Clinical trial NCT04600921
Conditions: Heart Failure With Reduced Ejection Fraction Heart Failure With Mid Range Ejection Fraction Implantable Cardioverter-Defibrillators Cardiac Resynchronization Therapy
Keywords: Ertugliflozin Sodium dependent glucose transporter-2 inhibitor (SGLT-2) Heart failure ICD CRT ventricular tachycardia (VT)
Sponsor: Medical University of Graz
Start date: 2021-06-24; Completion date: 2023-10-18
Enrollment: 55 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The recent study is planned to investigate the impact of Ertugliflozin on total burden of ventricular arrhythmias. Further objectives will be number of therapeutic interventions of implanted devices, atrial fibrillation, heart failure biomarker and changes in physical function quality of life, stress and anxiety.

Detailed description:
This is a randomized, double-blind (patients and physicians), placebo controlled multi-center study to evaluate the effect of ertugliflozin 5mg once daily (p.o.) for 52 weeks on the ventricular arrhythmic burden and markers of physical and mental well-being as well as biomarker for Heart Failure with reduced Ejection Fraction (HFrEF) and heart failure with mid-range ejection fraction (HFmrEF) patients with ICD±CRT therapy. The study will be conducted in 8 experienced sites in Austria with an aim to enrol 402 patients to evaluate the overall study hypothesis.

Therefore, three study visits will be carried out (baseline, 1-year follow-up visit and a telephone visit 4 weeks after visit 2). As part of the two on-site study visits, study-specific measures, a blood sample and an echocardiographic examination will be performed. The trial is completed by a telephone visit 4 weeks after the second on-site visit (week 52).

It is anticipated that the study will run for 30 months.

Arms: arm 1: The subject will receive Ertugliflozin 5mg. arm 2: The subject will receive Placebo 5mg.
Interventions: intervention 1: Ertugliflozin 5 mg intervention 2: Placebo 5mg
Intervention descriptions: intervention 1: The subject will receive Ertugliflozin 5mg orally once daily for 52 weeks. intervention 2: The subject will receive Placebo 5mg orally daily for 52 weeks.

Protocol documents:
Prot_000.pdf: 
 
 
Title: 
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Protocol No: 
Version 1.20 
 
22 December 2021 
 
 
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CLINICAL STUDY PROTOCOL 
 
 
Study Title: 
Ertugliflozin to Reduce Arrhythmic burden in ICD/CRT patientS (ERASe-Trial)  – 
a phase III Study 
Protocol Number: 
DvL–2020-01 
Product: 
Ertugliflozin 
Sponsor: 
Medical University of Graz (to be announced) 
Protocol Date: 
22 December 2021 
Protocol Version: 
1.20 clean 
Ethics number: 
32-492 ex 19/20 
EudraCT number: 
2020-002581-14 
Contact: 
Assoc. Prof. PD Dr. Dirk von Lewinski 
Mail: dirk.von-lewinski@medunigraz.at  
Phone: 0316/385 80684 
 
 
 
 
 
 
 
 


 
 
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CONTACT LIST 
Chief Investigators 
 
                         
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 
 
Univ.-Prof. Dr. Daniel Scherr 
Division of Cardiology 
Department of Internal Medicine 
Medical University of Graz 
Auenbruggerplatz 15 
8036 Graz, Austria 
Tel: +43 316 385 12544 
 
 
Biometrician (available, if needed) 
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 
MSD (Merck Sharp and Dohme) 
Project Management  
Univ. Prof. Dr. Harald Sourij and 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 
 
 


 
 
