Clinical trial NCT04509674
Conditions: Myocardial Infarction
Sponsor: Boehringer Ingelheim
Start date: 2020-12-16; Completion date: 2023-11-05
Enrollment: 6522 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a study in adults who had a heart attack (myocardial infarction). The purpose of this study is to find out whether a medicine called empagliflozin helps to lower the chances of having to go to the hospital for heart failure and whether it lowers the chances of dying from cardiovascular disease.

People who are in hospital may join the study soon after being treated for their heart attack. Participants are put into 2 groups by chance. One group takes 1 empagliflozin tablet a day. The other group takes 1 placebo tablet a day. Placebo tablets look like empagliflozin tablets but do not contain any medicine. All participants continue their standard treatment. Empagliflozin belongs to a class of medicines known as SGLT-2 inhibitors. Empagliflozin is a medicine that helps people with type 2 diabetes to lower their blood sugar. Researchers think that empagliflozin might also help people after heart attack who are at risk for heart failure, whether or not they have diabetes.

Participants are in the study for about 1 to 2 years. During this time, there are about 4 visits inperson, 2 visits are done either by phone or by use of an mobile application. Results between the empagliflozin and placebo groups are compared. The doctors also regularly check the general health of the participants.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Empagliflozin intervention 2: Placebo
Intervention descriptions: intervention 1: Empagliflozin intervention 2: Placebo

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106 RD-03 (18 0) / Saved on: 10 Jul 2019
Clinical Trial Protocol
 
Document Number:
c31546238-02
EudraCT No.
EU Trial No.
2019-001037-13
BI Trial No.
1245-0202
BI Investigational
Medicinal Product(s)
Jardiance®, empagliflozin
Title
EMPACT-MI: A streamlined, multicentre, randomised, parallel 
group, double-blind placebo-controlled superiority trial to evaluate 
the effect of EMPAgliflozin on hospitalisation for heart failure and 
mortality in patients with aCuTe Myocardial Infarction
Lay Title
EMPACT-MI: A study to test whether empagliflozin can lower the 
risk of heart failure and death in people who had a heart attack 
(myocardial infarction)
Clinical Phase
III
Clinical Trial Leader
Phone: +
, Fax: +
Coordinating 
Investigator
Phone: +
, Fax: +
Chair and co-chair 
Executive Committee 
Version and Date
Version: 2.0
Date: 20 Apr 2022
Page 1 of 73
Proprietary confidential information.
! 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Protocol date
03 Jul 2020
Revision date
20 Apr 2022
BI trial number
1245-0202
Title of trial
EMPACT-MI: A streamlined, multicentre, randomised, parallel 
group, double-blind placebo-controlled superiority trial to evaluate 
the effect of EMPAgliflozin on hospitalisation for heart failure and 
mortality in patients with aCuTe Myocardial Infarction
Coordinating 
Investigator
Phone: +
, Fax: +
Chair and co-chair 
Executive Committee 
Trial site(s)
Multi-centre trial
Clinical phase
III
Trial rationale
Acute myocardial infarction (MI) affects approximately 7 million 
individuals every year. Despite advancements in its treatment, a 
significant unmet need persists with more than one third of all MI 
patients having either died or developed heart failure (HF) after five 
years. The observed benefits of empagliflozin on mortality and 
hospitalisation for HF (HHF) in patients with T2D and established 
atherosclerotic CV disease in the EMPA-REG OUTCOME trial 
appeared independent of glucose control and provided a strong 
rationale to explore the effects of empagliflozin in populations with 
established HF. However, as these benefits were consistent in both 
patients with and without HF, a similarly strong rationale exists for 
exploring efficacy and safety of empagfliflozin in patients without 
established but at high risk of developing HF, frequently represented 
by patients with an acute MI. Further data with empagliflozin from 
animal studies have given additional support by showing benefits on 
cardiac remodelling and contractility in the post-acute MI setting.
This trial plans to evaluate efficacy and safety of empagliflozin in 


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patients with an acute MI, specifically related to effects on the risk of 
HHF and mortality. The main hypothesis is that early intervention 
with empagliflozin vs placebo on top of standard of care in this 
patient population reduces the subsequent risk of HHF and mortality.
Trial objective(s)
The main objective of this event-driven trial is to demonstrate the 
superiority of empagliflozin 10 mg once daily versus placebo, in 
addition to standard of care, for the reduction of the composite 
endpoint of time to first heart failure hospitalisation or all-cause 
mortality in high-risk patients hospitalised for acute MI.
Trial endpoints
Primary endpoint:
∀
Composite of time to first HHF or all-cause mortality 
Key secondary endpoints which are part of the testing strategy:
∀
Total number of HHF or all-cause mortality
∀
Total number of non-elective CV hospitalization or all-cause 
mortality
∀
Total number of non-elective all-cause hospitalisation or all-
cause mortality
∀
Total number of hospitalisation for MI or all-cause mortality
Other secondary endpoints:
∀
Time to CV mortality
Trial design
A streamlined, randomised, double-blind, parallel group, placebo 
controlled, multi-national and multicentre trial
Total number of patients
randomised
Approximately 5000 randomised.
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 6500. Such a 
decision would be made during recruitment and before any 
unblinding. The number of primary outcome events required is not 
affected by this consideration.
Number of patients on 
each treatment
Approximately 2500, but can be increased based on event accrual 
over time to approximately 3250
Diagnosis
Patients hospitalised for acute myocardial infarction with elevated 
risk of heart failure hospitalisation and mortality
Main inclusion and 
exclusion criteria
Main Inclusion Criteria: 
∀
Signed and dated written informed consent in accordance with 
ICH-GCP and local legislation prior to admission to the trial
∀
Diagnosis of spontaneous acute myocardial infarction (AMI): 
STEMI or NSTEMI with randomisation to occur no later than 14 
calendar days after hospital admission. For patients with an in-
hospital MI as qualifying event, randomisation must still occur 
within 14 days of hospital admission.
Spontaneous AMI is defined as MI with a primary etiology of an 
acute coronary artery disease pathology (e.g., plaque rupture/erosion, 
in-stent restenosis, stent thrombosis) rather than MI caused by supply-


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demand mismatch (e.g., sepsis, arrhythmia, anemia, or other 
condition).
Spontaneous AMI is established when there is evidence of myocardial 
necrosis in a clinical setting consistent with myocardial ischemia due 
to primary coronary event. Under these conditions, the following 
criteria have to be met for the diagnosis of spontaneous AMI:
Detection of rise and/or fall of cardiac enzymes (cardiac troponin, 
cTn or the MB fraction of creatinine kinase, CKMB) with at least one 
value above the 99th percentile of the upper reference limit (URL) or 
the local laboratory MI diagnosis cut-off value, together with 
evidence of myocardial ischemia with at least one of the following:
• Ischemic discomfort or other ischemia symptom(s)
• Electrocardiogram (ECG) characteristics of STEMI or NSTEMI 
including new or presumably new significant ST-segment-T wave 
(ST-T) changes
• Newly developed pathological Q waves or left bundle branch 
block (LBBB) in the ECG
• Imaging evidence of new loss of viable myocardium or new 
regional wall motion abnormality
in a pattern consistent with an ischemic etiology
• Identification of a coronary thrombus by angiography
∀
High risk of HF, defined as EITHER
a) Symptoms (e.g. dyspnea; decreased exercise tolerance; 
fatigue), or signs of congestion (e.g. pulmonary rales, 
crackles or crepitations; elevated jugular venous pressure; 
congestion on chest X-ray), that require treatment (e.g. 
augmentation or initiation of oral diuretic therapy; i.v. 
diuretic therapy; i.v. vasoactive agent; mechanical 
intervention etc.) at any time during the hospitalisation.
OR
b) Newly developed LVEF < 45% as measured by 
echocardiography, ventriculography, cardiac CT, MRI or 
radionuclide imaging during index hospitalisation.
∀
In addition at least one of the following risk factors:
-
Age > 65 years
-
Newly developed LVEF < 35%
-
Prior MI (before index MI) documented in medical records
-
eGFR < 60 ml/min/1.73m2 (according to creatinine from 
most recent local lab during the index hospitalisation and 
calculated with the CKD-EPI formula)
-
Atrial fibrillation (persistent or permanent ; if paroxysmal, 
only valid if associated with index MI)


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-
Type 2 diabetes mellitus (prior or new diagnosis)
-
NTproBNP >1,400 pg/mL for patients in sinus rhythm,
>2,800 pg/mL if atrial fibrillation; BNP >350 pg/mL for 
patients in sinus rhythm, >700 pg/mL if atrial fibrillation, 
measured at any time during hospitalisation
-
Uric acid >7.5 mg/dL (>446 μmol/L), measured at any 
time during hospitalisation
-
Pulmonary Artery Systolic Pressure [or right ventricular 
systolic pressure] >40 mmHg (non-invasive [usually 
obtained from clinically indicated post-MI 
echocardiography] or invasive, at any time during 
hospitalisation)
-
Patient not revascularized (and no planned 
revascularization) for the index MI (Includes e.g. patients 
where no angiography is performed, unsuccessful 
revascularization attempts, diffuse atherosclerosis not 
amenable for intervention; but does NOT include if 
revascularization was not performed due to nonobstructive 
coronary arteries)
-
3-vessel coronary artery disease at time of index MI
-
Diagnosis of peripheral artery disease (extracoronary 
vascular disease, e.g. lower extremity artery disease or 
carotid artery disease)
Main Exclusion Criteria:
∀
Diagnosis of chronic HF prior to index MI
∀
Systolic blood pressure < 90 mmHg at randomisation
∀
Cardiogenic shock or use of i.v. inotropes in last 24 hours before 
randomisation
∀
Coronary Artery Bypass Grafting planned at time of 
randomisation
∀
Current diagnosis of  Takotsubo cardiomyopathy
∀
Any current severe (stenotic or regurgitant) valvular heart disease
∀
eGFR < 20 ml/min/1.73m2 (using CKD-EPI formula based on 
most recent creatinine from local lab during hospitalisation) or on 
dialysis
∀
Type I diabetes mellitus
∀
History of ketoacidosis
Test product(s)
Empagliflozin
dose
10 mg q.d.
mode of 
administration
Oral (p.o.)
Comparator product(s)
Placebo
dose
Not applicable
mode of
administration
Oral (p.o.)
Duration of treatment
The trial is event-driven and all randomised patients will remain in 


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the trial until the total number of patients with investigator reported 
primary endpoint events is projected to reach a target of 532. 
Estimated trial duration is depending on event accrual and is 
projected to be approximately 26 months with a recruitment period of 
approximately 21 months. Therefore, individual treatment may range 
between approximately 5 and 26 months. The actual length of the 
recruitment may be extended beyond 21 months and the follow up 
may be adjusted to achieve the 532 primary endpoint events. The 
estimated total trial duration and length of the double-blind treatment 
period for each patient will vary accordingly.
Statistical methods
A hierarchical testing procedure will be applied from the primary 
endpoint to the set of key secondary endpoints 1 and 2. If the primary 
endpoint is significant at α=5% (two-sided), then a Hochberg step-up 
procedure will be applied to test the family of two key secondary
endpoints of
∀
Total number of HHF or all-cause mortality
∀
Total number of non-elective CV hospitalisations or all-cause 
mortality
at α=5%. If the null hypotheses for both of these two key secondary 
endpoints can be rejected, only then the third key secondary endpoint 
of:
∀
Total number of non-elective all-cause hospitalisations or all-
cause mortality
will be tested at α=5%. The fourth key secondary endpoint
∀
Total number of hospitalisations for MIs or all-cause mortality
will only be tested if all the hypotheses for key secondary endpoints 
1, 2 and 3 have been rejected.
The primary endpoint will be analysed using a Cox proportional 
hazards model with treatment, T2D at baseline (yes vs no), 
geographical region (North America, Latin America, Europe, Asia), 
age at baseline (continuous), eGFR (CKD-EPI) at baseline (<45 vs
45-<60 vs 60-<90 vs >=90 ml/min/1.73m2), LVEF at baseline (<35% 
vs ≥35%), persistent or permanent atrial fibrillation at baseline (yes vs 
no), prior MI at baseline (yes vs no), PAD at baseline (yes vs no) and 
smoking at baseline (current vs non-current) as covariates. The
primary analysis will be performed on the randomised (intention to 
treat) set.
It is planned that approximately 5000 patients will be randomised to 
accumulate a target of 532 primary outcome events within 21 months 
of recruitment and approximately additional 5 months of follow-up. 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 6500.


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FLOW CHART
Study periods
Screening 
Randomised Treatment Period
EoS10
F-up7
Visit
1
2a2
2b3
3
4
5-8
EoS
F-up
Time from 
Randomisation
Day
-14 to 1
Day 1
-
2 weeks
6 months
Every 6
months
-
Time window for visits
None
+4 days
+21 days
+21 days
-
EoS
+7 days
F2F or remote (R) visit
F2F
F2F
F2F
R
F2F
R
Telephone
Telephone
Informed consent
X
Patients’ preference for 
remote follow-up visits 
(mobile /web-based app 
vs telephone)1
X
Demographics
X
Medical history/ 
Concomitant diagnosis
X
Physical examination
X
Vital signs
X
Local laboratory tests
and clinical routine 
examinations
(X4)
X4
Urine pregnancy test5
X
X
Review of in-/exclusion 
criteria
X
X
Screening (register in 
IRT)
X
Randomisation (via IRT)
X
Dispense trial 
medication
X
X
(X)
All SAEs, AESIs, and 
AEs leading to 
discontinuation6
X
X
X
X
X
X
Assessment of 
Endpoints
X
X
X
X
X
X
Use of / adherence to 
trial medication
X
X8
X
X8
Concomitant therapy9
X
X
X
Additional collection of 
selected concomitant 
medication11
X
X
X
F2F = face-to-face; R = remote (phone and/or app); End of Study (EoS), synonym for End of Trial
(1)
The site personnel will discuss the different remote follow-up options with the patient during the 
screening to ensure the patients’ preferences are met. Patients are allowed to switch between the 
different remote contact options.
(2)
Day of randomisation / Day of first intake of trial medication.The trial medication should be taken after 
all trial related procedures are completed.
(3)
Day of discharge from hospital. Visit 2b will only be performed if the day of discharge is after day of 
randomisation.
(4)
Most recent local laboratory test, and the last results from clinical routine examinations e.g. 
echocardiography prior to randomisation to be used.
(5)
Women of childbearing potential only.
(6)
All Endpoints and SAEs/AESIs with start after randomisation must be reported immediately (within 24 
hours) in the relevant eCRF pages.


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(7)
For patients completing the treatment period according to the protocol, the investigators must report 
Endpoints and SAEs/AESIs reported by patient occurring the following 7 days after the patient’s 
individual EoS (within 24 hours). Thereafter the investigator should report only any cancers of new 
histology and exacerbations of existing cancer, trial treatment related SAEs and trial treatment related 
AESIs of which the investigator may become aware of, please see Section.5.2.1.2.1.
(8)
Include return of trial medication, if applicable.
(9)
If an SAE or AESI is reported, all relevant concomitant therapy that the patient received in the past and 
at the onset of an SAE or AESI should be reported, with the exception of the exempted events listed in 
Section 5.2.1.2.3.
(10)
The sponsor/CRO will notify the investigator when the required number of events is expected to be 
reached. All patients are expected to perform their last visit (EoS) within the proposed time schedule, 
named “Close-out period”, communicated via an investigator letter. For patients who discontinued trial 
treatment prematurely the information about Endpoints, SAEs, AESIs and their vital status continues to 
be collected until EoS, as close as possible to the time schedule defined in the protocol and in line with 
the follow-up method preferred by the patient. For the patients who withdraw consent for the trial, vital 
status should be collected during the Close-out period if allowed by local regulation, please see 
Sections 3.3.4.1 and 5.2.1.2.1.
(11)
Use of SGLT-2 inhibitor (or combined SGLT-1 and SGLT-2 inhibitor) other than the trial treatment.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................7
TABLE OF CONTENTS ........................................................................................................9
ABBREVIATIONS................................................................................................................12
1.
INTRODUCTION...............................................................................................15
1.1
MEDICAL BACKGROUND.............................................................................15
1.2
DRUG PROFILE................................................................................................15
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................16
1.4
BENEFIT - RISK ASSESSMENT.....................................................................16
1.4.1
Benefits.................................................................................................................16
1.4.2
Risks .....................................................................................................................17
1.4.3
Discussion.............................................................................................................21
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................22
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........22
2.1.1
Main objectives....................................................................................................22
2.1.2
Primary endpoint(s)............................................................................................22
2.1.3
Secondary endpoint(s) ........................................................................................22
2.2
FURTHER OBJECTIVES AND FURTHER ENDPOINTS ..........................22
2.2.1
Further objectives ...............................................................................................22
2.2.2
Further endpoints ...............................................................................................22
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................24
3.1
OVERALL TRIAL DESIGN.............................................................................24
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................25
3.3
SELECTION OF TRIAL POPULATION .......................................................26
3.3.1
Main diagnosis for trial entry ............................................................................27
3.3.2
Inclusion criteria .................................................................................................27
3.3.3
Exclusion criteria ................................................................................................29
3.3.4
Withdrawal of patients from treatment or assessments..................................30
3.3.4.1
Discontinuation of trial treatment .........................................................................31
3.3.4.2
Withdrawal of consent to trial participation .........................................................32
3.3.4.3
Patients lost to follow-up ......................................................................................32
3.3.4.4
Discontinuation of the trial by the sponsor...........................................................33
4.
TREATMENTS...................................................................................................34
4.1
INVESTIGATIONAL TREATMENTS ...........................................................34
4.1.1
Identity of the Investigational Medicinal Products..........................................34
4.1.2
Selection of doses in the trial and dose modifications......................................35
4.1.3
Method of assigning patients to treatment groups...........................................35


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4.1.4
Drug assignment and administration of doses for each patient......................35
4.1.5
Blinding and procedures for unblinding...........................................................37
4.1.5.1
Blinding.................................................................................................................37
4.1.5.2
Unblinding and breaking the code ........................................................................37
4.1.6
Packaging, labelling, and re-supply...................................................................37
4.1.7
Storage conditions...............................................................................................37
4.1.8
Drug accountability.............................................................................................38
4.2
TREATMENT COMPLIANCE........................................................................38
4.3
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................39
4.3.1
Other treatments and emergency procedures..................................................39
4.3.2
Restrictions ..........................................................................................................40
4.3.2.1
Restrictions regarding concomitant treatment ......................................................40
4.3.2.2
Restrictions on diet and life style..........................................................................40
4.3.2.3
Contraception requirements..................................................................................40
5.
ASSESSMENTS..................................................................................................41
5.1
ASSESSMENT OF EFFICACY........................................................................41
5.2
ASSESSMENT OF SAFETY.............................................................................41
5.2.1
Assessment of adverse events.............................................................................41
5.2.1.1
Definitions of AEs ................................................................................................41
5.2.1.2
Adverse event collection and reporting ................................................................45
5.3
OTHER ASSESSMENTS...................................................................................48
5.4
APPROPRIATENESS OF MEASUREMENTS..............................................48
6.
INVESTIGATIONAL PLAN.............................................................................49
6.1
VISIT SCHEDULE.............................................................................................49
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................49
6.2.1
Screening period..................................................................................................49
6.2.2
Treatment period(s)............................................................................................50
6.2.3
Trial completion and Follow-up period ............................................................51
6.2.4
Early discontinuation of trial medication and trial termination ....................52
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................53
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................53
7.2
PLANNED ANALYSES.....................................................................................55
7.2.1
General considerations .......................................................................................55
7.2.2
Primary endpoint analyses.................................................................................55
7.2.3
Secondary endpoint analyses .............................................................................56
7.2.4
Further endpoint analyses..................................................................................56
7.2.5
Safety analyses.....................................................................................................56
7.2.6
Interim Analyses .................................................................................................57
7.3
HANDLING OF MISSING DATA ...................................................................57
7.4
RANDOMISATION ...........................................................................................57
7.5
DETERMINATION OF SAMPLE SIZE .........................................................58


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........60
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................60
8.2
DATA QUALITY ASSURANCE ......................................................................61
8.3
RECORDS...........................................................................................................61
8.3.1
Source documents ...............................................................................................61
8.3.2
Direct access to source data and documents.....................................................62
8.3.3
Storage period of records ...................................................................................63
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................63
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........63
8.6
TRIAL MILESTONES.......................................................................................63
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................64
9.
REFERENCES....................................................................................................66
9.1
PUBLISHED REFERENCES............................................................................66
9.2
UNPUBLISHED REFERENCES......................................................................69
10.
APPENDICES.....................................................................................................70
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................71
11.1
GLOBAL AMENDMENT 1 ..............................................................................71


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ABBREVIATIONS
ACM
All cause mortality
AE
Adverse event
AESI
Adverse event of special interest
AKI
Acute Kidney Injury
ALCOA
Attributable, Legible, Contemporaneous, Original, Accurate
ALT
Alanine Aminotransferase
AMI
Acute Myocardial Infarction
ANCOVA
Analysis of Covariance
AST
Aspartate Aminotransferase
BI
Boehringer Ingelheim
BNP
Brain Natriuretic Peptide
CABG
Coronar Artery Bypass Grafting 
CI
Confidence interval
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration Equation
COVID-19
Coronavirus Disease 2019
CRA
Clinical Reasearch Associate
CRO
Clinical Research Organisation
CT
Computer Tomography
CTP
Clinical Trial Protocol
CV
Cardiovascular
CVD
Cardiovascular disease
DBL
Database Lock
DILI
Drug induced liver injury
DKA
Diabetic Ketoacidosis
DM
Diabetes Mellitus
DMC
Data Monitoring Committee
EC
Executive Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
eDC
Electronic Data Capture
eGFR
Estimated Glomerular Filtration Rate


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EoS
End of study, synonym for End of Trial
EoT
End of Treatment
F2F
Face-to-Face
FDA
Food and Drug Administration
F-up
Follow-up
GCP
Good clinical practice
HIPAA
Health Insurance Portability and Accountability Act
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IHD
Ischemic Heart Disease
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator site file
ITT
Intention To Treat
GMP
Good Manufacturing Practice
HbA1c
Glycosylated haemoglobin
HF
Heart Failure
HFrEF
Heart Failure with Reduced Ejection Fraction
HHF
Hospitalisation for heart failure
HR
Hazard Ratio
KA
Ketoacidosis
LBBB
Left Bundle Branch Block
LDL
Low-Density Lipoprotein
LLA
Lower Limb Amputation
LPLT
Last Patient Last Treatment
LVEF
Left Ventricular Ejection Fraction
MI
Myocardial Infarction
MRI
Magnetic Resonance Imaging
NCC
National Coordinator Committee
NSTEMI
Non-ST Elevation Myocardial Infarction
NT-proBNP
N-Terminal Pro-Brain Natriuretic Peptide


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PAD
Peripheral Artery Disease 
PT
Preferred Term
RAAS
Renin-Angiotensin-Aldosterone-System
REP
Residual Effect Period
RS
Randomised Set
SAE
Serious adverse event
SGLT-1
Sodium Glucose Co-Transporter 1
SGLT-2
Sodium Glucose Co-Transporter 2
SOC
System Organ Class
SOP
Standard Operating Procedure
STEMI
ST-Elevation Myocardial Infarction
SUSAR
Suspected Unexpected Serious Adverse Reaction
T1D
Type 1 diabetes mellitus
T2D
Type 2 diabetes mellitus
TMF
Trial Master File
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
ULN
Upper Limit of Normal
URL
Upper Reference Limit
UTI
Urinary Tract Infection
WOCBP
Women of childbearing potential


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Acute myocardial infarction (MI) is the most severe manifestation of ischemic heart disease, 
affecting approximately 7 million individuals every year. It ranks among the most significant 
causes of death and poor health across the globe and results in more than 1 million 
hospitalizations per year in the United States alone, with associated costs exceeding 450 
billion USD [P20-04407, R20-1515]. Heart Failure (HF) is the most common and severe 
complication of MI with over one third of all MI patients being either hospitalised for HF or 
dead after five years [R20-0201]. Moreover, MI constitutes the most important risk factor for 
HF with the risk of HF development at its highest immediately after and in the early (months) 
post-MI phase. The management of acute MI has improved in recent decades with the 
widespread implementation of early revascularization, dual antiplatelet treatment and 
intensification of secondary preventive measures, including cholesterol lowering therapies. 
The resulting reduced mortality has left a larger population at risk of HF development [R20-
0393]. Given the central etiological role of MI in HF development overall, all patients with 
an MI can be perceived to be at elevated risk of HF, although the risk magnitude will depend 
on various background factors. One of the most important determinants of poor outcome and 
progression to HF are factors associated with extensive myocardial injury, in turn reflected as 
impaired systolic function and early signs and/or symptoms of HF. Other more general 
characteristics and comorbidities, such as age, poor renal function and type 2 diabetes, are 
also of significant prognostic value with respect to both subsequent mortality and HF. As 
established chronic HF portends a particularly poor prognosis with high morbidity and 
mortality, early intervention in high-risk populations, including those with MI, to prevent 
progression to chronic HF would therefore be highly beneficial from the viewpoint of both 
patients and society.
1.2
DRUG PROFILE
Empagliflozin is an orally available, potent, and selective inhibitor of the renal Sodium 
Glucose Co-Transporter 2 (SGLT-2) receptor. Its selective inhibition reduces renal 
reabsorption of sodium and glucose. This leads to both increased urinary sodium and glucose 
excretion. While urinary sodium excretion returns to near normal within a few days of 
empagliflozin administration, the effect on urinary glucose continues for as long as the 
medication is used.
Empagliflozin has been developed for the treatment of type 2 diabetes mellitus (T2D), and 
has received marketing approval in various regions including for example the European 
Union, Latin American countries, USA and Japan where it is marketed under the brand name 
Jardiance®.
For a more detailed description of the drug profile please refer to the current Investigator’s
Brochure (IB) [c01678844] and local prescribing information for empagliflozin.
The Residual Effect Period (REP) of empagliflozin is 7 days. This is the period after the last
dose with measurable drug levels and/or pharmacodynamic effects are still likely to be 
present.


