Clinical trial NCT03087773
Conditions: Acute Myocardial Infarction
Keywords: Biomarker Heart failure SGLT-2 inhibitor Empagliflozin Randomized controlled trial
Sponsor: Medical University of Graz
Start date: 2017-05-11; Completion date: 2022-05-17
Enrollment: 476 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is planned to investigate the impact of Empagliflozin on biomarkers of heart failure in patients with myocardial infarction with and without type 2 diabetes mellitus within 6 months after the event.

Detailed description:
Type 2 diabetes mellitus (T2DM) is associated with an about two to three-fold increased risk for cardiovascular events as compared to subjects without diabetes.

Sodium-dependent glucose cotransporter 2 (SGLT-2) is mainly expressed in human kidneys and small intestinal cells. In the proximal tubule of the nephron SGLT-2 is responsible for the reabsorption of approximately 90% of the filtrated glucose. Inhibition of SGLT-2 was shown to increase renal glucose excretion and to lower glucose. Subsequently, a number of SGLT-2 inhibitors were developed and are currently approved for the treatment of type 2 diabetes.

Recently, Zinman et al published the results of the Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patient trial (EMPA REG OUTCOME TRIAL) where the cardiovascular impact of a glucose lowering regimen including Empagliflozin as compared to usual glucose control without an SGLT-2 inhibitor was investigated. The trial demonstrated an unexpected reduction in the primary composite endpoint, comprising cardiovascular death, non-fatal myocardial infarction and non-fatal stroke. The reduction was mainly driven by a 38% relative risk reduction in cardiovascular deaths; moreover they demonstrated an impressive 35% relative risk reduction in the secondary endpoint hospitalization for heart failure. Of note, the beneficial effects observed in the Empagliflozin group seem to occur very rapidly after commencing the treatment, as suggested by the early separation of the Kaplan-Meier curves. However, the mechanisms responsible for this finding remain unclear. Diuretic effects with subsequent impact on hemodynamics or potential cardioprotective effects of glucagon, which levels rise under the treatment with SGLT-2 inhibitors and the resulting rise in ketone bodies or a small increase in hematocrit have been suggested.

The aim of our trial is to investigate whether Empagliflozin treatment commenced within 72-h after acute myocardial infarction has an impact on heart failure in subjects with and without diabetes mellitus type 2.

Arms: arm 1: The subjects will receive Empagliflozin 10mg. arm 2: The subjects will receive placebo.
Interventions: intervention 1: Empagliflozin 10 mg intervention 2: Placebo Oral Tablet
Intervention descriptions: intervention 1: The subject will receive Empagliflozin 10 mg orally once daily for 26 weeks. intervention 2: The subject will receive Placebo orally once daily for 26 weeks.

Protocol documents:
Prot_000.pdf: 
 
 
Title: 
EMMY–TRIAL 
 
Protocol No: 
Version 2.17 
 
Date: 
17 October 2022 
   
 
1  
 
 
CLINICAL STUDY PROTOCOL 
 
 
Study Title: 
Impact of EMpagliflozin on cardiac function and biomarkers of heart failure in 
patients with acute MYocardial infarction (EMMY-Trial)  – a phase III Study 
Protocol Number: 
HS-2017-01 
Product: 
Empagliflozin 
Sponsor: 
Medical University of Graz 
Protocol Date: 
17 October 2022 
Protocol Version: 
2.17  
Ethics number: 
29-179 ex 16/17 
EudraCT number: 
2016-004591-22 
Contact: 
Dr. Norbert Tripolt, MSc. 
Mail: emmy@medunigraz.at 
Phone: 0316/385 78038  
 
 
 
 
Property of Medical University of Graz: 
May not be used, divulged or published without the consent of the Chief Investigators 
 
Financial support: Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria 
 


 
 
Title: 
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CONTACT LIST 
Chief Investigators 
Univ.-Prof. Dr. Harald Sourij 
Division of Endocrinology and Diabetology 
Department of Internal Medicine 
Medical University of Graz 
Auenbruggerplatz 15 
8036 Graz, Austria 
Tel: +43 316 385 81310 
Fax: +43 316 385 13428 
Assoc.-Prof. Dr.  Dirk von Lewinski 
Division of Cardiology 
Department of Internal Medicine 
Medical University of Graz 
Auenbruggerplatz 15 
8036 Graz, Austria 
Tel: +43 316 385 80684 
Fax: +43 316 385 13733 
Biometrician 
Ass.-Prof. Dr. Abderrahim Oulhaj 
College of Medicine and Health Sciences 
United Arab Emirates University 
P.O.Box 17666, Al-Ain 
United Arab Emirates 
Sponsor 
Medical University of Graz 
Auenbruggerplatz 2-4 
8036 Graz, Austria 
Funder 
Boehringer Ingelheim RCV GmbH & Co KG 
Dr. Boehringer-Gasse 5-11 
1121 Vienna, Austria 
Study Manager 
Dr. Norbert Tripolt, MSc. 
Division of Endocrinology and Diabetology 
Department of Internal Medicine 
Medical University of Graz 
Auenbruggerplatz 15 
8036 Graz, Austria 
Tel: +43 316 385 78038 
Fax: +43 316 385 13428 


 
 
Title: 
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Protocol No: 
Version 2.17 
 
Date: 
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Signatures: 
Principal Investigators: 
Assoz.-Prof. Dr. Harald Sourij                                            
 
Assoz.-Prof. Dr. Dirk von Lewinski                                      
 
Signature 
 
Signature 
 
Confidentiality Statement 
This document contains confidential information that must not be disclosed to anyone other than the sponsor, the 
investigator team, regulatory authorities and members of the Research Ethics Committee. 
Trials Sponsor: Medical University of Graz, Auenbruggerplatz 2-4, 8036 Graz 
 
 
 
 
 
 
     
 
 
 
 
 
 
 
 
 


 
 
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  Table of contents 
 
Synopsis ................................................................................................................................................ 10 
1. INTRODUCTION AND RATIONALE ....................................................................................................... 13 
1.1 Aim of the study ........................................................................................................................... 14 
1.2 Study hypothesis .......................................................................................................................... 14 
2. OBJECTIVES AND OUTCOMES ............................................................................................................. 14 
2.1 Primary objective ......................................................................................................................... 14 
2.2 Secondary objectives .................................................................................................................... 15 
2.3 Safety objectives .......................................................................................................................... 15 
2.4 Primary outcomes ........................................................................................................................ 15 
2.5 Secondary outcomes .................................................................................................................... 15 
3. STUDY DESCRIPTION .......................................................................................................................... 16 
3.1 Design .......................................................................................................................................... 16 
3.2 Duration of study ......................................................................................................................... 16 
4. STUDY POPULATION .......................................................................................................................... 16 
4.1 Inclusion criteria ........................................................................................................................... 16 
4.2 Exclusion criteria .......................................................................................................................... 17 
4.3 Withdrawal criteria ...................................................................................................................... 17 
4.4 Termination of the entire trial ...................................................................................................... 18 
4.5 Unblinding ................................................................................................................................... 18 
4.6. Tracking of drop out patients ...................................................................................................... 18 
5. VISIT PROCEDURES, MEASUREMENTS AND ASSESSMENTS ................................................................. 18 
5.1 Recruitment and screening .......................................................................................................... 18 
5.2 Randomisation ............................................................................................................................. 19 
5.3 Visit schedule ............................................................................................................................... 19 
5.4 Visit procedures ........................................................................................................................... 20 


 
 
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5.5 Description of procedures and measurements ............................................................................. 21 
5.5.1 Medical history and physical examination ............................................................................. 21 
5.5.2 ECG ....................................................................................................................................... 22 
5.5.3 Vital signs .............................................................................................................................. 22 
5.5.4 Body weight and height ......................................................................................................... 22 
5.5.5 Routine biochemistry ............................................................................................................ 22 
5.5.6 Blood sample collection and plasma extraction for biobanking .............................................. 23 
5.5.7 Echocardiography .................................................................................................................. 23 
5.5.8 Assessment of side effects and patient safety before discharge ............................................. 23 
5.6 Benefit-Risk Assessment ............................................................................................................... 23 
6. ADVERSE EVENTS (AE) ........................................................................................................................ 24 
6.1 Adverse Event description ............................................................................................................ 24 
6.2 Severity of Adverse Events ........................................................................................................... 24 
6.3 Causality of Adverse Events .......................................................................................................... 24 
6.4 Abnormal Laboratory Test Results ................................................................................................ 25 
6.5 Adverse events of Special Interest (AESIs) .................................................................................... 25 
6.5.1 Hepatic injury ........................................................................................................................ 25 
6.5.2 Decreased renal function ....................................................................................................... 25 
6.5.3 Metabolic acidosis, ketoacidosis and diabetic ketoacidosis (DKA) .......................................... 25 
6.5.4 Events involving lower limb amputation ................................................................................ 26 
6.6 Serious Adverse Events (SAE) ....................................................................................................... 26 
6.6.1 Reporting of SAEs .................................................................................................................. 27 
7. STATISTICAL ANALYSES ...................................................................................................................... 28 
7.1 Sample size and power considerations ......................................................................................... 28 
7.2 Data analysis ................................................................................................................................ 28 
8. DATA MANAGEMENT ......................................................................................................................... 28 
9. TREATMENT ....................................................................................................................................... 29 


 
 
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9.1 Study medication ......................................................................................................................... 29 
9.2 Method of administration ............................................................................................................ 29 
9.3 Special precautions for storage .................................................................................................... 29 
9.4 Dispensing of Study Drug ............................................................................................................. 29 
9.5 Return/Destruction of Study Drug ................................................................................................ 29 
10. REGULATORY, ETHICAL AND LEGAL ISSUES ....................................................................................... 30 
10.1 Declaration of Helsinki ............................................................................................................... 30 
10.2 Good Clinical Practice ................................................................................................................. 30 
10.3 Independent Ethics Committee/ competent authority................................................................ 30 
10.3.1 Initial Approval .................................................................................................................... 30 
10.3.2 Approval of Amendments .................................................................................................... 30 
10.3.3 Competent Authority ........................................................................................................... 30 
10.4 Insurance ................................................................................................................................... 30 
10.5 Informed Consent ...................................................................................................................... 30 
10.6 Subject Confidentiality ............................................................................................................... 31 
10.7 End of Trial ................................................................................................................................. 31 
10.8 Study Documentation and Data Storage ..................................................................................... 31 
11. ADMINISTRATIVE MATTERS ............................................................................................................. 32 
11.1 Source Data ................................................................................................................................ 32 
11.2 Language .................................................................................................................................... 32 
11.3 Data Collection ........................................................................................................................... 32 
11.4 Electronic Recording of data ....................................................................................................... 32 
11.5 Study Management Structure..................................................................................................... 33 
11.5.1 Trial Steering Committee (TSC) ............................................................................................ 33 
11.6 Monitoring ................................................................................................................................. 33 
11.7 Disclosure of data and publication .............................................................................................. 34 
12. REFERENCES..................................................................................................................................... 34 


 
 
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Appendix A Power and sample size calculation ...................................................................................... 36 
Appendix B Participating Study Centers ................................................................................................. 42 
Appendix C Echo Manual ....................................................................................................................... 45 
 ...................................................................................................................................................... 46 
 
 
Table of figures 
Figure 1 Summary of potential beneficial mechanisms of Empagliflozin used after MCI ......................... 14 
Figure 2 Study Flow Chart ...................................................................................................................... 16 
 
Table of tables 
Table 1 Visit schedule ............................................................................................................................ 20 
Table 2 Summary of blood tests at each study visit ................................................................................ 23 
Table 3 Diagnostic criteria for DKA ......................................................................................................... 26 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Abbreviations 
3-point MACE 
Major acute cardiovascular events (cardiovascular death, non-fatal myocardial infarction, non-
fatal stroke) 
ACR 
Albumin/Creatinine Ratio 
ADA 
American Diabetes Association 
AESI 
Adverse events of Special Interest 
ALAT 
Alanine-Aminotransferase 
ASAT 
Aspartate-Aminotransferase 
BASG 
Bundesamt für Sicherheit im Gesundheitswesen 
BMI 
Body mass index 
CHF 
Congestive Heart Failure 
CLTR 
Department for Clinical Trials 
CRF 
Case Report Form 
DKA 
Diabetic Ketoacidosis 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eGFR  
Estimated Glomerular Filtration Rate 
EMEA 
European Medicine Agency 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FDA 
Food and Drug Administration 
FPFV 
First Patient First Visit 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyl-Transferase 
HDL 
High Density Lipoprotein 
IMI 
Institute of Medical Informatics, Statistics and Documentation 
ISF 
Investigator Site File 
INS 
Institute Surveillance 
KKS 
Koordinierungszentrum für Klinische Studien 
LBBB 
Left bundle branch block 
LDL 
Low Density Lipoprotein 
LPLV 
Last Patient Last Visit 


 
 
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MCI 
Myocardial Infarction 
nt-proBNP 
N-terminal pro b-type natriuretic peptide 
NYHA 
New York Heart Association 
pH 
Pondus Hydrogenii 
RR 
Riva Rocci Blood Pressure Measurement 
SGLT-2 
Sodium-dependent glucose cotransporter 2 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T2DM 
Type 2 Diabetes Mellitus 
TAPSE 
Tricuspid Annular Plane Systolic Excursion 
TMF 
Trial Master File 
TMG 
Trial Management Group 
TSC 
Trial Steering Committee 
UKPDS 
United Kingdom Prospective Study 
ULN 
Upper Limit of Normal 
UTI 
Urinary Tract Infection 
WMSI 
Wall Motion Score Index 
 
 
 


 
 