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List of Trial Sites & Principal Investigators 
Trial Site 
Principal Investigator 
➢ Medizinische Universität Graz, Universitätsklinikum für Innere 
Medizin, Klinische Abteilung für Kardiologie 
Univ.-Prof. Dr. Daniel Scherr 
➢ Klinikum Klagenfurt, Klinische Abteilung für Innere Medizin 
und Kardiologie 
Prim. PD Dr. Hannes Alber 
➢ Ordensklinikum Linz Elisabethinen, Interne 2 – Kardiologie, 
Angiologie & Interne Intensivmedizin 
PD Dr. Martin Martinek 
➢ Klinik Ottakring, Wilhelminenspital, 3. Medizinische Abteilung 
mit Kardiologie mit Ambulanz 
OA Dr. Michael Nürnberg 
➢ Universitätsklinikum Innsbruck, Univ. Klinik für Innere Medizin 
III/ Kardiologie und Angiologie 
PD Dr. Markus Stühlinger 
➢ Landesklinikum Wiener Neustadt, 2. Medizinische Abteilung 
für Kardiologie, Nephrologie und Intensivmedizin 
Prim. Univ.Doz.Dr. Franz Roithinger 
➢ Universitätsklinikum AKH Wien, Universitätsklinikum für 
Innere Medizin II, Klinische Abteilung für Kardiologie 
Univ.-Prof. Dr. Marianne Gwechenberger 
➢ Kepler Universitätsklinikum Linz, Klinik für Kardiologie und 
Internistische Intensivmedizin 
Prim. PD Dr. Clemens Steinwender 
➢ Universitätsklinikum St. Pölten, Klinische Abteilung für Innere 
Medizin 3 
OA PD Dr. Deddo Mörtl 
Signatures: 
Chief Investigators: 
  
 
Univ.-Prof. Dr. Daniel Scherr 
Assoc.-Prof. Dr. Dirk von Lewinski                                      
 
 
 
 
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 
Table of contents ................................................................................................................................................... 4 
List of figures .......................................................................................................................................................... 7 
List of tables ........................................................................................................................................................... 7 
Abbreviations ......................................................................................................................................................... 8 
Synopsis ............................................................................................................................................................... 11 
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 and Secondary Objectives .............................................................................................................. 14 
2.2 Safety objectives ......................................................................................................................................... 14 
2.3 Primary outcomes ....................................................................................................................................... 15 
2.4 Secondary outcomes ................................................................................................................................... 15 
3. STUDY DESCRIPTION ........................................................................................................................................ 15 
3.1 Design ........................................................................................................................................................ 15 
3.2 Duration of study ........................................................................................................................................ 16 
4. STUDY POPULATION ......................................................................................................................................... 16 
4.1 Inclusion criteria ......................................................................................................................................... 16 
4.2 Exclusion criteria ......................................................................................................................................... 16 
4.3 Withdrawal criteria ..................................................................................................................................... 16 
4.4 Termination of the entire trial ..................................................................................................................... 17 
4.5 Unblinding .................................................................................................................................................. 17 
5. VISIT PROCEDURES, MEASUREMENTS AND ASSESSMENTS .............................................................................. 17 
5.1 Recruitment and screening ......................................................................................................................... 17 
5.2 Randomisation ............................................................................................................................................ 18 
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, echocardiography, ICD interrogation ............................................................................................ 21 
5.5.3 Vital signs ............................................................................................................................................ 21 
5.5.4 Body weight and height ....................................................................................................................... 21 
5.5.5 Routine biochemistry ........................................................................................................................... 21 
5.5.6 Blood sample collection and plasma extraction for biobanking ............................................................. 22 
5.6 Benefit-Risk Assessment ............................................................................................................................. 22 
6. ADVERSE EVENTS (AE) ...................................................................................................................................... 23 
6.1 Adverse Event description ........................................................................................................................... 23 
6.2 Severity of Adverse Events .......................................................................................................................... 23 
6.3 Causality of Adverse Events ......................................................................................................................... 23 
6.4 Abnormal Laboratory Test Results ............................................................................................................... 23 
6.5 Adverse events of Special Interest (AESIs) ................................................................................................... 24 
6.5.1 Hepatic injury ...................................................................................................................................... 24 
6.5.2 Decreased renal function ..................................................................................................................... 24 
6.5.3 Metabolic acidosis, ketoacidosis and diabetic ketoacidosis (DKA) ......................................................... 24 
6.5.4 Events involving lower limb amputation ............................................................................................... 25 
6.6 Serious Adverse Events (SAE) ...................................................................................................................... 25 
6.6.1 Reporting of SAEs ................................................................................................................................ 26 
7. STATISTICAL ANALYSES .................................................................................................................................... 26 
7.1 Sample size and power considerations ........................................................................................................ 26 
7.2 Data analysis ............................................................................................................................................... 28 
8. DATA MANAGEMENT ....................................................................................................................................... 28 
9. TREATMENT ..................................................................................................................................................... 28 
9.1 Study medication ........................................................................................................................................ 28 
9.2 Method of administration ........................................................................................................................... 29 
9.3 Special precautions for storage ................................................................................................................... 29 


