment, an attempt will be undertaken 
to identify groups of patients for which the proportionality assumption holds and a stratified 
Cox regression will be performed. The HR and corresponding CIs will be obtained from the 
stratified Cox model.
In addition a piecewise Cox model assuming proportional hazards in a series of consecutive 
time intervals as proposed by Collett (6) will be investigated.
7.4.4
Subgroup analyses
Subgroup variables will be explored as described in Section 6.4 for the primary endpoint. The
HR between the two treatments along with 95% CI and the p-value for test of treatment 
equality within each category of the subgroup as well as the p-value for the subgroup-by-
treatment interaction will be estimated by the Cox proportional hazard model including the 
same covariates as in the primary analysis of primary endpoint, the subgroup variable if not 
part of the covariates of the primary analysis model, and subgroup-by-treatment interaction. If 
the subgroup variable is a categorization of a continuous covariate, this covariate will be 
dropped from the subgroup model. A forest plot will be presented with the estimated HR and 
the two-sided 95% CI for each subgroup category. The CIF plots will also be presented for 
each subgroup category.
For subgroup analyses of baseline LVEF and baseline uric acid, the interaction p-values will 
be calculated using trend tests, taking into account that the subgroup categorizations are 
ordered. Assuming the difference between the adjacent subgroup is the same, each subgroup 
is coded as numeric value ordinally and fitted into the model as numeric covariate. The model 
also includes terms of subgroup variable and subgroup-by-treatment interaction. 


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If there are less than 14 patients with events in one subgroup, then this subgroup will not be 
included in the model. If this leaves only one subgroup, the subgroup analysis will not be 
conducted. 
For the continuous covariates baseline LVEF, baseline eGFR and age, the influence of the 
covariate will also be investigated on a continuous scale. For this purpose the continuous 
covariate will be added to the model if not already included and the interaction term of the 
continuous covariate and treatment will additionally be included into the model. The hazard 
ratio depending on the continuous covariate will be plotted and the interaction p-value will be 
reported. 
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
Occurrence of adjudicated HHF (first and recurrent)
Hospitalisation for heart failure will be analysed by a joint frailty model (JFM) that accounts 
for the dependence between recurrent HHF and CV death (7). The primary analysis will be 
based on all data available until completion of the planned treatment phase, including the data 
after end of treatment for patients not completing the treatment phase as planned.
Define Ti0 = 0 and let Ti1, Ti2,…, TiNi be the recurrent event times for person i, where Ni is the 
number of recurrent HHF events before Xi =min(Ci,Di), the minimum of an independent 
censoring time Ci and a dependent CV death time Di. The JFM is defined through the hazard 
functions for the recurrent event process and CV death
The recurrent heart failure hospitalisations intensity function for the i-th patient conditional on 
the patient specific random frailty, i, is given by ri and is proportional to the baseline 
intensity function, r0. The conditional hazard function for time to CV death for patient i is 
given by i, with the baseline hazard given by 0, and 1, 2 are p x 1 vectors of regression 
coefficients associated with vectors of covariates zi. The same covariates as for the analysis of 
the primary endpoint will be used, e.g. ß.1=treatment (empagliflozin, placebo), ß.2=region
(North America, Latin America, Europe, Asia and “other” including India, South Africa, and 
Australia), ß.3=baseline status of diabetes (diabetes, prediabetes, no diabetes) etc.
Patient specific independent random effects are denoted by i and are assumed to follow a 
gamma distribution with mean 1 and variance . The correlation of the recurrent events is 
quantified by , with higher values corresponding to greater within-patient correlation and 
also greater between-patient variability. The parameter  determines the relationship between 
the recurrent heart failure hospitalisations and time to CV death. When  < 0, higher frailty 
will result in a greater risk of recurrence and lower risk of terminal event (i.e. a negative 


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correlation between the frailties), and when  > 0, higher frailty will result in a greater risk of 
recurrence and is associated with a higher risk of CV death (i.e. a positive correlation between 
the frailties). 
Let tij and xi be the observed recurrent event times and follow-up, respectively. Denote by 	ij
and Δi, the indicator of the recurrent event at time tij and the indicator of CV death at time xi, 
respectively. The likelihood for person i is then given by the following:
Adopting piecewise constant hazards for the recurrent events and CV death allows estimation 
of the likelihood by Gaussian quadrature. The implementation of the used adaptive Gaussian 
quadrature techniques is incorporated into Proc NLMIXED of SAS 9.4. SAS Code following 
the strategy outlined in (9) will be used.
The size of the pieces for the piecewise constant hazards can be different and are determined 
separately for the terminal as well as recurrent event process with 10 pieces each. The nodes 
are defined by the empirical deciles of the recurrent or terminal events, respectively.
The joint frailty model using the multiplicative parametrization with non-normal random 
effects will be fitted using a likelihood-reformulation method (10). 
To improve convergence of the model, linear covariates (in case no interaction with treatment 
is modelled) will be standardized prior inclusion into the analysis and starting values for the 
model parameters will be determined using the following procedure: 
1) An exponential model will be fitted for the terminal event and a poisson regression 
model for the recurrent event process including the same covariates that are included 
in the final joint frailty model to get initial starting values for all parameters.
2) A simplified model without random effect  which is otherwise equal (regarding 
covariates, baseline hazards) to the joint frailty model is fitted using the values from 
step (1) as starting values for the parameters. The estimated coefficients from the 
simplified model will then be used as starting values for the parameters of the 
piecewise-constant joint frailty model.
The joint model gives two distinct hazard ratios:
HRHHF = exp{11} is the hazard ratio associated with the effect of treatment on the recurrent 
event rate of HHF, and HRCVD = exp{21} is the CV death hazard ratio.
Estimates and 95% CI for the hazard ratios and for  (relationship between the recurrent heart 
failure hospitalisations and CV death) will be given. 
The following sensitivity analyses will be conducted 

Based on the TS, including only any events up to 30 days after treatment 
discontinuation 

Instead of CV-death, jointly model HHF with all-cause mortality as the terminal 
events (otherwise same model as initially described)


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
The endpoint will be additionally evaluated based on investigator defined events for 
HHF and CV death (otherwise same as initially described model). 

A parametric joint gamma-frailty model will model the recurrent event component 
using a Poisson distribution and model the CV mortality component using a 
exponential distribution, conditional on the frailty parameter. Individual frailties are 
again assumed to follow a Gamma distribution. Thus HHF rates follow a negative 
binomial distribution and times to CV death follow a Lomax distribution (see (8)) 
(otherwise – e.g. covariates - same as initially described model).

The analysis will be repeated to include all events up to individual trial completion 
including the follow-up period (otherwise same as initially described model).

The analysis will be repeated to include only confirmed HHF which meet the CDISC 
guidance criteria for hospitalization for heart failure (i.e., confirmed by adjudication 
committee, but excluding those missing a physical sign or laboratory test, or both).  

The analysis will be repeated to include all events up to cutoff dates prior to COVID-
19 outbreak – cutoff (censoring) dates are 30Nov2019 for China and 31Dec2019 for 
all other countries.