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Synopsis 
Sponsor 
Medical University of Graz 
Auenbruggerplatz 2-4 
8036 Graz, Austria 
Principal Investigators 
Harald Sourij, MD, Associate Professor  
Dirk von Lewinski, MD, Associate Professor  
Indication 
Patients with acute myocardial infarction  
Study design and phase 
Randomized, prospective, placebo-controlled, double blind, multicenter 
study in patients with acute myocardial infarction – a Phase III study. 
Study Short Title 
Empagliflozin in acute myocardial infarction 
Keyword 
SGLT-2 inhibition, acute myocardial infarction, heart failure 
Aims of the trial 
Primary objective: 
The primary objective is to investigate the impact of Empagliflozin on 
biomarkers of heart failure in patients with myocardial infarction with and 
without type 2 diabetes mellitus within 6 months after the event. 
Secondary objective: 
To investigate  
-   Short term changes of nt-proBNP levels  
- Short term and intermediate term changes in echocardiography 
parameters  
- Change in levels of ketone body concentrations  
- Change in HbA1c levels 
- Change in body weight 
- Number of hospital re-admissions due to heart failure or other causes 
- Duration of hospital stay  
- All-cause mortality 
Outcome measures of the trial 
Primary outcome measures: 
- 
Difference in the change of nt-proBNP levels between treatment 
groups from randomization to week 26 
Secondary outcomes measures: 
- 
-Difference in the change of ejection fraction between treatment 
groups from randomization to week 26 
- 
-Difference in the change of ejection fraction between treatment 
groups from randomization to week 6 


 
 
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- 
Difference in the change of left ventricular diastolic function from 
randomization to week 26 
- 
Difference in the change of left ventricular diastolic function from 
randomization to week 6 
- 
Difference in the change of nt-proBNP levels between treatment 
groups from randomization to week 6 
- 
Difference in the change of HbA1c between treatment groups from 
randomization to week 26 (in subjects with known T2DM) 
- 
Difference in the change of body weight between treatment groups 
from randomization to week 6 
- 
Difference in the change of body weight between treatment groups 
from randomization to week 26 
- 
Difference in the change of blood beta-hydroxybutyrate levels 
between the treatment groups from randomization to week 6  
- 
Difference in the change of blood beta-hydroxybutyrate levels 
between the treatment groups from randomization to week 26  
- 
Difference in the number of hospital re-admissions due to heart 
failure between the treatment groups 
- 
Difference in the number of hospital re-admissions for any cause 
between the treatment groups 
- 
Difference in the duration of hospital stay between the treatment 
groups after initiation of the study treatment 
Number of patients 
476 patients 
Time schedule 
With reference to the trial: 
EC Submission: NOV/2016 
Local Authority Submission.:  NOV/2016 
First Patient In (FPFV):  11/MAY/2017 
Last Patient In: 
10/DEC/2021 
Last Patient Out (LPLV):  03/MAY/2022 
Data Base Lock:  17/MAY/2022 
First Results available: 
JUL/2022 
Clinical Study Report:  
SEP/2022 
With reference to patients: 
Duration of the treatment: 6 months 
Main inclusion criteria 
1)Myocardial infarction with evidence of significant myocardial necrosis 
defined as a rise in creatinkinase >800 U/l and a troponin T- or I level >10x 
ULN. In addition at least 1 of the following criteria must be met:  


 
 
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- Symptoms of ischemia  
- ECG changes indicative of new ischemia (new ST-T changes or new LBBB) 
- Imaging evidence of new regional wall motion abnormality 
2)18 – 80 years of age  
3)Informed consent has to be given in written form. 
4)eGFR > 45 ml/min/1.73m2  
5)Blood pressure before first drug dosing: RRsystolic >110mmHg 
6) Blood pressure before first drug dosing: RRdiastolic >70mmHg 
7) First intake of study medication f72h after myocardial infarction after 
performance of a coronary angiography 
Main exclusion criteria 
1)Any other form of diabetes mellitus than type 2 diabetes mellitus, history 
of diabetic ketoacidosis 
2)Blood pH < 7,32 
3)Known allergy to SGLT-2 inhibitors 
4)Haemodynamic instability as defined by intravenous administration of 
catecholamine, calciumsensitizers or phosphodiesterase inhibitors 
5)>1 episode of severe hypoglycemia within the last 6 months under 
treatment with insulin or sulfonylurea 
6) Patients currently being treated with any SGLT-2 inhibitor (dapagliflozin, 
canagliflozin, empagliflozin) or having received treatment with any SGLT-2 
inhibitor within the 4 weeks prior to the screening visit 
Study medication 
Active substance: Empagliflozin 
Commercial name:  Jardiance 
Manufacturer: Boehringer Ingelheim 
Treatment plan 
Empagliflozin, 10mg once daily orally administered or matched placebo  
 
 
 
 
 
 


 
 
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1. INTRODUCTION AND RATIONALE 
Type 2 diabetes mellitus (T2DM) is associated with an about two to three-fold increased risk for cardiovascular events 
as compared to subjects without diabetes1. The United Kingdom Prospective Study (UKPDS) was the first to 
demonstrate a reduction of macrovascular and microvascular complications in subjects with T2DM by an intensified 
glucose lowering treatment regimen with either insulin/sulfonylurea or metformin in the long term follow up2. After 
Rosiglitazone was removed from the European market due to remaining uncertainty about the cardiovascular safety 
of this drug, the Federal Drug Administration (FDA) and the European Medicine Agency (EMEA) have issued new 
guidelines for new antihyperglycemic drugs to be licensed, requiring a thorough assessment of cardiovascular safety 
and in most cases the performance of a large cardiovascular outcome trial3.  
Sodium-dependent glucose cotransporter 2 (SGLT-2) is mainly expressed in human kidneys and small intestinal cells. 
In the proximal tubule of the nephron SGLT-2 is responsible for the reabsorption of approximately 90% of the filtrated 
glucose4. Inhibition of SGLT-2 was shown to increase renal glucose excretion and to lower glucose. Subsequently, a 
number of SGLT-2 inhibitors were developed and are currently approved for the treatment of type 2 diabetes.  
Recently, Zinman B. et al published the results of the EMPA-REG-OUTCOME trial where the cardiovascular impact of 
a glucose lowering regimen including Empagliflozin as compared to usual glucose control without an SGLT-2 inhibitor 
was investigated5. The trial demonstrated an unexpected reduction in the primary composite endpoint, comprising 
cardiovascular death, non-fatal myocardial infarction and non-fatal stroke. The reduction was mainly driven by a 38% 
relative risk reduction in cardiovascular deaths; moreover they demonstrated an impressive 35% relative risk 
reduction in the secondary endpoint hospitalization for heart failure. Of note, the beneficial effects observed in the 
Empagliflozin group seem to occur very rapidly after commencing the treatment, as suggested by the early separation 
of the Kaplan-Meier curves. However, the mechanisms responsible for this finding remain unclear. Diuretic effects 
with subsequent impact on hemodynamics or potential cardioprotective effects of glucagon, which levels rise under 
the treatment with SGLT-2 inhibitors and the resulting rise in ketone bodies or a small increase in hematocrit have 
been suggested 6, 7.   
We hypothesize that Empagliflozin beneficially influences the increased pre- and afterload as well as it reduces the 
increased sodium reabsorption following myocardial damage with subsequent reduced cardiac output. Whether or 
not Empagliflozin has direct effects on myocardial remodelling has not been elucidated, yet. Moreover, recent animal 
data suggest that in failing heart ketone bodies seems to be increasingly important as energy source8. Empagliflozin 
has been shown to increase levels of ketone bodies, which might has a beneficial impact on the metabolism and 
energy supply of the failing heart9.  
In addition, although SGLT-2 is not expressed in human myocardium, direct, non-SGLT-2 mediated effects on the 
heart muscle cannot be excluded, given that the molecule is small in size.  
 


 
 
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Figure 1 Summary of potential beneficial mechanisms of Empagliflozin used after MCI 
 
The aim of this mechanistic study is to investigate the impact of Empagliflozin on cardiac function and biomarkers 
for heart failure in patients with acute myocardial infarction. Since previous trials in acute myocardial infarction using 
aldosterone blockers demonstrated that an early intervention might be crucial for a beneficial outcome10, we have 
chosen to start treatment within 72 hours after performance of a coronary angiography for acute myocardial 
infarction. 
1.1 Aim of the study 
The aim of this mechanistic study is to investigate the impact of Empagliflozin on cardiac function and biomarkers of 
heart failure in patients with acute myocardial infarction.  
1.2 Study hypothesis 
Treatment with the SGLT-2 inhibitor Empagliflozin, commenced early after acute myocardial infarction will reduce 
the biomarker for heart failure nt-proBNP more effectively than placebo within 6 months after the event. 
2. OBJECTIVES AND OUTCOMES 
2.1 Primary objective 
The primary objective is to investigate the impact of Empagliflozin on biomarkers of heart failure in patients with 
myocardial infarction with and without type 2 diabetes mellitus within 6 months after the event. 
 


 
 
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2.2 Secondary objectives 
To investigate  
- Short term changes of nt-proBNP levels  
- Short term and intermediate term changes in echocardiography parameters 
- Change in levels of ketone body concentrations 
- Change in HbA1c levels 
- Change in body weight 
- Number of hospital re-admissions due to heart failure or other causes 
- Duration of hospital stay  
- All-cause mortality  
2.3 Safety objectives  
- 
All-cause mortality 
- 
Number of serious adverse events 
- 
Number of hypoglycemic events 
- 
Number of genital infections 
- 
Number of ketoacidotic events 
- 
Changes in liver function parameters (AST, ALT, GGT) 
- 
Changes in renal function parameters (creatinine, eGFR) 
2.4 Primary outcomes 
Difference in the change of nt-proBNP levels between treatment groups from randomization to week 26 
2.5 Secondary outcomes 
- 
Difference in the change of ejection fraction between treatment groups from randomization to week 26 
- 
Difference in the change of ejection fraction between treatment groups from randomization to week 6 
- 
Difference in the change of left ventricular diastolic function from randomization to week 26 
- 
Difference in the change of left ventricular diastolic function from randomization to week 6 
- 
Difference in the change of nt-proBNP levels between treatment groups from randomization to week 6 
- 
Difference in the change of HbA1c between treatment groups from randomization to week 26 (in subjects 
with known diabetes mellitus Type 2) 
- 
Difference in the change of body weight between treatment groups from randomization to week 6 
- 
Difference in the change of body weight between treatment groups from randomization to week 26 
- 
Difference in the change of blood beta-hydroxybutyrate levels between the treatment groups from  
randomization to week 6  
- 
Difference in the change of blood beta-hydroxybutyrate levels between the treatment groups from  
randomization to week 26  
- 
Difference in the number of hospital re-admissions due to heart failure between the treatment groups 
- 
Difference in the number of hospital re-admissions for any cause between the treatment groups 


 
 
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- 
Difference in the duration of hospital stay between the treatment groups after initiation of the study 
treatment 
3. STUDY DESCRIPTION 
3.1 Design  
This is a randomized, double-blind (patients and physicians), placebo controlled multi-center study to evaluate the 
effect of Empagliflozin 10mg once daily (p.o.) for 26 weeks on cardiac function and biomarkers for heart failure in 
patients with acute myocardial infarction (Figure 1). The study will be conducted in 11 sites in Austria (Appendix B) 
with an aim to enrol 476 patients (Figure 2) to evaluate the overall study hypothesis.   
 
 
 
 
 
 
 
 
 
 
3.2 Duration of study 
It is anticipated that the study will run for 30 months.  
4. STUDY POPULATION 
We will study subjects after an acute myocardial infarction. We aim to recruit 150 subjects with established diabetes 
mellitus type 2. 
4.1 Inclusion criteria 
1) Myocardial infarction with evidence of significant myocardial necrosis defined as a rise in creatinkinase >800 U/l 
and a troponin T-level (or troponin I-level) >10x ULN. In addition at least 1 of the following criteria must be the 
met:  
- 
Symptoms of ischemia  
- 
ECG changes indicative of new ischemia (new ST-T changes or new LBBB) 
- 
 Imaging evidence of new regional wall motion abnormality 
2) 18 – 80 years of age  
238 assigned to Empagliflozin 
238 assigned to Placebo 
26 weeks 
26 weeks 
Primary endpoints 
Secondary endpoints 
476 patients will be enrolled 
Figure 2 Study Flow Chart 


 
 
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3) Informed consent has to be given in written form 
4) eGFR > 45 ml/min/1.73m2  
5) Blood pressure before first drug dosing: RRsystolic>110mmHg  
6) Blood pressure before first drug dosing: RRdiastolic>70mmHg 
7) First intake of study medication f72h after myocardial infarction after performance of a coronary angiography 
 
4.2 Exclusion criteria 
1) Any other form of diabetes mellitus than type 2 diabetes mellitus, history of diabetic ketoacidosis 
2) Blood pH < 7,32 
3) Known allergy to SGLT-2 inhibitors 
4) Haemodynamic instability as defined by intravenous administration of catecholamine, calciumsensitizers or 
phosphodiesterase inhibitors 
5) >1 episode of severe hypoglycaemia within the last 6 months under treatment with insulin or sulfonylurea 
6) Females of child bearing potential without adequate contraceptive methods (i.e. sterilisation, intrauterine device, 
vasectomised partner; or medical history of hysterectomy) 
7) Acute symptomatic urinary tract infection (UTI) or genital infection 
8) Patients currently being treated with any SGLT-2 inhibitor (dapagliflozin, canagliflozin, empagliflozin) or having 
received treatment with any SGLT-2 inhibitor within the 4 weeks prior to the screening visit 
 
 
4.3 Withdrawal criteria 
Subjects may be withdrawn from the study at the discretion of the Investigator or Sponsor due to a safety concern 
or if judged non-compliant with trial procedures. A subject must be withdrawn from treatment of the following 
applies: 
 
Subject chooses to withdraw from the study at any time 
 
Adverse event requires unblinding of the study medication 
 
Pregnancy or intention of becoming pregnant 
 
Intolerable adverse effects 
 
Major violation of the study protocol 
 
Occurrence of an exclusion criterion 
 
Other circumstances that would endanger the health of the subject if he/she were to continue his/her 
participation in the trial. 
Reasons for withdrawals and discontinuation of any subject from the protocol have to be recorded. 
 