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1.3
RATIONALE FOR PERFORMING THE TRIAL
In the EMPA-REG OUTCOME trial, among patients with established cardiovascular disease 
(CVD) and type 2 diabetes mellitus (T2D), a significant reduction in the primary endpoint 
(CV death, MI, or stroke) was seen, driven by a 38% relative risk reduction in CV death
[P15-09840]. In addition, there was a marked reduction of all-cause mortality (32%) and 
heart failure hospitalisation (HHF) (35%). The observed benefits on CV death and HHF were 
independent of levels of glycosylated haemoglobin (HbA1c), suggesting that the 
cardiovascular benefits were largely independent of its glucose-lowering mechanisms. The 
findings from the EMPA-REG OUTCOME trial provided a strong rationale to explore the 
effects of empagliflozin in populations with established HF, as currently investigated in the 
EMPEROR trials (BI trials 1245.110 and 1245.121). Recently, a reduced risk of HF and CV 
mortality was also observed for the SGLT2-inhibitor dapagliflozin in the DAPA-HF trial, 
extending previously observed benefits to patients with established HF with reduced ejection 
fraction (HFrEF) and without T2D [R19-3125]. Importantly, in the EMPA-REG OUTCOME 
trial there was no interaction between patients’ HF status at baseline and the observed 
benefits on HF and mortality, indicating potential not only for the treatment of HF but also 
for the prevention of HF in patients at risk but without a prior HF diagnosis. The risk 
reduction for HHF associated with empagliflozin treatment was 0.75 (95% CI 0.48-1.19) in 
patients with investigator-reported HF at baseline and 0.59 (95% CI 0.43-0.82) in patients 
without investigator-reported HF at baseline, and for all-cause mortality 0.79 (95% CI 0.52-
1.20) in patients with HF and 0.66 (0.51-0.81) in patients without HF at baseline. Moreover, 
in the overall trial population there was also a significant risk reduction with empagliflozin 
treatment for all-cause hospitalisation (HR 0.89 (95% CI 0.82-0.96)) [P17-11284]. There is 
currently equipoise with respect to efficacy and safety of empagfliflozin in the general acute 
MI population (including a majority of non-diabetic patients) as in the EMPA-REG 
OUTCOME trial, only patients with T2D were included, and in order to be eligible for 
inclusion, a recent MI (< 2 months) was not allowed. Finally, among the included T2D 
patients in the study, only a small proportion had an MI < 1 year of inclusion.
This trial plans to address a significant unmet need in the large acute MI population, 
specifically related to the risk of HHF and mortality: The trial is a randomised, double-blind, 
placebo-controlled trial among patients, irrespective of the presence or absence of T2D, 
hospitalised with a Type I acute MI [R20-0005] and at high risk for subsequent HHF and 
mortality. The main hypothesis is that early intervention with empagliflozin on top of 
standard of care in this patient population reduces the subsequent risk of HHF and mortality, 
compared to placebo.
1.4
BENEFIT - RISK ASSESSMENT
1.4.1
Benefits
In the EMPA-REG OUTCOME trial, empagliflozin provided a robust benefit on mortality 
and HHF in T2D patients with established CVD. Despite only enrolling T2D patients, the 
observed benefits appeared to be independent of the glucose-lowering effects, thus providing 
a rationale to study empagliflozin as treatment in HF patients with and without T2D [P16-
01253][P17-13145].


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Recently, in the DAPA-HF trial, benefits of the SGLT2-inhibitor dapagliflozin in established 
HF were confirmed in patients with established HFrEF with and without T2D [R19-3125]. 
The EMPEROR-Reduced trial, which studies the effects of empagliflozin in established 
HFrEF, is expected to complete in 2020. The benefits on HHF and mortality in the EMPA-
REG OUTCOME trial were similar in patients both with and without HF at baseline, 
indicating a potential for both treatment and prevention of HF. As patients with a high-risk 
MI (defined as signs or symptoms of HF or evidence of myocardial dysfunction resulting 
from the MI) are common and at high-risk of both HF and mortality, there is a strong reason 
to believe they could benefit from empagliflozin treatment. As patients with an acute or a 
recent MI were not included in the EMPA-REG OUTCOME trial, there is equipoise for 
further trials in this important patient population.
In addition, several acute MI animal studies in rats and pigs (both with and without T2D) 
showed multiple benefits from empagliflozin treatment in conjunction with and after the 
induced MI. Benefits included improved survival, less adverse remodelling, preserved 
cardiac contractility and less neurohormonal activation in animals treated with empagliflozin, 
compared to placebo [c01678844, P18-12030, P19-03216, P19-03653]. Further, in the 
EMPA-HEART trial, patients with established T2D and established ischemic heart disease
(IHD) experienced a reduction in left ventricular mass over time with treatment of 
empagliflozin, indicating that reverse remodelling as a result of empagliflozin treatment 
could be a likely mediator of the overall benefits [P19-08100].
In addition to potential risk reductions for HF and mortality, empagfliflozin may provide 
other benefits in a high-risk post-MI population, especially related to prevalent CV and renal 
comorbidities. In patients with T2D, empagliflozin is known to improve glucose control over 
time and also have a positive influence on other CV risk factors, including reductions in 
blood pressure and body mass index. Importantly, marked benefits on hard renal outcomes as 
well as a stabilization of the eGFR slope (after an initial modest decrease) were observed for 
empagliflozin in the EMPA-REG OUTCOME trial [P16-06807].
1.4.2
Risks
Known and potential risks for empagiflozin that are clinically relevant in an acute and post-
MI setting are outlined in the below Table 1.4.2: 1.


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Table 1.4.2: 1 Overview over trial related risks 
Known or potential risks of 
clinical relevance for this 
trial
Summary of data, rationale for the risk
Mitigation strategy
Investigational Medicinal Product: Empagliflozin
Hypoglycaemia
The risk of hypoglycaemia was increased 
only when empagliflozin was used 
concomitantly with insulin and/or 
sulfonylurea. The risk of hypoglycaemia in
patients without diabetes mellitus (DM) is 
considered very low. In a mechanistic 
study [c11963611-01], patients without 
DM had an increase of endogenous glucose 
production in response to glycosuria due to 
empagliflozin.
Patients with type 1 diabetes 
mellitus (T1D) are excluded from 
the study.  Investigators will advise 
patients on insulin or sulfonylureas 
to exercise additional caution in 
monitoring for hypoglycaemia 
when initiating trial medication.
Guidance for the investigator is 
provided in the IB.
Volume depletion
Empagliflozin may selectively reduce 
interstitial volume with minimal change in 
intravascular volume.
Polyuria and consequent dehydration and 
hypotension were identified as risks in 
patients treated with empagliflozin, 
especially patients with known CV disease, 
history of hypotension, taking diuretics or
other antihypertensive drugs, or elderly 
patients aged 75 years and older [P19-
02151]. In the EMPA-RESPONSE-AHF 
trial, empagliflozin was safe and well-
tolerated in patients with acute heart 
failure. [P20-00338]
Congested patients with ongoing 
diuretic therapy can be randomized 
but haemodynamically unstable or 
hypotensive patients are excluded.
Guidance for the investigator is 
provided in the IB. Information 
and recommendations to patients
are provided in the Informed 
Consent Form (ICF).
Diabetic ketoacidosis 
(DKA) /Ketoacidosis (KA)
Cases of DKA, including fatal cases, were 
reported in patients treated with SGLT2-
inhibitors. In patients treated with SGLT2-
inhibitors DKA may occur with lower than 
usual glucose values. The risk of DKA is 
increased in patients with lower than 
needed insulin intake, T1D, low 
carbohydrate intake, acute illness, major 
trauma, major surgery, severe dehydration 
or alcohol use.  In the recently published 
DAPA-HF trial that enrolled both diabetic 
and non-diabetic HF patients, the incidence 
of DKA in the DAPA arm was 0.1%.  
Among non-diabetics, no ketoacidosis 
events were reported [R19-3125].
Patients with T1D and prior KA 
are excluded from the trial.
Guidance for the investigator is 
provided in the IB. Training will be 
provided. Information and 
recommendations to patients are 
provided in the ICF.
KA is an adverse event of special 
interest (AESI) and requires 
detailed reporting by investigator 
in the electronic case report form 
(eCRF). 
Complicated urinary tract 
infections (UTI)
Cases of complicated UTI, including 
pyelonephritis and urosepsis have been
reported in patients treated with 
empagliflozin.
Guidance for the investigator 
provided in the IB. Information 
and recommendations to patients 
are provided in the ICF.
Necrotizing fasciitis of 
perineum (Fournier’s 
gangrene)
Rare cases of Fournier’s gangrene, 
including fatal cases, have been reported in 
patients treated with SGLT2-inhibitors.
Guidance for the investigator is 
provided in the IB. Information 
and recommendations to patients 


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Known or potential risks of 
clinical relevance for this 
trial
Summary of data, rationale for the risk
Mitigation strategy
Investigational Medicinal Product: Empagliflozin
are provided in the ICF.
Hypersensitivity
The risks of allergic skin reactions (e.g. 
rash, urticaria) and angioedema were 
identified for empagliflozin based on post-
marketing experience.
As with all drugs, the risk of severe and 
unexpected allergic reactions cannot be 
excluded.
Patients with hypersensitivity to 
empagliflozin or other SGLT2-
inhibitors are excluded from trial
participation.
Drug-induced liver injury 
(DILI)
No risk of DILI was identified for 
empagliflozin during the clinical 
development program. However, DILI can 
be severe and even lead to fatal outcome or 
need of liver transplant. Therefore, careful 
monitoring and assessment of patients for 
potential DILI is needed.
Hepatic injury is an AESI and 
requires detailed reporting by 
investigator in the eCRF.
If DILI is suspected additional 
information will be collected 
according to the DILI checklist.
Unblinded review of potential 
DILI cases will be performed by 
Data Monitoring Committee 
(DMC).
Lower limb amputation 
(LLA)
An increase of amputations in CANVAS (a 
clinical trial on canagliflozin) was 
observed. In a post-hoc analysis of all 
completed Phase II and III clinical trials of 
empagliflozin and its fixed dose 
combinations, including the ones with a
duration less than 3 months, the incidence 
of LLA in patients treated with 
empagliflozin was not higher compared to 
patients treated with placebo or other 
comparators.
No increase in the risk of LLA or 
potentially related AEs was observed in 
patients treated with empagliflozin 
compared with placebo in a meta-analysis 
of 3 large CV outcome trials (EMPA-REG 
OUTCOME, EMPEROR-Reduced, and 
EMPEROR-Preserved) [c32096554-01].
Risk of LLA has been described in 
the IB [c01678844]. Like for all 
diabetic patients it is important to 
counsel patients on routine 
preventative foot-care.LLA is an 
AESI and requires detailed 
reporting by investigator in the 
eCRF.
Renal safety
In clinical trials with patients with T2D, 
the incidence of renal impairment was 
similar to placebo. An initial decrease of 
estimated glomerular filtration rate (eGFR)
was seen in patients treated with 
empagliflozin, which improved and 
stabilized during continuous treatment or 
discontinuation of empagliflozin.
Cases of renal impairment, including those
requiring dialysis, have been reported in 
Decreased renal function fulfilling 
the definition of a SAE or an AE 
leading to discontinuation must be 
reported.
Unblinded review of cases of acute 
kidney injury will be performed by 
DMC.


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Known or potential risks of 
clinical relevance for this 
trial
Summary of data, rationale for the risk
Mitigation strategy
Investigational Medicinal Product: Empagliflozin
patients using SGLT2-inhibitors. In the 
EMPA-RESPONSE trial, empagliflozin 
was safe and well-tolerated in patients with 
acute HF, without evidence of 
empagliflozin being associated with renal 
impaiment [P20-00338].
Women of childbearing 
potential (WOCBP)
The safety of empagliflozin in pregnant 
women was not established.
In accordance with international 
regulatory guidelines, WOCBP are 
excluded from trial participation 
unless they agree to use a highly 
effective contraceptive method.
All WOCBP will undergo 
pregnancy testing before 
randomisation.
Known or potential risks in patients without T2D:
In the empagliflozin HF program, which includes the two ongoing large EMPEROR outcome 
trials and the two EMPERIAL exercise capacity trials (with more than 10,000 patients being 
followed up as of May 2020), the frequencies of overall adverse events (AE), severe AE, 
serious AE, and AE leading to treatment discontinuation reported in patients without T2D 
were similar or lower than the ones reported in patients with T2D, consistent with the known 
safety reporting described in the IB.
As of May 2020 based on blinded data review from the EMPEROR outcome trials, no new 
safety concerns has been raised in population without T2D.
An independent data monitoring committee (DMC) will be assigned to monitor the trial.   
The DMC will evaluate the unblinded data for potential safety signals on a quarterly basis.  
They will also analyse, at the DMC chair’s discretion, unblinded data at any point during the 
trial if data from other studies of empagliflozin or other SGLT2-inhibitors reveal previously 
unknown risks. Please refer to Section 8.7 for details.
Patients will be treated according to standard of care and trial medication will be given
on top of standard therapy. The investigator will also be able to change concomitant therapy 
to ensure sufficient standard of care for underlying conditions, such as hypertension and 
diabetes mellitus. Therefore, the placebo controlled trial design should not constitute a risk 
for the population in this trial.
Patients with current or planned use of an SGLT2-inhibitor at baseline are excluded. 
Moreover, in enrolled patients, if a strong need to treat with an SGLT2-inhibitor develops
during the trial according to the investigator (anticipated in some T2D patients), trial 
medication can be discontinued and the patient can instead be treated with open-label 
empagliflozin or another SGLT2-inhibitor. Follow-up of the patient will continue as per the 
intention-to-treat principle.


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Risk evaluation in relation with COVID-19
Patients with serious underlying medical conditions such as chronic heart disease and 
T2D are at higher risk for severe illness from coronavirus disease 2019 (COVID-19). 
Therefore, in case of local high risk of COVID-19 infection, on-site visits should be avoided 
as much as possible. In the event of restriction to visit the investigator site, a remote visit can 
be performed. This change is meant to keep the integrity of the trial and it will not affect the 
benefit-risk of empagliflozin.
There is no indication that empagliflozin may increase the risk of COVID-19 infection. As 
with any acute illness, empagliflozin during COVID-19 infection has the potential to increase 
the risk of ketoacidosis. The risk of ketoacidosis in case of acute illness is adequately 
addressed in the IB.
1.4.3
Discussion
A significant unmet need on patient and health care level related to excess risk of HF and 
mortality remains in patients with acute MI, and especially in those with high-risk features. 
Multiple pre-clinical and clinical trials have provided a strong rationale for the evaluation of 
efficacy and safety of empagliflozin in this population although clinical equipoise remains as 
all prior large scale trials with empagliflozin, and other SGLT2-inhibitors, have excluded 
patients with an acute or recent MI. In neighboring populations, empagliflozin has already 
demonstrated benefits on mortality and HF paired with a well established safety profile. The 
intended trial population for this trial is not considered to be at higher risk from a safety 
viewpoint as compared to previously or currently studied populations, thus allowing for a 
more streamlined trial approach, which includes focused safety reporting (serious adverse 
events and adverse events of special interest with respect to empagfliflozin and the post-MI 
setting), remote follow-up and blinded investigator event review instead of centralized 
adjudication, ultimately enabling continued evidence generation in an area of high unmet 
medical need.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main objective of this event-driven trial is to demonstrate the superiority of 
empagliflozin 10 mg once daily versus placebo, in addition to standard of care, for the 
reduction of the composite endpoint of time to first heart failure hospitalisation or all-cause 
mortality in high-risk patients hospitalised for acute MI.
2.1.2
Primary endpoint(s)
The primary endpoint is the composite of time to first heart failure hospitalisation or all-cause 
mortality, calculated from date of randomisation.
2.1.3
Secondary endpoint(s)
Key secondary endpoints, which are part of the confirmatory testing strategy, are:
∀
Total number of HHF or all-cause mortality
∀
Total number of non-elective CV hospitalisations or all-cause mortality
∀
Total number of non-elective all-cause hospitalisations or all-cause mortality
∀
Total number of hospitalisations for MI or all-cause mortality
Other secondary endpoints, not part of the confirmatory testing strategy, are:
∀
Time to CV mortality
All time-to-event endpoints are calculated from date of randomisation. CV mortality will 
include death of unknown cause. Non-elective hospitalisations include hospitalisations with 
unknown attribute of urgency.
2.2
FURTHER OBJECTIVES AND FURTHER ENDPOINTS
2.2.1
Further objectives
Further objectives are to evaluate additional details on efficacy and safety.
2.2.2
Further endpoints
∀
30-day all-cause hospitalisation calculated from date of discharge or randomisation, 
whichever comes latest, as a binary variable
∀
Number of days alive and out of hospital within the first 90 days, 6 months, 9 months and 
12 months after randomisation
∀
Time to first renal replacement therapy or renal transplantation


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∀
Time to first revascularisation
∀
Time to first HHF
∀
Time to all-cause mortality
∀
Time to first non-elective CV hospitalisation or all-cause mortality
∀
Time to first non-elective CV hospitalisation
∀
Time to first non-elective all-cause hospitalisation or all-cause mortality
∀
Time to first non-elective all-cause hospitalisation
∀
Time to first hospitalisation for MI or all-cause mortality
∀
Time to first hospitalisation for MI 
All time-to-event endpoints are calculated from date of randomisation.
A complete list of further endpoints will be given in the trial statistical analysis plan (TSAP).


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN
This is a streamlined, randomised, double-blind, parallel group, placebo controlled, multi-
national and multicentre trial. The key streamlining elements in the trial consist of mainly 
remote follow-up, focused safety collection, and blinded investigator review of events in 
place of centralized adjudication.
Trial participants have an acute type 1 MI and will be identified, screened and randomised 
within 14 calendar days of hospital admission. Patients who were admitted for other causes 
but have an acute MI in-hospital can also be included but randomisation still has to occur 
within the 14 days of admission. For all patients, early randomisation prior to hospital 
discharge is strongly encouraged.
Preliminary identification of potentially eligible patients can occur at any time during the 
hospitalisation, i.e. from hospital admission or in the cardiac catheterisation lab, to discharge. 
As an exception, identification of potential participants could also be performed after 
discharge, if still within the 14 day time window. For suitable patients, trial information will 
be provided and informed consent obtained before screening. In this trial, information related 
to the eligibility criteria will typically be available as part of clinical routine in the patient 
health care records. Before randomisation, a physical examination will be performed. Any 
blood samples will be analysed locally and as part of clinical routine. In case of initial 
ineligibility, patients may be re-screened at a later time point, as they can become eligible 
later during the same index hospitalisation.
Patients who fulfill the eligibility criteria will undergo individual randomisation to either 
empagliflozin 10 mg daily or matching placebo once daily in addition to usual standard of 
care. Usual standard of care is to be provided according to local, national and international 
guidelines and recommendations relevant for the management of acute MI and associated risk 
factors and comorbidities. Screening and randomisation can be performed on the same day.
The trial is event-driven and all randomised patients will remain in the trial until the total
number of patients with investigator reported primary endpoint events is projected to reach a 
target of 532. Estimated trial duration is approximately 26 months with a recruitment period 
of approximately 21 months. Consequently, individual treatment may range between 
approximately 5 and 26 months. The actual length of the recruitment may be extended 
beyond 21 months and the follow up may be adjusted to achieve the 532 primary endpoint 
events. The estimated total trial duration and length of the double-blind treatment period for 
each patient will vary accordingly. See also Section 3.3.
The number of primary endpoint events will be monitored continuously during the trial. As 
soon as the available data reliably suggests that the total number of patients with a 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 (EoS visit) within the proposed time schedule, “called Close-out period”, communicated 




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visit the study site. However, one in-person visit at 6 months serves as an opportunity for a 
longer interaction with the patient to address any trial related topics at length, comprehensive 
concomitant medication collection, and to provide additional supplies of trial medication. For 
the remote follow-up, all relevant trial information will be collected in a structured
questionnaire and/or interview. If requested by a trial participant or deemed necessary by the 
investigator at any time, an on-site trial visit can be conducted, either in place of or in 
addition to a pre-specified remote visit. Similarly, as in any clinical trial, study sites should be
ready to address any concerns, questions or event reporting from patients outside the pre-
specified follow-up time points.
All endpoints will be reviewed by the trained and blinded investigators, incorporating clinical 
judgment and objective pre-defined event criteria structured in the CRF. No central 
adjudication of the endpoints will be performed. A meta-analysis of 47 randomised controlled 
trials has demonstrated that treatment effect estimates were not different whether investigator 
reported or adjudicated events were used as a basis for the analysis, especially in trials where 
investigators were blinded [P20-00872]. Moreover, further support to use investigator reports 
instead of central adjudication comes from the SHIFT study, a chronic HF trial where there 
was approximately 85% confirmation of investigator-reported HHF events by central 
adjudication [R20-0249].
Patients should be receiving appropriate care as defined by their physician or practitioner for
all cardiovascular conditions according to the prevailing guidelines. For the acute MI, this 
may include, but is not limited to, myocardial revascularization, medication with anti-platelet 
agents, beta-blockers, RAAS-inhibitors and cholesterol lowering agents. Finally, adequate 
treatment, prevention and follow-up of relevant CV and non-CV comorbidities, including 
diabetes mellitus, must also be ensured.
For details regarding the choice of a placebo control refer to Section 1.4.2.
3.3
SELECTION OF TRIAL POPULATION
Approximately 5000 patients will be randomised into the trial. Approximately 450 sites are 
planned across multiple countries. Additional back-up countries and sites may be initiated, if 
deemed necessary.
The trial is event-driven and all randomised patients will remain in the trial until the total 
number of patients with investigator reported primary endpoint events will reach a target of 
532. If the accumulated blinded data suggests a slower accrual of primary outcome events 
over calendar time than projected (i.e. target 532 events needed with a planned number of 
5000 patients randomised), the number of patients randomised may be increased up to 6500, 
or trial duration may be prolonged.
Recruitment of T2D will be monitored on a regional level. Capping on a regional level may 
be applied to achieve a contribution of each region to the categories of patients with and 
without T2D.