The analysis will be repeated to include all events up to 7 days prior a reported SARS-
CoV-2 infection (based on broad scope SARS-CoV-2 infections)
In case the semi-parametric joint modelling cannot converge numerically with the existing 
SAS procedures, the parametric joint gamma-frailty model as described above may be used 
instead for the confirmatory analysis.
The number of HHF events per patients will be summarized descriptively. Additionally a 
negative binomial model will be fitted to the data of recurrent HHF. This will be done once 
including only treatment as covariate and once including all covariates as the primary model. 
Rate ratio and confidence intervals of both models will be reported. 
The mean cumulative incidence will be displayed for adjudicated recurrent HHF.
Subgroup analyses will be explored as outlined in Section 6.4 for adjudicated recurrent HHF. 
For subgroup analyses the term of subgroup (if not already part of the model) and subgroup 
by treatment will be added to the model of the recurrent event. If the subgroup variable is a 
categorization of a continuous covariate, this covariate will be dropped from the subgroup 
model. 
eGFR (CKD-EPI)cr slope of change from baseline
Slope in change from baseline of eGFR (CKD-EPI)cr will be analysed by a random coefficient 
model allowing for random intercept and random slope per patient. The model will include 
the factors treatment, sex, geographical region, and status of DM as fixed effects and eGFR 
(CKD-EPI)cr  at baseline (continuous), LVEF (continuous), age (continuous), time and 
interaction of treatment by time and interaction of eGFR (CKD-EPI)cr  at baseline 


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(continuous) by time as linear covariates and allow for randomly varying slope and intercept 
between patients. The model will include all on-treatment change from baseline data. 
Since the slope is run on the change from baseline data, the intercept will model the acute 
drop, whereas the long-term effect is modelled by the slope.
A plot of individual patient slopes and separately of individual patient intercepts will be 
provided per treatment and by eGFR at baseline.
Subgroup analyses as outlined in Section 6.4 will be explored for eGFR slope. The subgroup 
model will include additionally to the model described above, the subgroup if not already part 
of the model, subgroup by treatment and subgroup by treatment by time. If the subgroup 
variable is a categorization of a continuous covariate, this covariate will be dropped from the 
subgroup model. 
7.5.2
Other Secondary endpoints
Other secondary endpoints are exploratory. No correction for multiple hypotheses testing will 
be made.

Composite renal endpoint:  Time to first event of chronic dialysis or renal transplant 
or sustained* reduction of ≥40% eGFR (CKD-EPI)cr  or 
-
(for patients with eGFR (CKD-EPI)cr  ≥30 mL/min/1.73 m2 at baseline): sustained 
eGFR <15 mL/min/1.73m2
-
(for patients with eGFR (CKD-EPI)cr  <30 mL/min/1.73 m2 at baseline): sustained 
eGFR < 10 mL/min/1.73 m2
*An eGFR (CDK-EPI)cr reduction is considered sustained, if it is determined by two or more consecutive post-
baseline central laboratory measurements separated by at least 30 days (first to last of the consecutive eGFR 
values). If there is no additional measurement >= 30 days after the eGFR reduction is observed and the patient 
dies within 60 days of this measurement, then the eGFR reduction is also considered sustained. 
Chronic dialysis is regarded as chronic if the frequency of dialysis is twice or more per week 
for at least 90 days.

Time to first adjudicated HHF

Time to adjudicated CV death

Time to all-cause mortality

Time to onset of DM in patients with baseline pre-DM
All time-to-event endpoints will be reported in days. 


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The same model and data frame as used in the primary analysis of primary endpoint will be 
applied to all these time-to-event endpoints. If the endpoint does not include any cause of 
death, a CIF plot with all-cause mortality as competing risk will be displayed; otherwise, a 
CIF plot with causes of death not included in the endpoint as competing risk will be 
displayed. For all-cause mortality a Kaplan-Meier plot will be displayed. 
For time to first HHF and time to CV death, the analysis will be repeated based on 
investigator defined events. In addition, the analysis of time to CV death will be repeated to 
include all events up to 7 days prior a reported SARS-CoV-2 infection (based on broad scope 
SARS-CoV-2 infections)

Change from baseline in clinical summary score (HF symptoms and physical 
limitations domains) of the Kansas City cardiomyopathy Questionnaire (KCCQ) at 
week 52
Change from baseline in clinical summary score for HF symptoms and physical limitations 
domains of the KCCQ at week 52 will be evaluated by a mixed model for repeated measures 
(MMRM) including LVEF (continuous), age (continuous) and eGFR (CKD-EPI)cr at baseline 
(continuous) as linear covariates and, baseline score by visit, visit by treatment, sex, 
geographical region and status of diabetes at baseline as fixed effects. An additional factor of 
“week reachable” for the parameter in question, which for each patient is the theoretically 
reachable planned measurement based on the time of randomisation will adjust for the 
different planned study times.
All on-treatment data up to week 52 will be included and the analysis will be conducted on 
the treated set. 
A sensitivity analysis will be conducted including data after discontinuation (OC-AD) on the 
randomized set. 
An additional analysis will be performed for the Clinical Summary Score on OC-AD without 
imputing a worst score for patients who die.

Occurrence of all-cause hospitalisation (first and recurrent)
A similar joint frailty model as well as negative binomial regression model as in the HHF will 
be analysed for all-cause hospitalization. Instead of CV death, all-cause mortality will be 
jointly modelled as the terminal events in the joint frailty model.


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7.6
FURTHER ENDPOINTS
Time to event endpoints
Further time to event endpoints will generally be analysed in a Cox proportional hazards 
model similar to the primary analysis on RS. If the endpoint does not include any cause of 
death, a CIF plot with all-cause mortality as competing risk will be displayed; otherwise, a 
CIF plot with causes of death not included in the endpoint as competing risk will be 
displayed. 
If there are less than 14 patients with events, then only descriptive statistics will be presented.
Further time to event endpoints are the following:

Time from first to second adjudicated HHF

Time to first all-cause hospitalisation

Time to new onset of atrial fibrillation

Time to adjudicated MI (fatal or non-fatal)

Time to adjudicated stroke (fatal or non-fatal)

Time to adjudicated TIA

Time to first event of all-cause mortality or all cause hospitalisation

Time to first event of adjudicated CV death or adjudicated non-fatal MI

Time to first event of adjudicated CV death or adjudicated non-fatal stroke

Time to first event of adjudicated CV death, adjudicated non-fatal MI or adjudicated 
non-fatal stroke (3-point MACE)

Time to progression to macro albuminuria (defined as UACR >300 mg/g) from 
baseline for patients with baseline UACR ≤ 300 mg/g

Time to first new onset of sustained normo− or micro albuminuria (UACR ≤ 300 
mg/g) in patients with macro albuminuria at baseline

Time to first new onset of sustained normo albuminuria (UACR < 30 mg/g) in patients 
with micro- or macro albuminuria at baseline

Time to first event of composite renal endpoint1 or adjudicated CV death

Time to first event of composite renal endpoint1, adjudicated CV death or adjudicated 
HHF

Time to first event of composite renal endpoint1 or all-cause mortality


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
Time to first acute kidney injury (based on the preferred term)

Time to non-cardiovascular (non-CV) death (death cases not included in the definition 
of adjudicated CV death)

Time to first investigator defined CV hospitalization
1Composite renal endpoint defined as: chronic dialysis or renal transplant or sustained* reduction of ≥40% 
eGFR (CKD-EPI)cr  or 

(for patients with eGFR (CKD-EPI)cr  ≥30 mL/min/1.73 m2 at baseline): sustained 
eGFR <15 mL/min/1.73m2