 
 
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4.4 Termination of the entire trial 
Premature termination of the clinical trial will be considered when the risk-benefit ratio changes markedly for the 
patient, the use of the study medication is no longer justifiable, the sponsor believes it is necessary to terminate the 
clinical trial for safety reasons, when early evidence of the superiority or inferiority of a treatment group is obtained 
by an interim analysis or by other research results, or when the clinical trial proves to be impracticable. 
4.5 Unblinding 
In the case of a requirement to unblind study medication, one of the chief investigators needs to be informed to 
discuss the unblinding. The unblinding list is held by the Institute of Medical Informatics, Statistics and 
Documentation (IMI), Medical University of Graz, which is not involved in study investigations. 
 
4.6. Tracking of drop out patients 
In order to guarantee a 100% follow-up of the mortality in this study, we would like to apply to be able to call up the 
mortality data of the study participants from Statistics Austria for the period of study participation. This can increase 
the quality of the data even further and thus improves the significance of the study. 
 
4.7. Query of mortality data  
In the beginning of the year 2023, the study team would like to request a query from Statistic Austria regarding the 
mortality of the participating study patients.   
5. VISIT PROCEDURES, MEASUREMENTS AND ASSESSMENTS  
5.1 Recruitment and screening 
Sites will recruit competitively and sites will receive compensation for their work based on a per-patient fee. The 
clinic staff of the intensive care unit informs patients about the possibility of being enrolled in this study. No study-
related procedures are undertaken before obtaining informed consent. The study team in detail explains the study 
procedures and asks the participant about their willingness to participate in this research study. After informed 
consent is signed and obtained, participants are given a signed copy of the informed consent document and are 
assigned a screening identification number.  
After obtaining informed consent at the screening visit, subject´s eligibility will be further assessed and documented 
by using a source data form with a list of inclusion and exclusion criteria, medical history (including all medications 
past and current) will be acquired and the following measurements will be performed: body weight, height, blood 
pressure, ECG and blood parameters (see Table 2). Laboratory results up to 2 days before screening can be used to 
test eligibility for the trial. 
Subjects unable to provide written informed consent will not be included in the study. 
 


 
 
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5.2 Randomisation 
After screening, all eligible patients for the trial will be randomised into one of the two arms of the study via 
Randomiser Software (Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, 
http://www.randomizer.at), which will be programmed with a randomisation schedule provided by an independent 
statistician. The randomisation will be stratified by site, type 2 diabetes and by sex.  
Only the subject number and subject initials will be recorded in the case report form (CRF). The investigator will 
maintain a personal subject identification list (subject numbers with the corresponding subject names) to enable 
records to be identified. 
 
A summary of all visits and procedures has been outlined below (Table 1). A more detailed description of each visit 
and accompanying procedures can be found later in the protocol (5.4 - 5.5) 
5.3 Visit schedule 
 
Visit 1 (V1) 
Screening / 
Baseline 
Visit 2 (V2) 
(week 6 ± 2) 
Visit 3 (V3) 
 (week 12 ± 2) 
Visit 4 (V4) 
 (Week 26 ± 2) 
Visit 5 (V5) 
(4 weeks ±1w 
after V4) 
Informed Consent 
X 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
Randomisation 
X 
 
 
 
 
Demography, medical history 
X 
 
 
 
 
Concomitant medication 
X 
X 
X 
X 
 
Vital signs 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
Weight 
X 
X 
X 
X 
 
Physical examination 
X 
X 
 
X 
 
ECG 
X 
 
 
 
 
Cardiac ultrasound 
X 
X 
 
X 
 
Biobank sampling 
X 
X 
 
X 
 
nt-proBNP (local) 
X 
X 
X 
X 
 
Blood sampling  
X 
X 
X 
X 
 
Liver function parameters (AST, 
ALT, GGT) 
X 
X 
X 
X 
 
Renal 
function 
parameters 
(creatinine, eGFR) 
X 
X 
X 
X 
 
Adverse Events 
 
X 
X 
X 
X 


 
 
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Dispense medication 
X 
 
 
 
 
Drug accountability 
 
 
 
X 
 
Safety 
assessment 
before 
discharge 
X 
 
 
 
 
Table 1 Visit schedule 
 
 
 
5.4 Visit procedures 
Visit 1 - Screening/Enrolment Visit (Day 0 – hospital stay) 
 
Obtain informed consent of potential participant verified by signature on study informed consent form 
(10.5) 
 
Collect blood to check inclusion criteria (creatinkinase, troponin T (or troponin I), eGFR, blood pH, nt-
proBNP) (5.5.7) 
 
Collect and prepare blood samples for biobank (5.5.6) 
 
Perform echocardiography (5.5.7) 
 
Obtain demographic information, medical history, medication history, alcohol and tobacco use history 
(5.5.1) 
 
Record vital signs  (5.5.3) 
 
Measure body weight and body height (5.5.4) 
 
Verify inclusion/exclusion criteria (4.2 and 4.3) 
 
Randomize the subject (5.2) 
 
Dispense the study medication for trial period (9.4) 
 
Adjust concomitant antihyperglycemic medication  
 
Assessment of side effects and patient safety before discharge (5.5.8) 
 
Visit 2 - Follow up 1 Visit (Week 6 ± 2 weeks) 
 
Record adverse events as reported by participant or observed by investigator (6.1 – 6.6) 
 
Record vital signs (5.5.3) 
 
Measure body weight (5.5.4) 
 
Collect blood for routine biochemistry (5.5.5) 
 
Perform echocardiography (5.5.7) 
 
Record changes in medication  
 
Collect and prepare blood samples for biobank (5.5.8) 
 
Visit 3 - Safety Visit (Week 12 ± 2 weeks) 


 
 
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 
Record adverse events as reported by participant or observed by investigator (6.1 – 6.6) 
 
Record vital signs (5.5.3) 
 
Measure body weight (5.5.4) 
 
Collect blood for routine biochemistry (5.5.5) 
 
Record changes in medication 
 
Record participant’s adherence to treatment program  
 
 
 
 
Visit 4 - Follow-up 2 Visit (Week 26 ± 2 weeks) 
 
Record adverse events as reported by participant or observed by investigator (6.1 – 6.6) 
 
Record vital signs (5.5.3) 
 
Measure body weight (5.5.4) 
 
Collect blood for routine biochemistry (5.5.5) 
 
Perform echocardiography (5.5.7) 
 
Record changes in medication  
 
Collect and prepare blood samples for biobank (5.5.6) 
 
Record participant’s adherence to treatment program  
 
Drug accountability (5.5.11) 
 
Visit 5 - Telephone assessment (4weeks ± 1week after V4) 
 
Record adverse events as reported by participant (6.1 – 6.6) 
 
5.5 Description of procedures and measurements 
5.5.1 Medical history and physical examination 
A medical history will be performed at the screening visit to record illnesses, disorders and medications. This 
information needs to be updated on all follow-up visits. 
Physical examination will be performed at the Screening visit (study visit 1) according to local procedure. During this 
visit the physician will perform a physical examination with the focus on cardiac, lung and abdominal examination. 
Any abnormal, clinical significant findings must be recorded in the SDF (Source Data Form) as well as in the eCRF 
(Clincase). Any changes in subsequent visits as compared to the screening visit which fulfils the criteria of an AE must 
be recorded as an AE. Any changes in concomitant illness will be recorded as changes in medical history. Any changes 
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5.5.2 ECG 
An ECG will be performed at the screening visit. The ECG will be interpreted, signed and dated by the investigator 
before randomisation. 
5.5.3 Vital signs 
Pulse should be recorded at all visits after resting for five minutes in a sitting position. Systolic and diastolic blood 
pressure will be measured in sitting position at all visits. 
5.5.4 Body weight and height 
Weight should be measured at all visits. The same and calibrated pair of scales should preferably be used throughout 
the trial. Height will be recorded at the screening visit. BMI (body mass index) will be calculated as follows: BMI = 
weight (kg)/height2 (m2). 
5.5.5 Routine biochemistry  
Blood samples will be obtained at all visits after an 8 hour fast and processed by the local laboratory using standard 
methods’ for routine tests. Patients can take their regular morning medications but are asked that they do not take 
any of their diabetes medications on the morning of their study visit. Patients should bring their regular medication 
along to their study visits to be further advised by the doctor. See table 2 below for a detailed description of blood 
collection at each visit: 
 
Blood test 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Hematology (full blood count) 
X 
X 
X 
X 
HbA1c 
X 
X 
X 
X 
Sodium, Potassium, Chloride 
X 
X 
X 
X 
Calcium 
X 
X 
X 
X 
Phosphate 
X 
X 
X 
X 
Magnesium 
X 
X 
X 
X 
Iron, Ferritin, Transferrin 
X 
X 
X 
X 
Creatinkinase 
X 
X 
X 
X 
LDH (Lactatdehydrogenase) 
X 
X 
X 
X 
AST (Aspartate-Aminotransferase) 
X 
X 
X 
X 
CK MB 
X 
X 
X 
X 
ALT (Alanine-Aminotransferase) 
X 
X 
X 
X 
GGT (Gamma-Glutamyl-Transferase) 
X 
X 
X 
X 
CRP (C-reactive Protein) 
X 
X 
X 
X 
Creatinine 
X 
X 
X 
X 
eGFR 
X 
X 
X 
X 
Total cholesterol 
X 
X 
X 
X 
Triglycerides 
X 
X 
X 
X 
HDL (high density lipoprotein) 
X 
X 
X 
X 
LDL (low density lipoprotein) 
X 
X 
X 
X 
Troponin T (Troponin I) 
X 
 
 
 
NT-pro BNP 
X 
X 
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Fasting glucose 
X 
X 
X 
X 
Myoglobin 
X 
 
 
 
pH (arterial/venous) 
X 
 
 
 
Urine Albumin/Creatinine Ratio (ACR) 
X 
X 
 
X 
Table 2 Summary of blood tests at each study visit 
5.5.6 Blood sample collection and plasma extraction for biobanking 
Blood will be collected via venous puncture into 16ml serum, 6ml EDTA and 4ml sodium citrate vacutainers and 
centrifuged within 30 min of collection. Plasma should be transferred into Eppendorf tubes and stored at -80°C 
locally. In regular intervals these samples will be shipped on dry ice to the Biobank of the Medical University of Graz, 
where they will be stored at -80°C for future biomarker analyses. NT-proBNP and blood ketone bodies will be 
measured in batches from these stored biomarker samples. 
5.5.7 Echocardiography 
Echocardiography will be performed using locally available ultrasound devices. Left ventricular wall thickness and 
chamber diameter will be assessed. Left ventricular systolic function will be assessed in 4- and 2-chamber views using 
the modified Simpson`s rule. Regional systolic dysfunction will be classified using the WMSI (wall motion score index) 
and/or strain measurements. Left ventricular diastolic function will be measured using E as well as lateral and septal 
e`. Right ventricular function will be evaluated using Tricuspid Annular Plane Systolic Excursion (TAPSE). Left atrial 
volume index will be calculated from LA dimensions. Colour flow Doppler as well as continuous as well as pulsed 
wave Doppler will be used for detection of valve diseases. A detailed overview on the EMMY trial echocardiography 
sub-study is given in the Echo Manual (please see Appendix C). 
 
5.5.8 Assessment of side effects and patient safety before discharge 
Physical examination and a check of possible side effects will be performed before discharge at study visit 1. 
5.5.9 Faeces sampling 
Sampling will be performed using stool collection tubes by Sarstedt, Nümbrecht, Germany, using a stool collector 
(Süsse Stuhlfänger, Gudensberg, Germany). Directions for safe and hygienic fecal collection will be delivered to the 
probands in words as well as in pictograms. Bacterial DNA will be extracted from stool samples using the MagNA 
Pure LC DNA Isolation Kit III (Roche). The 16S rRNA gene will be amplified in a PCR reaction and sequenced with next-
generation sequencing technology (Roche Genome Sequencer FLX or Illumina MiSeq) and interpreted by the 
respective software analyzers. 
5.6 Benefit-Risk Assessment 
Empagliflozin has been studied in subjects with type 2 diabetes and demonstrated cardiovascular benefit in terms of 
reduction of a 3-point MACE composite endpoint as well as of hospitalization for heart failure5. However, it has not 
been studied shortly after myocardial infarction yet. Given that the drug is not causing hypoglycemic events per se, 
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Empagliflozin is used together with sulfonylurea or insulin, hypoglycemia might occur and therefore participants will 
be instructed to reduce concomitant antihyperglycemic medication accordingly.  
Fungal genital infections are the most common side effect of Empagliflozin and participants will be informed about 
this and instructed on prevention measures. Rarely, serious infections of the genitals and the area around the genitals 
have been reported. This infection, called necrotizing fasciitis of the perineum, is also referred to as Fournier’s 
gangrene. 
In people with type 2 diabetes mellitus, the risk for ketoacidosis is increased, in particular in situations such as insulin 
deficiency, alcohol abuse, exsiccosis or infections. 
There will be no direct beneficial effect for all participants, however, those participants with known diabetes mellitus 
type 2 randomised to the Empagliflozin group will benefit from the glucose lowering effect of the drug.  
Overall this trial aims to develop novel future strategies for heart failure prevention in subjects with acute myocardial 
infarction. 
6. ADVERSE EVENTS (AE) 
An AE is any untoward medical occurrence in a patient or clinical trial subject administered a medicinal product and 
which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavourable 
and unintended sign (including an abnormal laboratory finding), symptom, including an exacerbation of a pre-existing 
condition, or disease temporally associated with the use of the trial device/procedure, whether or not considered 
related to the treatment. 
All adverse events that occur during this study will be recorded on the adverse event case report forms. 
6.1 Adverse Event description 
For the purposes of the study, AEs will be followed up according to local practice until the event has stabilised or 
resolved, or the Follow-up Visit, whichever is the sooner. SAEs will be recorded throughout the study. 
6.2 Severity of Adverse Events 
Mild: Awareness of event(s) or sign(s) but easily tolerated 
Moderate: Discomfort enough to cause some interference with usual activity 
Severe: Incapacitating or causing inability to carry out usual activity 
6.3 Causality of Adverse Events 
Medical judgment should be used to determine the relationship, considering all relevant factors, including pattern 
of reaction, temporal relationship, de-challenge or re-challenge, confounding factors such as concomitant 
medication, concomitant diseases and relevant history. Assessment of causal relationship should be recorded in the 
case report forms.  
Yes: 
There is a reasonable causal relationship between the investigational product  administered and the AE.  
No: 
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6.4 Abnormal Laboratory Test Results 
All clinically significant abnormal laboratory test results besides Troponin T (Troponin I), creatinkinase, nt-proBNP 
occurring during the study will be recorded as adverse events.  
6.5 Adverse events of Special Interest (AESIs) 
The term AESI relates to any specific AE that has been identified at the project level as being of particular concern 
for prospective safety monitoring and safety assessment within this trial, e.g. the potential for AEs based on 
knowledge from other compounds in the same class. AESIs need to be reported to the Pharmacovigilance 
Department of Boehringer Ingelheim within the same timeframe that applies to SAEs. 
Patients with AESIs need to be followed up appropriately, regardless of the origin of the laboratory data (e.g. central, 
local etc.). The Investigator should consider which, if any, concomitant therapies should not be taken during 
evaluation.  Discontinued treatments can be reintroduced per Investigator discretion. 
The following are considered as AESIs: 
6.5.1 Hepatic injury 
A hepatic injury is defined by the following alterations of hepatic laboratory parameters after randomisation:  
- 
an elevation of AST and/or ALT g 3 fold ULN combined with an elevation of total bilirubin g 2 fold ULN 
measured in the same blood sample 
- 
an isolated elevation of ALT and/or AST g 5 fold ULN 
 