 
 
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9.4 Dispensing of Study Drug ............................................................................................................................ 29 
9.5 Return/Destruction of Study Drug ............................................................................................................... 29 
10. REGULATORY, ETHICAL AND LEGAL ISSUES..................................................................................................... 29 
10.1 Declaration of Helsinki .............................................................................................................................. 29 
10.2 Good Clinical Practice................................................................................................................................ 29 
10.3 Independent Ethics Committee/ competent authority ............................................................................... 29 
10.3.1 Initial Approval .................................................................................................................................. 29 
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 ........................................................................................................................... 31 
11.1 Source Data .............................................................................................................................................. 31 
11.2 Language .................................................................................................................................................. 32 
11.3 Data Collection ......................................................................................................................................... 32 
11.4 Electronic Recording of data...................................................................................................................... 32 
11.5 Study Management Structure ................................................................................................................... 32 
11.5.1 Trial Steering Committee (TSC) ........................................................................................................... 32 
11.6 Monitoring................................................................................................................................................ 32 
11.7 Disclosure of data and publication............................................................................................................. 33 
12. REFERENCES ................................................................................................................................................... 34 
 


 
 
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List of figures                                                                                                                                                           Page  
Figure 1  
 
 
 
 
 
 
 
 
 
 
Study Flow chart  
 
 
 
 
 
 
 
 
               16 
 
List of tables                                                                                                                                                             Page 
Table 1  
 
 
 
 
 
 
 
 
 
             
Visit schedule 
 
 
 
 
 
 
 
 
 
 
19 
 
Table 2 
Summary of blood tests at each study visit  
 
 
 
 
 
                22 
 
Table 3 
Diagnostic criteria for DKA 
 
 
 
 
 
 
 
 
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Abbreviations 
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 
CRT 
Cardiac resynchronisation therapy 
CV 
Cardiovascular 
DCM 
Dilative cardiomyopathy 
DKA 
Diabetic Ketoacidosis 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eGFR  
Estimated Glomerular Filtration Rate 
EMA 
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 
HFmrEF 
Heart Failure with Mid-Range Ejection Fraction 
HFrEF 
Heart Failure with Reduced Ejection Fraction 
ICD 
Internal Cardioverter Defibrillator 
IMI 
Institute of Medical Informatics, Statistics and Documentation 
ISF 
Investigator Site File 
INS 
Institute Surveillance 
KKS 
Koordinierungszentrum für Klinische Studien 


 
 
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LBBB 
Left bundle branch block 
LDL 
Low Density Lipoprotein 
LPLV 
Last Patient Last Visit 
MCI 
Myocardial Infarction 
nsVT 
Non sustained ventricular tachycardia 
nt-proBNP 
N-terminal pro b-type natriuretic peptide 
NYHA 
New York Heart Association 
pH 
Pondus Hydrogenii 
QoL 
Quality of life 
RR 
Riva Rocci Blood Pressure Measurement 
SGLT-2 
Sodium-dependent glucose cotransporter 2 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
sVT 
Sustained ventricular tachycardia 
T2DM 
Type 2 Diabetes Mellitus 
TMF 
Trial Master File 
TMG 
Trial Management Group 
TSC 
Trial Steering Committee 
ULN 
Upper Limit of Normal 
UTI 
Urinary Tract Infection 
VF 
Ventricular fibrillation 
VT 
Ventricular tachycardia 
ULN 
Upper Limit of Normal 
UTI 
Urinary Tract Infection 
 