(for patients with eGFR (CKD-EPI)cr  <30 mL/min/1.73 m2 at baseline): sustained 
eGFR <10 mL/min/1.73 m2
Chronic dialysis is regarded as chronic if the frequency of dialysis is twice or more per week for at least 90 days.
*An eGFR (CDK-EPI)cr reduction is considered sustained, if it is determined by two or more consecutive post-
baseline central laboratory measurements separated by at least 30 days (first to last of the consecutive eGFR 
values). If there is no additional measurement >= 30 days after the eGFR reduction is observed and the patient 
dies within 60 days of this measurement, then the eGFR reduction is also considered sustained
Continuous endpoints:
The following endpoints will be evaluated by mixed models repeated measures (MMRM) as 
defined in the protocol.
•
HbA1c change from baseline over time (OC-AD on the randomised set and OC-OT 
on the treated set)
•
SBP, DBP change from baseline over time (OC-AD on the randomised set and 
OC-OT on the treated set)
•
Weight change from baseline over time (OC-AD on the randomised set and OC-
OT on the treated set)
•
NT-pro BNP relative change from baseline over time (OC-AD on the randomised 
set and OC-OT on the treated set) (value will be transformed to the log scale 
before MMRM analysis. Estimates obtained from the model will then be back-
transformed and reported on the original scale.)
•
KCCQ overall summary score change from baseline at week 52 (OC-AD on the 
randomised set and OC-OT on the treated set) (model will include all timepoints 
up to week 52)
•
KCCQ individual domains change from baseline at week 52 (OC-AD on the 
randomised set and OC-OT on the treated set) (model will include all timepoints 
up to week 52)


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•
KCCQ total symptom score change from baseline at week 52 (OC-AD on the 
randomised set and OC-OT on the treated set) (model will include all timepoints 
up to week 52)
•
KCCQ based on patient-preferred outcome change from baseline at week 52 (OC-
AD on the randomised set and OC-OT on the treated set) (model will include all 
timepoints up to week 52)
•
UACR relative change from baseline over time (OC-AD on the randomised set 
and OC-OT on the treated set) (value will be transformed to the log scale before 
MMRM analysis. Estimates obtained from the model will then be back-
transformed and reported on the original scale.)
•
eGFR (CKD-EPI)cr change from baseline over time (OC-AD on the randomised 
set and OC-OT on the treated set)
As outlined in the protocol, the above endpoints will be analysed in a mixed model with 
repeated measures (MMRM), including age, LVEF and eGFR (CKD-EPI)cr at baseline as 
linear covariates and visit by treatment interaction, baseline by visit interaction, geographical 
region, sex and status of diabetes at baseline as fixed effects. An additional factor of “week 
reachable” for the parameter in question, which for each patient is the theoretically reachable 
planned measurement based on the time of randomisation will adjust for the different planned 
study times. 
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 OC-OT on the treated set.
Additionally subgroup analyses will be performed as follows:
HbA1c change from baseline will be evaluated by status of diabetes (non-DM, pre-DM, DM). 
NTproBNP change from baseline will be evaluated by baseline atrial fibrillation/atrial flutter
(as determined by baseline ECG). 
UACR will be evaluated by UACR at baseline (<30 mg/g, ≥30mg/g to ≤300mg/g, >300 
mg/g). 
In order to evaluate the mean effect on eGFR after approximately 3 years, the above described 
MMRM models will be used in the following way: a mean effect of the timepoints week 124, 
148 and 172 will be calculated. Of the three timepoints, only those with at least 5 patients 
with a measurement at that timepoint will be included in the average calculation. This will be 
done for the imputations of OC-OT and OC-AD. 
For MMRM subgroup analyses, the interaction term treatment-by-visit will be replaced by a 
treatment-by-subgroup-by-visit interaction term. 
To support analysis of renal function, eGFR throughout the trial will be categorized according 
to the following CKD staging: All calculations for the staging of renal function will be based 


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on the originally measured laboratory values, not on normalised values with BI standard 
reference ranges. 
Table 7.6: 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 for eGFR (CKD-EPI)cr will be provided.
In cases where urine albumin values are reported to be below the quantification limits (e.g. <3 
mg/L) the albumin / creatinine ratio is determined as missing and will not be replaced by 
estimated values. 
Transitions from baseline to last value on-treatment based on the following UACR categories: 
normal (<30mg/g), microalbuminuria (30-<=300 mg/g and macroalbuminuria (>300 mg/g) 
will be presented. 
For an evaluation of follow-up after discontinuation of trial medication an additional 
summary of the NT-proBNP, FG, eGFR, UACR, creatinine and the KCCQ endpoints as 
above will be produced. This summary will include descriptive statistics for baseline, actual 
values and change from baseline to last on-treatment value and follow-up, and change from 
last on-treatment assessment to follow-up.  The TS-FU patient set will the basis for this 
summary, but only those patients with a valid baseline, last value on treatment and follow-up 
value will be included in all displays. Analyses will be repeated for patients with at least 52 
weeks of cumulative exposure (excluding treatment gaps). FG analysis will also be conducted 
by DM status at baseline (3 categories). 
Analyses of change from baseline to LVOT and FU on the TS-FU outlined above will be 
additionally modelled, separately for LVOT and FU. An analysis of covariance (ANCOVA) 
model including treatment group, sex, geographical region and status of diabetes at baseline


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as fixed effects and baseline eGFR (CKD-EPI)cr (continuous), age (continuous), LVEF 
(continuous) and baseline of the endpoint (if not already included) as linear covariates will be 
used.
In addition to the ANCOVA models described above, descriptive statistics will be presented 
also for creatinine for the value at visit and change from baseline based on OC-AD on the 
randomised set and OC-OT on the treated set.
In addition to the analyses defined above, KCCQ clinical summary score, clinical symptoms 
and physical limitations domain will be analysed in two responder analyses (1) defining an 
increase of 5 points or more from baseline as improvement and (2) defining a reduction of 5 
points or more as deterioration. 
The frequency and percentage (relative to RS) of patients with improvement as well as the 
frequency and percentage of patients with deterioration at week 52 will be described. Patients 
lost to follow-up or who withdrew consent prior week 52 as well as patients who died prior 
week 52 will be considered as having a deterioration (no improvement) in KCCQ. 
Improvement and deterioration will be analysed in separate logistic regression models 
including treatment, age (continuous), eGFR (CKD-EPI)cr at baseline (continuous), region, 
sex, baseline LVEF (continuous), status of diabetes at baseline, and baseline value of the 
KCCQ domain analyzed. 
Win ratio:
An unmatched win ratio considering adjudicated CV death and adjudicated HHF will be 
analysed based on unmatched pairs. All patients randomised to empagliflozin will be 
compared to all patients randomised to placebo. Only common follow-up time will be 
considered for the comparison. Patients on empagliflozin are considered to have “won” the 
comparison if either the other patient has died due to CV causes while the patient on 
empagliflozin was still alive, or if both patients did not die due to CV causes, then if the other 
patient had more occurrences of HHF, or if the number of occurrences of HHF is the same but 
the time to the first occurrence of HHF is longer. The number of comparisons won is noted as 
NW. Patients on empagliflozin are considered to have “lost” the comparison if the 
empagliflozin patient died due to a CV cause while the patient on placebo was still alive, or if 
both patients did not die due to a CV cause, then if the patient on empagliflozin had more 
occurrences of HHF, or if the number of occurrences is the same but the time to the first 
occurrence of HHF is shorter for the empagliflozin patient. The number of comparisons lost is 
noted as NL. The win ratio is NW/ NL. 
The rules for winning and losing follow a modified Rogers 2014 (8) approach also 
considering the time to the first HHF event in case of a tie on the number of HHF events. The
analysis of the unmatched win ratio will be conducted as described in Pocock 2012 (11) . 