These laboratory findings constitute a hepatic injury alert and the patients showing these abnormalities need to be 
followed up according to medical judgement.  
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, unexplained coagulopathy, right 
upper quadrant abdominal pain, etc.) without laboratory results (ALT, AST, total bilirubin) available, the Investigator 
should make sure these parameters are analysed, if necessary in an unscheduled blood test. 
6.5.2 Decreased renal function 
Decreased renal function is defined by a creatinine value showing a g 2 fold increase from baseline and is above the 
ULN. 
For the AESI <decreased renal function= the Investigator shall collect an unscheduled laboratory sample for creatinine 
as soon as possible and initiate follow-up laboratory tests of creatinine according to medical judgement. 
6.5.3 Metabolic acidosis, ketoacidosis and diabetic ketoacidosis (DKA) 
In case of metabolic acidosis, ketoacidosis and DKA 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. 
DKA is defined by the diagnostic criteria in the table below, and as defined by the American Diabetes Association 
(ADA). 
Investigators should note that not all criteria in the table below need to apply for the diagnosis of DKA, and clinical 
judgment should also be taken into consideration. Due to its mechanism of action, Empagliflozin may potentially 


 
 
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modify the clinical presentation of DKA which may occur at lower plasma glucose levels than stated in the table 
below. 
 
 
DKA 
 
Mild 
Moderate 
Severe 
Plasma glucose (mg/dL) 
>250 
>250 
>250 
Arterial pH 
7.25-7.30 
7.00-7.24 
<7.00 
Serum bicarbonate (mEq/L) 
15-18 
10 to <15 
<10 
Urine ketones* 
Positive 
Positive 
Positive 
Serum ketones* 
Positive 
Positive 
Positive 
Effective serum osmolality (mOsm/kg)** 
Variable 
Variable 
Variable 
Anion gap*** 
>10 
>12 
>12 
Alteration in sensoria or mental obtundation 
Alert 
Alert/drowsy 
Stupor/coma 
Table 3 Diagnostic criteria for DKA 
* 
Nitroprusside reaction method 
** 
Calculation: 2[measured Na (mEq/L) + glucose (mg/dL)/18 
*** 
Calculation: (Na+) – (Cl- + HCO3-) (mEq/L) 
6.5.4 Events involving lower limb amputation 
This definition includes amputation (i.e. resection of a limb through a bone), disarticulation (i.e. resection of a limb 
through a joint) and auto-amputations (i.e. 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). 
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. 
6.6 Serious Adverse Events (SAE) 
An SAE is defined as any event that 
- 
Results in death; 
- 
Is immediately life-threatening*; 
- 
Requires hospitalisation or prolongation of existing inpatient’s hospitalisation**  
- 
Results in persistent or significant disability or incapacity; 
- 
Is a congenital abnormality or birth defect; 
* <Life-threatening= in the definition of <serious= refers to an event in which the subject was at risk of death at the time of the event; it does not 
refer to an event which hypothetically might have caused death if it were more severe. 
** <Hospitalisation= means any unexpected admission to a hospital department. It does not usually apply to scheduled admissions that were 
planned before study inclusion or visits to casualty (without admission). 
 


 
 
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Medical judgement should be exercised in deciding whether an adverse event/reaction is serious in other situations. 
Important adverse events/reactions that are not immediately life-threatening, or do not result in death or 
hospitalisation but may jeopardise a subject, or may require intervention to prevent one of the other outcomes listed 
in the definition above should also be considered serious. 
 
Patients may be hospitalised for administrative or social reasons during the study (e.g. days on which infusion takes 
place, long distance from home to site,). These and other hospitalisations planned at the beginning of the study do 
not need to be reported as a SAE in case they have been reported at screening visit in the source data and have been 
performed as planned. 
 
Worsening of the underlying disease or other pre-existing conditions 
Worsening of the underlying disease or of other pre-existing conditions will be recorded as an (S)AE in the (e)CRF. 
 
Changes in vital signs, ECG, physical examination, and laboratory test results 
Changes in vital signs, ECG, physical examination and laboratory test results will be recorded as an (S)AE in the (e)CRF 
, if they are judged clinically relevant by the investigator. 
 
 
6.6.1 Reporting of SAEs 
The Sponsor shall report (i.e., from signing the informed consent onwards through the trial defined follow-up period 
<please define>) all SAEs and non-serious AEs which are relevant for a reported SAE and Adverse Events of Special 
Interest (AESI) by fax or other secure method using BI IIS SAE form to the BI Unique Entry Point immediately (within 
twenty four (24) hours or next business day whichever is shorter). 
BI Unique Entry Point: 
Boehringer Ingelheim RCV GmbH & Co KG, 
Pharmacovigilance Austria 
Dr. Boehringer-Gasse 5-11, 1121 Vienna, Austria 
Phone: +43 (0) 1 80 105 2099 
Fax:  +43 (0) 1 80 105 6384 
E-mail: PV_local_Austria@boehringer-ingelheim.com  
 
For each adverse event, the investigator will provide the onset date, end date, intensity, treatment required, 
outcome, seriousness, and action taken with the investigational drug. The investigator will determine the 
expectedness of the investigational drug to the AEs as defined in the Listed Adverse Events section of the Boehringer 
Ingelheim’s (BI’s) Investigator Brochure for the Productor BI Drug Information e.g. Summary of Product 
Characteristics (SmPC) or Product Information (PI) for the authorised Study Drug provided by BI, 
The investigator does not need to actively monitor patients for adverse events once the clinical trial has ended. 
However, if the investigator becomes aware of an SAE(s) that occurred after the patient has completed the clinical 
trial (including any protocol specified follow-up period), it should be reported to BI if investigator considers it as 
relevant to the BI study drug.  


 
 
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The sponsor will report the SAE to the ethics committee and the local authorities as well as Boehringer Ingelheim 
Pharmacovigilance in accordance with the aforementioned SAE reporting instructions.  
 
A suspected unexpected serious adverse reaction (SUSAR) is designated as such according to Guideline 2001/20/EG. 
A serious adverse reaction is deemed unexpected when it is not listed in the corresponding basic document 
(Summary of Product Characteristics, IB, IMPD). 
7. STATISTICAL ANALYSES 
7.1 Sample size and power considerations 
Previous data showed that nt-proBNP levels decrease by about 50% within 6 months after acute myocardial 
infarction11. To detect a relative 40% larger reduction in nt-proBNP levels in the Empagliflozin group as compared to 
the placebo group with a power of 80% and an alpha-level of 0.05%, and assuming a correlation for nt-proBNP levels 
of 0.85, a sample size of 216 subjects in each group is necessary. To account for a dropout rate of about 10% each 
group will consist of 238 patients. 
7.2 Data analysis 
Patient characteristics will be summarized. Summaries of continuous variables will be presented as means and 
standard deviations, if normally distributed, and as medians and inter-quartile ranges for skewed data, whilst 
categorical variables will be presented as frequencies and percentages. The analysis will be performed according to 
the intention to treat principle. All statistical tests will be two-tailed with a 5% significance level. 
Analysis will be based on the intention to treat cohort, while a sensitivity analysis for the per-protocol group will be 
done in addition. A detailed statistical analysis plan including pre-specified subgroup analyses will be finalized ahead 
of database lock. 
8. DATA MANAGEMENT 
Data Management is the responsibility of the Medical University of Graz, Department of Endocrinology and 
Diabetology and the study Monitor. The subject and the biological material obtained from the subject will be 
identified by subject number, trial site and trial identification number. Appropriate measures such as encryption or 
deletion will be enforced to protect the identity of human subjects in all presentations and publications as required 
by local/ regional and national requirements. 
This study will capture and process data using an electronic Case Report Form (Clincase) which is a fully validated 
high quality electronic data capture system, which has a full audit trail and controlled level of access. Data and reports 
will be extracted from the database throughout the study to monitor progress and training will be provided to all 
study staff on use of the database. 


 
 
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9. TREATMENT 
9.1 Study medication 
Empagliflozin is a sodium-glucose cotransporter 2 (SGLT2)-inhibitor. It works by increasing the amount of sugar that 
leaves the body in the urine. The study dose is 10mg once daily in the morning, taken with or without food. Each 
tablet contains 10mg Empagliflozin or Placebo. The pharmaceutical form is a round, pale yellow, biconvex, bevel-
edged film-coated tablet debossed with <S10= on one side and the Boehringer Ingelheim logo on the other (tablet 
diameter: 9.1 mm). Empagliflozin has minor influence on the ability to drive and use machines. Patients should be 
advised to take precautions to avoid hypoglycemia while driving and using machines, in particular when Empagliflozin 
is used in combination with a sulfonylurea and/or insulin. Pharmacy (Anstaltsapotheke) at the University Hospital of 
Graz, Austria will pack the medication as 26 weeks supplies for study participants and label study medication 
according to current regulatory requirements. 
9.2 Method of administration 
The tablets can be taken with or without food, swallowed whole with water. If a dose is missed, it should be taken 
as soon as the patient remembers. A double dose should not be taken on the same day. 
9.3 Special precautions for storage 
The study drug must be kept locked in a locked secure area. For this study drug no particular storage conditions are 
required.  
9.4 Dispensing of Study Drug 
The study team shall dispense the study drug only to subjects entered into the study, under the direction of the PI or 
sub-investigators authorized to receive or dispense it. The study drugs will not be dispensed or supplied to any person 
not authorized to receive it. Each time a study drug is dispensed; there must be documentation in the sponsor 
provided log (drug accountability log) as to the amount dispensed, to whom it is dispensed, and the date and 
signature or initials of the person dispensing the drug. Subjects should be advised to follow the study protocol and 
as appropriate to protocol return all used and unused containers to the site at study visit 4 (week 26). Any 
discrepancies between the amounts used by the subjects and the amount returned should be documented. 
9.5 Return/Destruction of Study Drug 
Assure that unused supplies of the study drug are returned to the sponsor in accordance with sponsor requirements. 
Obtain authorization from the sponsor if unused supplies of the study drug will be disposed of at the end of the 
study. Maintain records of the return or disposition of the unused study drug, including the unused study drug 
amount, lot numbers and quantity, method of return or disposition, and any documentation related to shipment or 
destruction. At the end of the study ensure that all documentation regarding receipt, storage, dispensing, return of 
used containers, and accountability is complete and accurate. 


 
 
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10. REGULATORY, ETHICAL AND LEGAL ISSUES 
10.1 Declaration of Helsinki 
The investigator will ensure that this study is conducted in full conformity with the 1964 Declaration of Helsinki and 
all subsequent revisions. 
10.2 Good Clinical Practice 
The study will be conducted in accordance with the guidelines laid down by the International Conference on 
Harmonisation for Good Clinical Practice (ICH GCP E6 guidelines). 
10.3 Independent Ethics Committee/ competent authority 
10.3.1 Initial Approval 
Prior to the enrolment of subjects, the Ethics Committee at the Medical University of Graz must provide written 
approval of the conduct of the study at named sites, the protocol and any amendments, the Patient Information 
Sheet and Consent Form, any other written information that will be provided to the subjects, any advertisements 
that will be used and details of any subject compensation.  
 
10.3.2 Approval of Amendments 
Proposed amendments to the protocol and aforementioned documents must be submitted to the Ethics Committee 
for approval as instructed by the Sponsor. Amendments requiring approval may be implemented only after a copy 
of the approval letter has been obtained. 
Amendments that are intended to eliminate an apparent immediate hazard to subjects may be implemented prior 
to receiving Sponsor or the Ethics Committee approval. However, in this case, approval must be obtained as soon as 
possible after implementation. 
10.3.3 Competent Authority 
Clinical Trial Applications (EudraCT application and the documents required for the assessment) should be addressed 
to the Austrian Competent Authority, the Federal Office for Safety in Health Care (Bundesamt für Sicherheit im 
Gesundheitswesen, BASG) under the following address:  
 
Austrian Federal Office for Safety in Health Care (BASG)  
Austrian Agency for Health and Food Safety (AGES)  
Institute Surveillance (INS), Department for Clinical Trials (CLTR)  
Traisengasse 5  
A-1200 Vienna 
Austria 
10.4 Insurance 
Participant insurance according to legal requirements will be contracted. 
10.5 Informed Consent 
The participation of a subject in this clinical trial is voluntary. The investigator or a member of the research team will 
approach the patient to obtain informed consent. The background of the proposed study, the procedure, the follow-


 
 
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up schedule and all potential benefits and risks will be carefully explained to each subject. The person obtaining the 
informed consent shall: 
- 
Avoid any coercion or undue influence of subjects to participate 
- 
Not waive or appear to waive subject’s legal rights 
- 
Use language that is non-technical and understandable to the subject 
- 
Clarify the subject that his/her data are confidential and are encoded with a subject ID number during the 
investigation 
- 
Provide plenty of time for the subject to consider his/her participation 
- 
Include dated signatures of the subject and of the clinical investigator 
- 
Ask whether the subject has any questions about the study 
After a subject has received and read the patient information sheet and agrees to participate in the study, the 
informed consent form approved by the Ethics Committee must be signed by the subject prior to any study specific 
tests being performed. It will also be signed by the person responsible for collecting the informed consent. The 
original will be kept in the subjects study research notes (source documents), a copy will be given to the subject and 
a copy kept in their hospital notes. 
 