 
 
 
 
 
 
 
 


 
 
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AMENDMENT HISTORY 
Amendment No. 
Protocol Version  
Date  
Details of Changes made 
EC Submission 
1.16 
25-May-2020 
- 
Supplemental EC 
submission 
1.17 
17-Jul-2020 
Data analysis was changed 
1 
1.18 
04-Nov-2020 
Study Sites were added 
2 
1.19 
09-Aug -2021 
Clarification of inclusion criterion 2 
eCRF (HybridForms®) 
Time schedule 
3 
1.20 
22-Dec-2021 
Study site (Uniklinikum St. Pölten) was added 
Additional Information about SAE Reporting 
Timeframe correction of secondary outcomes 
 
 


 
 
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Synopsis 
Sponsor 
Medical University of Graz 
Auenbruggerplatz 2-4 
8036 Graz, Austria 
Coordinating Investigator 
Dirk von Lewinski, MD, Associate Professor  
Indication 
Patients with HFrEF or HFmrEF, and ICD±CRT therapy  
Study design and phase 
Randomized, prospective, placebo-controlled, double blind, multicenter, 
phase III study in patients with HFrEF or HFmrEF, and ICD±CRT therapy  
Study Short Title 
Ertugliflozin to Reduce Arrhythmic burden in ICD/CRT patientS 
Keyword 
SGLT-2 inhibition, heart failure, ICD, CRT, VT 
Aims of the trial 
The primary objective is to investigate the impact of Ertugliflozin on total 
burden of ventricular arrhythmias. Further objectives will be number of 
therapeutic interventions of implanted devices, atrial fibrillation, heart 
failure biomarker and changes in physical function quality of life, stress and 
anxiety.  
Outcome measures of the trial 
Primary outcome measures: 
Difference in number of sVT/VF episodes between treatment groups from 
randomization to week 52 
Secondary outcomes measures: 
Difference in nsVT episodes between treatment groups from randomization 
to week 52 
Difference in number of appropriate therapeutic ICD therapies between 
treatment groups from randomization to week 52 
Difference in the change of nt-proBNP levels between treatment groups 
from randomization to week 52 
Difference in the change of HbA1c between treatment groups from 
randomization to week 52 (in subjects with known T2DM) 
Difference in the number of hospital re-admissions due to heart failure 
between the treatment groups from randomization to week 56 
Difference in the duration of hospital stay between the treatment groups 
after initiation of the study treatment from randomization to week 56 
Difference in cardiovascular mortality between treatment groups from 
randomization to week 56 
Number of patients 
402 patients 
Time schedule 
With reference to the trial: 
EC Submission: NOV/2020 
Local Authority Submission: SEP/2020 
First Patient First Visit (FPFV): JUN/2021 


 
 