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Other types of further endpoints
For other types of endpoints e.g. occurrence of adjudicated HHF within 30 days after first 
adjudicated HHF, change in NYHA class at week 52, HCRU and EQ-5D, descriptive 
statistics will be provided. 
For NYHA class a shift table will also be provided for changes from baseline over time and 
for change from baseline to last value on treatment and last value in study and worst value in 
study. 
The number of patients shifting from normal (no pre-diabetes) to pre-diabetes or diabetes as 
well as shifts from pre-diabetes to diabetes will be summarized. 
Pharmacokinetic analysis
Descriptive statistics of trough concentrations of empagliflozin will be presented for patients, 
where PK data is available. 
7.7
EXTENT OF EXPOSURE
There will be three methods of calculating exposure:
a.
First intake to last intake of study drug, including off-treatment periods
b. First intake to last intake of study drug, excluding off-treatment periods
c.
Overall observational period (randomisation until end of follow-up for vital status, see 
censoring for all-cause mortality in Section 6.8.3)
Descriptive statistics tables with mean, standard deviation (SD), median and range of the 
number of days a patient was on treatment will be provided. These tables will also provide the 
sum-total of the time (in years) that all patients were on treatment.
Frequency tables of number and percentage of patients belonging to categorical ranges of 
exposure weeks will be provided as well. Following are the categories of exposure-ranges (in 
weeks): 0 to <12 weeks, ≥12 to <26 weeks, ≥26 to <52 weeks, ≥52 to <78 weeks, ≥78 to <104 
weeks, ≥104 to <156 weeks, ≥156 weeks. Categorical ranges may be adapted based on the 
actual duration of the study. 
7.8
SAFETY ANALYSIS
The safety analysis will be based on the treated set (TS), treatment will be evaluated as 
randomised. 
The AE analysis will include all adverse events (including outcome events as reported by the 
investigator).
While tables will generally display results by randomised treatment, listings will reflect 
whether a measurement/AE occurred on or off treatment.


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7.8.1
Adverse events
Unless otherwise specified, the analyses of adverse events will be descriptive in nature and 
will be based on the number of patients with AEs and not on the number of AEs.
AEs will be coded using the most recent version of the Medical Dictionary for Regulatory 
Activities (MedDRA) coding dictionary. 
Definitions of Boehringer Ingelheim customized MedDRA Queries (BIcMQs) for new 
MedDRA versions are maintained by the BI dictionary maintenance group. 
For analysis multiple AE occurrence data on the CRF will be collapsed into an AE provided 
that all of the following applies:
•
All AE attributes are identical (including LLT, intensity, action taken, therapy required, 
seriousness, reason for seriousness, relationship, outcome, AE of special interest and also 
additional information of specific AEs or AESIs such as source of sepsis (urinary tract or 
not) 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 summarization of AE data, please refer to (2), (12).
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 
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’. 
In Section 15.3 general AE analyses tables will present only on-treatment AEs (applying the 
rule of 7 days for assignment as on-treatment) for the treatments groups (exceptions for 
urinary tract malignancies, hepatic events, lower limb amputations and bone fractures as well 
as adjudicated events see below). When looking at BIcMQs or standardized MedDRA queries
(SMQs) and including all AEs up to completion of the trial, the time at risk for each patient 
will be calculated up to the individual day of trial completion (see Section 6.8).  
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.
The tables presenting frequency of AEs by SOC/PT and frequency of SAEs by SOC/PT will 
be repeated in Section 16.1.13.1 with treatment-specific post-treatment phase included, 
hereby also incidence rates for the post-treatment phase will be presented.


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For listings, AEs will be assigned to one of the treatment phases of Screening, Placebo, 
Empa 10, Placebo post-treat, Empa 10 post-treat, post-study. 
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 patients with adverse events of special interest (AESIs),
for patients with serious adverse events, for patients with drug related serious AEs, for 
patients with fatal events, for patients with AEs leading to discontinuation, and for patients 
with drug-related AEs.
The frequency of patients with adverse events occurring with incidence in preferred term 
greater than 2% by treatment will also be presented. 
Overall AE summaries, AEs by SOC and PT, SAEs and AEs leading to discontinuation will 
additionally be investigated by subgroups as outlined in Table 6.4: 1. 
Fatal AEs will be summarized up to end of the trial, also separately for those adjudicated as 
CV and those adjudicated non-CV cause. 
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 patients with non-serious adverse events occurring with 
incidence in preferred term greater than 5% by treatment,

Adverse Events per arm for disclosure on EudraCT by treatment”

Non-serious Adverse Events for disclosure on EudraCT  by treatment

Serious Adverse Events for disclosure on EudraCT  by treatment
For further details, see also (13).
7.8.1.3 Adverse events of special interest (AESIs)
Hepatic injury
Adverse events reported as AEs of special interest relating to hepatic injury as specified in the 
protocol will be summarised. 
Additionally Hepatic injury AEs will be summarized based on an 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)


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
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. This presentation will be repeated by DM status at baseline (DM vs no 
DM). Hepatic injury SAEs and hepatic injury AEs leading to disc based on the above SMQ
definition will be presented.
In addition to the ‘7-day-on-treatment approach’, a ‘30-day-on-treatment approach’ will be 
presented for the overall hepatic adverse events based on the SMQ definition. 
Patients with hepatic injury will be listed.
For presentations on adjudicated hepatic events, refer to Section 7.8.1.5.
Decreased renal function
Adverse events reported as AEs of special interest relating to decreased renal function as 
specified in the protocol will be summarised. 
A frequency table of patients with AEs of acute renal failure by treatment, primary SOC and 
preferred term will additionally be provided based on the narrow standardized MedDRA 
query (SMQ) Acute renal failure (20000003). 
This presentation will be repeated by the subgroups as outlined in Table 6.4: 1. SAEs and AEs 
leading to disc based on the 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 decreased renal function will be listed.
Ketoacidosis
A frequency tables of patients with AEs related to ketoacidosis will be presented by treatment, 
primary SOC and preferred term for investigator defined cases and for the broad and narrow 
BIcMQ definition of diabetic ketoacidosis. 
For the narrow BIcMQ diabetic ketoacidosis (DKA), AEs leading to discontinuation and an 
analysis by sex and diabetes status (type 1 diabetes, type 2 diabetes, pre-diabetes and normal 
(no pre-diabetes)) will be presented. 
For the broad BIcMQ diabetic ketoacidosis (DKA), SAEs will be presented. 
For presentations on adjudicated events, refer to Section 7.8.1.5.


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Patients with DKA based on the narrow and broad BIcMQ or investigator defined 
ketoacidosis will be listed. 
Events leading to lower limb amputation
A frequency table of patients with AEs leading to lower limb amputation as identified by the 
investigator by treatment, primary SOC and preferred term will be provided.
A separate table for AEs leading to lower limb amputation which are leading to 
discontinuation will be presented. 
For events leading to lower limb amputations in addition to the ‘7-day-on-treatment approach’ 
all adverse events that occurred between first study drug intake up to trial completion will be 
presented (following censoring rules like non-fatal outcome events). For both approaches, 
SAEs will be presented. 
Lower limb amputations (up to trial completion) will additionally be summarised by renal 
function, level of first amputation, reason for first amputation, history of PAOD, previous 
amputation and status of DM at baseline (DM / no-DM). 
Patients with lower limb amputation will be listed.
7.8.1.4 Specific AEs
Hypoglycaemic events
The investigator will record for each AE whether it represents a hypoglycaemic event and, if 
so, record additional information to assess the intensity of the hypoglycaemic event. On the 
basis of this information the hypoglycaemic event will be 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 glucose concentration < 3.0 
mmol/L (< 54 mg/dL): event accompanied by typical symptoms of hypoglycaemia but 
no need for external assistance

symptomatic hypoglycaemia and glucose concentration > 3.9 mmol/L (70 mg/dL)

symptomatic hypoglycaemia and glucose concentration not measured

asymptomatic hypoglycaemia: event not accompanied by typical symptoms of 
hypoglycaemia but with a measured glucose concentration ≤ 3.9 mmol/L (≤ 70 
mg/dL)
Confirmed hypoglycaemic adverse event are defined as hypoglycaemic adverse events that 
had a glucose concentration ≤ 70 mg/dL or required assistance.
Different tables will be shown for (i) patients with investigator defined asymptomatic or 
symptomatic hypoglycaemia, and (ii) patients with confirmed hypoglycaemic adverse events, 