10.6 Subject Confidentiality 
The investigator must ensure that the subject’s privacy is maintained. On the CRF or other documents submitted to 
the Sponsors, subjects will be identified by a subject ID number only. Documents that are not submitted to the 
Sponsor (e.g., signed informed consent form) should be kept in a strictly confidential file by the investigator. The 
investigator shall permit direct access to subjects’ records and source document for the purposes of monitoring, 
auditing, or inspection by the Sponsor, authorised representatives of the Sponsor, Regulatory Authorities and Ethic 
Committees. 
10.7 End of Trial 
The trial will end after the last subject has completed the follow-up telephone assessment (Study visit 5). All patients 
will be reviewed by a clinician at their last study visit in order to arrange return to appropriate routine clinical care 
pathways. 
10.8 Study Documentation and Data Storage 
The investigator must retain essential documents until notified by the Sponsor, and at least for 15 years after study 
completion, as per the Sponsor’s requirements. Subject files and other source data (including copies of protocols, 
CRFs, original reports of test results, correspondence, records of informed consent, and other documents pertaining 
to the conduct of the study) must be kept for the maximum period of time permitted by the institution. Documents 
should be stored in such a way that they can be accessed/data retrieved at a later date, either in paper or 
electronically. Consideration should be given to security and environmental risks. 
No study document will be destroyed without prior written agreement between the Sponsor and the investigator.  


 
 
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11. ADMINISTRATIVE MATTERS 
11.1 Source Data 
Source documents comprise the CRF and hospital records, laboratory records and correspondence. All documents 
will be stored safely in a confidential manner at the performing site. The subject will be referred to by a unique study 
subject number/code, their initials and date of birth on all study-specific documentations. The only exceptions will 
be the signed Consent Forms, Subject Identification log and subject clinical file, all of which will be stored securely by 
the clinical site. Source data will be made available for internal and external audits or inspections by regulatory 
authorities to authorised personnel only. 
As a minimum requirement the following data must be source data verifiable in source documentation other than 
the eCRF: 
 
Existence of subject (subject identifier, subject number and date of birth) 
 
Confirmation of participation in the trial (subject identification number (ID), trial ID and signed and dated 
informed consent forms) 
 
Diagnosis/ indication under investigation 
 
Visit dates 
 
Data from AEs, safety information form and pregnancy forms 
 
Relevant medical history, concomitant illness 
 
Reason for exclusion or withdrawal 
 
11.2 Language 
CRFs will be in German. Generic names for concomitant medications should be recorded in the CRF wherever 
possible. All written material to be used by subjects must use vocabulary that is clearly understood, and be in the 
language appropriate for the study site. 
11.3 Data Collection 
All data collected will be documented in the source documents and eCRF (Clincase). 
11.4 Electronic Recording of data 
This study will capture and process data using Clincase (electronic data capture) which will be built by Institute for 
Medical Informatics, Statistics and Documentation, Medical University of Graz. Clincase is a fully validated high 
quality electronic data capture system, which has a full audit trail and controlled level of access. Data and reports 
will be extracted from the database throughout the study to monitor progress and training will be provided to all 
study staff on use of the database. The Investigator must ensure that the data is recorded in the eCRFs as soon as 
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11.5 Study Management Structure 
11.5.1 Trial Steering Committee (TSC) 
A Trial Steering committee (TSC) comprised by all principal investigators and chaired be the Co-Chief investigators 
will be responsible for overseeing the progress of the trial. A TSC Charter will be devised to list the roles and 
responsibilities of the TSC members. TSC will be convened at least biannually either in person or by teleconference. 
11.6 Monitoring 
A monitoring plan will be devised based on risk analysis and described in detail in the monitoring manual. During the 
course of the trial the Monitor will visit the trial sites to ensure that the protocol is adhered to, that all issues have 
been recorded and to perform source data verification. The study will be monitored periodically by a Clinical Trial 
Monitor responsible for this study. 
Initiation visits will be completed at all trial centres prior to the recruitment of participants, and will consist of review 
of protocol and trial documents, training with respect to trial procedures (informed consent, SAE reporting, inclusion 
and exclusion criteria), review of recruitment strategy, review of site facilities and equipment, review of GCP 
principles, essential document receipt, collection and filing, and archiving and inspection. Copies of the trial specific 
procedure manuals and related documents will be given to the investigators. The approved version of the protocol 
should be followed at all times, and any significant protocol deviations will be documented in a Protocol Deviation 
Form and any significant deviations will be recorded on a Protocol Violation Form submitted to the study 
coordination centre and Sponsor as soon as possible. The investigators will allow the monitors to: 
- 
inspect the site, the facilities, device management and materials used for the trial 
- 
meet all members of the team involved in the trial, and ensure all staff working on the trial are experienced 
and appropriately trained, and have access to review all of the documents relevant to the trial 
- 
have access to the electronic case record forms and source data 
- 
discuss with the investigator and site staff trial progress and any issues on a regular basis 
The monitor will ensure that: 
- 
A percentage of records will be inspected for confirmation of existence, eligibility based on the results of 
the Risk Assessment 
- 
100 % of consent forms will be reviewed along with all SAE’s. 
- 
there is adherence to the protocol, including consistency with inclusion/exclusion criteria 
- 
there is GCP and regulatory compliance 
- 
trial documentation is complete and up to date (e.g. correct versions of documents being used, source data 
captured) and relevant documents are collected for the Trial Master File (TMF) 
- 
the monitored eCRFs have been completed correctly and accurately, and all entries correspond to data 
captured in source documents 
The Monitor must be given direct access to the source documents (original documents, data and records). Direct 
access includes permission to examine, analyse, verify and reproduce and record reports that are important to 
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All information dealt with during such visits will be treated as strictly confidential. At the end of the trial, close out 
visits will be performed by the monitor after the final participant visit has been completed and prior to database lock. 
During this visit the monitor will verify that all trial close out activities are completed – all queries resolved, missing 
data completed, monitoring completed, archiving arrangements in place, ISF completed and TMF documents 
collected, and end of trial notification. Each investigator will also be notified that an audit or inspection may be 
carried out - by the sponsor, sponsor's representatives or the host institution, or regulatory authorities - at any time, 
before, during or after the end of the trial. The investigator must allow the representatives of the audit or inspection 
team: 
- 
to inspect the site, facilities and material used for the trial, 
- 
to meet all members of his/her team involved in the trial, 
- 
to have direct access to trial data and source documents, to consult all of the documents relevant to the 
trial. If an Investigator is informed of an impending audit or inspection, the trial coordination centre should 
be notified immediately. 
 
11.7 Disclosure of data and publication 
Information concerning the study, patent applications, processes, scientific data or other pertinent information is 
confidential and remains the property of the Sponsor. The investigator may use this information for the purposes of 
the study only. Verbal or written discussion of results prior to study completion and full reporting should only be 
undertaken with written consent from the Sponsor. Therefore all information obtained as a result of the study will 
be regarded as CONFIDENTIAL, at least until appropriate analysis and review by the investigators is completed. 
Permission from the Trial Steering Committee is necessary prior to disclosing any information relative to this study 
outside of the Steering Committee. 
 
 
 
 
 
 
 
12. REFERENCES 
1. 
Emerging Risk Factors C, Seshasai SR, Kaptoge S, Thompson A, Di Angelantonio E, Gao P, Sarwar 
N, Whincup PH, Mukamal KJ, Gillum RF, Holme I, Njolstad I, Fletcher A, Nilsson P, Lewington S, 
Collins R, Gudnason V, Thompson SG, Sattar N, Selvin E, Hu FB & Danesh J. Diabetes mellitus, 
fasting glucose, and risk of cause-specific death. N Engl J Med 2011 364 829-841. 
2. 
Holman RR, Paul SK, Bethel MA, Matthews DR & Neil HA. 10-year follow-up of intensive glucose 
control in type 2 diabetes. N Engl J Med 2008 359 1577-1589. 


 
 
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3. 
Bethel MA & Sourij H. Impact of FDA guidance for developing diabetes drugs on trial design: from 
policy to practice. Curr Cardiol Rep 2012 14 59-69. 
4. 
DeFronzo RA, Davidson JA & Del Prato S. The role of the kidneys in glucose homeostasis: a new 
path towards normalizing glycaemia. Diabetes Obes Metab 2012 14 5-14. 
5. 
Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen 
OE, Woerle HJ, Broedl UC, Inzucchi SE & Investigators E-RO. Empagliflozin, Cardiovascular 
Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med 2015 373 2117-2128. 
6. 
Muskiet MH, van Raalte DH, van Bommel EJ, Smits MM & Tonneijck L. Understanding EMPA-REG 
OUTCOME. Lancet Diabetes Endocrinol 2015 3 928-929. 
7. 
Ceriello A, Genovese S, Mannucci E & Gronda E. Understanding EMPA-REG OUTCOME. Lancet 
Diabetes Endocrinol 2015 3 929-930. 
8. 
Aubert G, Martin OJ, Horton JL, Lai L, Vega RB, Leone TC, Koves T, Gardell SJ, Kruger M, Hoppel CL, 
Lewandowski ED, Crawford PA, Muoio DM & Kelly DP. The Failing Heart Relies on Ketone Bodies 
as a Fuel. Circulation 2016 133 698-705. 
9. 
Briand F, Mayoux E, Brousseau E, Burr N, Urbain I, Costard C, Mark M & Sulpice T. Empagliflozin, 
via Switching Metabolism Toward Lipid Utilization, Moderately Increases LDL Cholesterol Levels 
Through Reduced LDL Catabolism. Diabetes 2016 65 2032-2038. 
10. 
Adamopoulos C, Ahmed A, Fay R, Angioi M, Filippatos G, Vincent J, Pitt B, Zannad F & Investigators 
E. Timing of eplerenone initiation and outcomes in patients with heart failure after acute 
myocardial infarction complicated by left ventricular systolic dysfunction: insights from the 
EPHESUS trial. Eur J Heart Fail 2009 11 1099-1105. 
11. 
Eggers KM, Lagerqvist B, Venge P, Wallentin L & Lindahl B. Prognostic value of biomarkers during 
and after Non-ST-Segment Elevation Acute Coronary Syndrome. JACC 2009 54 357-364. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Appendix A Power and sample size calculation  
 
 
 
 
 
 
 
 
 
 
 


 
 
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Appendix B Participating Study Centers 
1) Study Center Feldkirch (No.1): 
PI: Assoz.-Prof. Dr. Christoph Saely 
Carinagasse 47 
A-6807 Feldkirch 
Tel.: 05522/303-2600 
         05522/303-7510 
E-Mail:  christoph.saely@lkhf.at 
2) Study Center Graz (No.2): 
PI: Assoz.-Prof. Dr. Dirk von Lewinski        
Innere Medizin - Klin. Abteilung für Kardiologie 
Auenbruggerplatz 15 
8036 Graz 
Tel.: 0316/ 385 80684 
E-Mail:  dirk.von-lewinski@medunigraz.at 
3) Study Centre Klagenfurt (No.3): 
PI: Prim. PD Dr. Hannes Alber 
Abteilung für Innere Medizin und Kardiologie  
Klinikum Klagenfurt am Wörthersee 
Feschnigstraße 11 
9020 Klagenfurt am Wörthersee 
Tel.: +43 463 538-31203 
Fax.: +43 463 538-31209 
E-Mail: hannes.alber@kabeg.at  
 
4) Study Centre Kardinal Schwarzenberg Klinikum Schwarzach (No.5) 
PI: OA Dr. Gerhard Mayrhofer 
Kardinal Schwarzenberg Klinikum Schwarzach im Pongau 
Innere Medizin 
5620 – Schwarzach im Pongau, Kardinal Schwarzenbergplatz 1 
Tel.:  +43 (0)–6415 7101 - 0 
E-Mail: herzkatheter@ks-klinikum.at     


 
 
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5) Study Centre Salzburg (No.6): 
PI: Univ.-Prof. Dr. Uta Hoppe 
Universitätsklinik für Innere Medizin II, Kardiologie und internistische Intensivmedizin 
Landeskrankenhaus Salzburg 
Müllner Hauptstraße 48,  
5020 Salzburg  
Tel.: +43 (0) 5 7255 – 25601 
E-Mail: u.hoppe@salk.at  
6) Study Centre Vienna (No.7): 
PI: Assoz.-Prof. Dr. Jolanta Siller-Matula 
Universitätsklinik für Innere Medizin II 
Klinische Abteilung für Kardiologie 
Währinger Gürtel 18-20,  
1090 Wien 
Tel.: 01/404000 
E-Mail: jolanta.siller-matula@meduniwien.ac.at 
7) Study Centre Vienna Rudolfstiftung (No.8): 
PI: Univ.-Prof. Dr. Franz Weidinger 
Krankenanstalt Rudolfstiftung  
2.Medizinische Abteilung mit Kardiologie und internistischer Intensivmedizin 
Juchgasse 25 
1030 Wien 
Tel.: +43 1 711 65 – 2207  / Fax: + 43 1 711 65 - 2209 
E-Mail:  franz.weidinger@wienkav.at  
 
8) Study Centre LKH Süd-West Standort West 
PI: Dr. Peter Zechner 
LKH Graz Süd-West Standort West 
Department für Kardiologie und Intensivmedizin 
Göstinger Strasse 22 
8020 Graz 
Tel.: + 43 (0)316 5466 6466 
E-Mail: petermichael.zechner@kages.at  


 
 