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Last Patient First Visit (LPFV): JAN/2023 
Last Patient Last Visit (LPLV):  JAN/2024 
Data Base Lock: APR/2024 
First Results available: JUN/2024 
Clinical Study Report: JUN/2024 
With reference to patients: 
Duration of the treatment: 12 months 
Main inclusion criteria 
1) HFrEF or HFmrEF, and ICD±CRT therapy > 3 months  
2) At least 10 documented VT episodes (either nsVT or sVT ± ICD treatment) 
within the last 12 months plus: 
- nt-proBNP > 500pg/mL or 
- LV-EF < 35% or 
- hospitalization for heart failure within the last 12 months or 
- >100nsVTs within the last 12 months 
->1 sVT/VF within the last 12 months 
3) Informed consent has to be given in written form. 
4) eGFR > 30 ml/min/1.73m2  
5) Blood pressure before first drug dosing: RRsystolic >100mmHg 
6) Blood pressure before first drug dosing: RRdiastolic >60mmHg 
7) 18 – 80 years of age 
Main exclusion criteria 
1) Any other form of diabetes mellitus than type 2 diabetes mellitus, history 
of diabetic ketoacidosis 
2) Ongoing ventricular arrhythmia 
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) Planned catheter ablation for ventricular arrhythmia 
7) Planned explantation of ICD, or planned up/downgrade to/from CRT-D 
device 
Study medication 
Active substance: Ertugliflozin 
Commercial name:  Steglatro 
Manufacturer: MSD 
Treatment plan 
Ertugliflozin, 5mg once daily orally administered or matched placebo  
 
 
 


 
 
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1. INTRODUCTION AND RATIONALE 
Sodium-dependent glucose cotransporter 2 (SGLT2) is mainly expressed in human kidneys and small intestinal cells. 
In the proximal tubule of the nephron SGLT2 is responsible for the reabsorption of approximately 90% of the filtrated 
glucose. Inhibition of SGLT2 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. CV 
outcome trials, required by the European Medicines Agency (EMA) and Federal Drug Administration (FDA) have 
proven additional beneficial effects on cardiovascular outcome in various compounds of that class. Empagliflozin 
could even show significant positive effects on mortality(1). More consistent and most pronounced was the effect of 
reducing heart failure hospitalisation. Most recently, data of dapagliflozin was published (DAPA-HF)(2) extending 
these beneficial effects to non-diabetic heart failure patients, significantly reducing the primary endpoint of CV death 
and worsening heart failure as well as CV-mortality alone and even all course mortality.  
As dose-response modelling indicates that ertugliflozin 5 mg and 15 mg result in near maximal urinary glucose 
excretion (UGE) in patients with type 2 diabetes mellitus, providing 87% and 96% of maximal inhibition, respectively 
(product information Steglatro), the lower dose can be expected to be comparably efficient and will therefore be 
used in this study. This is also confirmed by the data of a recent pooled analysis of previous phase III trials with 
ertugliflozin showing a reduction in HbA1c of only 0.1% (3). 
Ventricular arrhythmias are a typical feature of advanced heart failure with reduced ejection fraction (HFrEF) or heart 
failure with mid-range ejection fraction (HFmrEF), and account for a large proportion of cardiac death in this 
population. Implantation of an ICD is a class IA recommendation in the ESC heart failure guidelines both in secondary 
prevention and primary prevention (IB for DCM patients)(4). Additional CRT function is a class IA recommendation in 
all of these patients with QRS duration >150ms in sinus rhythm(4). Since arrhythmias occur independent of the type 
of cardiomyopathy (ischemic, dilative, idiopathic) the unifying phenotype of altered contractility and elevated 
diastolic pressure and potentially increased systemic inflammation itself must be regarded as the trigger of these 
arrhythmias(5).  
Therefore, every improvement of heart failure should result in a reduction of ventricular arrhythmias. This has been 
shown extensively for beta-blockers(6), aldosterone-antagonists(7; 8), and ARNIs(9; 10). Large outcome studies with 
ACE inhibitors did only give limited insight in the type of arrhythmic events, their causes, and the effect of the 
treatments(11; 12), while studies analysing the rate of ventricular arrhythmias did show a significant reduction in 
these events(13). 
Previous data showed that SGLT-2 inhibitor dapagliflozin (DAPA-HF) improved primary outcome in a HFrEF 
population comparable to sacubitril/valsartan in the PARADIGM trial(9) (both trials with a NNT of 21). Therefore, a 
comparable impact on heart failure morbidity and ventricular arrhythmias can be assumed for both drugs. Moreover, 
Martens et al. reported on a highly significant reduction of ventricular arrhythmias after initiation of 
sacubitril/valsartan in a retrospective analysis of 151 patients with an observation period of 6 months. The number 
of VT/VF episodes declined by more than two thirds(10).  
Mortality in patients on ICD therapy is high despite optimal medical treatment. The study by Martens is a 
retrospective analysis of data of patients that were followed throughout the observation period of 364 days. 