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Further, monitoring will be conducted with respect to proportions of patients included in the 
following two subgroups: patients included based on LVEF 35-<45% without
signs/symptoms/treatment of congestion; and patients randomised post-discharge; with the 
aim of either group not corresponding to more than 1/3rd of total trial population. The final 
decision on capping will be based on the recommendation from the EC during the recruitment 
period.
Recruitment of patients for this trial is competitive, i.e. screening will stop at all sites at the 
same time once a sufficient number of patients has been screened to deliver the required 
number of randomised patients. Investigators will be notified about screening completion and 
will not be allowed to screen additional patients thereafter. The recruitment period may be 
extended for individual countries, if necessary, to achieve their reasonable contribution to the 
global trial population. For the same reason, recruitment may be ended in individual countries 
or regions.
Re-screening (if a patient is not eligible initially) is allowed once. In case of re-screening, the 
patient should first be declared a screening failure in the eCRF and the Interactive Response 
Technology (IRT) with the original patient number. Upon re-screening, the IRT system will 
allocate a new screening number for the patient.
If a patient is randomised in error (does not meet all inclusion criteria or meets one or more 
exclusion criteria on the day of randomisation), the sponsor/CRO should be contacted 
immediately.
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the Investigator Site File (ISF) irrespective of whether they have been treated 
with trial medication or not.
3.3.1
Main diagnosis for trial entry
In order to qualify for trial entry, patients must be hospitalised with a spontaneous acute MI
(AMI) defined as MI with a primary etiology of an acute coronary artery disease pathology 
(e.g., plaque rupture/erosion, in-stent restenosis, stent thrombosis) rather than MIs caused by 
supply-demand mismatch (e.g., sepsis, arrhythmia, anemia, or other condition). Patients with 
an in-hospital spontaneous AMI are also eligible. In addition, patients should further be 
selected based on an elevated risk of HHF and mortality defined as signs/symptoms/treatment
of congestion, and/or a left ventricular ejection fraction <45% and one additional enrichment 
criterion will be requested (see Section 3.3.2). Patients must be randomised no later than 14 
calendar days after hospital admission. Early randomisation, prior to discharge, is strongly 
encouraged. Please refer to Section 8.3.1 (Source Documents) for the documentation 
requirements pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
1. Of full age of consent (according to local legislation, at least ≥18 years) at screening.
2.
Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial.


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3. Male or female patients. Women of childbearing potential (WOCBP)1 must be ready 
and able to use highly effective methods of birth control per ICH M3 (R2) that result
in a low failure rate of less than 1% per year when used consistently and correctly. A 
list of contraception methods meeting these criteria is provided in the patient 
information and in Section 4.3.2.3.
4. Diagnosis of spontaneous AMI: STEMI or NSTEMI with randomisation to occur no 
later than 14 calendar days after hospital admission. For patients with an in-hospital 
MI as qualifying event, randomization must still occur within 14 days of hospital 
admission.
Spontaneous AMI is defined as MI with a primary etiology of an acute coronary 
artery disease pathology (e.g., plaque rupture/erosion, in-stent restenosis, stent 
thrombosis) rather than MI caused by supply-demand mismatch (e.g., sepsis, 
arrhythmia, anemia, or other condition).
Spontaneous AMI is established when there is evidence of myocardial necrosis in a 
clinical setting consistent with myocardial ischemia due to primary coronary event. 
Under these conditions, the following criteria have to be met for the diagnosis of 
spontaneous AMI:
Detection of rise and/or fall of cardiac enzymes (cardiac troponin, cTn or the MB
fraction of creatinine kinase, CKMB) with at least one value above the 99th
percentile of the upper reference limit (URL) or the local laboratory MI diagnosis
cut-off value, together with evidence of myocardial ischemia with at least one of
the following:
∀
Ischemic discomfort or other ischemia symptom(s)
∀
Electrocardiogram (ECG) characteristics of STEMI or NSTEMI including new or 
presumably new significant ST-segment-T wave (ST-T) changes
∀
Newly developed pathological Q waves or left bundle branch block (LBBB) in the 
ECG
∀
Imaging evidence of new loss of viable myocardium or new regional wall motion 
abnormality in a pattern consistent with an ischemic etiologyIdentification of a 
coronary thrombus by angiography
5. High risk of HF, defined as EITHER
a) Symptoms (e.g. dyspnea; decreased exercise tolerance; fatigue), or signs of 
congestion (e.g. pulmonary rales, crackles or crepitations; elevated jugular venous 
pressure; congestion on chest X-ray), that require treatment (e.g. augmentation or 
                                                
1 A woman is considered of childbearing potential, i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile.
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. 
Tubal ligation is NOT a method of permanent sterilisation. A woman who underwent tubal ligation is still 
considered as WOCBP. However tubal ligation is considered as a method of highly effective birth control.
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.


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initiation of oral diuretic therapy; i.v. diuretic therapy; i.v. vasoactive agent; 
mechanical intervention etc.) at any time during the hospitalization.
OR
b) Newly developed LVEF < 45% as measured by echocardiography, 
ventriculography, cardiac CT, MRI or radionuclide imaging during index 
hospitalisation.
6. In addition at least one of the following risk factors:
-
Age > 65 years,
-
Newly developed LVEF < 35%,
-
Prior MI (before index MI) documented in medical records,
-
eGFR < 60 ml/min/1.73m2 (using CKD-EPI formula based on creatinine from 
local lab at any time during index hospitalisation),
-
Atrial fibrillation (persistent or permanent ; if paroxysmal, only valid if associated 
with index MI),
-
Type 2 diabetes mellitus (prior or new diagnosis),
-
NT-proBNP >1,400 pg/mL for patients in sinus rhythm, >2,800 pg/mL if atrial 
fibrillation; BNP >350 pg/mL for patients in sinus rhythm, >700 pg/mL if atrial 
fibrillation, measured at any time during hospitalisation,
-
Uric acid >7.5 mg/dL (>446 μmol/L), measured at any time during hospitalisation,
-
Pulmonary Artery Systolic Pressure [or right ventricular systolic pressure] >40 
mmHg (non-invasive [usually obtained from clinically indicated post-MI 
echocardiography] or invasive, at any time during hospitalisation),
-
Patient not revascularized (and no planned revascularization) for the index MI
(Includes e.g. patients where no angiography is performed, unsuccessful 
revascularization attempts, diffuse atherosclerosis not amenable for intervention; 
but does NOT include if revascularization was not performed due to 
nonobstructive coronary arteries),
-
3-vessel coronary artery disease at time of index MI,
-
Diagnosis of peripheral artery disease (extracoronary vascular disease, e.g.  lower 
extremity artery disease or carotid artery disease).
3.3.3
Exclusion criteria
1. Diagnosis of chronic HF prior to index MI.
2. Systolic blood pressure < 90 mmHg at randomisation.
3. Cardiogenic shock or use of i.v. inotropes in last 24 hours before randomisation.
4. Coronary Artery Bypass Grafting planned at time of randomisation.
5. Current diagnosis of Takotsubo cardiomyopathy.
6. Any current severe (stenotic or regurgitant) valvular heart disease.
7. eGFR < 20 ml/min/1.73m2 (using CKD-EPI formula based on most recent creatinine 
from local lab during index hospitalisation) or on dialysis.
8. Type I diabetes mellitus.
9. History of ketoacidosis.


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10. Current use or planned treatment with an SGLT-2 inhibitor or combined SGLT-1 and 
2 inhibitor. Discontinuation of a SGLT-2 inhibitor or combined SGLT-1 and 2 
inhibitor for the purposes of enrolment in the trial is not permitted.
11. Contraindication for using empagliflozin or any other SGLT-2 inhibitor.
12. Any physical or mental condition significantly affecting the patient’s ability to 
participate in the Investigator’s opinion.
13. Any other clinical condition that would jeopardise patient’s safety while participating 
in this study, or may prevent the patient from adhering to the trial protocol in the 
Investigator’s opinion.
14. Presence of any other disease than the acute MI or its immediate complications with a 
life expectancy of <1 year in the opinion of the investigator.
15. Current or previous randomisation in one of the empagliflozin heart failure trials (i.e. 
trials 1245.110, 1245.121, 1245-0167, 1245-0168, 1245-0204) or currently enrolled in 
another investigational device or drug trial, or less than 30 days since ending another 
investigational device or drug trial, or receiving other investigational treatment(s). 
Patients participating in purely observational trial will not be excluded.
16. Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
3.3.4
Withdrawal of patients from treatment or assessments
Patients may discontinue trial treatment or withdraw consent to trial participation as a whole
(“withdrawal of consent”) with very different implications; please see Sections 3.3.4.1 and 
3.3.4.2 below.
This is a long-term outcome trial and an excessive withdrawal rate can have a severe negative 
impact on the scientific value of the trial. The Intention To Treat (ITT) analysis requires that 
all randomised patients be followed until trial end even if the trial medication was
temporarily interrupted, discontinued or never started. Therefore, every effort should be made 
to keep the patients in the trial: if possible on treatment, or at least to collect important trial
data. Patients are encouraged to notify the site in cases of treatment discontinuation even 
outside regular follow-up time points, in order for a timely discussion and decision on 
whether treatment should be reinstated, re-evaluated or permanently stopped. Requests from 
patients for on-site visits should also be accommodated.
If a patient is withdrawn from the trial the sponsor/CRO should be informed immediately 
about each individual case.
Measures to control the withdrawal rate include careful patient selection, appropriate 
explanation of the trial requirements and procedures prior to trial enrolment, as well as the
explanation of the options for follow-up of patients in case of withdrawal.
The decision to discontinue trial treatment or withdraw consent to trial participation and the 
reason must be documented in the patient files and eCRF. If applicable, consider the 
requirements for Adverse Event collection reporting (please see Sections 5.2.1.2.1 and 
5.2.1.2).


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3.3.4.1
Discontinuation of trial treatment
A patient should discontinue trial treatment if:
∀
If it is the patient’s wish, without need for justification.
∀
The patient has repeatedly demonstrated non-compliance with important trial procedures 
and, in the opinion of both the investigator and sponsor representative, is not willing or 
able to adhere to the trial requirements in the future.
∀
The patient needs to take a concomitant medication that interferes with the investigational 
medicinal product. Please see Section 4.3.2.
∀
The patient can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events, other diseases, or pregnancy).
In all cases where a patient has discontinued trial medication, the possibility to restart therapy 
should be considered if medically justified. With the exception of short and temporary 
interruptions, patients are encouraged to contact site whenever and as soon as they 
discontinue trial medication so that a timely assessment of the potential to restart therapy can 
be performed by the investigator or designee. If the patients do not notify the site, the 
assessment must be performed in conjunction with the regular follow-up visits. For further 
information, please see Section 4.1.4.
If the patient nonetheless discontinues trial treatment prematurely, every effort should be 
made for the patient to take part in the regularly scheduled trial visits and have all trial
procedures performed except those pertaining to drug intake. It is also expected that every 
effort should be made to follow-up on the collection of all SAEs, AESIs and endpoint events 
to have a complete dataset without missing data. If a patient is not willing to return for the 
on-site visit after 6 months (visit 4), then this visit should be conducted by phone.
Patients that are not actively taking trial medication may be less motivated to adhere to the
scheduled trial visits. In potential cases where a patient is no longer willing to complete all 
follow-up measures, the following sequence of options should be considered and discussed if 
allowed by local regulations:
Option 1
Conduct all remaining trial visits remotely using phone (direct contact) + 
medical records review
Option 2
Conduct yearly trial visits and EoS Visit remotely using phone (direct contact) 
+ medical records review
Option 3
Conduct all remaining trial visits remotely using web-based application (only) 
and EoS Visit using phone (direct contact) + medical records review
Option 4
Conduct the EoS Visit only using phone (direct contact) + medical records 
review
Option 5
No direct contact with the patient, indirect collection of information only, e.g. 
medical records review
Vital status should be collected at the EoS during the Close-out period for all patients if 
allowed by local regulations.
Patients will be asked to choose the most rigorous form of follow-up that they are willing to.


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If a patient becomes pregnant during the trial, the trial medication will be stopped, the patient
will be followed up during the trial and until birth or termination of the pregnancy (see
further details in Section 5.2.1.2).
If new efficacy/safety information becomes available, Boehringer Ingelheim will review the
benefit-risk-assessment and, if needed, pause or discontinue the trial treatment for all patients 
or take any other appropriate action to guarantee the safety of the trial patients.
3.3.4.2
Withdrawal of consent to trial participation
Patients may withdraw their consent to trial participation at any time without the need to 
justify the decision. This is a long-term outcome trial and an excessive withdrawal rate can 
have a severe negative impact on the scientific value of the trial.
If a patient wants to withdraw consent, the investigator should be involved in the discussion 
with the patient and explain the difference between trial treatment discontinuation and 
withdrawal of consent to trial participation, as well as explain the options for continued 
follow-up after trial treatment discontinuation, please see Section 3.3.4.1 above. In the event 
of patient withdrawal from trial participation, all assessments should occur at the patient’s 
EoS visit with completion of the eCRF.
Vital status should be collected during the Close-out period for patients that withdraw 
consent from trial participation, if allowed by local regulations.
3.3.4.3
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 patient.
∀
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.
∀
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.


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3.3.4.4
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site.
2. New efficacy or safety information invalidating the earlier positive benefit-risk-
assessment, please see Section 3.3.4.1.
3. Deviations from GCP, the trial protocol, or the contract impairing the appropriate conduct 
of the trial.
Further follow up of patients affected will occur as described in Section 3.3.4.1.
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
The trial medication will be provided by Boehringer Ingelheim Pharma GmbH & Co.KG.
4.1.1
Identity of the Investigational Medicinal Products
Table 4.1.1: 1 Test product 1
Substance:
Empagliflozin
Pharmaceutical formulation:
Film-coated tablet
Source:
Boehringer Ingelheim GmbH & Co. KG
Unit strength:
10 mg
Posology:
1 tablet once daily
Method and route of administration:
Oral
Table 4.1.1: 2 Test product 2
Substance:
Placebo matching empagliflozin 10 mg
Pharmaceutical formulation:
Film-coated tablet
Source:
Boehringer Ingelheim GmbH & Co. KG
Unit strength:
Not applicable
Posology:
1 tablet once daily
Method and route of administration:
Oral


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4.1.2
Selection of doses in the trial and dose modifications
Empagliflozin 10 mg and 25 mg are approved for the treatment of T2D.
In the EMPA-REG-OUTCOME trial both doses were administered to patients with T2D and 
showed to be equally effective in reducing CV mortality, all-cause mortality, and HHF.
In a subgroup analysis, empagliflozin improved the outcome of CV mortality and HHF with a 
similar magnitude in patients with low or high levels of HbA1c at baseline and irrespective of 
the dose of empagliflozin [P18-10152]. This indicates the risk reduction for this outcome is 
independent of the degree of glycaemic control at baseline, suggesting that these benefits can 
be achieved with the 10 mg dose similar to the 25 mg dose in the non-diabetic population. 
The mechanism of action is supported by studies in healthy volunteers where both doses were 
associated with a glucosuria of about 50g per day.
Given the lower exposure with empagliflozin 10 mg and similar general safety, and similar 
observed CV, HHF and mortality effects for both doses, empagliflozin 10 mg once daily has 
been selected as the dose in this trial.
For further details see current version of the IB [c01678844].
4.1.3
Method of assigning patients to treatment groups
After the assessment of all inclusion and exclusion criteria, each eligible patient will be 
randomised to receive empagliflozin 10 mg or matching placebo according to a 
randomisation plan in a 1:1 ratio.  The assignment will occur in a blinded fashion at visit 2a
via IRT stratified by established T2D (yes, no) and region (North America, Latin America, 
Europe, Asia). Note that the medication number is different from the patient number (the 
latter is generated during screening via the IRT System).
To facilitate the use of the IRT, the Investigator or delegate will receive a manual including
all necessary instructions for using the system. A copy of the manual will be available in the
ISF.
Patient assignment to a treatment group will be determined by a computer generated random
sequence. Access to the randomisation code will be controlled and documented - for further
details please refer to Section 4.1.5.1 and 4.1.5.2. For information on capping, please refer to 
Section 3.3.
Using this procedure, relevant parties will be blinded to the treatment group assignment.
4.1.4
Drug assignment and administration of doses for each patient
Patients who qualify will be randomised to treatment groups as described in Section 4.1.3. 
Trial medication will be dispensed by the investigator in a double-blind manner. 
IRT will be used to allocate trial medication to patients. At Visit 2a patients will be assigned
one medication kit for a 6 months treatment period and 6 weeks of reserve. At Visit 4 patients
will be assigned medication kits for a 6, 12 or 18 months treatment period, depending on 


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when the randomisation took place – see Table 4.1.4: 1. Each medication kit contains 6
weeks of reserve.
During the COVID-19 pandemic, there might be situations that would not allow a patient to 
come to the site for Visit 4. If the investigator judges it as favourable and safe to continue 
trial medication, trial medication might be shipped from the site to the patient (for more 
details see Section 6.2.2).
Additional medication kits can be assigned to patients, e.g. in the event of treatment 
prolongation. The trial medication may then be shipped by courier from site to patient, if 
legally acceptable according to local regulations.
Treatment starts on the day of Visit 2a and ends on the EoS visit (or in the event of premature 
discontinuation, the time when the permanent withdrawal takes place). For further details 
regarding packaging please refer to Section 4.1.6. For return of trial medication please refer 
to Section 6.2.3.
From the start of the treatment period patients will be instructed to take the trial medication
once daily with a glass of water. Empagliflozin can be taken with or without food.
To ensure a dose interval of about 24 hours, the medication should be taken in the morning at
approximately the same time every day including the days of study visits. If a dose is missed
by more than 12 hours, that dose should be skipped and the next dose should be taken as
scheduled. No double doses should be taken.
In case trial medication was discontinued for a temporary reason or by the patient without a
medical indication, trial treatment can be resumed at any time until EoS. Trial medication 
should be restarted if and as soon as medically justified (see also Section 3.3.4.1
and 4.3.1).
Table 4.1.4: 1
Dispense of medication kits – visualising amount and timing of 
dispense depending on the randomisation of the patient
Trial duration months
1 - 3
4 - 6
7 – 9
10 - 12
13 - 15
16 – 18
19 - 21
22 - 26
Patients examples
Randomisation period
Follow-up 
period*
Randomised month 1
X
-
-
-
3X
-
-
-
-
-
-
-
-
-
-
-
Randomised month 3
X
-
-
-
3X
-
-
-
-
-
-
-
-
-
-
Randomised month 7
X
-
-
-
2X
-
-
-
-
-
-
-
Randomised month 10
X
-
-
-
2X
-
-
-
-
-
Randomised month 13
X
-
-
-
X
-
-
-
Randomised month 16
X
-
-
-
X
-
(*) If the trial is prolonged (beyond 26 months) additional medication kits can be assigned
X = Medication kit(s) dispensed


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4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
Patients, investigators, and everyone involved in trial conduct or analysis or with any other
interest in this double-blind trial will remain blinded with regard to the randomised treatment 
assignments until after database lock.
The access to the randomisation code will be kept restricted until its release for analysis.
The DMC will be provided with unblinded data in order to allow them to review efficacy and
safety and to fulfil their tasks as outlined in the DMC charter. An independent team, not 
otherwise involved in the conduct of the trial, will provide the unblinded results to the DMC.
4.1.5.2
Unblinding and breaking the code
Emergency unblinding will be available to the investigator via IRT. Emergency unblinding 
should be rare and it must only be used in an emergency situation when the identity of the 
trial drug must be known to the investigator in order to provide appropriate medical treatment 
or otherwise assure safety of trial participants. The reason for unblinding must be 
documented in the source documents and/or appropriate CRF page.
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 for processing in the 
Pharmacovigilance database system and not be shared further.
The patient could continue trial medication after unblinding.
4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI or a designated CRO. They 
will be packaged and labelled in accordance with the principles of Good Manufacturing 
Practice (GMP). Re-supply to the sites will be managed via an IRT system, which will also 
monitor expiry dates of supplies available at the sites.
For details of packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A
temperature log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the Clinical Research 
Associate (CRA) (as provided in the list of contacts) must be contacted immediately.


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4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered by the sponsor
when the following requirements are fulfilled:
∀
Approval of the clinical trial protocol by the Institutional Review Board (IRB) / 
Independent Ethics Committee (IEC),
∀
Availability of a signed and dated clinical trial contract between the sponsor/CRO and the 
investigational site,
∀
Approval/notification of the regulatory authority, e.g. competent authority,
∀
Availability of the curriculum vitae of the Principal Investigator,
∀
Availability of a signed and dated clinical trial protocol,
∀
Availability of the proof of a medical license for the Principal Investigator,
∀
For USA: Availability of FDA Form 1572.
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics.
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each patient, and the return to the sponsor/CRO or
warehouse / drug distribution centre or alternative disposal of unused products.
If applicable, the sponsor or warehouse / drug distribution centre will maintain records of the 
disposal.
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates,
and the unique code numbers assigned to the investigational medicinal product and trial
patients. The investigator or designee will maintain records that document adequately that the
patients were provided the doses specified by the Clinical Trial Protocol (CTP) and reconcile
all investigational medicinal products received from the sponsor. At the time of return to the
sponsor or appointed CRO, the investigator or designee must verify that all unused or
partially used drug supplies have been returned by the clinical trial patient and that no
remaining supplies are in the investigator’s possession.
4.2
TREATMENT COMPLIANCE
The patients are requested to bring all remaining trial medication including empty package 
material with them when attending any on-site visits. The site personnel will register the 
medication kits (a pill count will not be performed).
At every trial visit (on-site and remote) patients will be asked if they have complied to the 
trial treatment regimen.
If the patients indicate non-adherence to the trial medication the investigator or designee will 
carefully interview the patient, assess and address reasons for non-adherence, and repeat 
information about importance of treatment compliance and the purpose/conduct of the trial.
Randomised patients will not be discontinued for poor compliance without prior discussion
between the investigator and the monitor.