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9) Study Centre BHB Eisenstadt 
PI: Prim. Dr. Rudolf Maximilian Berger, FESC 
Krankenhaus mit Öffentlichkeitsrecht der Barmherzigen Brüder Eisenstadt 
Johannes von Gott Platz 1 
7000 Eisenstadt 
T: +43 2682 60182100 
E-Mail: rudolf.berger@bbeisen.at     
 
10) Study Centre Universitätsklinikum St. Pölten 
PI: PD Dr. Deddo Mörtl 
Universitätsklinikum St. Pölten 
Klinische Abteilung für Innere Medizin 3 
Dunant-Platz 1  
3100 St. Pölten 
T: +43 2742 9004 22577 
E-Mail: deddo.moertl@stpoelten.lknoe.at    
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Appendix C Echo Manual 
1 Preamble 
This manual is a summary of all echocardiographic images and loops that should be assessed as part of the EMMY 
trial echocardiography sub-study. All information given here is based upon the publications <Recommendations for 
Cardiac Chamber Quantification by Echocardiography in Adults: An Update from the American Society of 
Echocardiography and the European Association of Cardiovascular Imaging=, published by Lang et al in 2015 and 
<Recommendations for the Evaluation of Left Ventricular Diastolic Function by Echocardiography: An Update from 
the American Society of Echocardiography and the European Association of Cardiovascular Imaging=, published by 
Nagueh et al in 2016. 
1.1 Equipment 
All study centres will use their own equipment. The echo machines should be maintained adequately and of best 
available quality. The framing rate should be set to the highest possible value (preferable at least > 50 fps). 
1.2 Saving images and loops 
For the best quality in the echocardiographic evaluation of the heart function we need either full loops, here 
preferably 4 cardiac cycles independent of sinus rhythm or atrial fibrillation (please adjust the saving options of your 
ultrasound system), or images as indicated. Please note that the loops and images should not include any 
measurements. Record these raw images and loops in an anonymized file. We recommend at this point to create 
two different files for each patient: one for your clinical usage and one with anonymized raw data. The anonymized 
file should be named as <last name = study ID= and <first name = baseline (0) or follow up (1)=. Birth date and date 
of exam as well as gender should be included in the file. You may save it on USB-sticks or DICOM-DVDs. The raw data 
will be transferred to Graz and measured by an ESC certified investigator (KA). 
 


 
 
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1.3 What do we need for analysis? 
Every file must include – if the quality is sufficient – loops and images of the (1-3) parasternal long axis including M-
mode of the dimensions of the left ventricle and M-mode of the dimensions of the aorta/left atrium; (4, 5) parasternal 
short axis on the level of the papillary muscle and on the level of the apex; (6-12) apical 4-chamber view with and 
without colour Doppler including one image with pulsed wave Doppler at the leaflets of the opened mitral valve and 
tissue Doppler on the medial mitral annulus and continuous wave Doppler at the origin of a tricuspid regurgitation 
(gradient over tricuspid valve); (13, 14) native apical 2-chamber view; (15) native apical 3-chamber view; and (16, 17) 
one loop of the apical 5-chamber view with colour Doppler and one image with the continuous wave Doppler in the 
aortic outflow tract. ECG leads should be connected to the echocardiography machine and ecg tracings should be 
recorded on each loop or image. 
 
Figure 3 Example of an anonymised patient data input 


 
 
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2 Echocardiographic measurements 
2.1 The parasternal long axis (1-3) 
In this axis one loop is required (1). Additionally, saved images of the linear measurements of the left ventricle (2) 
and the aorta/left atrium (3) each measured in M-mode.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 4 Example of an M-mode in the parasternal long axis (left: left ventricle; right: aorta/left atrium) 


 
 
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Figure 3 Example of a parasternal long axis (loop should be recorded) 


 
 
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2.2 The parasternal short axis (4, 5) 
In the parasternal short axis, 2 loops should be obtained and saved: at the level of the papillary muscles (4) and at 
the level of the apex (5) 
 
 
 
 
 
 
 
 
 
 
 
2.3 The apical 4-
chamber view (6-12) 
In the apical 4-chamber view one native loop is required (6). Make sure to record the left and right ventricles and the 
left atrium in the full length. If the left atrium can’t be recorded at full length together with the left ventricle, you 
should record an extra loop with focus on the left atrium (7). 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 5 Example of an apical 4-chamber view (left: focus on the left ventricle; right:  focus on the left atrium) 
Figure 4 Examples of the parasternal short axis (left: level of the papillary muscles; right: level of the apex) 


 
 
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Record a loop with colour Doppler placed on the left atrium (8; assessment of mitral regurgitation) and a loop with 
colour Doppler placed on the right atrium (9; assessment of tricuspid regurgitation). After recording loop #9 
(tricuspid regurgitation), place the continuous wave Doppler directly on the origin of the jet, if present (10). The 
measured signal can then be used to gain information about the pulmonary artery systolic pressure. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
To finish the recordings in the apical 4-chamber view, two more images need to be recorded: one image with the 
pulsed wave Doppler placed on the leaflets of the opened mitral valve (11; assessment of E and A wave) and the 
pulsed wave Doppler with tissue Doppler placed on the medial mitral annulus (12; assessment of é). Both, E and é 
are main parameters in the evaluation of the diastolic function (Nagueh et al. 2016).  
Figure 6 Left: Example of a mitral regurgitation (colour Doppler placed on the left atrium); right: Example of a tricuspid 
regurgitation (colour Doppler placed on the right atrium) 
Figure 7 Example of a continuous wave 
Doppler placed on the origin of a tricuspid 
regurgitation, the signal can be used to gain 
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2.4 The apical 2 chamber view (13, [14]) 
Like the apical 4 chamber view, left ventricle and left atrium should be recorded in full length (13). If the left atrium 
can’t be recorded in full length together with the left ventricle, an additional loop with focus on the left atrium should 
be recorded (14; assessment of the left atrial volume with the Biplane Area-Length Method). No further loops or 
images are required. 
 
 
 
 
 
 
 
 
2.5 
The apical 3 chamber view (15) 
In the apical 3 chamber view the left ventricle at full length, left atrium and aortic root must be visible (15). No further 
loops or images are required. 
 
Figure 8 Example of the assessment of the diastolic heart function: Left: pulsed wave Doppler placed on the leaflets of the 
opened mitral valve; right: pulsed wave Doppler with tissue Doppler placed on the medial mitral annulus 
Figure 9 Example of an apical 2-chamber view (left: focus on the left ventricle; right: focus on the left atrium) 


 
 
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2.6 The apical 5 chamber 
view (16 17) 
In the apical 5 chamber view, one loop with colour Doppler over the aortic valve should be recorded (16). Finally, 
one image with the continuous wave Doppler placed directly on the aortic valve should be recorded (17).  
 
 
 
Figure 10 Example of an apical 3-chamber view 
Figure 11 Example of an apical 5-chamber view (Left: colour Doppler placed over the aorta to gain information of an aortic 
regurgitation; right: continuous wave Doppler placed on the position of the aortic valve (measurement of gradients) 


 
 
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3 Summary 
- 
      ECG recordings on each loop or Image 
PLAX 
1 
Loop of the PLAX 
2 
Image with M-mode of the left ventricular dimensions 
3 
Image with M-mode of the aortic root and the left atrium 
 
PSAX 
4 
Loop of the PSAX at the level of the papillary muscles 
5 
Loop of the PSAX at the level of the apex 
 
Apical 4 chamber view 
6 
Native loop of the 4-chamber view with focus on the left ventricle 
7 
Native loop of the 4-chamber view with focus on the left atrium 
8 
Loop of the 4-chamber view with colour Doppler placed on the left atrium 
9 
Loop of the 4-chamber view with colour Doppler placed on the right atrium 
10 
Image of the tricuspid regurgitation signal (CW Doppler on origin of jet into right atrium) 
11 
Image of E and A wave (PW Doppler placed on the leaflets of the opened mitral valve) 
12 
Image of septal é (TVI and PW Doppler placed on the medial mitral annulus) 
 
Apical 2 chamber view 
13 
Native loop of the 2-chamber view with focus on the left ventricle 
14 
Native loop of the 2-chamber view with focus in the left atrium 
 
Apical 3 chamber view 
15 
Native loop of the 3-chamber view with focus on the left ventricle (left atrium and aortic root must be 
visible) 
 
Apical 5 chamber view 
16 
Loop of the 5-chamber view with colour Doppler placed on the aortic valve/left ventricle 
17 
Image of aortic blood outflow velocity (CW Doppler placed directly on the aortic valve) 
 
 
 

SAP_001.pdf: 
Statistical Analysis Plan 
 EMMY trial 
SAP version 1.10: Impact of EMpagliflozin on cardiac function and biomarkers of heart failure in patients with acute MYocardial infarction 
(EMMY-Trial) – a phase III Study 
Date of Version 25/04/2022 
Page 1 of 21 
Statistical Analysis Plan 
SAP Signatures 
I give my approval for the attached SAP entitled Impact of the Empagliflozin on cardiac function and 
biomarkers of heart failure in patients with acute Myocardial infarction, Version 1.10. 
Statistician (Author) 
Name: Abderrahim Oulhaj 
Signature: 
Date: 
 
 25/April/2022
Statistician Reviewer (As applicable) 
Name: Harald Sourij 
Signature: 
Date: 
 25/April/2022
Principal Investigator 
Name: Dirk von Lewinski 
Signature: 
Date: 
25/April/2022
TRIAL FULL TITLE 
Impact of EMpagliflozin on cardiac function and biomarkers of 
heart failure in patients with acute MYocardial infarction 
(EMMY-Trial) 
SAP VERSION 
1.10 
SAP VERSION DATE 
25/April/2022 
TRIAL STATISTICIAN 
Prof. Abderrahim Oulhaj, PhD 
Protocol Version  
(SAP associated with) 
HS-2017-01 
TRIAL PRINCIPAL 
INVESTIGATOR 
Profs. Harald Sourij and Dirk von Lewinski 
SAP AUTHOR(s) 
Prof. Abderrahim Oulhaj, PhD, Prof. Harald Sourij and Prof. Dirk 
von Lewinski 


Statistical Analysis Plan 
 EMMY trial 
SAP version 1.10: Impact of EMpagliflozin on cardiac function and biomarkers of heart failure in patients with acute MYocardial infarction 
(EMMY-Trial) – a phase III Study 
Date of Version 25/04/2022 
Page 2 of 21 
 
Table of Contents 
Abbreviations and Definitions ................................................................................................................. 4 
1 
Introduction...................................................................................................................................... 5 
1.1 
Preface .................................................................................................................................... 5 
1.2 
Scope of the analyses ............................................................................................................. 6 
2 
Study Objectives and Endpoints ...................................................................................................... 6 
2.1 
Study Objectives .................................................................................................................... 6 
2.1.1 
Primary objectives ............................................................................................................. 6 
2.1.2 
Secondary objectives ......................................................................................................... 6 
2.1.3 
Safety objectives ................................................................................................................ 7 
2.2 
Endpoints ................................................................................................................................ 7 
2.2.1 
Primary endpoint ................................................................................................................ 7 
2.2.2 
Secondary endpoints .......................................................................................................... 7 
3 
Study Methods ................................................................................................................................. 8 
3.1 
General Study Design and Plan .............................................................................................. 8 
3.2 
Inclusion-Exclusion Criteria and General Study Population ................................................. 8 
3.2.1 
Inclusion criteria ................................................................................................................ 8 
3.2.2 
Exclusion criteria ............................................................................................................... 9 
3.3 
Randomization and Blinding .................................................................................................. 9 
3.4 
Study Assessments ............................................................................................................... 10 
4 
Sample Size ................................................................................................................................... 10 
5 
General Analysis Considerations ................................................................................................... 11 
5.1 
Timing of Analyses .............................................................................................................. 11 
5.2 
Analysis Populations ............................................................................................................ 11 
5.2.1 
Intention to Treat Population (ITT) ................................................................................. 11 
5.2.2 
Per Protocol Population (PP) ........................................................................................... 11 
5.2.3 
Safety Population ............................................................................................................. 12 
5.3 
Covariates and Subgroups .................................................................................................... 12 
5.3.1 
Data transformation ......................................................................................................... 12 
5.3.2 
Covariates adjustment ...................................................................................................... 12 
5.3.3 
Subgroup analysis ............................................................................................................ 12 
5.3.4 
Multi-centre Studies ......................................................................................................... 13 
5.4 
Missing Data ........................................................................................................................ 13 
5.5 
Interim Analyses and Data Monitoring (as applicable) ....................................................... 14 
5.6 
Multiple Testing ................................................................................................................... 14 
6 
Summary of Study Data................................................................................................................. 14 
6.1 
Subject Disposition .............................................................................................................. 14 
1.1 
Enrollment ............................................................................................................................ 15 


Statistical Analysis Plan 
 EMMY trial 
SAP version 1.10: Impact of EMpagliflozin on cardiac function and biomarkers of heart failure in patients with acute MYocardial infarction 
(EMMY-Trial) – a phase III Study 
Date of Version 25/04/2022 
Page 3 of 21 
 
1.2 
Allocation ............................................................................................................................. 15 
1.3 
Follow-Up ............................................................................................................................ 15 
1.4 
Analysis ................................................................................................................................ 15 
6.2 
Treatment Compliance ......................................................................................................... 16 
7 
Efficacy Analyses .......................................................................................................................... 16 
7.1 
Primary Efficacy Analysis ................................................................................................... 16 
7.2 
Secondary Efficacy Analyses ............................................................................................... 17 
7.2.1 
Secondary Efficacy analysis I .......................................................................................... 17 
7.2.2 
Secondary Efficacy analysis II......................................................................................... 17 
7.2.3 
Secondary Efficacy analysis III ....................................................................................... 18 
7.2.4 
Secondary Efficacy analysis IV ....................................................................................... 18 
7.3 
Analyses of Secondary Endpoints ........................................................................................ 18 
8 
Safety Analyses ............................................................................................................................. 18 
8.1 
Extent of Exposure ............................................................................................................... 19 
8.2 
Pregnancies........................................................................................................................... 19 
8.3 
Clinical Laboratory Evaluations........................................................................................... 19 
9 
Reporting Conventions .................................................................................................................. 19 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
 EMMY trial 
SAP version 1.10: Impact of EMpagliflozin on cardiac function and biomarkers of heart failure in patients with acute MYocardial infarction 
(EMMY-Trial) – a phase III Study 
Date of Version 25/04/2022 
Page 4 of 21 
 