 
 
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Therefore, severely ill patients and at least those who died within these 12 months were not analysed. Obviously, 
these patients tend to have the highest burden of ventricular arrhythmias. Therefore, event rate in the Martens study 
is underestimated.  
More reliable data on event rates derive from prospective randomized trials such as the RAFT study. They report a 
rate of VTs of ~2 per year (11278 appropriate ICD detections in 5953.6 patient-years of follow-up) in a cohort of 
patients with severely reduced left ventricular ejection fraction (<30%).  
Within another increased-risk population treated in the SHIELD trial 58% of the placebo-group experienced “all-cause 
shocks plus symptomatic tachyarrhythmias terminated by ATP”. The overall number of episodes was 1595 in 214 
patients (average of ~7.5/patient and year).  
1.1 Aim of the study 
The aim of this mechanistic study is to investigate the impact of ertugliflozin on the ventricular arrhythmic burden, 
physical function, quality of life and biomarkers in heart failure in patients with ICD±CRT therapy.  
1.2 Study hypothesis 
Treatment with the SGLT-2 inhibitor ertugliflozin will reduce sVT/VF episodes more effectively than placebo within 
12 months. 
2. OBJECTIVES AND OUTCOMES 
2.1 Primary and Secondary Objectives 
The primary objective is to investigate the impact of ertugliflozin on ventricular arrhythmia burden. Further 
objectives will be the number of therapeutic interventions of implanted devices, atrial fibrillation, heart failure 
biomarker and changes in physical function, quality of life, stress and anxiety.  
2.2 Safety objectives  
- 
All-cause mortality 
- 
Number of serious adverse events 
- 
Number of hypoglycaemic events 
- 
Number of genital infections 
- 
Number of ketoacidotic events 
- 
Number of ventricular electric storm episodes 
- 
Changes in liver function parameters (AST, ALT, GGT) 
- 
Changes in renal function parameters (creatinine, eGFR) 


 
 
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2.3 Primary outcome 
Difference in number of sVT/VF episodes between treatment groups from randomization to week 52 
2.4 Secondary outcomes 
Secondary outcomes measures: 
Difference in nsVT episodes between treatment groups from randomization to week 52 
Difference in number of appropriate therapeutic ICD therapies between groups from randomization to week 52 
Difference in the change of nt-proBNP levels between treatment groups from randomization to week 52 
Difference in the change of HbA1c between treatment groups from randomization to week 52 (in subjects with 
known T2DM) 
Difference in the number of hospital re-admissions due to heart failure between the treatment groups from 
randomization to week 56 
Difference in the duration of hospital stay between the treatment groups after initiation of the study treatment from 
randomization to week 56 
Difference in cardiovascular mortality between treatment groups from randomization to week 56 
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 ertugliflozin 5mg once daily (p.o.) for 52 weeks on the ventricular arrhythmic burden and markers of physical 
and mental well-being as well as biomarker for heart failure in HFrEF and HFmrEF patients with ICD±CRT therapy. 
The study will be conducted in 8 experienced sites in Austria with an aim to enrol 402 patients (Figure 1) to evaluate 
the overall study hypothesis.   
 