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i.e. hypoglycaemic adverse events that had a glucose concentration ≤ 70 mg/dL or required 
assistance.
Subgroup analyses on confirmed events with respect to age category, sex, race, renal function 
and diabetes background (type 1 diabetes, type 2 diabetes, pre-diabetes and normal (no pre-
diabetes)) will be performed.
Time to the onset of the first confirmed hypoglycaemia will be displayed using a cumulative 
incidence function.
In addition the number of patients with hypoglycaemia according to SMQ (20000226) will be 
presented.
Patients with hypoglycaemic events will be listed. 
UTI and genital infections
The following additional specific adverse events will also be assessed and be tabulated by 
treatment group:

Genital infections (BIcMQ ‘Infections” narrow subsearch “Genital tract infections 
predisposed to by glucosuria”  and investigator assessment)

UTI (BIcMQ “Infections” narrow subsearch “UTI predisposed by glucosuria” and
investigator assessment)
Genital infections episodes based on investigator assessment will additionally be summarised 
by type (fungal balanitis or fungal vulvovaginitis, genital infection other than fungal balanitis 
or fungal vulvovaginitis), intensity (mild, moderate or severe), how the event was treated (no 
treatment, therapy assigned and number of antimicrobials needed to treat) and whether 
leading to discontinuation of treatment. The number of episodes per patient will also be 
presented.
UTIs episodes based on investigator assessment will additionally be summarised by intensity 
(mild, moderate or severe), anatomical location (upper UTI, lower UTI, asymptomatic 
bacteriuria), occurrence of pyelonephritis or urosepsis, how the event was treated (no 
treatment, therapy assigned and number of antimicrobials needed to treat) and whether 
leading to discontinuation of treatment. The number of episodes per patient will also be 
presented.
For UTIs based on the BIcMQ narrow subsearch the subgroups as outlined in Table 6.4: 1
will be presented. The same will be done for genital infections based on the BIcMQ narrow 
subsearch. Additionally they will be analysed by presence/absence of history of chronic or 
recurrent UTI or genital infection respectively.
Complicated urinary tract infections defined as serious adverse events of BIcMQ narrow 
subsearch ‘UTI predisposed by glucosuria’, all events of sub-BIcMQ ’Renal infections 
predisposed by glucosuria’, all events of PT Urosepsis will be presented. 
Complicated genital infection: defined as all serious events using the BIcMQ narrow 
subsearch  ‘Genital tract infections predisposed to by glucosuria’ and all event of the narrow 


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subsearch ‘Complicated genital tract infections predisposed to by glucosuria’ will also be 
presented. 
UTIs leading to discontinuation based on the BIcMQ narrow subsearch will be presented, the 
same will be repeated for genital infections leading to discontinuation based on the BIcMQ 
narrow subsearch . 
Cumulative incidence functions will also be created for time to onset of the first UTI and for 
time to onset of the first genital infections, both based on the respective BIcMQ narrow 
subsearch . 
Patients will UTIs or genital infections will be listed. 
Pyelonephritis and sepsis 
The following specific adverse event will also be tabulated by treatment group:

Acute Pyelonephritis (based on investigator assessment): patient incidence overall and 
by sex

Pyelonephritis or urosepsis (based on the sub-BIcMQ ‘Renal infections predisposed
by glucosuria’ and the PT ‘Urosepsis’): patient incidence overall, by sex and by status 
of DM at baseline (DM / no-DM)

Sepsis (based on investigator assessment): patient incidence overall, by source of 
infection (UTI,  not UTI or missing) and by sex and source of infection
Patients with pyelonephritis or sepsis 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’ and 
investigator definition). Investigator defined fractures will be reported separately for traumatic 
and non-traumatic bone fractures.
For bone fractures based on the BIcMQ the subgroups as outlined in Table 6.4: 1 will be 
presented. Separate tables for bone fractures based on the BIcMQ, which are serious and 
those which are leading to discontinuation will be presented. 
For overall bone fracture based on the BIcMQ in addition to the ‘7-day-on-treatment 
approach’ all adverse events that occurred between first study drug intake up to trial 
completion will be presented (following censoring rules like non-fatal outcome events). 
Patients with bone fractures will be listed.
Urinary tract malignancies:
Urinary tract cancerogenicity will be shown based on the BIcMQ ‘Malignancies’ – broad 
sub-search 14.1 ‘Urinary bladder and tract malignancies’ and broad sub-search 14.2 ‘Renal 
malignancies’ :
Presentation will be done ordered by HLT. 


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Frequency tables of patients with urinary tract malignancies by treatment, high level term and 
preferred term will be provided.  
For urinary tract malignancies in addition to the ‘7-day-on-treatment approach’ all adverse 
events that occurred between first study drug intake up to study end will be presented 
(following censoring rules like non-fatal outcome events). 
There will be an additional analysis including all patients who had a minimum cumulative 
study drug exposure of 6 months (excluding treatment gaps). All AEs starting from date when 
6 months cumulative exposure was reached up to individual day of trial completion will be 
shown (following censoring rules like non-fatal outcome events). 
Patients with urinary tract malignancies will be listed. 
Volume depletion
Volume depletion will be based on the BIcMQ ‘Volume depletion of non-haemorrhagic cause 
and subsequent hypotension’ – narrow sub-search 2 ‘Volume depletion and hypotension due 
to dehydration’.
A frequency table of patients with volume depletion by treatment, primary SOC and preferred 
term will be provided. 
For volume depletion events the subgroups as outlined in Table 6.4: 1 will be presented. 
Separate tables for volume depletion events, which are serious and those which are leading to 
discontinuation will be presented. 
Patients with volume depletion will be listed.
A cumulative incidence function will be used to display the time to first volume depletion 
event.
For the analysis of laboratory data, refer to Section 7.8.2.
Hypotension:
Frequency table of patients with symptomatic hypotension as defined by the investigator on 
the eCRF tick box by treatment, primary system organ class and preferred term will be 
provided.
Symptomatic hypotension will be presented by whether the intensity of diuretic medication 
was reduced and by whether the intensity of non-diuretic antihypertensive therapy was 
reduced. 
Additionally hypotension will be presented by treatment, primary system organ class and 
preferred term. Hypotension is defined as preferred terms of the BIcMQ ‘Volume depletion of 
non-haemorrhagic cause and subsequent hypotension’ – narrow sub-search 2 ‘Volume 