 
Abbreviations and Definitions 
 
AE 
Adverse Event 
CRF 
Case Report Form 
IMP 
Investigational Medical Product 
SAP 
Statistical Analysis Plan 
 
 
 


Statistical Analysis Plan 
 EMMY trial 
SAP version 1.10: Impact of EMpagliflozin on cardiac function and biomarkers of heart failure in patients with acute MYocardial infarction 
(EMMY-Trial) – a phase III Study 
Date of Version 25/04/2022 
Page 5 of 21 
 
1 Introduction 
1.1 Preface 
 
Type 2 diabetes mellitus (T2DM) is associated with an about two to three-fold increased risk 
of cardiovascular events as compared with subjects without diabetes. The United Kingdom 
Prospective Study (UKPDS) was the first to demonstrate a reduction of macrovascular and 
microvascular complications in subjects with T2DM by an intensified glucose lowering 
treatment regimen with either insulin/sulfonylurea or metformin after long term follow up. 
After Rosiglitazone was removed from the European market due to ongoing uncertainty about 
the cardiovascular safety of this drug, the Federal Drug Administration (FDA) and the 
European Medicine Agency (EMEA) have issued new guidelines for new antihyperglycaemic 
drugs to be licensed, requiring a thorough assessment of cardiovascular safety and in most 
cases the performance of a large cardiovascular outcome trial. Sodium-dependent glucose 
cotransporter 2 (SGLT-2) is mainly expressed in human kidneys and small intestinal cells. In 
the proximal tubule of the nephron SGLT-2 is responsible for the reabsorption of 
approximately 90% of the filtrated glucose. Inhibition of SGLT-2 was shown to increase renal 
glucose excretion and to lower plasma glucose. Subsequently, a number of SGLT-2 inhibitors 
were developed and are currently approved for the treatment of T2DM.  
 
Zinman B. et al published the results of the EMPA-REG-OUTCOME trial where the 
cardiovascular impact of a glucose lowering regimen including Empagliflozin as compared to 
usual glucose control without an SGLT-2 inhibitor was investigated. The trial demonstrated an 
unexpected reduction in the primary composite endpoint, comprising cardiovascular death, 
non-fatal myocardial infarction and non-fatal stroke. The reduction was mainly driven by a 
38% relative risk reduction in cardiovascular deaths; moreover they demonstrated an 
impressive 35% relative risk reduction in the secondary endpoint hospitalization for heart 
failure. Of note, the beneficial effects observed in the Empagliflozin group seem to occur very 
rapidly after commencing the treatment, as shown by the early separation of the Kaplan-Meier 
curves. However, the mechanisms responsible for this finding remain unclear. Diuretic effects 
with subsequent impact on hemodynamics or potential cardioprotective effects of glucagon, 
whose levels rise under the treatment with SGLT-2 inhibitors and the resulting rise in ketone 
bodies or a small increase in haematocrit have been suggested as potential mechanisms. 


Statistical Analysis Plan 
 EMMY trial 
SAP version 1.10: Impact of EMpagliflozin on cardiac function and biomarkers of heart failure in patients with acute MYocardial infarction 
(EMMY-Trial) – a phase III Study 
Date of Version 25/04/2022 
Page 6 of 21 
 
We hypothesize that Empagliflozin beneficially influences the increased cardiac pre- and 
afterload as well as reducing the increased sodium reabsorption following myocardial damage 
with subsequent reduced cardiac output. Whether or not Empagliflozin has direct effects on 
myocardial remodelling has yet to be elucidated, yet. Moreover, recent animal data suggest that 
in failing heart ketone bodies seems to be an increasingly important as energy source. 
Empagliflozin has been shown to increase levels of ketone bodies, which might has a beneficial 
impact on the metabolism and energy supply of the failing heart. In addition, although SGLT-
2 is not expressed in human myocardium, direct, non-SGLT-2 mediated effects on the heart 
muscle cannot be excluded, given that the molecule is small in size. 
 
1.2 Scope of the analyses 
 
These analyses will assess the efficacy and safety of Empagliflozin in improving cardiac 
function and biomarkers of heart failure in patients with acute myocardial infarction and will 
be included in the clinical study report. 
2 Study Objectives and Endpoints 
2.1 Study Objectives 
 
The aim of this study is to investigate the impact of Empagliflozin on cardiac function and 
heart failure biomarkers in patients with acute myocardial infarction. 
2.1.1 
Primary objectives 
 
The primary objective is to investigate the impact of Empagliflozin on NT-proBNP (a heart 
failure biomarker) in patients with myocardial infarction within 6 months after 
randomization. 
2.1.2 
Secondary objectives 
 
Secondary objectives are as follows:  
- Short term changes in NT-proBNP levels  
- Short term and intermediate term changes in echocardiography parameters 
- Change in levels of ketone body concentrations 
- Change in HbA1c levels 


Statistical Analysis Plan 
 EMMY trial 
SAP version 1.10: Impact of EMpagliflozin on cardiac function and biomarkers of heart failure in patients with acute MYocardial infarction 
(EMMY-Trial) – a phase III Study 
Date of Version 25/04/2022 
Page 7 of 21 
 
- Change in body weight 
- Number of hospital re-admissions due to heart failure or other causes 
- Duration of hospital stay 
- All-cause mortality  
2.1.3 
Safety objectives 
 
- All-cause mortality 
- Number of serious adverse events 
- Number of severe hypoglycaemic events (i.e. requiring third party assistance) 
- Number of genital infections 
- Number of ketoacidotic events 
- Changes in liver function parameters (AST, ALT, GGT) 
- Changes in renal function parameters (creatinine, eGFR) 
 
2.2 Endpoints 
2.2.1 
 Primary endpoint 
 
The primary endpoint is the change in NT-proBNP levels from randomization to week 26. 
2.2.2 
 Secondary endpoints 
 
Secondary endpoints include the following: 
 
- Change of NT-proBNP between treatment groups from randomization to week 6 
- Change of ejection fraction (EF) between treatment groups from randomization to week 26 
- Change of ejection fraction between treatment groups from randomization to week 6 
- Change of left ventricular diastolic function (LVDF) from randomization to week 26 
- Change of LVDF from randomization to week 6  
- Change of HbA1c between treatment groups from randomization to week 26 (in subjects 
with known diabetes mellitus Type 2 at randomization) 
- Change of body weight between treatment groups from randomization to week 6 
- Change of body weight between treatment groups from randomization to week 26 
- Change of blood beta-hydroxybutyrate levels between the treatment groups from 
randomization to week 6  


Statistical Analysis Plan 
 EMMY trial 
SAP version 1.10: Impact of EMpagliflozin on cardiac function and biomarkers of heart failure in patients with acute MYocardial infarction 
(EMMY-Trial) – a phase III Study 
Date of Version 25/04/2022 
Page 8 of 21 
 
- Change of blood beta-hydroxybutyrate levels between the treatment groups from 
randomization to week 26  
- Difference in hospital re-admissions rate due to heart failure after discharge (of the 
myocardial infarction event leading to trial inclusion) between the treatment groups 
- The difference in the number of hospital re-admissions for any cause between the treatment 
groups 
- The difference in the duration of hospital stay between the treatment groups after 
randomization 
3 Study Methods 
3.1 General Study Design and Plan 
 
This is a two arms randomized controlled multi-centre, parallel-group, double-blinded trial. 
The control group is a placebo and the treated group is Empagliflozin. The aim of the trial is 
to show superiority of Empagliflozin over placebo. Randomization was carried out by 
stratifying according to site, T2DM status and sex. 
 
3.2 Inclusion-Exclusion Criteria and General Study Population 
3.2.1 
Inclusion criteria 
 
1. Myocardial infarction with evidence of significant myocardial necrosis defined as a rise in 
creatinine kinase >800 U/l and a troponin T-level (or troponin I-level) >10x ULN. In 
addition, at least 1 of the following criteria must be the met:  
- Symptoms of ischemia. 
- ECG changes indicative of new ischemia (new ST-T changes or new LBBB). 
- Imaging evidence of new regional wall motion abnormality. 
2. 18 – 80 years of age. 
3. Informed consent has to be given in written form. 
4. eGFR > 45 ml/min/1.73m2. 
5. Blood pressure before first drug dosing: systolic blood pressure>110mmHg. 
6. Blood pressure before first drug dosing: diastolic blood pressure>70mmHg. 
7. First intake of study medication f72h after myocardial infarction after performance of a 


Statistical Analysis Plan 
 EMMY trial 
SAP version 1.10: Impact of EMpagliflozin on cardiac function and biomarkers of heart failure in patients with acute MYocardial infarction 
(EMMY-Trial) – a phase III Study 
Date of Version 25/04/2022 
Page 9 of 21 
 
coronary angiography. 
3.2.2 
Exclusion criteria 
 
1. Any other form of diabetes mellitus than type 2 diabetes mellitus, history of diabetic 
ketoacidosis. 
2. Blood pH < 7,32. 
3. Known allergy to SGLT-2 inhibitors. 
4. Haemodynamic instability as defined by intravenous administration of catecholamine, 
calciumsensitizers or phosphodiesterase inhibitors. 
5. >1 episode of severe hypoglycaemia within the last 6 months under treatment with insulin 
or sulfonylurea. 
6. Females of child bearing potential without adequate contraceptive methods (i.e. 
sterilisation, intrauterine device, vasectomised partner; or medical history of 
hysterectomy). 
7. Acute symptomatic urinary tract infection (UTI) or genital infection. 
8. Patients currently being treated with any SGLT-2 inhibitor (dapagliflozin, canagliflozin, 
empagliflozin) or having received treatment with any SGLT-2 inhibitor within the 4 weeks 
prior to the screening visit. 
 
3.3 Randomization and Blinding  
 
After screening, all eligible patients for the trial were randomized into one of the two arms of 
the study via Randomiser Software (Institute for Medical Informatics, Statistics and 
Documentation, Medical University of Graz, http://www.randomizer.at), which is 
programmed with a randomisation schedule provided by an independent statistician. The 
randomization was stratified by site, T2DM and by sex. Only the subject number and subject 
initials were recorded in the case report form (CRF). The investigator maintains a personal 
subject identification list (subject numbers with the corresponding subject names) to enable 
records to be identified. 
 
Blinding of the medication was done by the pharmacy at the University Hospital in Salzburg, 
Austria. The pharmacy received the randomization list from the Institute for Medical 


Statistical Analysis Plan 
 EMMY trial 
SAP version 1.10: Impact of EMpagliflozin on cardiac function and biomarkers of heart failure in patients with acute MYocardial infarction 
(EMMY-Trial) – a phase III Study 
Date of Version 25/04/2022 
Page 10 of 21 
 
Informatics, Statistics and Documentation at the Medical University of Graz, Austria by the 
independent statistician. The pharmacy distributed then the blinded medication to the study 
sites. The independent statistician and the pharmacists are otherwise not involved in the 
EMMY trial. 
 
3.4 Study Assessments  
 
Data are collected according to the following schedule: 
 
 
 
4 Sample Size  
 
Previous data showed that NT-proBNP levels decrease by about 50% within 6 months after 
acute myocardial infarction. To detect a relative 40% larger reduction in NT-proBNP levels 


Statistical Analysis Plan 
 EMMY trial 
SAP version 1.10: Impact of EMpagliflozin on cardiac function and biomarkers of heart failure in patients with acute MYocardial infarction 
(EMMY-Trial) – a phase III Study 
Date of Version 25/04/2022 
Page 11 of 21 
 
in the Empagliflozin group as compared to the placebo group with a power of 80% and an 
alpha-level of 0.05%, and assuming a correlation for NT-proBNP levels of 0.85, a sample 
size of 216 subjects in each group is necessary. To account for a dropout rate of about 10% 
each group will consist of 238 patients. A detailed document regarding power and sample 
size calculation is annexed to this SAP. 
5 General Analysis Considerations 
5.1 Timing of Analyses 
 
The trial will end after the last subject has completed the follow-up telephone assessment 
(Study visit 5). All patients will be reviewed by a clinician at their last study visit in order to 
arrange return to appropriate routine clinical care pathways. The data analysis will be 
performed on data transferred to the file data_emmy_YYMMDD, having been documented 
as meeting the cleaning and approval requirements and after the finalization and approval of 
this SAP document. 
 
5.2 Analysis Populations 
5.2.1 
Intention to Treat Population (ITT) 
 
The ITT population includes all patients who were randomized and received at least one dose 
of the study medication (i.e. Empagliflozin or Placebo). The ITT population will be used for 
the primary efficacy analysis.  
5.2.2 
Per Protocol Population (PP) 
 
The PP population will include all patients in the ITT population who completed week 26 
evaluation without any major protocol violations. More specifically, the PP population will 
include all patients in the ITT population excluding: 
a- Patients not fulfilling inclusion/exclusion criteria at baseline, which was identified after 
randomization and first treatment dosing but who remained in the trial as no safety 
concern was considered by the principal investigators. 
b-  Patients who did not complete week 26 evaluation 
c-  Patients who took study medication for less than 75% of the study duration (study 


Statistical Analysis Plan 
 EMMY trial 
SAP version 1.10: Impact of EMpagliflozin on cardiac function and biomarkers of heart failure in patients with acute MYocardial infarction 
(EMMY-Trial) – a phase III Study 
Date of Version 25/04/2022 
Page 12 of 21 
 
duration = 26 +/- 2 weeks) 
The list of potentially important protocol deviations will be identified, reviewed, and 
finalized prior to the release of the database. 
5.2.3 
Safety Population 
 
All patients who were randomized and received at least one confirmed dose of study 
medication (i.e. Empagliflozin or Placebo) and provided any post-baseline safety 
information.  
 