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4.3
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.3.1
Other treatments and emergency procedures
The use of medication for the treatment of MI and HF will be at the discretion of the 
Investigator and/or other treating physician, and should be in accordance with local, national 
and international guidelines.
All concomitant (additional) medications and other therapies should be recorded on the
appropriate pages of the electronic Case Report Form (CRF).
Sequence and timing of initiation of concomitant therapies in relation to trial medication is 
left at the discretion of the investigator. However, initiation of RAAS inhibitor(s) and trial 
medication within 24 hours of each other is not recommended. For further details see the ISF.
During potential episodes of fluid loss, for instance due to gastrointestinal illness, careful 
monitoring of volume status, concomitant blood pressure therapies and electrolytes is 
recommended and temporary interruption of the trial medication should be considered until 
the fluid loss is corrected.
Concomitant antidiabetic medications should be adjusted individually as clinically indicated
by the patient’s usual diabetes care provider. Additional guidance is provided in the IB.
Restrictions of antidiabetic background therapy are described in Section 4.3.2.
Hypoglycaemia
Patients with and without T2D experiencing repeated or severe symptoms such as
nervousness, sweating, intense hunger, trembling, weakness and palpitations should contact
the investigator or another healthcare professional, as these symptoms might be suggestive of
hypoglycaemia. In the case of hypoglycaemia, 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.
Ketoacidosis
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


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suspected, the trial medication should be discontinued, the patient should be evaluated, and
prompt treatment should be initiated.
Patients who may be at higher risk of ketoacidosis while taking empagliflozin include
patients on a very low carbohydrate diet (as the combination may further increase ketone
body production), patients with an acute illness, pancreatic disorders suggesting insulin
deficiency (e.g. history of pancreatitis or pancreatic surgery), insulin dose reduction 
(including insulin pump failure), alcohol abuse, severe dehydration, and patients with a 
history of ketoacidosis. Empagliflozin should be used with caution in these patients. In 
patients requiring insulin, caution should be taken when the dose of insulin is reduced.
In clinical situations known to predispose to ketoacidosis (e.g. prolonged fasting due to acute
illness or surgery), the investigator should consider monitoring for ketoacidosis and
temporarily discontinue the trial medication.
There are no trial specific emergency procedures to be followed.
4.3.2
Restrictions
4.3.2.1
Restrictions regarding concomitant treatment
The use of any SGLT-2 inhibitors or combined SGLT-1 and 2 inhibitors during the trial, is 
prohibited as long as the patient is taking trial medication and up to 7 days after last trial 
medication intake.
If the patient is in need of an SGLT-2 inhibitor or combined SGLT-1 and 2 inhibitors during 
the trial, this may be given at the discretion of the investigator, and can be initiated at 
minimum 7 days after trial medication discontinuation. The patient will still remain in the
trial.
4.3.2.2
Restrictions on diet and life style
None. For diet and risk of ketoacidosis refer to Section 4.3.1.
4.3.2.3
Contraception requirements
WOCBP participating in the trial must use a highly effective method of birth control per ICH 
M3 (R2) that results in a low failure rate of less than 1% per year when used consistently and 
correctly if their sexual partner is a man able to father a child. Acceptable methods meeting 
these criteria is provided below and in the patient information.
∀
Combined (estrogen and progestogen containing) hormonal birth control that prevents
ovulation (oral, intravaginal, transdermal)
∀
Progestogen-only hormonal birth control that prevents ovulation (oral, injectable,
implantable)
∀
Intrauterine device or intrauterine hormone-releasing system
∀
Bilateral tubal occlusion
∀
Vasectomised partner
∀
True sexual abstinence


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
The investigator is responsible for reviewing the endpoints. Investigators are blinded to trial
treatment and will receive dedicated training on event review prior to trial initiation. 
Investigators assigned to the trial after initiation will also undergo event review training for 
subsequent qualification. Hospitalisation for HF will be reviewed by the investigators based 
on clinical judgement and objective criteria assessed in relevant source documents and 
documented in a structured eCRF.
For the all-cause mortality component of the primary endpoint, only the date of death will be 
required. Investigators will further be requested to categorize deaths as CV or non-CV 
mortality based on best available information, clinical judgment and guidance in the eCRF. 
Investigators will also be requested to categorize hospitalisations into elective and non-
elective hospitalisations. MI events will be collected in the eCRF as reported by the 
investigator.
Detailed information with event criteria and instructions how to report the endpoint events is 
available in the event review charter (access through the eDC and in the ISF).
5.2
ASSESSMENT OF SAFETY
5.2.1
Assessment of adverse events
5.2.1.1
Definitions of AEs
5.2.1.1.1
Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following should also be considered as an AE:
∀Worsening of the underlying disease or of other pre-existing conditions
∀Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the investigator.
If such abnormalities already exist prior to randomisation, they will be considered as baseline 
conditions and should be collected in the CRF.


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5.2.1.1.2
Serious adverse event
A serious adverse event (SAE) is defined as any AE, which fulfils at least one of the 
following criteria:
-
results in death,
-
is life-threatening, which refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe,
-
requires inpatient hospitalisation or prolongation of existing hospitalisation
-
results in persistent or significant disability or incapacity,
-
is a congenital anomaly / birth defect,
-
is deemed serious for any other reason if it is an important medical event when based 
on appropriate medical judgement which may jeopardise the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions. Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalisation or development of dependency or abuse.
5.2.1.1.3
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as 
defined above.
The latest list of “Always Serious AEs” can be found in the eDC system. A copy of the latest 
list of “Always Serious AEs” will be provided upon request. These events should always be 
reported as SAEs as described in Section 5.2.1.2.
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the drug and must be reported as 
described in Section 5.2.1.2.
5.2.1.1.4
Adverse events of special interest
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor/CRO within the 
same timeframe that applies to SAEs, please see Section 5.2.1.2.1.
The following are considered as AESIs:
Contrast induced acute kidney injury (AKI)
Contrast induced AKI in this trial is defined as a creatinine increase of >44 μmol/L (0.5 
mg/dl) or >25% increase within 72 hours of contrast administration, in the absence of 
alternative more likely explanations. In the report the investigator will be asked to provide 
supporting information (creatinine values and time points in relation to contrast 


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administration) as available. It is important to note that lab values alone do not automatically 
fulfil the definition above and that clinical judgment should be applied.
Ketoacidosis
If metabolic acidosis, ketoacidosis and DKA is suspected further investigations should be
done according to the medical judgment and the clinical course until a diagnosis is made
and/or the patient is recovered.
Due to its mechanism of action, empagliflozin may potentially modify the clinical
presentation of ketoacidosis which may occur at lower plasma glucose levels in patients with
DM and potentially also in non-diabetic patient population. The diagnosis of ketoacidosis in
these patients can be based on arterial pH ≤7.30, serum bicarbonate levels <15 mmol/L and
measurement of serum beta-hydroxybutrate levels. Other diagnostic criteria which can
support the diagnosis of ketoacidosis are urine ketones and anion gap >10 mmol/L.
Investigators should note that not all criteria mentioned above need to apply for the diagnosis
of ketoacidosis, and clinical judgment should also be taken into consideration.
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, including the presence or 
development of lower extremity peripheral artery disease.
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters:
∀
an elevation of AST (Aspartate Aminotransferase) and/or ALT (Alanine 
Aminotransferase) ≥3 fold ULN combined with an elevation of total bilirubin ≥2 fold 
ULN measured in the same blood draw sample, or in samples drawn within 30 days of 
each other, or,
∀
aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN.


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No central laboratory assessments are planned in this trial for liver enzymes or serum 
bilirubin.
Based on local laboratory data, if any of the above abnormalities are reported during the 
course of the trial this constitute a hepatic injury alert. The patients showing these local 
laboratory 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 available 
laboratory results (ALT, AST, total bilirubin), the investigator should make sure these 
parameters are analysed, by performing appropriate local laboratory blood tests. Should the 
results meet the criteria of hepatic injury alert, the procedures described in the DILI checklist 
should be followed.
5.2.1.1.5
Causal relationship of AEs
Medical judgement should be used to determine whether there is a reasonable possibility of a 
causal relationship between the adverse event and the given trial medication, considering all 
relevant factors, including pattern of reaction, temporal relationship, de-challenge or re-
challenge, confounding factors such as concomitant medication, concomitant diseases and 
relevant history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship
could be:
∀
The event is consistent with the known pharmacology of the drug.
∀
The event is known to be caused by or attributed to the drug class.
∀
A plausible time to onset of the event relative to the time of drug exposure.
∀
Evidence that the event is reproducible when the drug is re-introduced.
∀
No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).
∀
The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).
∀
An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced).
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.


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∀
Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).
∀
Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.
5.2.1.2
Adverse event collection and reporting
The investigator shall maintain and keep detailed records of all AEs specified below in the 
patient files.
The following must be collected and documented on the appropriate eCRF(s) by the
investigator:
•
From randomisation onwards until the individual patient’s end of trial (EoS) 
participation:
-all AESIs (serious and non-serious)
-SAEs
-AEs leading to discontinuation of trial medication for at least 7 consecutive days 
(serious and non-serious)
The EoS visit coincides with individual patient’s last day of trial medication administration 
with the exception of patients with early treatment discontinuation.
•
After the individual patient’s EoS:
-the investigator does not need to actively monitor the patient for new AEs but must
report all SAEs and AESIs up to EoS + 7 days.
After this  EoS + 7 days period the investigator then should only report any 
occurrence of cancer and trial treatment related SAEs and trial treatment related 
AESIs of which the investigator may become aware of by any means of
communication, e.g. phone call.
All AEs should be reported into the eCRF as long as the site has access to the EDC system.
After that, the reporting  pursues on the BI paper SAE form (see Section 5.2.1.2.1).
The rules for Adverse Event Reporting exemptions still apply, please see Section 5.2.1.2.3.
Vital Status Data Collection
Patients who discontinue trial medication prematurely, who agree to be contacted further but 
do not agree to physical visits, should be followed up as described in Section 3.3.4.1, 
withdrawal from trial treatment.
5.2.1.2.1
AE reporting to the sponsor/CRO and timelines
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
SAE or AESI in the AE- and SAE eCRF pages immediately (within 24 hours). The same 
timeline applies if follow-up information becomes available. In specific occasions, the 


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investigator could inform the sponsor/CRO upfront via telephone. This does not replace the 
requirement to complete the SAE eCRF page.
With receipt of any further information to these events, the SAE eCRF page has to be 
updated. For follow-up information the same rules and timeline apply as for initial 
information. All (S)AEs, including those persisting after individual patient’s end of trial must 
be followed up until they have resolved, have been assessed as “chronic” or “stable” , or no 
further information can be obtained.
In exceptional cases when the eDC is unavailable for longer than 24 hours, the following 
applies:
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
existing SAE or AESI, on the BI paper 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).
Once the eDC is available again, information from the BI SAE form should be entered in the
applicable eCRF pages.
5.2.1.2.2
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in the 
clinical trial and has taken trial medication, the investigator must report any drug exposure 
during pregnancy in a trial participant immediately (within 24 hours) by means of Part A of 
the Pregnancy Monitoring Form to the sponsor’s/CRO’s unique entry point.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s/CRO’s unique entry point on the Pregnancy 
Monitoring Form for Clinical Studies (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Studies (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Studies is to be completed. If 
there is an SAE and/or AESI associated with the pregnancy the SAE page must be completed 
in addition.
5.2.1.2.3
Exemptions to SAE reporting
Protocol specified exempted events listed below should be collected immediately on the 
appropriate eCRF page only.
Primary and secondary end point components to be exempted irrespective of their causality 
assessment by the investigator, to protect the integrity of the trial:
∀
Hospitalisation for heart failure
∀
Myocardial infarction
∀
Other CV events
∀
CV mortality


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In addition, the following SAEs that are occurring at some frequency independent of drug 
exposure in the trial population are exempted from expedited reporting, and should be 
collected on the appropriate eCRF page(s) only. 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.
∀
Post procedural haemorrhage
∀
Gastrointestinal haemorrhage
∀
Haematuria
∀
Non-cardiac chest pain
∀
Respiratory tract infection including Respiratory tract infection bacterial, Respiratory 
tract infection fungal and Respiratory tract infection viral, excluding COVID-19 
infection
∀
Pneumonia, excluding COVID-19 pneumonia
∀
Syncope
All the above stated events should be considered exempted only if the event does not qualify 
as AESI.
Regardless of relationship to trial medication, these events will not be reported by the
sponsor/CRO to regulatory agencies or IECs in an expedited manner unless they qualify as an
AESI (for definition of AESI, see Section 5.2.1.1.4) with fulfilment of expedited regulatory 
safety reporting requirements.
Although the primary endpoint of the trial includes non-CV mortality (all-cause mortality), 
the sponsor/CRO is of the opinion that certain non-CV fatal cases may potentially constitute 
new safety information about empagliflozin (e.g., fatal hepatic AE, fatal serious cutaneous 
AE).
Therefore, non-CV SAEs, including cases of non-CV mortality, will be required to be 
immediately reported by the investigator to the sponsor/CRO. For further information on 
reporting and timelines see Section 5.2.1.2.1.
An independent DMC will monitor the safety data in the trial on an ongoing basis. Reported 
SAEs that are protocol exempted events will be collected in the CRFs and evaluated by the 
DMC. These events will not be collected on the SAE CRF 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 direct and appropriate
action to provide care for the patient and to decide whether or not the trial medication should
be discontinued.


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5.3
OTHER ASSESSMENTS
Physical examination including vital signs
A physical examination, including at minimum an evaluation of the cardiovascular and 
pulmonary system and assessment of vital signs (blood pressure and pulse rate), will be 
performed at Visit 2a/randomisation. If available in the local medical records, the most recent 
height and weight information from the index hospitalisation can be used, or should 
otherwise be measured.
Local laboratory tests
The most recent serum creatinine before randomisation must be collected from local 
laboratory at baseline to derive eGFR based on the using the CKD-EPI equation (see below).
CKD-EPI equation
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.
The CKD-EPI equation considers the race as an adjustment factor, therefore the race must be 
known for accurate estimation.
The following laboratory tests from the index hospitalisation before randomisation should be 
entered in the eCRF if available:
∀
NT-proBNP (highest value)
∀
BNP (highest value)
∀
Uric acid (highest value)
∀
Haemoglobin (most recent value)
∀
Potassium (most recent value)
∀
HbA1c (most recent value)
∀
LDL cholesterol (most recent value)
5.4
APPROPRIATENESS OF MEASUREMENTS
The measures conducted at baseline reflect the current clinical practice across the different 
countries.
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 primary and secondary endpoints are accepted for evaluation of efficacy and safety of an 
oral drug administered to patients with MI and/or HF, and they are widely used in respective 
pivotal phase III MI and HF trials.
Therefore, the appropriateness of all measurements applied in this trial is given.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
All patients are to adhere to the visit schedule as specified in the Flow chart. If any visit has 
to be rescheduled, subsequent visits should follow the original visit date schedule.
The remote visits will be conducted by means of mobile/web-based application, telephone or 
telemedicine (Telehealth). The site personnel will discuss the different options with the 
patient during the screening to ensure the patients’ preferences are met. Patients are allowed 
to switch between the different remote contact options.
Patients using the mobile/web-based application to complete the questionnaire will receive 
push-notifications to remind of their upcoming visits. If the questionnaire has not been 
completed within the defined visit window site/call center personnel will be alerted and 
proceed to call the patient.
In cases where the patients using mobile/web-based application have indicated potential 
occurrence of an endpoint event, safety related or medication adherence issue, the site 
personnel will contact the patient via telephone for additional information.
In conjunction with all visits, remote or on-site, site personnel will additionally screen local 
medical records for endpoint events, SAEs and AESIs.
Should the patient during the structured interview or via the mobile/web-based application 
indicate that a safety related issue has occurred, site personnel will collect relevant 
information, e.g. from medical records needed for reporting the event/endpoint.
The investigator is responsible for reviewing the endpoints. For further information see
Section 5.1 and the event review charter.
The site personnel will refer to the investigator if the patient seeks medical advice or requires
medical attention.
If requested by the patient or deemed necessary by the investigator at any time, an on-site
trial visit can be conducted, either in place of or in addition to a pre-specified remote visit. 
Similarly, as in any clinical trial, trial sites should be ready to address any concerns, questions
or event reporting from patients outside the pre-specified follow-up time points.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
Please refer to the Flow Chart and Section 5 for details of the procedures performed at each
visit.
6.2.1
Screening period
No trial procedures should be performed unless the patient has consented to taking part in the 
trial.


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Following informed consent, the patient will undergo Visit 1/screening assessments as
indicated in the Flow chart. The assessments must all fall within the acceptable screening
visit window but do not need to be performed on the same day. The patient should be
registered in IRT as a screened patient.
The investigations for the main diagnosis for inclusion are to be completed and documented
per standard of care as a prerequisite to consideration for trial participation. Patients will be
included in the trial based on patient interview and available information in the medical 
records.
Relevant medical history/baseline conditions will be documented using pre-specified 
categories as given in the eCRF.
If the patient meets the entry criteria, Visit 2a/randomisation must occur within 14 days of 
hospital admission and investigators should strive for randomisation prior to hospital 
discharge. If the patient does not meet the entry criteria following Visit 1/screening
procedures, the patient should be registered as a screen failure in IRT.
A physical examination, including collection of vital signs will be performed at Visit 
2a/randomisation. Selected local laboratory tests will be collected if available as indicated in 
Section 5.3.
6.2.2
Treatment period(s)
Randomisation can occur at the same day as the screening visit.
After a final check of all in- and exclusion criteria, eligible patients will be randomised at
Visit 2a using IRT. All Visit 2a assessments must be performed before the first dose is taken 
in hospital.
For patients that are still hospitalised after Visit 2a assessment of safety, endpoints and 
updates of concomitant medication will take place at Visit 2b/ day of hospital discharge.
WOCBP will receive a pregnancy test to bring back home in order to perform the test at the 
EoS Visit.
Visit 3, to be performed 14 days after randomisation, will be conducted remotely by means of 
telephone or via mobile/web-based application. Thereafter, visits every 6 months after 
randomisation will be scheduled as specified in the Flow Chart. Information on safety and 
endpoint events, and adherence to trial medication will be collected at all visits.
Information on concomitant therapy will be collected up to and including Visit 4.
Information on specific concomitant medication (SGLT-2 inhibitor (or combined SGLT-1 
and SGLT-2 inhibitor)) will be collected on all visits.


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Visit 4, 6 months after randomisation is an on-site visit. Patients should bring their trial 
medication with them at this visit in order for site personnel to confirm treatment adherence. 
Trial medication for the remaining treatment period will be dispensed at this visit and 
allocation of new kit number(s) will be managed through the IRT.
In exceptional cases, e.g. during the COVID-19 pandemic, if it is not recommended to 
conduct Visit 4 at the trial site, it may be performed at patient’s home or remotely (via 
telephone and/or internet based means of communication). In the event of a remote Visit 4
trial medication may be shipped by courier from site to patient, if legally acceptable 
according to local regulations and considered safe for patient to continue treatment.
It is important that any remote Visit 4 is discussed with and approved by the sponsor/CRO to 
ensure delivery of trial medication fulfil the trial specific and country-specific requirements.
The remaining visits will be conducted remotely, but on-site visits replacing remote visits or 
arranged as additional visits should be arranged if requested by patient or considered deemed 
necessary by investigator.
At any time during the treatment period the investigator is allowed to adjust and optimise the 
medical 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 4.3.2).
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
Trial completion and Follow-up period
All patients still in the trial at the time when the required number of primary outcome events 
are expected to be reached will be contacted via telephone by the investigator or designee. 
The proposed time schedule for this last remote visit will be communicated via an 
investigator letter to the sites.
During the EoS Visit occurrence of safety and endpoint events will be assessed, and
adherence to trial medication and use of specific concomitant medication will be recorded.
Patients on trial medication will be asked to stop their trial medication and to return the 
unused drugs to the site per agreement with the site personnel.
During the 7 days following EoS patients are asked to report any AESIs, SAEs including 
endpoint events to the investigator or designee.
After the patients have completed the trial standard of care should be provided according to 
local, national and international guidelines and recommendations.


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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.
6.2.4
Early discontinuation of trial medication and trial termination
If trial medication is prematurely discontinued, the reason for discontinuation must be 
collected and reported if applicable. Patients who discontinue trial medication prematurely 
should continue to follow scheduled visits until EoS. For patients reluctant to attend the 
scheduled visits after prematurely discontinuing trial medication, the importance of further 
trial assessments should be emphasized and discussed.
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
Eligible patients will be randomised to receive empagliflozin or matching placebo in a 1:1 
ratio, stratified according to established T2D status (yes, no) and geographical region (North 
America, Latin America, Europe, Asia). The primary endpoint is the composite of time to 
first HHF or all-cause mortality. The statistical model will be a Cox proportional hazards 
model adjusting for stratification factors as well as further baseline covariates known to be 
prognostic for the primary endpoint, see Section 7.2.2. The hazard ratio and its confidence 
limits will be determined for evaluating superiority of empagliflozin to placebo.
The key secondary endpoints are defined as:
1. Total number of HHF or all-cause mortality
2. Total number of non-elective CV hospitalisations or all-cause mortality
3. Total number of non-elective all-cause hospitalisations or all-cause mortality
4. Total number of hospitalisations for MI or all-cause mortality
7.1
NULL AND ALTERNATIVE HYPOTHESES
A hierarchical testing procedure will be applied from the primary endpoint to the set of key 
secondary endpoints 1 and 2. If, and only if, the primary endpoint is significant at α=5% 
(two-sided) and shows superiority of empagliflozin versus placebo, then a Hochberg step-up 
procedure [R20-0113] will be applied to test the family of two key secondary endpoints of
∀
Total number of HHF or all-cause mortality
∀
Total number of non-elective CV hospitalisations or all-cause mortality
at α=5% (two-sided). If the null hypotheses for both of these two key secondary endpoints 
can be rejected and both show superiority of empagliflozin versus placebo, only then the third 
key secondary endpoint of:
∀
Total number of non-elective all-cause hospitalisations or all-cause mortality
will be tested at α=5% (two-sided). The fourth key secondary endpoint
∀
total number of hospitalisations for MI or all-cause mortality
will only be tested if all the hypotheses for the primary and key secondary endpoints 1, 2 and 
3 have been rejected and all show superiority of empagliflozin versus placebo. This ensures 
strong control of the family-wise error rate, see Figure 7.1: 1.


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Figure 7.1: 1 Multiple testing strategy
For all primary and key secondary endpoints, superiority for empagliflozin versus placebo 
will be evaluated with a two-sided test in the following structure:
Null hypothesis: There is no difference regarding the risk of the endpoint in question between 
empagliflozin versus placebo
Alternative hypothesis: There is a difference regarding the risk of the endpoint in question 
between empagliflozin versus placebo
Two-sided 95% confidence intervals will be given for the hazard ratio (HR) (primary 
endpoint) and rate ratio (key secondary endpoints).
The Hochberg step-up procedure controls family-wise error rate at 5% for the family of the 
two key secondary endpoints, if there is a non-negative correlation for the two endpoints of 1) 
total number of HHF or all-cause mortality, and 2) total number of non-elective CV 
hospitalization or all-cause mortality. This is assumed to hold true as the total number of 
HHF is a subset of all non-elective CV hospitalizations.
Other secondary endpoints will be evaluated in an exploratory manner.