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depletion and hypotension due to dehydration’ (30000090) but excluding terms of the narrow 
subsearch 1 ‘Volume depletion due to dehydration’(30000089).
For hypotension events based on the project-defined subsearch the subgroups as outlined in 
Table 6.4: 1 will be presented. 
The presentation of hypotension events based on investigator defined symptomatic 
hypotension will be repeated to show only events happening in the first 30 days after 
treatment start. 
Separate tables for hypotension (BIcMQ) events, which are serious and those which are 
leading to discontinuation will be presented. 
Separate tables for symptomatic hypotension events, which are serious and those which are 
leading to discontinuation will be also presented. 
Patients with symptomatic hypotension events will be listed.
Additional subgroup analyses for selected adverse events of special interest or specific 
adverse events and other safety topics of interest are described in Section 9.7.
7.8.1.5 Events qualifying for external adjudication by the CEC and Hepatic External 
Adjudication and Adjudication of ketoacidosis
An independent external CEC regularly reviews events and evaluates whether pre-specified 
criteria for these adjudication endpoints are met. Details on composition of the CEC, 
responsibilities and clinical event definitions are provided in the separate CEC Charter. 
Adjudication assessments will be incorporated into the database.
Details of the adjudication process are described in the CEC charter.
Cardiological/neurological adverse events:
Frequency tables will be provided based on SOC and preferred term for events qualifying for 
adjudication. This will include all trigger events up to the end of the study. 
The number of patients with confirmed events per event type and breakdown of event subtype 
will be presented. This will be done for all CEC confirmed events up to the end of the study
as well as up until completion of the planned treatment phase. Information will be provided 
for all patients as well as for patients with SARS-CoV-2 infection defined by broad scope 
SARS-CoV-2 infections. For the analysis in patients with SARS-CoV-2 infection, only events 
with adjudicated onset date between 7 days prior infection and completion of the planned 
treatment phase will be shown.
A listing will be provided, that shows the trigger events and result of adjudication.
Hepatic adverse events:
Frequency tables summarizing the relatedness and severity will be provided including all 


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adjudicated events up to 30 days after treatment stop. A listing will show all trigger events 
and adjudication results. 
Ketoacidosis:
Frequency tables summarizing the adjudication results will be provided including all 
adjudicated events up to 7 days after treatment stop. A listing will show all trigger events and 
adjudication results. 
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 
medication.  Off-drug is not viewed as wrong medication for the listing.
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 relevant 
time. Off-treatment periods will be counted towards the treatment taken before the off-
treatment period for the table. The table will include all adverse events by SOC and PT. 
7.8.1.7 Adverse event incidence rates
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, respectively HLT, and PT.
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
For ‘each row of a table’ (e.g. displaying an SOC), time at risk is calculated using start of first 
AE summarized 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:


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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.
7.8.1.8 COVID-19 related analyses
The subgroup of patients with SARS-CoV-2 infection will be analysed. SARS-CoV-2 
infections will be defined as narrow scope by the BIcMQ SARS-CoV-2 infections. All 
analyses will be repeated using a broad scope defined as BIcMQ SARS-CoV-2 infections
including the preferred term “Suspected Covid-19”.
An overview of adverse events will be presented for this subgroup of patients. Additionally 
the number of patients with adverse events, the number of serious AEs and AEs leading to 
discontinuation of study treatment will be presented by treatment, primary system organ class 
and preferred term. Only adverse events with onset date 7 days prior SARS-CoV-2 infection 
until the end of the on-treatment period will be included. 
A listing will be prepared presenting all SARS-CoV-2 infections.
To assess the reporting of adverse events before and after the start of the COVID-19 outbreak, 
the number of patients with AEs including incidence rates will be presented for both time 
periods. The same cutoff dates as defined in Section 7.5.1 will be used.
7.8.2
Laboratory data
Standard safety tables will not include eGFR or creatinine, as those are shown separately as 
described in Section 7.6. 
For continuous safety laboratory parameters standardized and normalized values will be 
derived as well as the differences to baseline. The process of standardization and 
normalization as well as standard analyses for safety laboratory data are described in the BI 
guidance for the Display and Analysis of Laboratory Data (14). All analyses considering 
multiple of times upper limit of normal (ULN) will be based on original and not normalized 
data.
Laboratory parameters will be shown in conventional units. Where conventional units differ 
from SI units, analyses will be repeated on SI units in the appendix. 
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 (14)].
Baseline for safety laboratory parameters will be the last available measurement before the 
start of randomised trial medication. 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 worst value).


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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. 
Frequency tables will summarise the number of patients with potentially clinically significant 
abnormalities as defined for the current XLAB macro. 
Only patients with at least one available on-treatment value will be included in the analysis of 
an individual laboratory parameter. 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 until 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. A scatter plot of peak ALT against peak 
total bilirubin will be presented with reference lines for 3 x ULN ALT and 2 x ULN total 
bilirubin, including an indicator for treatment received.  Details on patients with elevated liver 
enzymes will be listed.
For the following parameters: uric acid, total cholesterol, HDL-C, LDL-C, triglycerides, 
haemoglobin and haematocrit the time course of changes will be assessed. The analysis will 
be performed by applying MMRM models to OC-AD data (on the randomised set) and 
respectively 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 normalization.
The parameters LDL-C/HDL-C ratio and non-HDL cholesterol will be evaluated descriptively 
over time based on OC-AD data (on the randomised set) and OC-OT data (on the treated set). 
These analyses will be conducted on data before any normalization. 
For an evaluation of follow-up after discontinuation of trial medication an additional 
summary of haemoglobin, haematocrit, uric acid and lipid parameters will be produced. This 
summary will include descriptive statistics for baseline, actual values and change from 


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baseline to last on-treatment value and follow-up, and change from last on-treatment 
assessment to follow-up.  The TS-FU patient set will the basis for this summary, but only 
those patients with a valid baseline, last value on treatment and follow-up value will be 
included in all displays. Analyses will be repeated for patients with at least 52 weeks of 
cumulative exposure (exluding treatment gaps). 
Analyses of change from baseline to LVOT and FU on the TS-FU outlined above will be 
additionally modelled, separately for LVOT and FU. An ANCOVA model including 
treatment group, sex, geographical region and status of diabetes at baseline as fixed effect and 
baseline eGFR (CKD-EPI)cr (continuous), age (continuous), LVEF (continuous) and baseline 
of the endpoint as linear covariates will be used.
7.8.3
Vital signs
An MMRM analysis for heart rate over time will be provided based on OC-AD on the 
randomised set and OC-OT on the treated set imputations. The model will follow the MMRM 
analysis described in Section 7.6.
Note that heart rate refers to the eCRF question on pulse rate. 
7.8.4
ECG
Clinically relevant abnormalities found at physical examination or ECG at Visit 2 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 summarized descriptively. 
7.8.5
Others
Frequency of pregnancies and pregnancy outcomes will be listed by treatment.
Results of the Modified Rankin Scale will be summarized descriptively. 


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8.
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BI-KMED-BDS-HTG-0045: "Reporting of Clinical Trials and Project Summaries", 
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Beyersmann J, Allignol A, Schumacher M.
Competing risks and multistate models with R. New York: Springer 2012 [R16-3839]
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Collett D.
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Rogers JK, Yaroshinsky A, Pocock SJ, Stokar D, Pogoda J. Analysis of recurrent 
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Rogers JK, Pocock SJ, McMurray JJV, Granger CB, Michaelson EL, Ostergren J, et 
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9
Li Lu, Chenwei Liu, Analysis of Correlated Recurrent and Terminal Events Data in 
SAS®. NESUG 2008 [R20-1940]
10
Liu L, Yu Z 
A likelihood reformulation method in non-normal random effects models. 
Stat Med 2008; 27 (16): 3105–3124 [R19-4129]
11
Pocock SJ, Ariti CA, Collier TJ, Wang D
The win ratio: a new approach to the analysis of composite endpoints in clinical trials 
based on clinical priorities.
Eur Heart J 2012; 33: 176 - 182 [R16-4813]
12
BI-KMED-BDS-HTG-0041: "Analysis and Presentation of Adverse Event Data from 
Clinical Trials", current version; KMED.
13
BI-KMED-BDS-QRG-0010: “Reference Guide for the preparation of AE, SAE 
outputs for results disclosure on clinicaltrials.gov and EudraCT (EU-CTR)", current 
version; KMED.
14
BI-KMED-BDS-HTG-0042: "Handling, Display and Analysis of Laboratory Data", 
current version; KMED.
15
001-MCS-40-113: "Clinical Trial Report (CTR) Phase I - IV, Interim Reports and 
Other Associated Regulatory Documents” , current version; IDEA for CON.