 
 
 
 
 
 
 
201 assigned to Ertugliflozin 
201 assigned to Placebo 
52 weeks 
52 weeks 
Primary endpoints 
Secondary endpoints 
402 patients will be enrolled 


 
 
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3.2 Duration of study 
It is anticipated that the study will run for 30 months.  
4. STUDY POPULATION 
We will study subjects with HFrEF or HFmrEF and ICD±CRT therapy with ≥10 episode of non-sustained VT within the 
last 12 months before enrolment. We aim to recruit >30% of subjects with established type 2 diabetes mellitus. 
4.1 Inclusion criteria 
1) HFrEF or HFmrEF and ICD±CRT therapy > 3 months  
2) At least 10 documented VT episodes (either nsVT or sVT ± ICD treatment) within the last 12 months plus 
- nt-proBNP > 500pg/mL or 
- LV-EF < 35% or 
- hospitalization for heart failure within the last 12 months or 
- >100nsVTs within the last 12 months- > 1 sVT/VF within the last 12 months 
3) Informed consent has to be given in written form. 
4) eGFR > 30 ml/min/1.73m2  
5) Blood pressure before first drug dosing: RRsystolic >100mmHg 
6) Blood pressure before first drug dosing: RRdiastolic >60mmHg 
7) 18 – 80 years of age  
4.2 Exclusion criteria 
1) Any other form of diabetes mellitus than type 2 diabetes mellitus, history of diabetic ketoacidosis 
2) Ongoing ventricular arrhythmia 
3) Known allergy to SGLT-2 inhibitors 
4) Hemodynamic instability as defined by intravenous administration of catecholamine, calcium-sensitizers or 
phosphodiesterase inhibitors 
5) >1 episode of severe hypoglycaemia within the last 6 months under treatment with insulin or sulfonylurea  
6) Planned catheter ablation for ventricular arrhythmia within upcoming 12 months 
7) Planned explantation of ICD, or planned up/downgrade to/from CRT-D device within upcoming 12 months 
8) Existing therapy with SGLT-2 inhibitors 
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 
Figure 1 Study Flow Chart 


 
 
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▪ 
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. 
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 after 25 and 50% of patients completed the trial, 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. 
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 EP/arrhythmia service 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 14 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, by type 2 diabetes and by eGFR < 60 vs ≥ 60. 
Only the subject number 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) 
 
 


 
 
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5.3 Visit schedule 
 
Visit 1 (V1) 
Screening / Baseline 
Visit 2 (V2) 
 (Week 52 ± 4) 
Visit 3 (V3) 
(4 weeks ±1w after V2) 
Informed Consent 
X 
 
 
Inclusion/exclusion criteria 
X 
 
 
Randomisation 
X 
 
 
Demography, medical history 
X 
 
 
Concomitant medication 
X 
X 
 
Vital signs 
X 
X 
 
Height 
X 
 
 
Weight 
X 
X 
 
Physical examination 
X 
X 
 
ECG 
X 
 
 
Cardiac ultrasound 
X 
X 
 
Biobank sampling 
X 
X 
 
ICD interrogation 
X 
X 
 
nt-proBNP (local) 
X 
X 
 
Blood sampling  
X 
X 
 
Liver function parameters (AST, 
ALT, GGT) 
X 
X 
 
Renal 
function 
parameters 
(creatinine, eGFR) 
X 
X 
 
Adverse Events 
 
X 
X 
Dispense medication 
X 
 
 
Drug accountability 
 
X 
 
Safety 
assessment 
before 
discharge 
X 
 
 
Table 1: visit schedule (visit 3 telephone visit only) 
 
 


 
 
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5.4 Visit procedures 
Visit 1 - Screening/Enrolment Visit (Day 0) 
▪ 
Obtain informed consent of potential participant verified by signature on study informed consent form 
(10.5) 
▪ 
Collect blood for routine biochemistry and to check inclusion criteria (eGFR, nt-proBNP) (5.5.5) 
▪ 
Collect and prepare blood samples for biobank (5.5.6) 
▪ 
Obtain demographic information, medical history, medication history and tobacco use history (5.5.1) 
▪ 
Perform ECG, echocardiography, ICD interrogation (5.5.2) 
▪ 
Record vital signs  (5.5.3) 
▪ 
Measure body weight and body height (5.5.4) 
▪ 
Verify inclusion/exclusion criteria (4.1 and 4.2) 
▪ 
Randomize the subject (5.2) 
▪ 
Dispense the study medication for trial period (9.4) 
▪ 
Adjust concomitant antihyperglycaemic medication  
▪ 
Assessment of side effects and patient safety before discharge 
 