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The trial is considered positive, if the null hypothesis of the primary endpoint can be rejected 
and the result is more favorable for empagliflozin versus placebo (HR<1).
7.2
PLANNED ANALYSES
7.2.1
General considerations
The primary efficacy analysis will be based on the randomised set (RS) including all 
randomised patients. Analyses will be performed according to the intention-to-treat principle, 
with the use of all available data (on and off treatment) through the trial. This equates a 
treatment-policy estimand. Supplementary analyses investigating a hypothetical estimand 
using on-treatment data only will be specified below.
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.
Baseline will be defined as the last available measurement before randomisation.
Important protocol deviations will be defined in a separate document.
7.2.2
Primary endpoint analyses
The primary endpoint will be analysed using a Cox proportional hazards model [R07-4680] 
with treatment, T2D at baseline (yes vs no), geographical region (North America, Latin 
America, Europe, Asia), age at baseline (continuous), eGFR (CKD-EPI) at baseline (<45 vs 
45-<60 vs 60-<90 vs >=90 ml/min/1.73m2), LVEF at baseline (<35% vs ≥35%), persistent or 
permanent atrial fibrillation at baseline (yes vs no), prior MI at baseline (yes vs no), 
peripheral artery disease (PAD) at baseline (yes vs no) and smoking at baseline (current vs 
non-current) as covariates. Breslow’s method for dealing with ties will be used. The hazard 
ratio for the effect of treatment (empagliflozin versus placebo) and its 95% confidence limits 
will be estimated and presented with the two-sided p-value for the null hypothesis of equality 
based on the Wald chi-squared statistic.
The time to the event will be calculated by (event date – randomisation date) + 1. All events 
observed after randomisation until end of trial will be included in the analysis. Patients who 
do not have an event during the trial 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 earliest. Time 
to censoring will be calculated by (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 the time to first occurrence of these events will be considered for the primary 
analysis.
To detect any heterogeneity in the treatment effect among patients with established T2D and 
without established T2D, a subgroup analysis will be performed by including the status of 
established T2D by treatment interaction term into the Cox model.


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Standard subgroup analyses of the primary endpoint include e.g. geographical region, age, 
sex, race, LVEF and eGFR. More details will be specified in the TSAP.
A sensitivity analysis will be provided using only on-treatment data. This analysis will be 
based on the Treated Set (TS) only including any events up to 7 days after treatment 
discontinuation. Patients who do not have an event during the trial will be censored at the 
individual day of discontinuation of trial medication +7 days or the last day that the patient 
was known to be free of the event, whichever is earliest.
7.2.3
Secondary endpoint analyses
Comparisons between treatment groups regarding the key secondary endpoint of total number 
of HHF or all-cause mortality will be performed using a negative binomial regression model. 
The negative binomial model will include factors for treatment and all covariates specified 
for the primary endpoint analysis model. The analysis will be adjusted for differences in 
observation time. Regression coefficients together with 95% confidence intervals will be used 
to quantify the effect of treatment, comparing empagliflozin to placebo.
The key secondary endpoints of total number of non-elective CV hospitalisations or all-cause 
mortality, total number of non-elective all-cause hospitalisations or all-cause mortality and 
total number of hospitalisations for MI or all-cause mortality will be analysed in the same 
way as the total number of HHF or all-cause mortality.
Time to CV mortality will be analysed using a Cox proportional hazards model with the same 
covariate adjustment as for the primary endpoint.
7.2.4
Further endpoint analyses
Comparisons between treatment groups regarding the binary endpoint variable 30-day all 
cause hospitalisation will be performed using a logistic regression model adjusting for the 
same covariates as in the primary analysis model. The likelihood-ratio test will be used to test 
for the difference between treatments. Adjusted odds ratios together with 95% confidence 
intervals will be used to quantify the effect of treatment, comparing empagliflozin with 
placebo as the reference.
The continuous endpoint days alive and out of hospital until day 90 after randomisation will 
be analysed descriptively. Days alive and out of hospital until 6 months, 9 months and 12 
months after randomisation will be analysed using the same approach.
Time-to first event endpoints will be analysed in the same way as the primary endpoint.
The details of analyses will be defined in the TSAP prior to unblinding.
7.2.5
Safety analyses
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities 
(MedDRA). Standard BI summary tables and listings will be produced. All adverse events 


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with an onset between start of treatment and end of the REP, a period of 7 days after the last 
dose of trial medication, will be assigned to the on-treatment period for evaluation.
All treated patients (TS) will be included in the safety analysis and treatment will be analysed 
as randomised. In general, safety analyses will be descriptive in nature and will be based on 
BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events, i.e. all adverse events occurring between start of treatment and end of the 
REP. Adverse events that start before first trial medication intake and deteriorate under 
treatment will also be considered as ‘treatment-emergent’.
Frequency and causal relationship of adverse events will be tabulated by system organ class 
(SOC) and preferred term (PT) after coding according to the current version of the Medical 
Dictionary for Drug Regulatory Activities (MedDRA) at database lock.
Reasons for discontinuation of trial medication will be tabulated.
Adverse events of special interst as identified by the investigator will be tabulated by primary 
SOC and PT. Adverse events of special interest are:
∀
Contrast induced AKI
∀
Ketoacidosis
∀
Events leading to Lower limb amputation
∀
Hepatic injury
The details of these analyses will be specified in the TSAP.
7.2.6
Interim Analyses
No interim analysis is planned, but a DMC will be in place with tasks as described in Section
8.7.
7.3
HANDLING OF MISSING DATA
There will be no imputation of data for safety data or time-to-event efficacy endpoints. 
Missing data for time-to-event and all key secondary endpoints will be handled by censoring 
and under missing-at-random assumption. Patients discontinuing the treatment prematurely 
will still be followed for the primary endpoint, all-cause mortality and all other endpoints 
including the key secondary endpoints.
7.4
RANDOMISATION
Patients will be randomized in blocks to double-blind treatment via interactive response 
technology (IRT). Approximately equal number of patients will be randomised to receive 
empagliflozin 10 mg or placebo using a 1:1 ratio. Randomisation will be stratified by
∀
Established T2D (yes, no)
∀
Geographical region (North America, Latin America, Europe, Asia)


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BI will arrange for the randomisation and the packaging and labelling of trial medication. The 
randomisation list will be generated using a validated system, which involves a pseudo-
random number generator so that the resulting treatment will be both reproducible and non-
predictable. The block size will be documented in the Clinical Trial Report. Access to the 
codes will be controlled and documented.
7.5
DETERMINATION OF SAMPLE SIZE
The trial is intended to show a reduction in the composite endpoint of time to first event of 
HHF or all-cause mortality with empagliflozin versus placebo. A Cox proportional hazards 
model will be used to analyse the primary endpoint. The trial is designed to achieve a power 
of 85% for a two-sided test at level α=5% if the analysis is performed at the number of 
accumulated events in Table 7.5: 1. The calculation assumes to show superiority of 
empagliflozin versus placebo based on a 1:1 randomisation ratio.
The expected hazard ratio for the comparison of empagliflozin versus placebo is 0.75 based 
on results from EMPA-REG OUTCOME and other SGLT2-inhibitor studies [P16-01253, 
R19-3125]. To account for drop-in to active SGLT2-inhibitor treatment, the assumed overall 
hazard ratio is 0.77 and requires at least 532 primary outcome events to show superiority with 
a power of 85% based on two-sided  α=5 % and 1:1 randomisation ratio.
The initial determination of sample size to reach the anticipated 532 primary outcome events 
is as follows:
The yearly event rate in the placebo group is assumed to be 12.5% based on previous similar 
trial populations and including that the standard of care changed over time with better 
prognosis to date [R20-0260, R20-0257, R20-0201]. Assuming a yearly event rate of 12.5% 
in the placebo arm and 9.77% in the empagliflozin arm, accounting for 1% yearly drop out, 
an estimated 12 months recruitment and an estimated minimum follow-up of 12 months, a 
number of 3312 patients would need to be randomised to provide the 532 primary outcome 
events.
Table 7.5: 1 sumarizes the total number of patients and events needed assuming different 
event rates and hazard ratios. The calculations were performed using the Freedman formula.


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Table 7.5: 1
Total number of events and sample sizes required to show superiority 
with 85% power, 2-sided α=5%, 1:1 randomisation ratio for different 
hazard ratios
Power
HR
Total 
number of 
events 
needed
Event rate 
Placebo at 1 
year (%)
Event rate Empa 
at 1 year (%)
Total sample 
size for 2 
treatment 
groups
85%
0.75
440
12.5%
9.53%
2772
0.77
532
12.5%
9.77%
3312
0.80
726
12.5%
10.1%
4454
Calculations consider a trial drop out rate of 1% per year, a 12 months recruitment period and 
an estimated follow-up of at least 12 months.
Sample size calculation was performed using ADDPLAN version 6.
During trial conduct the recruitment progress was slower than initially planned and associated 
event accumulation was slower than anticipated. Therefore the decision was taken to increase 
the sample size to 5000 patients based on blinded study data to avoid a substantial 
prolongation of overall study duration. The required number of primary outcome events of 
532 is not affected by this decision.
With 5000 randomised patients and assuming a yearly event rate of 12.5% in the placebo arm 
and 9.77% in the empagliflozin arm, accounting for 1% yearly drop out and an estimated 21 
months recruitment, an estimated minimum follow-up of 5 months would provide the 532 
primary outcome events. Calculations consider a non-linear recruitment over time and were 
performed with RPACT version 3.0.4.
The event rate and recruitment progress will be assessed in a blinded manner and in an on-
going basis to keep track of the progress of the trial. If reliable event predictions suggests a 
slower accrual of primary outcome events over calendar time than projected (i.e. a target of
532 events needed with a planned number of 5000 patients randomised), the number of 
patients randomised may be increased up to 6500, or trial duration may be prolonged.


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND
ADMINISTRATIVE STRUCTURE
The trial will be carried out in accordance with the Medical Devices Directive (93/42/EEC)
and the harmonised standards for Medical Devices (ISO 14155, current version).
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU directive
2001/20/EC / EU regulation 536/2014 and other relevant regulations. Investigators and site 
staff must adhere to these principles. Deviation from the protocol, the principles of ICH GCP 
or applicable regulations as will be treated as “protocol deviation”.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient.
The investigator will inform the sponsor/CRO immediately of any urgent safety measures 
taken to protect the trial patients against any immediate hazard, as well as of any serious 
breaches of the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor
with regard to publication of the results of this trial are described in the investigator contract. 
As a rule, no trial results should be published prior to finalisation of the Clinical Trial Report.
The certificate of insurance cover is made available to the investigator and the patients, and is
stored in the ISF.
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB / IEC and competent authority 
(CA) according to national and international regulations. The same applies for the
implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH-GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the investigator as part of the trial records. A signed copy of the
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.”
The patient must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the patient’s own free will with the 
informed consent form after confirming that the patient understands the contents. The 


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


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If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
The trial design is streamlined with extra work for collaborating site personnel being kept to a 
minimum. Only essential data will be collected with the focus being on readily identifiable 
and important clinical outcomes.
The primary data collected will be from carefully structured interviews.
The following data will be recorded directly on the eCRF (i.e. no prior written or electronic 
record of data), and to be considered to be source data:
∀
Data entered by the patient in the mobile/web-based application
∀
Data collected from the structured telephone interview
Additional medical information will be sought for Enpoints, SAEs and AESIs, and may 
include the collection of records held the study site, other hospitals, or the patient’s own 
doctors, or from electronic sources and registries.
For the eCRF, data below must be derived from source documents, for example:
∀
Patient identification: gender, year of birth (in accordance with local laws and 
regulations)
∀
Patient participation in the trial (substance, trial number, patient number, date patient was 
informed)
∀
Dates of patient’s visits, including dispensing of trial medication
∀
Medical history (including trial indication and concomitant diseases, if applicable)
∀
Medication history
∀
AEs leading to treatment discontinuation, SAEs, AESIs and events exempted from 
expedited reporting (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.
8.3.2
Direct access to source data and documents
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). They may review all CRFs and informed consents. The accuracy of the data will 


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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 GCP.
8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor/CRO:
The sponsor/CRO must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with
regulatory requirements.
Exemptions from expedited reporting are described in Section 5.2.1.2.3.
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 7 and 12 of the WHO GCP 
handbook.
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the following exceptions:
Personalised treatment data may be given to the patient’s personal physician or to other 
appropriate medical personnel responsible for the patient’s welfare. Data generated at the site
as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities.
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first patient in the whole trial signs the 
informed consent.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial
(“Last Patient Completed”).The “Last Patient Last Treatment” (LPLT) date is defined as 
the date on which the last patient in the whole trial is administered the last dose of trial 
treatment (as scheduled per protocol or prematurely). Individual investigators will be notified 
of SUSARs occurring with the trial medication until 30 days after LPLT at their site.
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.
Database Lock (DBL) milestone is accomplished after quality review, query resolution, 
treatment unblinding, data transformation and determination that the data is ready
for analysis.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor/CRO with the intention to resume it.


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Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the respective laws.
A final report of the clinical trial data will be written only after all patients have completed 
the trial in all countries (EU or non-EU) to incorporate and consider all data in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
A Coordinating Investigator is responsible to coordinate investigators at the different sites 
participating in this trial. Tasks and responsibilities are defined in a contract.
An Executive Committee (EC) consisting of independent experts (including the Coordinating 
Investigator of this trial) and sponsor representatives will be established to support the 
sponsor in designing the trial and successful execution. The composition of the EC will be 
documented in the Trial Master File (TMF). The tasks and responsibilities will be agreed in 
contracts between the EC members and the sponsor and also summarised in an EC charter. 
The EC will assess the baseline characteristics of the patients in an ongoing blinded manner 
and if needed, may take appropriate steps, which may include restrictions to enrolment for 
certain subpopulations.
A National Coordinator Committee (NCC) will be established and will consist of the leading
expert(s) in each of the participating countries. The NCs will support the sponsor/CRO 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 CRO.
A Data Monitoring Committee (DMC) will be established. Members of the DMC are
independent of BI, they are physicians experienced in the treatment of the disease under
investigation and a statistician. The DMC will evaluate safety data. While DMC members
may be unblinded, measures are in place to ensure the blinding for everyone else involved in
the trial. Regular DMC meetings will be held at specified intervals. The DMC will
recommend continuation, modification or termination of the trial as detailed in the DMC
charter. DMC recommendations as well as the final BI decision will be reported to the
appropriate Regulatory Authorities (RAs)/ Health Authority (Has), IRBs/ECs, and to
investigators as requested by local law. The tasks and responsibilities of the DMC are
specified in a charter.
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the ISF.


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The CRO will have access to the BI web portal Clinergize to access documents provided by 
the sponsor for distribution to the investigators.
BI has appointed a Clinical Trial Leader (CT Leader), responsible for coordinating all 
required activities, in order to
-
manage the trial in accordance with applicable regulations and applicable BI- and 
CRO SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate oversight of vendors.
The organisation of the trial in the participating countries will be performed by a CRO with 
which the responsibilities and tasks will have been agreed and a written contract filed before 
initiation of the clinical trial.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to both BI and CRO SOPs. A list of responsible persons and relevant local 
information can be found in the ISF.
An IRT vendor will be used in this trial. Details will be provided in the IRT manual made 
available in the ISF.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
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. 2015. 373 (22), 2117-2128
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. 2016. 37 (19). 1526-1534
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. 
2016. 375 (4), 323 - 334
P17-11284
Fitchett D, et al. Effects of empagliflozin on 
risk for cardiovascular death and heart 
failure hospitalization across the spectrum
of heart failure risk in the EMPA-REG 
OUTCOME® trial. European Heart Journal. 
2017. 39. 363-370
P17-13145
Inzucchi SE, Zinman B, Fitchett D, Wanner 
C, Ferrannini E, Schumacher M, et al. How 
does empagliflozin reduce cardiovascular 
mortality? Insights from a mediation 
analysis of the EMPA-REG OUTCOME 
trial. Diabetes Care. 2018. 41 (2). 356-363
P18-10152
Inzucchi SE, Kosiborod M, Fitchett D, 
Wanner C, Hehnke U, Kaspers S, et.al. 
Improvement in cardiovascular outcomes 
with empagliflozin is independent of 
glycemic control. Circulation. 2018. 
138(17): 1904-1907


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P18-12030
Oshima H, et al. Empagliflozin, an SGLT2 
Inhibitor, Reduced the Mortality Rate after 
Acute Myocardial Infarction with 
Modification of Cardiac Metabolomes and 
Antioxidants in Diabetic Rats. Journal of 
Pharmacology and Experimental 
Therapeutics. March 2019. 368 (3) 524-534
P19-03216
Santos-Gallego CG, et al. Empagliflozin 
Ameliorates Adverse Left Ventricular 
Remodeling in Nondiabetic Heart Failure by 
Enhancing Myocardial Energetics. J Am 
Coll Cardiol. 2019. Apr 23;73(15):1931-
1944
P19-02151
Verma S, McMurray JJV. SGLT2 inhibitors 
and mechanisms of cardiovascular benefit: a 
state-of-the-art review. Diabetologia. 2018. 
61: 2108-2117
P19-03653
Yurista SR, et al. Sodium-glucose co-
transporter 2 inhibition with empagliflozin 
improves cardiac function in non-diabetic 
rats with left ventricular dysfunction after 
myocardial infarction. European Journal of 
Heart Failure. 2019. 21. 862–873.
P19-08100
Verma S, Mazer CD, Yan AT, Mason T, 
Garg V, Teoh H, et al, EMPA-HEART 
CardioLink-6 Investigators, Effect of 
empagliflozin on left vventricular mass in 
patients with type 2 diabetes and coronary 
artery disease: the EMPA-HEART 
CardioLink-6 randomized clinical trial. 
Circulation. 2019. 140 (21). 1693-1702
P20-00338
Damman K, et al. Randomized, double-
blind, placebo-controlled, multicentre pilot 
study on the effects of empagliflozin on 
clinical outcomes in patients with acute 
decompensated heart failure (EMPA-
RESPONSE-AHF). Eur J Heart Fail. 2020. 
22. 713-722
P20-00872
Ndounga Diakou LA, Trinquart L, 
Hróbjartsson A, Barnes C, Yavchitz A, 
Ravaud P, Boutron I. Comparison of central 
adjudication of outcomes and onsite 
outcome assessment on treatment effect 
estimates. Cochrane Database of Systematic 


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Reviews 2016, Issue 3. Art. No.: 
MR000043.
P20-04407
Reed GW, Rossi JE, Cannon CP. Acute 
myocardial infarction. Lancet. 2017. 389.
197–210
R07-4680
Collett D. Modelling Survival Data in 
Medical Research. A CRC Press Company.
2003.
R19-3125
McMurray JJV, Solomon SD, Inzucchi SE, 
Kober L, Kosiborod MN, Martinez FA, et 
al, DAPA-HF Trial Committees and 
Investigators. Dapagliflozin in patients with 
heart failure and reduced ejection fraction. 
N Engl J Med. 2019; 381:1995-2008
R20-0113
Dmitrienko A, D’Agostino Sr RB, Huquec
MF. Key multiplicity issues in clinical drug 
development. Statistics in medicine. 2013, 
32 1079–1111
R20-0201
Desta L, Jernberg T, Spaak J, Hofman-Bang 
C, Persson H. Risk and predictors of 
readmission for heart failure following a 
myocardial infarction between 2004 and 
2013: A Swedish nationwide observational 
study. Int.Journal of Cardiology. 2017. 
Volume 248. 221-226
R20-0249
Tyl B, et al. "Abstract 11480: Comparison 
of Outcome Adjudication by Investigators 
and by a Central Endpoint Committee 
(CEC) in Heart Failure Trials: Experience 
of the Shift Heart Failure Study." 
Circulation. 2019. 140(Suppl_1). A11480-
A11480 
R20-0257
Beygui F, Cayla G, Roule V, Roubille F, 
Delarche N, Silvain J, et al, ALBATROSS 
Investigators. Early aldosterone blockade in 
acute myocardial infarction: the 
ALBATROSS randomized clinical trial. J 
Am Coll Cardiol. 2016. 67. 1917-1927
R20-0260
Dickstein K, Bebchuk J, Wittes J. The high-
risk myocardial infarction database 
initiative. Prog Cardiovasc Dis. 2012. 54.
362-366




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10.
APPENDICES
Not applicable


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
20 Apr 2022
EudraCT number
EU number
2019-001037-13
BI Trial number
1245-0202
BI Investigational Medicinal 
Product(s)
Jardiance®, empagliflozin
Title of protocol
EMPACT-MI: A streamlined, multicentre, 
randomised, parallel group, double-blind placebo-
controlled superiority trial to evaluate the effect of 
EMPAgliflozin on hospitalisation for heart failure 
and mortality in patients with aCuTe Myocardial 
Infarction
Global Amendment due to urgent safety reasons
N/A
Global Amendment
X
Section to be changed
Synopsis: Chair and co-chair Executive Committee
Description of change
Address of Chair changed
Rationale for change
Chair moved location
Section to be changed
Synopsis: Total number of patients randomised; 
Number of patients on each treatment; Duration of 
treatment; Statistical methods
Description of change
Increased sample size and adjusted recruitment and 
treatment duration
Rationale for change
The recruitment was slower than initially planned 
and associated event accumulation was slower than 
anticipated. Therefore the decision was taken to 
increase the sample size to avoid a substantial 
prolongation of overall trial duration
Section to be changed
Synopsis: Main inclusion and exclusion criteria
Description of change
Details are added to Inclusion criterion No. 4 and 
to the risk factor Pulmonary Artery Systolic 
Pressure
Rationale for change
Details are added for clarification
Section to be changed
Flow Chart: Footer No. 7 and 10
Description of change
Details how to follow-up patients completing the 
treatment period as planned and those prematurely 
discontinuing are added
Rationale for change
Further clarification required on patient 
management and data collection during the study 
and at study end


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Section to be changed
1.4.2; Table 1.4.2 :1
Description of change
Removal of text related to LLA which erroneously 
referred to text in ICF in column Mitigation 
Strategy.
Rationale for risk updated in column Summary of 
data
Rationale for change
To harmonize the content in the protocol with the 
ICF and the updated information in the IB
Section to be changed
3.1 and Figure 3.1: 1
Description of change
a) Recruitment and treatment duration are updated
b) Details how to manage patients completing the 
study are added
Rationale for change
a) The recruitment was slower than initially 
planned and associated event accumulation was 
slower than anticipated. Therefore the decision was 
taken to increase the sample size to avoid a 
substantial prolongation of overall trial duration. 
The recruitment and treatment period were 
adjusted accordingly.
b) Further clarification was required on patient 
management at the end of study
Section to be changed
3.3
Description of change
a) Increased sample size and adjusted recruitment 
and treatment duration
b) Removal of the 25% cap of patients with 
established T2D
c) Allow for extension or shortening of recruitment 
period on country level or regional level
Rationale for change
a) The recruitment was slower than initially 
planned and associated event accumulation was 
slower than anticipated. Therefore the decision was 
taken to increase the sample size to avoid a 
substantial prolongation of overall trial duration. 
The recruitment and treatment period were 
adjusted accordingly
b) Strengthening generalisability of trial results to 
overall population including type 2 diabetes
c) To achieve reasonable contribution and 
distribution across countries and regions
Section to be changed
3.3.1 and 3.3.2
Description of change
a) Details to clearly describe the main diagnosis for 
the trial are added in section 3.3.1 and in inclusion 
criterion No. 4.
b) Right ventricular systolic pressure is added to 
the risk factor Pulmonary Artery Systolic Pressure
Rationale for change
Details are added for clarification
Section to be changed
3.3.4.1 and 3.3.4.2


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Description of change
Details explaining how to follow-up patients are 
added
Rationale for change
Further clarification required on patient 
management and data collection during the study 
and at study end
Section to be changed
4.1.4; Table 4.1.4 :1
Description of change
The table visualising the amount and timing of 
dispense of medication kit are adapted to reflect 
the revised treatment period
Rationale for change
Changes to the treatment period require 
modification to the table
Section to be changed
4.3.2.3
Description of change
Removed text in brackets mentioning partner of 
participating WOCBP
Rationale for change
Removed for clarification
Section to be changed
6.1
Description of change
Description of call centers are removed
Rationale for change
Call centers are not used in this study
Section to be changed
7.5
Description of change
Increased sample size and adjusted recruitment and 
treatment duration
Rationale for change
The recruitment was slower than initially planned 
and associated event accumulation was slower than 
anticipated. Therefore the decision was taken to 
increase the sample size to avoid a substantial 
prolongation of overall trial duration. The
recruitment and treatment period were adjusted 
accordingly.
Section to be changed
9.1
Description of change
Reference to definition of T1 MI removed
Rationale for change
Definition of T1 MI replaced by detailed 
description of spontaneous AMI
Section to be changed
9.2
Description of change
Reference to trial 1245-0171 added
Rationale for change
Reference to results in the trial 1245-0171 made in 
section 1.4.2


 
 
 
APPROVAL / SIGNATURE PAGE 
Document Number: 
 
Technical Version Number:
Document Name: 
                                                                                                                 
 
Title: 
                                                                                                                   
Signatures (obtained electronically) 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Boehringer Ingelheim 
Page 2 of 2
Document Number: 
Technical Version Number:
(Continued) Signatures (obtained electronically) 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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SAP_001.pdf: 
001-MCS-50-415_RD-01 (3.0) / Saved on: 18 Jan 2021
 
TRIAL STATISTICAL ANALYSIS PLAN
c38811533-02
BI Trial No.:
1245-0202
Title:
EMPACT-MI: A streamlined, multicentre, randomised, parallel 
group, double-blind placebo-controlled superiority trial to 
evaluate the effect of EMPAgliflozin on hospitalisation for heart 
failure and mortality in patients with aCuTe Myocardial 
Infarction
Including Protocol Amendment 1 <1245-0202>-protocol-version-
02 [c31546238-02]
Investigational
Product(s):
Jardiance®, empagliflozin
Responsible trial 
statistician(s):
Phone: +
Date of statistical 
analysis plan:
26 MAY 2023
Version:
Revised 
Page 1 of 45
Proprietary confidential information
! 2023 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.