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9.
ADDITIONAL SECTIONS
9.1
REGIONS AND COUNTRIES
Countries will be assigned to regions following the assignment of the IRT system, which is 
outlined in Table 9.1:1.  Listed countries include currently planned backup countries. 
Table 9.1: 1
Regions and countries
Region
Country
Asia
China
Japan
Korea
Singapore
Europe
Belgium
Czech Republic 
Germany
Hungary
Italy
Netherlands
Poland 
Romania
Spain
UK
Latin America
Argentina
Brazil
Colombia
Mexico
North America
Canada
US
Other
Australia
India
South Africa
9.2
CONCOMITANT MEDICATION
Definitions of medication groups (such as ARBs, diuretics) will be based on World Health 
Organization Drug Dictionary (WHO DD) and will be stored in the PDMAP.  


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9.3
DEFINITION OF DM AT BASELINE
Table 9.3: 1
DM at baseline
Diabetes status at 
baseline
Definition
T1DM
Patients who fulfil one of the following:
-
investigator-reported medical history of diabetes on the 
medical history page 
AND
-
type of diabetes is T1DM
T2DM
Patients who do not have T1DM but fulfil one of the following:
-
investigator-reported medical history of diabetes on the 
medical history page OR
-
any pre-treatment HbA1c value >= 6.5 OR
-
stratification via IRT in group of diabetes with either
missing assessment of history of diabetes on the medical 
history page, or 
no pre-treatment measurement of HbA1c available and
investigator reported ‘no’ for the medical history of 
diabetes


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Table 9.3: 1
DM at baseline (cont.)
Diabetes status at 
baseline
Definition
Pre-DM
Patient who fulfil one of the following:
-
investigator reported ‘no’ for the medical history of
diabetes on the medical history page AND
no pre-treatment HbA1c >=6.5 and a pre-treatment
HbA1c value of >=5.7 and <6.5
OR
-
stratification via IRT in group of pre-diabetes with either
o
missing assessment of history of diabetes on the
medical history page and no pre-treatment
HbA1c >=6.5 or
o
no pre-treatment measurement of HbA1c and
investigator reported ‘no’ for the medical history
of diabetes
      OR
-
missing assessment of history of diabetes on the medical
history page AND all pre-treatment HbA1c <6.5 and a
pre-treatment HbA1c value of >=5.7 and <6.5 and
stratification via IRT in group of no diabetes
Normal (excluding pre-
DM)
Patients not meeting the criteria of DM or pre-DM


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9.4
ADDITIONAL SUB-GROUP ANALYSIS FOR REGIONAL SUBMISSIONS
Disposition and demographics of the subpopulation for patients from USA and subgroup 
analyses for patient from the USA vs non-USA will be included in the appendix of the CTR. 
Efficacy endpoints evaluated will be primary endpoint, time to cardiovascular (CV) death, 
time to first HHF, HHF (first and recurrent) and renal slope. Safety will be summarized for 
patients from the USA.  
Additional subgroup analyses will be conducted by region, baseline eGFR (>=90, 60 to <90, 
45 to <60, 30 to <45, and <30), and by ethnicity for the same endpoints (primary endpoint, 
time to cardiovascular (CV) death, time to first HHF, HHF (first and recurrent) and renal 
slope). For baseline eGFR (5 category) subgroup analysis, the interaction p-value will be 
calculated using a trend test.
Additional country or region-specific analyses will be conducted for patients from East-Asia 
(China, Japan and Korea), China, and Japan and included into the country-specific submission 
documents as also outlined in (15). Primary endpoint, time to cardiovascular (CV) death, time 
to first HHF, HHF (first and recurrent) and renal slope will be presented. Main adverse event 
overviews, disposition, demographics will be presented.
9.5
INTERIM ANALYSES 
An interim analysis will be conducted by the DMC as outlined in the CTP. If based on the 
interim analysis it is decided to stop the trial for overwhelming efficacy, this analysis used by 
the DMC will be considered the primary analysis for the primary endpoint. This analysis will 
be repeated using the data of the final database lock. All other analyses including analyses of 
the key secondary endpoints will be conducted on the final database lock to provide most 
complete available data. 
Only events that occurred up to one day prior the predefined interim analysis cut-off date will 
be considered for the analysis of the primary endpoint as well as CV death at interim. Patients 
without events up to this time will be censored at the predefined interim analysis cut-off date. 
9.6
DETERMINATION OF SAMPLE SIZE
The trial is designed to achieve a power of 90% for a two-sided test with α=0.05 and hazard 
ratio 0.80. To achieve this at least 841 patients with a primary event are required. 
Including the interim analysis with Hwang, Shih and De Cani α-spending function at 60% 
information with parameter γ = -8 will diminish the power only slightly to 89.98%.
The drop-out rate from the trial is assumed to be very low (<1% per year) and is not 
considered for determination of sample size.
A 10% yearly event rate in the placebo group is assumed. Assuming an accrual period of 18 
months and a follow-up period of 20 months, it was planned to randomise 4126 patients to 
accrue 841 events. 
The event rate and recruitment progress is assessed in a blinded manner during recruitment 
before any interim unblinding. If the accumulated blinded data suggests a slower accrual of 


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primary outcome events over calendar time than originally projected, then the number of 
randomised patients may be increased to a maximum of 6000 patients. Operationally, the 
recruitment period would be extended and could continue up to 6 months before the target 
number of events is expected to be achieved. The number of confirmed primary outcome 
events will not be affected by this consideration and will remain 841 events.
While monitoring the event rate in the above described manner, it was planned to include 
approximately 5750 patients in the trial.
9.7
FURTHER SAFETY ANALYSES
The following analyses will be provided:
PT Fall
Number of patients with fall (PT only) will be presented by baseline LVEF (<50, 50 to <60, 
>=60). 
A cumulative incidence function will be used to display the time to first fall.
The number of patients with fall and concomitant (+/- 7 days) occurrence of volume 
depletion (narrow BIcMQ), hypotension (narrow BIcMQ), ventricular tachyarrthymia (SMQ) 
or hypoglycaemia (inv-def. or narrow SMQ) will be presented.
Acute renal failure (defined by narrow SMQ)
In addition to the analyses described in section 7.8.1.3 number of patients with acute renal 
failure will presented who have concomitant (defined as onset within +/- 7 days respectively 
+/- 30 days) of onset of volume depletion (narrow BIcMQ), PTs Dehydration or Volume 
depletion, or symptomatic hypotension (investigator-defined).
In addition to the subgroups as outlined in Table 6.4: 1 the number of patients with acute renal 
failure will be presented by baseline use of NSAIDs. 
The number of patients with acute renal failure within 30 days after on-treatment start of 
selected medication among those who were not treated with the medication at baseline will be 
presented for any diuretics, loop or high-ceiling diuretics, ACE-inhibitor, ARB or ARNi, and 
for NSAIDs.
Ventricular Tachyarrhythmia
The number of patients with ventricular tachyarrhythmia (VT, defined by narrow SMQ 
Ventricular Tachyarrhythmia) will be presented. VT will also be reported by intensity 
(without incidence rates). Separate tables will be provided for patients for patients with 
serious VTs, for patients with drug related VTs, for patients with fatal VTs, for patients with 
VTs leading to discontinuation and by prevalence of ICD/CRT-D at baseline.