5.3 Covariates and Subgroups 
 
5.3.1 
Data transformation 
Data might be transformed on a logarithmic scale in case of non-normality distribution. 
 
5.3.2 
Covariates adjustment 
 
All analyses, including the primary analysis, will be adjusted for the variables used when 
stratifying the randomization. These variables are Sex and T2DM status. We will not be able 
to adjust for the variable centre as this might introduce too many categories. Analysis will 
also be adjusted for baseline levels of the dependent variables. 
5.3.3 
 Subgroup analysis 
 
Subgroup analyses will focus on the evidence for a difference in treatment effects using the 
interaction term. Subgroup-specific treatment effect estimates will be presented only if the 
interaction effect is judged to be statistically significant. Interaction effects will be 
investigated for the following variables: 
- 
T2DM 
- 
Previous cardiovascular events (myocardial infarction or stroke) 
- 
 Previous myocardial infarction 
- 
 History of heart failure 
- 
 Age 
- 
 Sex 


Statistical Analysis Plan 
 EMMY trial 
SAP version 1.10: Impact of EMpagliflozin on cardiac function and biomarkers of heart failure in patients with acute MYocardial infarction 
(EMMY-Trial) – a phase III Study 
Date of Version 25/04/2022 
Page 13 of 21 
 
- 
Renal function 
- 
LV-EF 
- 
Baseline levels of the dependent variable. Here the interaction will be investigated using 
the original dependent variable and/or by categorizing this dependent variable into a 
clinically relevant number of categories. Percentiles will be used if there are no prior 
clinical cut offs.  
Forest plots will be produced to illustrate subgroup effects and interactions. If needed, three 
way interactions will also be included (e.g. to investigate the interaction between treatment, 
NT-proBNP and CK). 
5.3.4 
Multi-centre Studies 
 
Because this study was not designed to detect centre effects with specific power, all centres 
will be grouped and analyses will be carried out as a whole. However, we will perform an 
exploratory analysis for centre effects with respect to each of the dependent variables. 
Qualitative and/or quantitative treatment-by-centre interactions will be investigated in this 
case. For the purpose of analysis, a small site will be defined as a site with < 4 ITT subjects 
in either treatment arm. Small sites will be ranked in descending order based on the total 
number of ITT subjects of the sites. The first small site will be pooled with the next small 
site, or with more sites if needed, until the pooled site/analysis centre has at least 4 ITT 
subjects in both the arms. The algorithm will continue down the list, and if the last few small 
sites are pooled but fail to be adequately large, they will be combined with the previously 
pooled smallest site/analysis centre.  
 
5.4 Missing Data 
 
Missing data will be imputed for some efficacy analyses described in the next sections (see 
section: efficacy analyses).  Missing values will be imputed at all visits using the Multiple 
Imputation with Chained Equation (MICE) approach. Ten imputed data sets with all visit 
values filled in will be generated. The analysis will be performed on each of the 10 imputed 
datasets, which will produce estimates of treatment effect and the standard error of that 
estimate. Finally, the set of estimates and standard errors will be analysed by the mice R 
package to produce overall (pooled) estimates, confidence intervals, and P-values for the 


Statistical Analysis Plan 
 EMMY trial 
SAP version 1.10: Impact of EMpagliflozin on cardiac function and biomarkers of heart failure in patients with acute MYocardial infarction 
(EMMY-Trial) – a phase III Study 
Date of Version 25/04/2022 
Page 14 of 21 
 
treatment effect. 
 
 
5.5 Interim Analyses and Data Monitoring (as applicable) 
 
No interim analyses are planned for this study 
 
5.6 Multiple Testing 
 
There is no need to control for the overall type 1 error using a multiple testing procedure 
since there is only one single primary efficacy endpoint.  
6  Summary of Study Data 
 
All summary tables will be structured with columns for each treatment and overall in the 
order (Overall, Placebo, Empagliflozin) and will be annotated with the total population size 
relevant to that table, including any missing observations. All continuous variables will be 
summarized using the following descriptive statistics: n (non-missing sample size), mean, 
standard deviation. The frequency and percentages (based on the non-missing sample size) of 
observed levels will be reported for all categorical variables. Demographic and clinical 
characteristics to be summarized will include all baseline variables. P-values will be added to 
compare baseline characteristics between Placebo and Empagliflozin groups. 
 
Summary tables will be provided overall and also, if adequate, stratified according to: 
variables used in stratifying the randomization (i.e. Sex, T2DM status and Site), variables 
used in the subgroup analysis, and by visit.  
 
6.1 Subject Disposition 
 
A graphic showing an overview of the recruitment rate overall and by treatment groups will 
be provided. Also, a flow diagram will be provided as shown below: 
 
 
 


Statistical Analysis Plan 
 EMMY trial 
SAP version 1.10: Impact of EMpagliflozin on cardiac function and biomarkers of heart failure in patients with acute MYocardial infarction 
(EMMY-Trial) – a phase III Study 
Date of Version 25/04/2022 
Page 15 of 21 
 
 
 
 
 
 
 
 
 
Flow Diagram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tables showing the number of patients reaching v1 only, v1-v2, v1-v3 and v1-v4 will be 
Assessed for eligibility (n=  ) 
Excluded (n=   ) 
   Not meeting inclusion criteria (n=  ) 
   Declined to participate (n=  ) 
   Other reasons (n=  ) 
Analysed (n=  ) 
 Excluded from analysis (give reasons) (n=  ) 
Lost to follow-up (give reasons) (n=  ) 
Discontinued intervention (give reasons) (n=  ) 
Allocated to Empagliflozin (n=  ) 
 Received allocated intervention (n=  ) 
 Did not receive allocated intervention (give 
reasons) (n=  ) 
Lost to follow-up (give reasons) (n=  ) 
Discontinued intervention (give reasons) (n=  ) 
Allocated to Placebo (n=  ) 
 Received allocated intervention (n=  ) 
 Did not receive allocated intervention (give 
reasons) (n=  ) 
Analysed (n=  ) 
 Excluded from analysis (give reasons) (n=  ) 
Randomized (n=  ) 
1.1 Enrollment 
1.2 Allocation 
1.4 Analysis 
1.3 Follow-Up 


Statistical Analysis Plan 
 EMMY trial 
SAP version 1.10: Impact of EMpagliflozin on cardiac function and biomarkers of heart failure in patients with acute MYocardial infarction 
(EMMY-Trial) – a phase III Study 
Date of Version 25/04/2022 
Page 16 of 21 
 
displayed according to the treatment groups. The same information will be provided about 
missing data on the primary endpoint.  
 
The absolute change in nt-proBNP levels from randomization to week 26 denoted by 
8change_proBNP9 and will be derived as follows: 
change_proBNP = proBNP_w1 - proBNP_w26 
where proBNP_w1 stands for the level of nt-proBNP at randomization (w1), and 
proBNP_w26 stands for the level of nt-proBNP at week 26. 
The percentage change in nt-proBNP denoted as 8perc_change_proBNP9 will be derived as 
follows: 
perc_change_proBNP = (proBNP_w1 - proBNP_w26)/proBNP_w1 
where proBNP_w1, and proBNP_w26 are defined as above.   
 
6.2 Treatment Compliance 
Treatment compliance will be assessed by remaining pill count. The pill count is checked at 
the monitoring visits. 
7 Efficacy Analyses 
 
Efficacy analyses performed using the intent-to-treat (ITT) population will be considered as 
primary, whereas efficacy analyses performed using the per-protocol (PP) population will be 
considered as supportive. 
 
7.1  Primary Efficacy Analysis 
 
The primary efficacy endpoint is the change in NT-proBNP from baseline to week 26. This 
primary endpoint will be analysed on the ITT population using a linear mixed effect model 
(LMEM) where the dependent variable is the NT-proBNP and the fixed effects are treatment, 
visit, treatment by visit interaction, the stratification factors Sex andT2DM and the level of 
NT-proBNP at baseline. The random effect component will include patients and unstructured 
covariance will be assumed for the within-subject errors. In case of non-convergence 
problems other covariance structures, such as compound symmetry, will be applied until the 
problem is resolved.  


Statistical Analysis Plan 
 EMMY trial 
SAP version 1.10: Impact of EMpagliflozin on cardiac function and biomarkers of heart failure in patients with acute MYocardial infarction 
(EMMY-Trial) – a phase III Study 
Date of Version 25/04/2022 
Page 17 of 21 
 
 
In this analysis, no missing data will be imputed. It will be handled by using the LMEM 
which assumes the data to be missing at random (MAR process).   At week 26, estimates of 
mean values, the mean differences between the treatment groups and the associated 2-sided 
95% confidence interval will be derived from the LMEM model through the use of estimated 
marginal means (or LS-means).  
To claim superiority of Empagliflozin over Placebo, this primary efficacy analysis must show 
a statistically significant effect of treatment at an alpha level of 5% and two-sided test 
direction.  
  
7.2 Secondary Efficacy Analyses 
 
To support the interpretation of the primary efficacy analysis, some robustness and/or 
sensitivity analyses will be performed on the primary efficacy endpoint. However, the 
conclusion of superiority for comparison of the primary endpoint between the two treatment 
groups is purely based on results of the primary efficacy analysis. 
  
Secondary efficacy analyses will be performed to assess robustness of the results against 
missing data, analysis population, and the statistical model used.  
7.2.1 
Secondary Efficacy analysis I 
 
To assess the sensitivity of the above primary efficacy analysis to missing data, analysis will 
also be conducted on the ITT population with missing values being imputed at all visits using 
the Multiple Imputation with Chained Equation (MICE) approach as described in section 5.4. 
Ten imputed data sets with all visit values filled in will be generated.  The primary efficacy 
analysis described above will then be performed on each of the 10 imputed datasets, which will 
produce estimates of treatment effect and the standard error of that estimate. Finally, the set of 
estimates and standard errors will be analyzed by mice package to produce overall (pooled) 
estimates, confidence intervals, and P-values for the treatment effect. 
7.2.2 
Secondary Efficacy analysis II 
 
To assess the sensitivity of the above primary efficacy analysis to the analysis population, we 
will conduct the same primary efficacy analysis as above but by using the Per protocol 


Statistical Analysis Plan 
 EMMY trial 
SAP version 1.10: Impact of EMpagliflozin on cardiac function and biomarkers of heart failure in patients with acute MYocardial infarction 
(EMMY-Trial) – a phase III Study 
Date of Version 25/04/2022 
Page 18 of 21 
 
population instead of the ITT. 
7.2.3 
Secondary Efficacy analysis III 
 
In this analysis, we use the absolute change in NT-proBNP from baseline to week 26 as the 
primary endpoint. This endpoint will be analyzed on the ITT population, with no imputation 
of missing values, and by using a multiple linear regression model where the dependent 
variable is the absolute change in NT-proBNP and the independent variables are treatment, 
Sex, T2DM and baseline level of NT-proBNP.  
7.2.4 
Secondary Efficacy analysis IV 
 
In this analysis, we use the percent change in NT-proBNP from baseline to week 26 as the 
primary endpoint. This endpoint will be analyzed on the ITT population, with no imputation 
of missing values, and by using a multiple linear regression model where the dependent 
variable is the percent change in NT-proBNP and the independent variables are treatment, Sex, 
T2DM and baseline level of NT-proBNP.  
 
7.3 Analyses of Secondary Endpoints 
 
The change from randomization to week 26 of all continuous secondary endpoints will be 
analysed in the same way as the primary efficacy endpoint as follows: 
Analysis population: ITT 
Missing data: no imputation to be performed. Missing data will be implicitly handled by using 
the LMEM which assumes the data to be missing at random (MAR process). 
Statistical model: LMEM with unstructured covariance matrix. At week 26, estimates of mean 
values, the mean differences between the treatment groups and the associated 2-sided 95% 
confidence interval will be derived from the LMEM model through the use of Least square 
means (LS-means). 
 
8 Safety Analyses 
The safety section of the analysis will contain a descriptive listing of the following tables: 
 
All-Cause Mortality: A table of all cases of deaths due to any cause, with number and frequency 


Statistical Analysis Plan 
 EMMY trial 
SAP version 1.10: Impact of EMpagliflozin on cardiac function and biomarkers of heart failure in patients with acute MYocardial infarction 
(EMMY-Trial) – a phase III Study 
Date of Version 25/04/2022 
Page 19 of 21 
 
of such events in each arm/group of the clinical study. 
Serious Adverse Events: A table of all anticipated and unanticipated serious adverse events, 
grouped by organ system, with number and frequency of such events in each arm/group of 
the clinical study.  
This table will also include the reporting of cases of diabetic ketoacidosis. 
8.1 Extent of Exposure 
If appropriate use standard text: <The summary statistics will be produced in accordance with 
section 9.= 
8.2 Pregnancies  
If pregnancies were recorded during the trial, descriptive information on the outcome will be 
provided. 
8.3  Clinical Laboratory Evaluations 
Summary statistics on laboratory measurements will be tabulated. For baseline values, 
differences in normal ranges between sites will be provided. 
The primary outcome, NTproBNP, is assessed at the central lab. If measurement in the central 
lab are not possible (e.g. missing biomarker sample), NTproBNP measurement from the local 
lab will be accepted for the analysis. 
9 Reporting Conventions 
P-values g0.001 will be reported to 2 significant figures; p-values less than 0.001 will be 
reported as <<0.001=. The mean, standard deviation, and any other statistics other than 
quantiles, will be reported to one decimal place greater than the original data. Quantiles, such 
as median, or minimum and maximum will use the same number of decimal places as the 
original data.  
 
 


Statistical Analysis Plan 
 EMMY trial 
SAP version 1.10: Impact of EMpagliflozin on cardiac function and biomarkers of heart failure in patients with acute MYocardial infarction 
(EMMY-Trial) – a phase III Study 
Date of Version 25/04/2022 
Page 20 of 21 
 


Statistical Analysis Plan 
 EMMY trial 
SAP version 1.10: Impact of EMpagliflozin on cardiac function and biomarkers of heart failure in patients with acute MYocardial infarction 
(EMMY-Trial) – a phase III Study 
Date of Version 25/04/2022 
Page 21 of 21