Boehringer Ingelheim
TSAP for BI Trial No: 1245-0202
c38811533-02
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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.................................................................................................6
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ......................7
5.
ENDPOINTS(S).....................................................................................................7
5.1
PRIMARY ENDPOINT(S)...................................................................................7
5.2
SECONDARY ENDPOINT(S).............................................................................7
5.2.1
Key secondary endpoint(s) ...................................................................................7
5.2.2
Secondary endpoint(s)...........................................................................................7
5.3
FURTHER ENDPOINT(S) ..................................................................................7
5.4
OTHER VARIABLE(S)........................................................................................8
6.
GENERAL ANALYSIS DEFINITIONS...........................................................10
6.1
TREATMENT(S) ................................................................................................10
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................11
6.3
SUBJECT SETS ANALYSED ...........................................................................11
6.4
SUBGROUPS.......................................................................................................12
6.5
POOLING OF CENTRES..................................................................................14
6.6
HANDLING OF MISSING DATA AND OUTLIERS ....................................14
6.6.1
Imputation methods ............................................................................................14
6.6.2
Missing data.........................................................................................................15
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS....................17
6.8 
CALCULATION OF TIME TO EVENT .........................................................18
6.8.1
Start date..............................................................................................................19
6.8.2
Date of event.........................................................................................................19
6.8.3
Censoring .............................................................................................................19
6.8.4
Time at risk for count variables.........................................................................20
7.
PLANNED ANALYSIS ......................................................................................21
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .........21
7.2
CONCOMITANT DISEASES AND MEDICATION......................................22
7.3
TREATMENT COMPLIANCE ........................................................................22
7.4
PRIMARY ENDPOINT(S).................................................................................23
7.4.1
Primary analysis of the primary endpoint(s)....................................................23
7.4.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the 
primary endpoint(s) ............................................................................................24
7.5
SECONDARY ENDPOINT(S)...........................................................................25
7.5.1
Key secondary endpoint(s) .................................................................................25
7.5.1.1
Primary analysis of the key secondary endpoint(s)...............................................25
7.5.1.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the key 
secondary endpoint(s) ...........................................................................................26
7.5.2
(Other) Secondary endpoint(s)...........................................................................27
7.6
FURTHER ENDPOINT(S) ................................................................................27


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7.7
EXTENT OF EXPOSURE .................................................................................28
7.8
SAFETY ANALYSIS..........................................................................................29
7.8.1
Adverse Events ....................................................................................................29
7.8.1.1
Assignment of AEs to treatment ...........................................................................30
7.8.1.2
AE summaries .......................................................................................................31
7.8.1.3
Adverse events of special interest (AESIs) ...........................................................32
7.8.1.4
Specific AEs..........................................................................................................33
7.8.1.5
AEs while patients taking wrong medication........................................................34
7.8.1.6
Adverse event incidence rates ...............................................................................34
7.8.2
Laboratory data...................................................................................................35
7.8.3
Vital signs.............................................................................................................36
7.8.4
ECG ......................................................................................................................36
7.8.5
Others ...................................................................................................................36
8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION .............37
9. 
REFERENCES ....................................................................................................38
10.
ADDITIONAL SECTIONS................................................................................39
10.1
DETAILED DESCRIPTION OF PRIMARY ENDPOINT ............................39
10.2
DETAILED DESCRIPTION OF (KEY) SECONDARY ENDPOINTS 
AND FURTHER ENDPOINTS .........................................................................39
10.3
ADDITIONAL ANALYSES FOR REGIONAL SUBMISSIONS..................40
10.3.1 
Time windows ......................................................................................................40
10.3.2 
Treatment Compliance .......................................................................................42
10.3.3 
Concomitant diseases and medication...............................................................42
10.3.4 
Further endpoints................................................................................................42
10.3.5 
Safety Analyses ....................................................................................................43
10.4
REGIONS AND COUNTRIES..........................................................................43
11.
HISTORY TABLE..............................................................................................45


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LIST OF TABLES
Table 6.1: 1
Treatment regimens / study intervals................................................................10
Table 6.3: 1
Subject sets analysed ........................................................................................11
Table 6.4: 1
Categories of baseline covariates for subgroup analyses .................................13
Table 6.7: 1
Time windows ..................................................................................................18
Table 7.8.1: 1 Auto-coding for exempted AEs and AESIs......................................................30
Table 10.3.1:1Time windows for regional analyses................................................................41
Table 10.4:1 Regions and countries.......................................................................................44
Table 11: 1
History table .....................................................................................................45


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ANCOVA
Analysis of Covariance
BNP
Brain Natriuretic Peptide
CABG
Coronary artery bypass grafting
CI
Confidence interval
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration Equation
COVID-19
Coronavirus-Disease 2019
CRT-D
Cardiac resynchronization therapy with defibrillator
CRT-P
Cardiac resynchronization therapy without defibrillator
CV
Cardiovascular
DAOH
Days alive and out of hospital
eGFR
Estimated Glomerular Filtration Rate
HbA1c
Glycosylated haemoglobin
HHF
Hospitalisation for Heart Failure
ICD
Implantable cardioversion defibrillator
LDL
Low-Density Lipoprotein
LVEF
Left Ventricular Ejection Fraction
MI
Myocardial infarction
NSTEMI
Non-ST Elevation Myocardial Infarction
NT-proBNP
N-Terminal Pro-Brain Natriuretic Peptide
OC-AD
Observed Cases including data after treatment discontinuation
OC-OT
Observed Cases on-treatment
PCI
Percutaneous coronary intervention
RS
Randomised Set
SCR
Screened Set
SGLT-2
Sodium Glucose Co-Transporter 2
STEMI
ST Elevation Myocardial Infarction
T2D
Type 2 Diabetes
TS
Treated Set


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3.
INTRODUCTION
As per ICH E9, the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This TSAP assumes familiarity with the Clinical Trial Protocol (CTP), including Protocol 
Amendments. In particular, the TSAP is based on the planned analysis specification as written 
in CTP Section 7 “Statistical Methods and Determination of Sample Size”. Therefore, TSAP 
readers may consult the CTP for more background information on the study, e.g., on study 
objectives, study design and population, treatments, definition of measurements and variables, 
planning of sample size, 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
None.
5.
ENDPOINTS(S)
5.1
PRIMARY ENDPOINT(S)
The primary endpoint is specified in the CTP section 2.1.2 as the composite of time to first 
heart failure hospitalisation (HHF) or all-cause mortality, calculated from date of 
randomisation. 
For detailed specifications refer to the ‘Event review charter and guidance for EMPACT-MI’ 
(1). Further programming specifications are given in Section 10.
5.2
SECONDARY ENDPOINT(S)
5.2.1
Key secondary endpoint(s)
Key secondary endpoints are specified in the CTP section 2.1.3. as 
∀
Total number of HHF or all-cause mortality 
∀
Total number of non-elective cardiovascular (CV) hospitalisations or all-cause 
mortality 
∀
Total number of non-elective all-cause hospitalisations or all-cause mortality 
∀
Total number of hospitalisations for myocardial infarction (MI) or all-cause mortality
For detailed specifications refer to the ‘Event review charter and guidance for EMPACT-MI’ 
(1). Further programming specifications are given in Section 10.
5.2.2
Secondary endpoint(s)
One other secondary endpoint is specified in the CTP section 2.1.3 as time to CV mortality. 
For further clarification:
∀
CV death includes death with unknown cause.
5.3
FURTHER ENDPOINT(S)
Further endpoints are specified in the CTP section 2.2.2.
For further clarification:


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∀
Time to first revascularisation will be derived from the eCRF page ‘concomitant 
targeted non-drug therapies’ and includes percutaneous coronary intervention (PCI) or 
coronary bypass artery grafting (CABG) not pre-planned at randomisation
∀
Time to first renal replacement therapy or renal transplantation will be derived from 
the eCRF page ‘concomitant targeted non-drug therapies’ and includes chronic renal 
replacement therapies only, defined by a renal replacement therapy lasting for at least 
90 days. 
∀
For the endpoint 30-day all-cause hospitalisation, patients who died within the 30 days 
will be counted as an event.
Further endpoints added include:
∀
Time to first HHF or CV death 
∀
Time to first implantable cardioversion defibrillator (ICD) or cardiac 
resynchronization therapy with defibrillator (CRT-D) or cardiac resynchronization 
therapy without defibrillator (CRT-P) for patients without any of ICD, CRT-D or 
CRT-P at baseline. ICD/CRT at baseline will be derived via the tick boxes on the 
eCRF medical history page
∀
Time to first chronic renal replacement therapy or renal transplantation or renal death 
(renal death defined as a death event with primary AE leading to death in narrow SMQ 
‘Acute Renal Failure’)
∀
Time to first hospitalisation for MI or fatal MI (fatal MI based on CV death sub-
category ‘Acute myocardial infarction’ according to event review charter) 
∀
Total number of hospitalisations for MI or death due to MI
5.4
OTHER VARIABLE(S)
Treatment exposure
Treatment exposure is defined as time from first intake to last intake of study drug, including 
off-treatment periods.
Overall observational period
The overall observational period (until vital status follow-up) is defined as time from 
randomization until end of follow-up for vital status, see censoring for all-cause mortality in
Section 6.8.3.
The observational period (until individual day of trial completion) is defined as time from 
randomization until individual day of trial completion, see Section 6.8.3.
Treatment compliance
Treatment compliance will be defined per scheduled visit as a binary variable. If there is more 
than one reported visit in the visit window as defined in Section 6.7, the patient will be 


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defined as being compliant with study drug if the duration within the visit window for which 
the patient reported to be compliant with study drug is >=50%. If the duration within the visit 
window for which the patient has missing data for study drug compliance is >50%, the study 
treatment compliance will be missing. For a given time window, only the period up until the 
earliest of date of permanent treatment stop and date of last compliance report will be used. 
The TS will be used for analysis. 


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
There will be four 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. Temporary 
discontinuations and following re-starts will not be collected in the eCRF. The treatment 
phase is defined from first study drug intake to last study drug intake.
The purpose of the definitions below is to describe all the different study/treatment intervals, 
in which a patient can participate in during the course of the trial. 
Table 6.1: 1
Treatment regimens / study intervals
Label
Interval
Start date 
Screening
Screening
Date of informed consent
Placebo/
Empagliflozin 10mg
Treatment
Date of first administration of study 
medication
Post-treatment 
Post-treatment
Date of last administration of study 
medication + 1 day
Post study
Post study
Date of trial completion +1 day
The efficacy analyses will follow the intention-to-treat (ITT) principle in assigning patients to 
treatment groups, i.e. patients will be analysed as randomised. Safety analyses will also assign 
patients to the treatment group as randomised.
The on-treatment phase which will be used e.g. in analyses of adverse events (see Section 7.8) 
starts at first study drug intake and includes the time up to 7 days after the last intake of study 
medication (the residual effect period).
If a patient erroneously receives the wrong trial drug, all subsequent medication packs 
dispensed to the patient will correspond to the treatment group to which the patient was 
randomised. Therefore, the adverse events will be analysed as per randomised treatment, 
which is expected to reflect the prevailing treatment. 
In the exceptional case that a patient took the wrong treatment, adverse events may occur 
while being on the wrong treatment. Analyses of this data are described in Section 7.8.1.5.


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6.2
IMPORTANT PROTOCOL DEVIATIONS
An important protocol deviation (iPD) is a protocol deviation that may significantly impact 
the completeness, accuracy, and/or reliability of the trial data or that may significantly affect a 
subject’s right, safety, or well-being. Refer to the Protocol Deviations Management Plan for 
documentation of iPD categories and management of important PDs (iPDs), see (2) and (3).
Handling of iPDs in analysis is included in the DV domain specifications and stored within 
the TMF in EDMS. iPDs will be presented based on the randomised set (definition of 
randomised set see Section 6.3).
6.3
SUBJECT SETS ANALYSED
The following subject sets are defined:
∀
Screened Set (SCR)
Consists of all patients screened for the trial, with informed consent given 
∀
Randomised set (RS)
This patient set includes all randomised patients, whether treated or not. A patient  
randomised in error after death (i.e. a mis-randomization) will be excluded.
∀
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
Table 6.3: 1
Subject sets analysed
Subject set
Class of endpoint
SCR
RS
TS
Primary and key secondary endpoints 
primary analysis
on-treatment analysis (incl. data 
up to treatment stop + 7 days)
(other) Secondary and further 
endpoints 
X
Safety endpoints & treatment 
exposure
X
Demographic/baseline endpoints
X
(X)
Disposition
X
(X) An additional TS presentation of the demographic/baseline endpoints may be provided in the End of Text 
(EoT) section, if subject numbers for RS and TS are clearly different (see Section 7.1).


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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, except for 
descriptive analyses of adverse events.
If there is missing information for any of the subgroups, where data is also collected in the 
Interactive Response Technology (IRT) system, then the information as transferred from IRT 
will be used to assign a patient to a certain category. This applies to potential capping criteria 
‘time of randomization’. 
For the stratification factor T2D, the updated information from IRT will be used for all 
analyses.
For subgroup analyses of variables with ordered categories, 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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Table 6.4: 1
Categories of baseline covariates for subgroup analyses
Variable
Categorization
Efficacy endpoints1
Safety2
T2D 
T2D, no T2D
X
X
Age [years]
< 65
≥65
X
<50
50-<65
65-<75
>=75
X
X
Sex
Male
Female
X
X
Region3
North America
Latin America
Europe
Asia
X
X
Ethnicity
Hispanic/ Latino
Not Hispanic/ Latino
X
X
Race
White
Black/ African-American
Asian
Other including mixed race
X
X
eGFR at baseline (CKD-EPI), in 
[mL/min/1.73m^2]
>=90
60 to <90
45 to <60
30 to <45
<30
X
X
>=60
<60
X
Baseline Systolic Blood Pressure
<110 mmHg
110- <130 mmHg
>=130 mmHg
X
Baseline Left Ventricular Ejection 
Fraction (LVEF) before 
randomisation
>=35%
<35%
X
History of MI
Yes
No
X
Time from index MI diagnosis to
randomisation
<= median
> median 
X


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Table 6.4: 1
Categories of baseline covariates for subgroup analyses (cont.)
Variable
Categorization
Efficacy endpoints1
Safety2
Signs, symptoms of HF that 
required treatment during index 
hospitalisation
Yes
No
X
Lowest LVEF during index 
hospitalisation 
<45%
>=45%
X
ACE/ARB/ARNI use at baseline
Yes
No
X
MRA use at baseline
Yes
No
X
Loop or high ceiling diuretic use 
at baseline
Yes
No
X
Betablocker use at baseline
Yes
No
X
Type of index MI
STEMI
NSTEMI
X
1 Subgroups planned for the primary and key secondary endpoints as well as for time to first HHF or CV death. 
2 X means subgroups planned for overall Adverse Event (AE) summaries, SAEs by System Organ Class (SOC) and Preferred Term (PT), and 
AEs leading to treatment discontinuation.
3 Region categorisation: see Table 10.4:1
6.5
POOLING OF CENTRES
This section is not applicable because centre/country is not included in the statistical model. 
For country-specific or regional analyses, please see Section 10.3.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
6.6.1
Imputation methods
For patients who discontinue the trial treatment prematurely, all efforts will be made to follow 
patients for survival and for any other endpoints including the primary and secondary 
endpoints until the end of the trial. 
Imputation of missing covariates in multivariate Cox regression models, for total events (i.e. 
first plus recurrent) analyses and other statistical analysis models (including MMRM models, 
ANCOVA models and logistic regression analysis)
To avoid excluding patients from Cox regression analyses, models and for total events (i.e. 
first plus recurrent) analyses or other statistical models due to missing covariates the 
following steps will be followed. If there is missing information on covariates for Cox 
regression analyses, models and for total events (i.e. first plus recurrent) analyses or other 
statistical models, the overall population (randomised set) median of the corresponding 
variable will be imputed for continuous covariates and the most frequent category, based on 


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the randomised set, will be imputed for categorical covariates. For subgroup analyses, only 
patients with available data (either from eCRF or, if missing in eCRF, from IRT) for the 
subgroup variable will be included in the subgroup analysis. For the evaluation of eGFR 
changes, baseline eGFR will not be imputed. 
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 (4).
Missing admission dates for hospitalisations after the index hospitalisation 
The index hospital admission date is mandatory for a patient to be randomised and will not be 
missing. Hence, the below rules apply to all hospital admission dates excluding the index 
hospitalisation. If a non-index hospital admission date is missing or partially given then define 
a range of possible admission dates:
∀
The lower bound is the maximum of:
o
Randomisation
o
The earliest possible date from the partial admission date, if not missing
o
The latest complete discharge date from hospitalisations that are definitively 
before the hospitalisation, i.e. either the index hospitalisation or with 
admission dates prior to the earliest possible admission date
∀
The upper bound is the minimum of: 
o
Last non-fatal follow-up
o
The latest possible date from the partial admission date, if not missing
o
The latest possible discharge date of the hospitalisation, if not missing
If there is a linked adverse event onset date and it is between the upper and lower bound then 
this is used as the admission date.
If the linked adverse event onset date is after the upper bound, then the upper bound is used.
Otherwise in all other cases the lower bound is used as the admission date.
Missing information on discharge date for index hospitalisation
If an index hospitalisation discharge date is missing or partially given then define a range of 
possible discharge dates:
∀
The lower bound is the maximum of:
o
Index hospitalisation admission date
o
The earliest possible date from the partial discharge date, if not missing
o
Randomisation date, if IRT indicates discharge was not prior to randomisation
∀
The upper bound is the minimum of:
o
Randomisation date-1, if IRT indicates discharge was prior to randomisation
o
Last non-fatal follow-up
o
The latest possible date from the partial discharge date, if not missing
o
Any admission date after the index hospitalisation
o
Visit 2b visit date
Take the maximum of the upper and lower bounds


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Missing information on discharge dates for hospitalisations after the index hospitalisation
If a non-index hospitalisation discharge date is missing or partially given then define a range 
of possible discharge dates:
∀
The lower bound is the maximum of:
o
The admission date on the same hospitalisation
o
The earliest possible date from the partial discharge date, if not missing
∀
The upper bound is the minimum of:
o
Last non-fatal follow-up
o
The latest possible date from the partial discharge date, if not missing
o
Any admission date from later hospitalisations, i.e. those with later admission 
dates
If there is a linked adverse event end date and it is between the upper and lower bound then 
this is used as the discharge date. Otherwise take the maximum of the upper and lower 
bounds.
Missing or partial start dates for concomitant targeted non-drug therapy after randomisation 
(from eCRF page ‘concomitant targeted non-drug therapies)
Missing or partial date information for start dates will be replaced according to general 
Boehringer Ingelheim (BI) rules described in the BI guidance for handling of missing and 
incomplete AE dates (4).
Death date
For patients with a record of death captured on the electronic case report form (eCRF) with 
missing or only partial death date from all available sources, the death date will be derived. 
The latest date of any of the following dates will be used: event onset and end dates from 
either the AE page, the hospitalisation page, by using also imputed AE and hospitalisation 
dates, individual day of trial completion, last date known to be alive+1day. In case of a 
partially missing date, if the subsequently derived date is before the first day (or after the last 
day) of the month/year given as a partial date, the first day (or last day) of the month/year will 
be used. 
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. For cases where only the 
month or month and year is given, take the earliest possible date in line with the month or 
month and year of the partial date given that is not prior to the randomisation date.
Missing information on the date of trial medication stop
If the date is partially or completely missing, use the minimum of the following dates:
∀
Date of death
∀
Trial completion (End of Study Participation Date)
∀
Longest extrapolated treatment duration (assuming 1 tablet/day)
∀
(in case of a partially missing date) last day of the year/month given as the partial date. 
In case of a partially missing date, if the imputed date is before the first day of the month/year 
given as the partial date, the first day of the month/year will be used. 