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In addition the number of VT episodes per patient based on the SMQ definition and
considering only the PT VT only will be presented.
Sepsis
In addition to the analyses described in section 7.8.1.4 investigator defined sepsis with source 
of infection Non-UTI and separately with missing source of infection will be presented by age 
(5 cat.), eGFR (5 cat.) and DM Status (2 cat.).
The number of patients with sepsis defined by narrow SMQ “Sepsis” excluding the PT 
Urosepsis will be presented overall and by age (5 cat.), sex, eGFR (5 cat.) and DM status (2 
cat.).
Volume Depletion/Hypotension 
Volume depletion and hypotension (both based on BIcMQ) as defined in section 7.8.1.4 will 
be presented additionally by baseline SBP (<110, 110 – 120, > 120).
Other topics:
For the following safety topics a frequency table by treatment, primary system organ class and
preferred term and a subgroup analysis by diabetes status at baseline (2 cat.) will be
presented:
Allergic skin reactions (defined by BIcMQ ‘Skin eruptions’, subsearch 1.2 ‘Allergic
skin reactions excl. angioedema and application site reactions’(30000132))
Increased urination (PT-based defined, stored in PDMAP)
Thirst (PT-based defined, stored in PDMAP)
Serum lipids increased (defined by BIcMQ ‘Lipid metabolism disorders’, subsearch 3
‘Hyperlipidaemia’ (30000131))
Angioedema (defined by narrow BIcMQ Angioedema excl. Urticaria (30000130), overall 
and separately for terms including and excluding the term “urticaria”)
Hypersensitivity reactions (defined by narrow SMQ ‘Hypersensitivity’ (20000214))
Genital infection
Genital infection as defined in section 7.8.1.4 (narrow BIcMQ) will be presented additionally 
by sex and DM status (2 cat.).
Hypoglycaemia
Investigator reported confirmed hypoglycaemia (see section section 7.8.1.4 for definition) will 
be presented by baseline use of sulfonylureas, by baseline use of insulin, by baseline use of 
sulfonylureas or insulin.


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-
YY)
Author
Sections 
changed
Brief description of change
Final
21-FEB-2017
None
This is the final TSAP without any 
modification
Revised 
23-JAN-2020
4, 6.6.1, 
6.8.2, 6.8.3, 
7.4.1, 7.4.2, 
7.5.1
Exclude FU period from ITT efficacy 
analyses and add sensitivity analysis 
including all events for primary 
endpoint and key secondary endpoint 
of recurrent HHF. 
4, 7.5.1
Include baseline by time interaction in 
the slope model
5.3
Add time to investigator reported CV 
hospitalization.
Definition of CV hospitalisation 
clarified
Fasting plasma glucose was changed to 
fasting glucose because it was 
measured in serum and not plasma
5.4, 6.3, 6.4, 
7.6 and 
where 
applicable
Clarification of follow-up set, 
clarification of win ratio to take into 
account CV death, clarification of 
definition of atrial fibrillation at 
baseline vs history of atrial fibrillation, 
clarification of patient-preferred KCCQ 
score, other minor clarifications
6.1, 7.8.1.6
Add analysis of AEs accounting for 
treatment switchers
6.2 and 
where 
applicable
change important protocol “violations” 
to “deviations” and other minor 
wording changes. 
6.2
Clarifications in iPD table
6.2, 6.3
Changes to IPD D2.02 and TS-FU set
to reflect change in CTP with regards 
to open label SGLT-2 inhibitor use
after EOT visit
6.3, 7.6
Add PK set
6.4
Adjustment of some subgroup analyses 
both for safety and for efficacy. Some 
subgroups added/replaced.
Based on recommendation from the 
Executive Steering Committee, the 
subgroup analyses specified in the 
TSAP was reduced to the clinically 
most meaningful ones. 
6.4, 7.8.1
Update of planned subgroup analyses 
for safety. 
6.6, 7.5.2
KCCQ-CSS add sensitivity without 
imputation
6.6.1
Imputation of missing covariates 
added. 


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Table 10: 1
History table (cont.)
Version
Date
(DD-MMM-
YY)
Author
Sections 
changed
Brief description of change
6.6.2 and 
6.8.2
Clarification of time at risk and missing 
data imputations 
6.7
Add definition of baseline medication
6.8.2
Since recurrent event analyses are 
based on adjudicated event dates and 
duration of hospital stays is not 
adjudicated, only the onset dates of the 
events are considered for the analysis.
7.1
Modified focussed baseline 
presentations (e.g. show HbA1c only 
for patients with DM, show atrial 
fibrillation also by AF at baseline, 
include LVEF , do not include height, 
LDL, HDL)
7.2
Modified presentation of medication 
and non-medication therapy as baseline 
and separately newly introduced after 
baseline
7.4
Clarified the primary estimand of the 
trial 
7.4.2
Additional sensitivity analyses added
7.4.2
Clarified definition of investigator 
reported endpoints.
7.4.4
Section on trend test removed since not 
applicable due to update on subgroups
7.5.1
Joint frailty clarification on analysis 
details
7.5.1
Clarify that other secondary endpoints 
are exploratory
7.5.1
Add individual patient slope and 
intercept plots by eGFR at baseline. 
7.5.1
Multiple imputation for eGFR slope 
analysis was removed. Under missing 
at random assumption, the specified 
multiple imputation approach is 
asymptotically equivalent to the 
maximum likelihood estimate and 
therefore not required in addition.
7.5.2
Negative binomial regression model for 
occurrence of all-cause hospitalisation 
(first and recurrent) added.
7.5.2
Modify renal endpoint as per protocol 
amendment


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Table 10: 1
History table (cont.)
Version
Date
(DD-MMM-
YY)
Author
Sections 
changed
Brief description of change
7.5.2, 7.6
Specify MMRM in condensed form (do 
not include individual terms in case 
already included as interaction terms 
with visit or treatment) to be in line 
with BI internal standards on MMRMs.
Align wording for MMRM term status 
of diabetes at baseline as well as factors 
to be included in MMRMs for the other 
secondary as well as further endpoints.
7.6
Responder analyses (improvement and 
deterioration of 5 points or more from 
baseline) for KCCQ clinical summary 
score, clinical symptoms and physical 
limitations domain was added.
7.6
Add NTproBNP change from baseline 
by atrial fibrillation or flutter at 
baseline
7.6
Rules defining ‘win’ and ‘lose’ for the 
win ratio calculation were modified.
7.6
Add analysis to mean change from 
baseline after approximately 3 years
7.8.1
Changes in the safety analysis strategy 
in line with empagliflozin strategy (e.g. 
look specifically into urinary tract 
malignancy instead of overall 
malignancy, delete VTE, deleted other 
significant AEs, update of BIcMQ 
definitions, add hypotension)
9.3
Clarification of diabetes definition
9.5
Handling of cut-off date for interim 
analysis clarified. 
9.5
Clarification of primary analysis in 
case of interim stopping 
9.6
Region and ethnicity subgroup analyses 
added to regional analyses for US
Throughout 
and section 
9.6
Include wording from the protocol to 
the TSAP and clarify sample size
Revised
12-FEB-2021
6.2
Clarification on iPD
6.4, 7.4.4, 
Addition of baseline uric acid to 
subgroups and define trend test for 
baseline uric acid and baseline LVEF 
subgroup analyses
6.8.3, 
7.8.1.1
Clarifications with regard to censoring 
rules
7,
7.4.2, 
7.5.1
7.5.2
7.8.1.5
Addition of sensitivity analyses for 
COVID-19
7.8.1.4
Insert word “narrow” for clarification


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Table 10: 1
History table (cont.)
7.8.1.8
Addition of safety analyses for patients 
with SARS-CoV-2 infection
9.4
Addition of baseline eGFR (5 
categories) subgroup for regional 
submission
9.7
Addition of safety analyses to support 
labelling and special topics of interest