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Missing information on concomitant therapy dates (not for concomitant targeted non-drug 
therapies)
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 the medication is reported as not started before index hospital admission, and the imputed 
start date contradicts this then the start date is imputed to the day of index hospital admission 
if this is in the range of possible dates and can resolve the contradiction.
If prior steps lead 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. 
Missing information on reference ranges for local laboratory values 
Missing information on reference ranges for local laboratory values will be imputed according 
to (5). 
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
For all covariates used for adjustment in all analysis models, except for analyses based on 
endpoints derived from eGFR over time, baseline will be defined as the last available 
measurement before randomization, including measurements at the day of randomization. 
Since the protocol specifies, that all measurements are taken at Visit 2a before any intake of 
trial medication, all measurements at the date of randomisation are assumed to qualify as 
baseline assessments. 
For NT-proBNP, BNP and uric acid, the CTP specifies that the highest value during index 
hospitalisation before randomisation will be collected in the eCRF. These will be used as 
baseline values. 
For all other variables and all subgroup definitions given in Table 6.4:1, baseline will be 
defined as the last available measurement before start of study drug.
Measurements taken after the first intake of randomised trial medication will be considered 
on-treatment values if they have been obtained up to the end of the parameter specific follow-
up period (7 days for AE analyses and 1 day for creatinine) and will be assigned to the 
randomised study drug for efficacy and safety analyses. 
Measurements taken after the end of the parameter specific follow-up period after the last 
intake of study drug will be considered post-treatment values.
The time windows for the visits after randomisation start relative to the day of first study drug 
administration. These time windows are defined based on the planned number of days after 
the date of first administration of study drug. The midpoint between two post-baseline visits 


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defines the end of a time window, with the midpoint being included in the time window of the 
preceding visit. These windows will be used in the analysis of treatment compliance over time 
and in regional analyses of eGFR over time (see Section 10).
Table 6.7: 1
Time windows 
Time window (days from first 
study drug intake)
Visit number
Visit label
Planned days
Start
End
Treatment compliance
3
Week 2
15
2
98
4
Month 6/ 
Week 26
181
99
271
5
Month 12/ 
Week 52
361
272
451
6
Month 18/ 
Week 78 
541
452
631
7
Month 24/ 
Week 104
721
632
811
8
…
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 for patients not treated) and end 
date continued on or after date of first study medication intake (randomisation for patients not 
treated).  
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


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6.8.1
Start date
In general, e.g. for defining the primary endpoint, the time to first event will be derived from 
the date of randomisation. 
If study drug administration happened before calling IRT, the date of first drug administration 
will be used as start date.
For AE analyses according to Section 7.8.1, the date of first study drug intake will be used as 
the start date.
6.8.2
Date of event
For time-to-event endpoints including hospitalisations, the investigator-reported hospital 
admission date will be used for hospitalisation components. 
For time-to-death endpoints, the death date will be used rather than the date of first onset of 
the fatal AE.
For composite outcomes, e.g. time to first occurrence of all-cause mortality or HHF, the 
earliest date of the corresponding components will be used.
For events with multiple possible episodes, such as non-elective all-cause hospitalisation, the 
onset date of the first episode will be used, unless noted otherwise. The same applies to time-
to-AE analysis.
The primary analysis includes all events up to individual day of trial completion including the 
period after the End of Study (EoS) visit (if available). 
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 all-cause mortality and HHF).
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. 
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 death date 
∀
last hospital admission or discharge date
∀
end of treatment date


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∀
last visit date (excluding visits with type ‘medical records review only’ and excluding 
End of Study visit)
∀
End of study participation date (excluding visits with type ‘medical records review 
only’)
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
∀
last date known to be alive from the vital status page (for patients still alive after 
start of study closure) or last known alive date from End of Study page (for 
patients with unknown vital status after start of study closure)
Endpoints of any cause-specific death, e.g. CV death 
The same censoring rule as for all-cause mortality applies, and in addition, date of death if 
died from other causes than the one specified in the endpoint.
Composite endpoints 
Of those, only patients that are included in the analyses for all components of the composite 
endpoint will be included in the analysis of the composite.
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 treatment stop + x days
For any analyses until a certain number of x days after treatment discontinuation (e.g. 
sensitivity analyses until 7 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.
6.8.4
Time at risk for count variables
The time at risk for count variables (e.g. the key secondary endpoints of total number of HHF 
and death) will be calculated from the date of randomization up until individual day of trial 
completion. 
If study drug administration happened before calling IRT, the date of first drug administration 
will be used as start date.


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7.
PLANNED ANALYSIS
For End-Of-Text  tables, the set of summary statistics is: N / Mean / Standard Deviation (SD)
/ Standard Error (SE) / Minimum (Min) / lower quartile (Q1)/ Median / upper quartile (Q3)/ 
Maximum (Max). The 1st and 99th percentiles might be substituting minimum and maximum 
in tables with open-ended values to safeguard against implausible extremes.
Geometric means and ranges will be added to the presentation or replace the presentation of 
mean and standard deviation for parameters that follow a log-normal distribution rather than a 
normal distribution. 
Statistical parameters will be displayed to a defined number of decimal places as specified in 
the BI guideline “Standards for Reporting of Clinical Trials and Project Summaries” (6).
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 European Clinical Trials Database
(EudraCT) will be provided. Enrolment will be summarised by country and by age group for 
reporting in EudraCT (7).
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 disposition table will be repeated by subgroup of patients from Ukrainian sites vs non-
Ukrainian sites. The reason for not randomising screened patients will be summarized 
descriptively. 
The frequency of patients with iPDs will be presented by treatment group for the randomised 
set (RS). The frequency of patients in different analysis sets will also be presented for each 
treatment group.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Demographics and baseline characteristics will be analysed based on the RS. Demographics 
will be repeated on the TS if the analysis sets differ by more than 1%. Standard descriptive 
analysis and summary tables will be presented. These summary tables will include description 
of subgroup variables detailed in Table 6.4:1 and variables collected on screening and 
randomization visit. Descriptive analysis of the following variables measured at baseline will 
be presented: Age, BMI, time from index admission to randomization, systolic blood pressure 
, diastolic blood pressure, pulse rate, weight, eGFR, LVEF, NT-pro-BNP, BNP, uric acid, 
haemoglobin, potassium, HbA1c and LDL cholesterol. HbA1c will be presented for patients 


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with diabetes at baseline. Descriptive analysis of variables from index hospitalization will be 
presented, as well as a cross-table for lowest LVEF from index hospitalization (before 
randomization) by treatment required for HF signs/symptoms. 
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 IRT provider.  
The covariate and subgroup analysis variable ‘History of MI’ will be derived including data 
from two eCRF pages, the enrichment criteria page and the medical history page. The variable 
will be set to ‘Yes’ if any of the two pages indicates a history of MI.
The covariate ‘peripheral artery disease (PAD) at baseline’ will be derived including data 
from two eCRF pages, the enrichment criteria page and the medical history page. The variable 
will be set to ‘Yes’ if any of the two pages indicate PAD. 
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report using the RS by treatment 
group. 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 for those at the day of discharge. In 
addition, a table showing all concomitant medications taken at the day of the 6-months visit 
and one table showing all concomitant medications cumulative from baseline or introduced up 
until the 6-months visit. Separate summaries of lipid-lowering drugs, anti-thrombotic drugs, 
anti-coagulant drugs (with subcategories) and thrombolytic drugs at baseline, at day of 
discharge and at day of the 6-months visit will be presented, as well as a table showing 
medication cumulative from baseline or newly introduced until the 6-months visit. The 
frequency of patients starting any non-study drug SGLT-2 inhibitor during study will be 
displayed, as well as time-to first start of any non-study drug SGLT-2 inhibitor using 
cumulative incidence functions adjusting for the competing risk of death.
In the RS, medical history by treatment group will be presented, and relevant baseline 
conditions will be presented by SOC and PT. In addition, descriptive statistics are planned for 
concomitant non-drug procedures starting after randomisation by treatment group and by type 
of procedure.
For regional analyses on concomitant medication use please see Section 10.
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the report. The number and 
percentage of patients reporting compliance will be reported per scheduled visit as defined in 
Section 5.4. The TS will be used for analysis.
The analysis on compliance with study drug will be repeated by subgroup of patients from 
Ukrainian sites vs non-Ukrainian sites. 


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7.4
PRIMARY ENDPOINT(S)
The primary estimand of this trial is the treatment-policy estimand. 
7.4.1
Primary analysis of the primary endpoint(s)
The primary analysis will be based on RS, using all data available until individual day of trial 
completion, including the data after end of treatment for patients not completing the treatment 
phase as planned and including data up until a follow-up visit, if available. This equates a 
treatment-policy estimand. Please see Section 10.1 for detailed definition of the primary 
endpoint derivation.
The primary endpoint will be analysed using a Cox proportional hazards model with 
treatment, T2D at baseline (yes vs no), geographical region (North America, Latin America, 
Europe, Asia), age at baseline (continuous), eGFR (CKD-EPI) at baseline (<45 vs 45-<60 vs 
60-<90 vs >=90 ml/min/1.73m2), LVEF at baseline (<35% vs ≥35%), persistent or permanent 
atrial fibrillation at baseline (yes vs no), prior MI at baseline (yes vs no), peripheral artery 
disease (PAD) at baseline (yes vs no) and smoking at baseline (current vs non-current) as 
covariates. Since the stratification factors are included in the model as covariates, no stratified 
Cox regression will be used. eGFR will be derived from serum creatinine at baseline 
according to Section 7.8.2. Breslow’s method for dealing with ties will be used. 
The hazard ratio for the effect of treatment (empagliflozin versus placebo) and its two-sided 
95% Wald confidence limits will be estimated and presented with the two-sided p-value for 
the null hypothesis of equality based on the Wald chi-squared statistic. A hazard ratio of less 
than one will favour empagliflozin.
The proportional hazard assumption will be checked. 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. In 
addition a piecewise Cox model assuming proportional hazards in a series of consecutive time 
intervals as proposed by Collett (8) might be investigated.
The probability of the primary endpoint event over time will be displayed by treatment using
Kaplan Meier estimates, which includes the presentation of certain quantiles of the failure 
times (e.g. 5%, 7.5%, 10%, 15% quantiles) and Kaplan-Meier rates after specific
number of days.
Centre is not included in the statistical model due to the large number of centres involved in 
this trial (approximately 400 planned centres).
A hierarchical testing procedure will be followed for the assessment of the primary and key 
secondary endpoints as described in the CTP section 7.1. 
A hierarchical testing procedure will be applied from the primary endpoint to the set of key 
secondary endpoints 1 and 2. If, and only if, the primary endpoint is significant at α=5% (two-
sided) and shows superiority of empagliflozin versus placebo, then a Hochberg step-up 
procedure [R20-0113] will be applied to test the family of two key secondary endpoints of 
∀
Total number of HHF or all-cause mortality


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∀
Total number of non-elective CV hospitalisations or all-cause mortality
at α=5% (two-sided). 
The Hochberg step-up procedure will be applied as follows: If the largest p-value of the two 
key secondary endpoints is below or equal to 5%, both null hypotheses of the key secondary 
endpoints listed above will be rejected. If both show superiority for empagliflozin over 
placebo, confirmatory testing of the two remaining key secondary endpoints will follow via a 
hierarchical testing approach at α=5% (two-sided). Otherwise, if the smaller p-value of the 
two key secondary endpoints listed above is below or equal to 2.5% only the corresponding 
null hypothesis can be rejected. In this case, the null hypotheses of the two remaining key 
secondary endpoints will be tested in an exploratory manner only. 
7.4.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the primary 
endpoint(s)
Sensitivity analyses
The following sensitivity analyses will be conducted:
∀
To investigate the influence of actual treatment intake, a Cox regression analysis 
(model as specified above) including only on-treatment data, i.e. only data up to 
treatment stop + 7 days and using the TS
∀
To investigate the influence of start of prohibited medication, a Cox regression 
analysis (model as specified above) including only data up to first start of any non-
study drug SGLT-2 inhibitor (alone or in combination)
∀
To investigate the influence of covariate adjustment, a Cox regression analysis with 
model including only treatment and stratification factors (region and T2D status) as 
covariate, not adjusting for any other covariates
∀
To investigate the influence of investigator-based collection of HHF events, a Cox 
regression analysis (model as specified above) on the composite of time to first 
investigator-reported broad HHF or all-cause mortality, using the definition of HHF as 
in Section 10.1 and additionally including hospitalisations with criteria outlined in
Section 10.1 but:
a) irrespective of electivity of the corresponding hospitalisation
b) irrespective of the presence of signs, symptoms or laboratory findings
c) irrespective of treatment for HF
d) irrespective of all of electivity, presence of signs, symptoms and laboratory 
findings and treatment for HF (combination of a, b and c)
∀
To investigate the influence of Covid-19, a Cox regression analysis excluding all 
Covid-19 related deaths (any fatal AE in narrow BIcMQ of Sars-Cov-2 infection) 
from the primary endpoint
∀
To investigate the treatment effect if the conflict in Ukraine did not occur 
(hypothetical estimand): Using a Cox regression analysis (model as specified in 
primary analysis) applied to all patients from the RS and in which for patients from 
Ukrainian sites only data up until the last day before the start of conflict in Ukraine 
(intercurrent event) will be included (date: 23rd February 2022).
A forest plot will be presented with the estimated HR and the two-sided 95% CI for each 
sensitivity analysis. The Kaplan Meier curves (or cumulative incidence functions with 


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competing event for Covid-19 related death for the sensitivity analysis excluding Covid-19 
related deaths) will also be presented for each sensitivity analysis.
A Kaplan-Meier curve of time to censoring for primary endpoint will be presented in order to
assess whether there was differential censoring between treatment groups. For this analysis, a 
primary endpoint event will be counted as censoring and a censoring for the primary outcome 
will be counted as an event.
Patients with a hospitalization with primary cause heart failure will be listed. 
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 the 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 another categorization of a 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 Kaplan Meier curves will also be 
presented for each subgroup category.
If there are less than 14 patients with event in one subgroup (or overall), then this subgroup 
will not be included in the model (for overall <14 patients with event, the model will not be 
applied). If this leaves only one subgroup, the subgroup analysis will not be conducted. 
Subgroups without any event in one or both treatment groups may be combined with other 
subgroups. For subgroup variables with ordered categories, if there are <14 patients with 
event in one subgroup, the subgroup may be combined with a neighboring one
For the continuous covariates, baseline eGFR and age, the treatment effect will also be 
investigated on a continuous scale for the covariate. For this purpose the continuous covariate 
will be added to the model, if not already included, the categorized variable will be dropped 
from the model 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 ENDPOINT(S)
7.5.1
Key secondary endpoint(s)
Key secondary endpoints will be analysed using the RS. 
7.5.1.1
Primary analysis of the key secondary endpoint(s)
Comparisons between treatment groups regarding the count endpoint variable of total number 
of HHF or all-cause mortality will be performed using a negative binomial regression model 
adjusting for all covariates as specified in the analysis model for the primary endpoint, and 
using log(observation time) as an offset variable. Observation time for the negative binomial 


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regression model is based on the individual day of trial completion (as defined in Section 6.8). 
Differences in least squares means will be calculated and corresponding p-value used for 
hypothesis testing. Regression coefficients together with 95% confidence intervals will be 
used to quantify the effect of treatment, comparing empagliflozin to placebo as the reference.
For clarification, the negative binomial regression model will use an exponential baseline 
intensity function.
In the event that this analysis fails to converge, the model will be repeated including only 
treatment, region, T2D and the offset variable.
The key secondary endpoints of total number of non-elective CV hospitalisations or all-cause 
mortality, total number of non-elective all-cause hospitalisations or all-cause mortality and 
total number of hospitalisations for MI or all-cause mortality will be analysed in the same 
way as the total number of HHF or all-cause mortality.
The negative binomial model assumptions will be checked. In case the model fit is 
inappropriate in that the deviance value is much larger than the degrees of freedom, a model 
using the Sandwich-type estimator for the standard error will be performed. 
Non-parametric mean cumulative function curves will be used for graphical presentation for 
all key secondary endpoints.
7.5.1.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the key secondary 
endpoint(s)
Sensitivity analyses
The following sensitivity analyses will be conducted, always including the same covariates as 
in the primary analysis unless stated otherwise:
∀
To investigate the influence of actual treatment intake, a negative binomial model 
including only on-treatment data, i.e. only data up to treatment stop + 7 days and using 
the TS
∀
To investigate the influence of start of prohibited medication, a negative binomial 
model including only data up to first start of any non-study drug SGLT-2 inhibitor 
(alone or in combination)
∀
To investigate the influence of covariate adjustment, a negative binomial model 
including only treatment and stratification factors (region and T2D status) as 
covariate, not adjusting for any other covariates
∀
Only for endpoint ‘total number of HHF or all-cause mortality’: To investigate the 
influence of investigator-based collection of HHF events, a negative binomial 
regression model (model as specified above) on the composite total number of 
investigator-reported broad HHF or all-cause mortality, using the definition of HHF as 
in Section 10.1 and additionally including hospitalisations with criteria outlined in
Section 10.1 but:
o
irrespective of electivity of the corresponding hospitalisation
o
irrespective of the presence of signs, symptoms or laboratory findings
o
irrespective of treatment


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o
irrespective of electivity, presence of signs, symptoms and laboratory findings 
and treatment (combination of a, b and c)
∀
To investigate the influence of Covid-19, a negative binomial model excluding all 
Covid-19 related deaths from the key secondary endpoints
∀
To investigate the treatment effect if the conflict in Ukraine did not occur 
(hypothetical estimand): Using a negative binomial model applied to all patients from 
the RS and in which for patients from Ukrainian sites only data up until the last day 
before the start of conflict in Ukraine (intercurrent event) will be included (date: 23rd 
February 2022).
A forest plot will be presented with the estimated rate ratio and the two-sided 95% CI for each 
sensitivity analysis. Non-parametric mean cumulative function curves will also be presented 
for each sensitivity analysis.
Subgroup analyses
Subgroups will be explored as outlined in Section 6.4 for all key secondary endpoints. For 
subgroup analyses the term of subgroup (if not already part of the model) and subgroup by 
treatment interaction will be added to the model. If the subgroup variable is another
categorization of a covariate, this covariate will be dropped from the subgroup model. 
If there is <5 events, <5 patients or <90 days at risk in any treatment group of a subgroup (or 
overall), then this subgroup will not be included in the model (for <5events, <5 patients or 
<90 days at risk overall, the model will not be applied). If this leaves only one subgroup, the 
subgroup analysis will not be conducted. Subgroups without any events in one or both 
treatment groups may be combined with other subgroups. For subgroup variables with 
ordered categories, if there are <5 events, <5 patients or <90 days at risk in any treatment 
group of a subgroup, the subgroup may be combined with a neighboring one.
7.5.2
(Other) Secondary endpoint(s)
Other secondary endpoints will be analysed using the RS and are exploratory. No correction 
for multiple hypotheses testing will be made.
Time to CV mortality will be analysed using a Cox proportional hazards model with the same 
covariate adjustment as for the primary endpoint. Cumulative incidence functions with 
competing event of non-CV death will be used for graphical presentation. A frequency table 
of the subcategories of CV death will be given.
7.6
FURTHER ENDPOINT(S)
Further endpoints will be analysed using the RS. 
For clarification, to derive the endpoints ’30-day all-cause hospitalisation’ and ‘Days alive 
and out of hospital’ all hospitalisations will be included (i.e. non-elective and elective 
hospitalisations), except for elective hospitalisations that had been pre-planned at 
randomisation. Please also refer to Section 10.2.
Comparisons between treatment groups regarding the binary endpoint variable ‘30-day all 
cause hospitalisation’ (calculated from date of discharge or randomisation, whatever comes 


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latest) will be performed using a logistic regression model adjusting for the same covariates as 
in the primary analysis model. Patients who died within the 30 days will be counted as an 
event. Only patients with at least 30-day observation time for all-cause hospitalisation and 
death will be analysed (i.e. patients with observation time <30 days due to withdrawal or lost-
to-follow-up will be excluded from this analysis). Patients with discharge date of the index 
hospital admission being equal to the day of death will be excluded in this analysis. The 
likelihood-ratio test will be used to test for the difference between treatments. Adjusted odds 
ratios together with 95% confidence intervals will be used to quantify the effect of treatment, 
comparing empagliflozin with placebo as the reference. 
The continuous endpoint days alive and out of hospital until day 90 after randomisation will 
be analysed descriptively. Days alive and out of hospital until 6 months, 9 months and 12 
months after randomisation will be analysed using the same approach. 6 months is considered 
180 days, 9 months is considered 270 days and 12 months is considered 365.25 days.
Days alive and out of hospital (DAOH) will be summarised as a percentage (9) as follows:
The follow-up time for analyses of DAOH until day 90 after randomisation is defined as the 
minimum of 90 days after randomisation, or time between randomisation and individual day 
of trial completion except for patients who died within the first 90 days, where 90 days is 
considered as the DAOH follow-up time. Days alive and out of hospital (DAOH) for each 
patient is calculated as follow-up time subtracted by the number of days in hospital during the 
90 days after randomisation as well as the number of days being dead within the first 90 days. 
Percentage DAOH until day 90 is defined as DAOH until day 90 divided by the DAOH 
follow-up time of each patient multiplied by 100. The same approach will be taken for DAOH 
until 6 months, 9 months and 12 months. 
Time-to first event endpoints will be analysed in the same way as the primary endpoint 
primary model. Kaplan Meier curves will be presented for visualisation. If the time-to-event 
endpoint does not include all-cause mortality, cumulative incidence curves will be used 
instead.
For time to first HHF or CV death subgroup analyses as defined in Section 6.4 will be 
performed. 
For the two endpoints time to CV death and time to first HHF or CV death, sensitivity 
analyses will be done to investigate the influence of the conflict in Ukraine on the results. In 
these sensitivity analyses, a Cox regression will be applied in which for patients from 
Ukrainian sites only data up until the last day before the conflict in Ukraine started will be 
included (date: 23rd February 2022). In addition, categories of death will be shown by 
subgroup of Ukrainian sites vs non-Ukrainian sites.
7.7
EXTENT OF EXPOSURE
Extent of exposure will be analysed on the TS. Extent of exposure is defined in Section 5.4. 
Descriptive statistics tables with mean, SD, median and range of the number of 
days/months/years 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.


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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):  <12 weeks, ≥12 to <26 weeks, ≥26 to <52 weeks, ≥52 to <78 weeks, ≥78 to <104 
weeks, ≥104 weeks. Categorical ranges may be adapted based on the actual duration of the 
study. 
The analysis on extent of exposure will be repeated by subgroup of patients from Ukrainian 
sites vs non-Ukrainian sites. Overall observational time (until vital status follow-up) and 
overall observation time (until individual day of trial completion) as defined in Section 5.4
will be analysed on the RS using the same descriptive statistics.
7.8
SAFETY ANALYSIS
The safety analysis will be based on the 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 an AE occurred during on-treatment or post-treatment phase.
7.8.1
Adverse Events
Unless otherwise specified, the analyses of AEs will be descriptive in nature. All analyses of 
AEs will be based on the number of subjects with AEs and NOT on the number of AEs.
AEs will be coded using the current version of the Medical Dictionary for Regulatory 
Activities (MedDRA) coding dictionary. 
Definitions of BI customised MedDRA Queries (BIcMQs) for new MedDRA versions are 
maintained by the BI dictionary maintenance group. 
For further details on summary of AE data, please refer to (4), (10).
For a subset of adverse events exempted from expedited reporting and AESIs auto-coding is 
applied, because these are collected via tick-boxes in the eCRF. Please see Table 7.8.1:1 for 
auto-coding applied.


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Table 7.8.1: 1 Auto-coding for exempted AEs and AESIs
Exempted event or AESI from CTP
Derived preferred term from auto-coding 
Heart Failure
Cardiac failure
Myocardial infarction
Myocardial infarction
Non-cardiac chest pain
Non-cardiac chest pain
Post-procedural heamorrhage
Post procedural heamorrhage
GI bleeding
Gastrointestinal haemorrhage
Haematuria
Haematuria
Respiratory tract infection (not COVID-19)Respiratory tract infection
Pneunomia (not COVID 19)
Pneumonia
Syncope
Syncope
Contrast induced acute kidney injury
Nephropathy toxic
Ketoacidosis
Ketoacidosis
Hepatic Injury
Liver injury
7.8.1.1 Assignment of AEs to treatment
The analysis of AEs will be based on the concept of treatment-emergent AEs. That means that 
all AEs occurring between first drug intake till 7 days after last drug intake will be assigned to 
the randomised treatment. All AEs occurring before first drug intake will be assigned to 
‘screening’ and all AEs occurring after last drug intake + 7 days will be assigned to ‘post 
treatment’, except if otherwise specified. For details on the treatment definition, see Section 
6.1.
In Section 15.3 of the CTR, general AE analysis tables will present only on-treatment AEs 
(applying the rule of 7 days for assignment as on-treatment) for the treatment groups, unless 
otherwise defined. In section 15.3, only SAEs, AEs leading to study drug discontinuation of at 
least 7 days or AESIs will be displayed. 
Appendix 16.1.13.1 of the CTR will include an analysis (overall summary table, frequency of 
AEs by SOC / PT, frequency of SAEs by SOC/PT) where AEs and SAEs are assigned to the 
following phases: Screening, each treatment group, post-treatment for each treatment group.
For these tables, all AEs which were collected will be displayed (including non-serious AEs 
that neither led to study drug discontinuation nor qualified as AESI).
For listings, AEs will be assigned to one of the following treatment phases: Screening, 
Placebo, Empa 10, Post Placebo, Post Empa.
Please refer to Section 7.8.1.3 on certain AESIs with additional definitions for the duration of 
the ‘on-treatment’ phase.


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7.8.1.2 AE summaries
An overall summary of patients with at least one AE expected to be reported in this trial will 
be presented: This will include any serious adverse events, AEs leading to study drug 
discontinuation of at least 7 days or AESIs.
The frequency of patients with AEs will be summarised by treatment, primary system organ 
class and preferred term. Incidence rates as defined in Section 7.8.1.6 will generally be 
included. 
Separate tables based on AEs expected to be reported in this trial will be provided for: 
∀
for patients with serious adverse events, 
∀
for patients with drug-related serious AEs,
∀
for patients with AEs leading to permanent treatment discontinuation,
∀
for patients with fatal AEs, 
∀
for patients with drug-related AEs,
∀
for patients with an AE of special interest (AESI), separately for each AESI category
The frequency of patients with adverse events to be reported in this trial 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.
In addition, AEs leading to death will be listed and a summary table for all fatal AEs up to 
individual day of trial completion will be given. Patients with AEs leading to permanent 
treatment discontinuation will also be listed.
The system organ classes and PTs will be sorted by decreasing frequency (within SOC). 
Customized sorting orders may also be used based on trial needs, e.g. SOC sorted by 
frequency.
Sensitivity analyses will be performed to investigate the influence of the conflict in Ukraine 
on the results. The overall AE summary table, tables showing patients with AEs by SOC/PT, 
SAEs by SOC/PT and fatal AEs will be repeated in which for patients from Ukrainian sites 
only data up until the last day before the conflict in Ukraine started will be included (date: 
23rd February 2022). 
Additionally, the following analyses will be reported in Appendix 16.1.13.1 of the CTR for 
disclosure on EudraCT and clinicaltrials.gov (see (7) for further details), based on AEs to be 
reported in this trial:
∀
Frequency [N (%)] of patients with non-serious AEs occurring with incidence in 
preferred term greater than 5% by treatment,


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∀
AEs per arm for disclosure on EudraCT by treatment
∀
Non-serious AEs for disclosure on EudraCT by treatment
∀
Serious AEs for disclosure on EudraCT by treatment
Refer to Section 10.3 for regional analyses. 
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. 
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 permanent treatment 
discontinuation will be presented separately.
In addition to the ‘7-day-on-treatment approach’, a ‘30-day-on-treatment approach’ will be 
presented for the overall hepatic injury adverse events. 
Patients with hepatic injury will be listed.
Ketoacidosis
A frequency table of patients with AEs related to ketoacidosis will be presented by treatment, 
primary SOC and preferred term for investigator reported cases and separately for the narrow 
BIcMQ definition of diabetic ketoacidosis. The presentation of investigator-reported cases 
will be repeated by T2DM status at baseline (T2DM vs no T2DM).
Patients with diabetic ketoacidosis based on the narrow BIcMQ (30000019) or investigator 
reported ketoacidosis will be listed. 
Adverse 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.
For events leading to lower limb amputations in addition to the’ 7 -day-on-treatment 
approach’ all AEs that occurred between first study drug intake up to individual day of trial 
completion will be presented (following censoring rules like non-fatal outcome events).
Adverse event leading to lower limb amputations (up to individual day of trial completion) 
will additionally be summarised by level of first amputation and reason for first amputation. 
Patients with adverse events leading to lower limb amputation will be listed.
Contrast induced acute kidney injury


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A frequency table of patients with AEs of contrast induced acute kidney injury as identified
by the investigator by treatment, primary SOC and preferred term will be provided. Based on 
number of patients with events, subgroup analyses by eGFR at baseline may be performed. 
Separate tables for contrast induced acute kidney injury events, which are serious and those 
which are leading to discontinuation will be presented. 
Patients with contrast induced acute kidney injury will be listed including their baseline 
eGFR. 
Additional analyses on AESIs
Appendix 16.1.13.1 of the CTR will include subgroup analyses for selected AESI concepts. 
AESI concepts to be analysed include ketoacidosis (narrow BIcMQ ‘Ketoacidosis’ 
(30000019)), hepatic injury (investigator-defined) and AEs leading to lower limb amputation 
(investigator defined). The following subgroups will be considered: sex (male vs female), race 
(White vs Black or African American vs Asian vs Other incl. mixed race), age (<50 vs 50-<65 
vs 65-<75 vs >=75), eGFR (<30 vs 30-<45 vs 45-<60 vs 60-<90 vs >=90) and T2D (yes vs 
no). For these analyses, only AEs to be reported in this trial will be included (i.e. SAEs, AEs 
leading to treatment discontinuation of at least 7 days or AESIs). The Treated Set will be used 
and analyses include AEs occurring between first drug intake till 7 days after last drug intake. 
7.8.1.4 Specific AEs
Serious hypoglycaemia or hypoglycaemia leading to study drug discontinuation of at least 7 
days
The number of patients with hypoglycaemia according to narrow SMQ (20000226) will be 
presented, including only SAEs and AEs leading to study drug discontinuation.
Subgroup analyses on events with respect to T2D status at baseline (yes vs no) will be 
performed. Separate tables for hypoglycemia events, which are serious and those which are 
leading to permanent treatment discontinuation will be presented. 
Patients with such events will be listed. 
Serious hypotension or hypotension leading to study drug discontinuation of at least 7 days
Hypotension by treatment, primary system organ class and preferred term will be provided, 
including only SAEs and AEs leading to study drug discontinuation. Hypotension is defined 
as preferred terms of the BIcMQ ‘Volume depletion and hypotension due to dehydration’ 
(30000090) but excluding preferred terms of dehydration and hypovolaemia.
Separate tables for hypotension events, which are serious and those which are leading to 
permanent treatment discontinuation will be presented. 
Patients with such events will be listed.


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Serious volume depletion or volume depletion leading to study drug discontinuation of at 
least 7 days
Volume depletion will be based on the BIcMQ ‘Volume depletion and hypotension due to 
dehydration’ (30000090).
A frequency table of patients with volume depletion by treatment, primary SOC and preferred 
term will be provided including only SAEs and AEs leading to study drug discontinuation.
Separate tables for volume depletion events, which are serious and those which are leading to 
permanent treatment discontinuation will be presented. 
Patients with such events will be listed.
Serious acute renal failure or acute renal failure leading to study drug discontinuation of at 
least 7 days
A frequency table of patients with AEs related to acute renal failure by treatment, primary 
SOC and preferred term will be provided based on the narrow SMQ ‘Acute renal failure’
(20000003), including only SAEs and AEs leading to permanent study drug discontinuation. 
Subgroup analyses by eGFR at baseline will be performed. Separate tables for acute renal 
failure events, which are serious and those which are leading to permanent treatment 
discontinuation will be presented. 
Patients with such events will be listed.
Sensitivity analyses will be performed to investigate the influence of the conflict in Ukraine 
on the results. Frequency tables on patients with AESIs or specific AEs will be repeated in 
which for patients from Ukrainian sites only data up until the last day before the conflict in 
Ukraine started will be included (date: 23rd February 2022). In addition, for AEs leading to 
lower limb amputation the frequency table showing all AEs up until trial completion will be 
repeated using this censoring approach for Ukrainian patients. 
7.8.1.5 AEs while patients taking wrong medication
A listing will be provided for AEs that occurred while a patient was taking the wrong study 
medication. If such a patient is identified, an additional adverse event table that assigns the 
adverse events to the actual treatment taken will be presented. A patient who took both the 
assigned treatment and at least one tablet of the wrong treatment, will be counted as at risk in 
both treatment groups for the respective relevant time. The table will include all adverse 
events expected to be reported in this trial (SAEs, AEs leading to study drug discontinuation 
and AESIs) by SOC and PT. 
7.8.1.6 Adverse event incidence rates
For AE tables showing patients with events, in addition to the frequency tabulations, time-
adjusted adverse event analyses will be performed.


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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 first 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 individual 
day of trial completion, 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 for patients with AE is 
calculated using start of first AE summarised in this row; e.g. for patients with an AE in a 
specified SOC, time at risk = date of start of first AE with specified PT in this SOC – start of 
study treatment + 1.
The AE incidence rate per 100 patient years will then be calculated as follows:
Incidence rate per 100 patient years (pt-yrs) = 100 * number of patients with AE / time at risk 
(AE) [years].
In a similar way, the time at risk and incidence rate for the post-treatment period is derived. 
Here the start date is the start date of the post-treatment phase instead of the study treatment 
start date.
7.8.2
Laboratory data
No safety laboratory parameter will be collected after randomization as per global CTP. 
For laboratory parameters, including serum creatinine, standardized values will be analysed.
Laboratory parameters will be shown in conventional units. Where conventional units differ 
from SI units, analyses will be repeated on SI units. Normalized values of baseline laboratory 
data will be presented in Appendix 16.1.13.1. The process of standardization and 
normalization is described in the BI guidance for the Display and Analysis of Laboratory Data
(11).
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. 
Descriptive statistics will be provided by treatment group for baseline values. 
For regional analyses, please see Section 10.3.


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7.8.3
Vital signs
Heart rate and blood pressure (diastolic and systolic) at baseline will be summarised 
descriptively based on the RS as part of the baseline characteristics. 
7.8.4
ECG
Not applicable.
7.8.5
Others
Frequency of pregnancies and pregnancy outcomes will be listed by treatment.


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8.
TIMEPOINT OF RELEASE OF TREATMENT 
INFORMATION
The treatment information will be released to unblind the trial database after the last patient 
has completed their End-of-Study/Follow-up visit and all data has been entered and cleaned as
defined in the “Data Ready to be Unblinded and/or Final Trial Closure Notification” (RUN) 
form.


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9.
REFERENCES
1.
c38770730: Event review charter and guidance for EMPACT-MI
2.
c38770729: Protocol Deviation Management Plan
3.
c35802484-01: Integrated Quality Risk Management Plan
4.
BI-KMED-BDS-HTG-0035: “Handling of Missing and Incomplete AE Dates”, current 
version; Veeva Vault.
5.
BI-KMED-BDS-MAN-0025: “Handling of incomplete reference ranges”, current 
version; Veeva Vault.
6.
BI-KMED-BDS-HTG-0045: "Standards for Reporting of Clinical Trials and Project 
Summaries", current version; Veeva Vault.
7.
BI-KMED-BDS-QRG-0010: “Preparation of tables for results disclosure", current 
version; Veeva Vault.
8.
Collett D.
Modelling survival data in medical research.
Chapman and Hall/CRC 2003 [R07-4680]
9.
R22-1038: Ariti CA, Cleland JG, Pocock SJ, et al. Days alive and out of hospital and 
the patient journey in patients with heart failure: Insights from the candesartan in heart 
failure: assessment of reduction in mortality and morbidity (CHARM) program. Am 
Heart J. 2011;162(5):900-906. doi:10.1016/j.ahj.2011.08.003
10. BI-KMED-BDS-HTG-0066: "Analysis and Presentation of Adverse Event Data from 
Clinical Trials", current version; Veeva Vault.
11. BI-KMED-BDS-HTG-0042: "Handling, Display and Analysis of Laboratory Data", 
current version; Veeva Vault.
12. BI-KMED-COPS-BUP-0007: “Clinical Bridging Study Waiver (BSW) and Subgroup 
Analysis (SGA) Reports for Asian countries”, current version; Veeva Vault.
13. 001-MCS-40-113: "Clinical Trial Report (CTR) Phase I - IV, Interim Reports and Other
Associated Regulatory Documents”, current version; Veeva Vault.


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10.
ADDITIONAL SECTIONS
10.1
DETAILED DESCRIPTION OF PRIMARY ENDPOINT
Only the events satisfying HHF criteria of “Event review charter and guidance for EMPACT-
MI”, will be included into the analysis:
∀
eCRF documents that the hospitalisation was non-elective (this includes 
hospitalisations with unknown attribute of urgency)
∀
eCRF documents that the date of hospital discharge is at least one day after hospital 
admission (only non-missing admission and discharge dates will be used, the 
discharge date must be after the admission date based on the lowest level of 
information available in those dates)
∀
The primary cause for hospitalisation in eCRF is documented as “Heart Failure” 
which is supported by documented in eCRF evidences of signs or symptoms of heart 
failure (lab and imaging findings are considered as signs) that required treatment:
o
‘Did the patient have new or worsening symptoms, signs or laboratory findings 
of heart failure?’ = Yes AND
o
‘Was therapy for heart failure initiated or intensified?’=Yes
o
For clarification: 

If the response to ‘Did the patient have new or worsening symptoms,
signs or laboratory findings of heart failure?’ is Yes, but all single 
symptoms, all single signs and all single lab findings are=No, this 
criterion is not seen as fulfilled 

If the response to  'Was therapy for heart failure initiated or intensified’ 
=Yes, but all single therapies = No, this criterion is not seen as fulfilled
The date of the HHF is defined as the date of the corresponding hospital admission. 
10.2
DETAILED DESCRIPTION OF (KEY) SECONDARY ENDPOINTS AND 
FURTHER ENDPOINTS
∀
According to the ‘Event review charter and guidance for EMPACT-MI’ and for 
further clarification: A hospitalisation will be analysed as a hospitalisation if the date 
of hospital discharge is at least one day after the date of hospital admission (only non-
missing admission and discharge dates will be used, the discharge date must be after 
the admission date based on the lowest level of information available in those dates)
∀
For clarification: For the key secondary endpoint ‘Total number of HHF or all-cause 
mortality’ a hospitalisation will be included in the analysis if it satisfies the criteria for 
an HHF as defined in Section 10.1
∀
Non-elective hospitalisations always include hospitalisations with unknown attribute 
of urgency
∀
CV hospitalizations include 


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o
hospitalisations with primary reason heart failure
o
hospitalisations with primary reason MI
o
hospitalisations with primary reason any other CV causes
∀
Given the acute nature of an MI, a hospitalisation with primary reason MI will always 
be analysed as a non-elective hospitalisation
10.3
ADDITIONAL ANALYSES FOR REGIONAL SUBMISSIONS
Appendix 16.1.13.2 of the CTR will include the below regional analyses.
Disposition and demographics of the subpopulation for patients from USA and subgroup 
analyses for patient from the USA vs non-USA will be performed. Efficacy endpoints 
evaluated will be primary endpoint and key secondary endpoints. Safety will be summarized 
for patients from the USA.  
Additional country or region-specific analyses will be conducted for patients of Asian race 
from East-Asia (China, Japan and Korea), China, Japan and India and included into the 
country-specific submission documents as also outlined in (12) and (13). The primary 
endpoint, all key secondary endpoints, secondary and further endpoints will be presented. 
Main adverse event overviews, disposition, demographics will be presented.
For East-Asia and Japan, the region-specific analyses include subgroup analyses for the 
primary, key secondary endpoints and main AE tables for subgroups defined in Section 6.4, 
except region, ethnicity and race within the local population. Analyses for the primary 
endpoint will be done using Cox regression and for key secondary endpoints via negative 
binomial regression models. The rules for not applying these models in subgroup analyses as 
described above still apply (i.e. for the primary endpoint see Section 7.4.2: if there are less 
than 14 patients with event; for key secondary endpoints see Section 7.5.1.2: if there are <5 
events, <5 patients or <90 days at risk in any treatment group of a subgroup). 
10.3.1 
Time windows
Patients from Bulgaria, Germany, Hungary and Serbia only:
Patients from these countries have an additional visit 3b and regional visit windows are 
specified in Table 10.3.1:1 below. These windows will be used in the additional regional 
analysis of compliance over time and eGFR over time.


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Table 10.3.1:1 Time windows for regional analyses
Time window (days after first 
study drug intake)
Visit number
Visit label
Planned days
Start
End
Creatinine/eGFR and treatment compliance
2a
Baseline 1
1
NA
1
3
Week 2
15
2
53
3b
Month 3/ 
Week 13
91
54
136
4
Month 6/ 
Week 26
181
137
271
5
Month 12/ 
Week 52
361
272
451
6
Month 18/ 
Week 78 
541
452
631
7
Month 24/ 
Week 104
721
632
811
8
…
1 Only values taken prior to the start of treatment with randomised study drug can be considered baseline values. Time windows will be used 
for assignment of measurements to scheduled visits.
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 residual effect 
period) are considered. For eGFR (lab value), all measurements taken up to 1 day after last 
permanent treatment stop date are considered on-treatment. 
Observed case including data after treatment discontinuation (OC-AD):
All available data are considered, including values obtained on treatment or post-treatment.
On-treatment (for OC-OT analysis) or all post-randomisation (for OC-AD analysis) eGFR 
and compliance (for compliance, only OC-OT analysis) measurements will be assigned to 
visits based on time windows around the planned visit dates (see Table 10.3.1:1). These time 
windows are defined based on the planned number of days after the date of first study drug 
intake. 
For eGFR, only one observation per time window will be selected for a 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. 
eGFR over time will be listed as well as clinically significant abnormalities based on eGFR 
over time.


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10.3.2 
Treatment Compliance
Including patients from Bulgaria, Germany, Hungary and Serbia only:
Treatment compliance will be summarised as per Section 5.4, but using the regional visit 
windows as per Table 10.3.1:1.
10.3.3 
Concomitant diseases and medication
Including patients from Bulgaria, Germany, Hungary and Serbia only:
Concomitant medication use will be summarised by Anatomical-Therapeutic-Chemical 
classification level 3 (ATC3) and preferred name. Summaries will be presented for 
concomitant therapies newly introduced after baseline until study end. Separate summaries of 
lipid-lowering drugs, anti-thrombotic drugs, anti-coagulant drug (with subcategories) and 
thrombolytic drugs newly introduced after baseline until study end will be presented, as well 
as a table showing medication at baseline or newly introduced after baseline (including after 
visit 4). 
Including patients from Japan only:
Concomitant medication use at the End of Study visit will be summarised by Anatomical-
Therapeutic-Chemical classification level 3 (ATC3) and preferred name. Separate summaries 
of lipid-lowering drugs, anti-thrombotic drugs, anti-coagulant drug (with subcategories) and 
thrombolytic drugs will be presented.
10.3.4 
Further endpoints
Including patients from Bulgaria, Germany, Hungary and Serbia only:
eGFR will be calculated based on standardized serum creatinine. Change in eGFR (CKD-EPI) 
from baseline over time (at 2 weeks, 3 months/13 weeks and 6 months/26 weeks) will be 
analysed in a mixed model with repeated measures (MMRM). The analysis will include 
baseline age as linear covariate, the fixed categorical effects of treatment at each visit, 
geographical region, T2D at baseline, gender, LVEF at baseline (<35% vs ≥35%), persistent
or permanent atrial fibrillation at baseline (yes vs no), prior MI at baseline (yes vs no), 
peripheral artery disease (PAD) at baseline (yes vs no), smoking at baseline (current vs non-
current) and the fixed continuous effects of baseline eGFR at each visit. The MMRM analyses 
will be performed using on-treatment data only (OC-OT)  and will be repeated on all data 
including measurements after treatment stop (OC-AD).
An unstructured covariance structure will be used to model the within-patient errors. 
Change in eGFR (CKD-EPI) from baseline to last value on treatment (or last value in study) 
will be evaluated by an ANCOVA model, including eGFR at baseline and age as linear 
covariates and treatment group, geographical region, T2D at baseline, gender, LVEF at 
baseline (<35% vs ≥35%), persistent or permanent atrial fibrillation at baseline (yes vs no), 
prior MI at baseline (yes vs no), peripheral artery disease (PAD) at baseline (yes vs no) and 
smoking at baseline (current vs non-current) as covariates. 


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For MMRM and ANCOVA analysis on eGFR (OC-AD) the randomised set will be used, 
while for the on-treatment analysis (OC-OT) the treated set will be used.  Descriptive 
statistics will be calculated for the value at the scheduled visit and change from baseline based 
on OC-AD on the randomised set and OC-OT on the treated set. 
10.3.5 
Safety Analyses
Including patients from Germany and Serbia only:
The frequency of patients with AEs will be summarised by treatment, primary SOC and PT. 
Separate tables will be given for all SAEs, AEs leading to discontinuation and separately for 
each AESIs. 
Including all patients, as a specific request from PMDA:
A frequency table of patients with AEs related to ‘in-stent thrombosis’ by treatment, primary 
SOC and preferred term will be provided based on the broad BITS ‘Device related thrombosis 
associated with MI’. Patients with device related thrombosis associated with MI will be listed.
10.4
REGIONS AND COUNTRIES
Countries will be assigned to regions following the assignment of the IRT system, which is 
outlined in Table 10.4:1. Listed countries include currently planned backup countries. 


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Table 10.4:1 Regions and countries
Region
Country
North America
USA
Canada
Latin America
Argentina
Brazil
Europe
Australia
Bulgaria
Denmark
France
Germany
Hungary
Israel
Netherlands
Poland
Romania
Russia
Serbia
Spain
Ukraine
Asia
China
India
Japan
Korea


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11.
HISTORY TABLE
Table 11: 1
History table
Version
Date
(DD-MMM-
YY)
Author
Sections 
changed
Brief description of change
1 
10 MAY 2022
None
This is the final TSAP 
Revised
26 MAY 2023
5.3
Clarification of derivation of baseline ICD/CRT 
at added.
6.4
Subgroups Atrial fibrillation at baseline and 
revascularization for index MI deleted. Endpoint 
‘Time to first HHF or CV death’ added for 
subgroup analyses.
6.6.1
Clarification about using imputation for 
covariates for other statistical models added.
6.8.3
Date a patient switched to option 5 excluded 
from censoring as date is included in visit dates 
already.
7.1
Clarification about derivation of covariate and 
subgroup variable ‘history of MI’ added. 
Clarification about derivation of covariate ‘PAD 
at baseline’ added.
7.4.2
Clarification added for subgroup analyses if the 
subgroup is another categorization of a covariate.
7.5.1.1
Clarification added, including for when the 
Sandwich type estimator will be used.
7.5.1.2
Clarification added for subgroup analyses if the 
subgroup is another categorization of a covariate.
7.6
Added subgroup analyses for time to first HHF 
or CV death.
Clarification about derivation of 30-day-all-cause 
hospitalisation and DAOH added.
7.8.1.3
Analysis of ketoacidosis by T2D added
Analyses on AESI concepts by subgroup added.
7.8.1.4
Update of naming of the BIcMQs related to 
hypotension.
7.8.2
Clarification that laboratory values will be 
standardized, while normalized laboratory values 
will be shown in appendix 16.1.13.1.
10.1
Correction of typo: Discharge date must be after 
admission date instead of the other way round.
10.2
Correction of typo: Discharge date must be after 
admission date instead of the other way round.
Clarification that details apply in the same way 
for further endpoints.
Clarification that for endpoint ‘Total number of 
HHF or all-cause mortality’ a hospitalisation will 
be included if it fulfils criteria of a an HHF as 
defined for the primary endpoint component.
10.3
Clarification of subgroup analyses within 
regional Japanese / East-Asian population added.
10.3.1
Listings of eGFR to be included for specified 
countries.
10.3.4
Clarification added for eGFR calculation