Visit 2 - Follow-up Visit (Week 52 ± 4 weeks) 
▪ 
Record adverse events as reported by participant or observed by investigator (6.1 – 6.5) 
▪ 
Perform echocardiography, ICD interrogation (5.5.2) 
▪ 
Record vital signs (5.5.3) 
▪ 
Measure body weight (5.5.4) 
▪ 
Collect blood for routine biochemistry (5.5.5) 
▪ 
Record changes in medication (5.5.1) 
▪ 
Collect and prepare blood samples for biobank (5.5.6) 
▪ 
Record participant’s adherence to treatment program  
▪ 
Drug accountability (9.5) 
 
Visit 3 - Telephone assessment (4weeks ± 1week after V2) 
▪ 
Record adverse events as reported by participant (6.1 – 6.6) 
 
 
 
 
 


 
 
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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 
(HybridForms®). 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 in medications will be recorded in the eCRF. 
5.5.2 ECG, echocardiography, ICD interrogation 
An ECG, echocardiography, and ICD interrogation will be performed at the screening visit. In our study, ICDs are 
interrogated both with telemedicine (home-monitoring) and during on-site ICD follow-ups. 
Patients will be offered to be included in our home-monitoring program. Currently, already 80% of patients have a 
home-monitoring device and routinely (every 4 months) transmit their data. In case of an alarm (sustained VT/VF) 
the data is transmitted automatically. In addition, all patients, regardless if they have a home-monitoring device or 
not, will be checked in the outpatient clinic on a yearly basis. 
All arrhythmic events are recorded in the patient database. For this study, the number of episodes recorded during 
the study period will be tallied up. 
All tests 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 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: 
 
 


 
 
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Blood test 
Visit 1 
Visit 2 
Haematology (full blood count) 
X 
X 
HbA1c 
X 
X 
Sodium, Potassium, Chloride 
X 
X 
Calcium 
X 
X 
Phosphate 
X 
X 
Magnesium 
X 
X 
Iron, Ferritin, Transferrin 
X 
X 
Creatine Kinase 
X 
X 
LDH (Lactatdehydrogenase) 
X 
X 
AST (Aspartate-Aminotransferase) 
X 
X 
CK MB 
X 
X 
ALT (Alanine-Aminotransferase) 
X 
X 
GGT (Gamma-Glutamyl-Transferase) 
X 
X 
CRP (C-reactive Protein) 
X 
X 
Creatinine 
X 
X 
eGFR 
X 
X 
Total cholesterol 
X 
X 
Triglycerides 
X 
X 
HDL (high density lipoprotein) 
X 
X 
LDL (low density lipoprotein) 
X 
X 
NT-pro BNP 
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 and 10ml EDTA 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. Additional biomarkers will be measured in batches from these stored 
biomarker samples. 
 
5.6 Benefit-Risk Assessment 
Ertugliflozin has been studied in subjects with type 2 diabetes as monotherapy as well as in combination with DDP-
inhibitors as well as metformin. A cardiovascular safety study is ongoing(14). However, it has not been studied with 
respect to cardiac arrhythmias, yet. Other SGLT-2 inhibitors already finished the cardiovascular outcome trials(1; 15-
17) demonstrating cardiovascular safety and beneficial effects, most prominent with respect to heart failure. A class 
effect can be assumed. Moreover, first data is published, demonstrating beneficial cardiovascular effects in non-
diabetic patients with heart failure, too. As heart failure per se is a trigger for ventricular arrhythmias, every 
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With respect to diabetes it can to be taken as given that the drug is not causing hypoglycaemic events per se, 
hypoglycaemia appears not to be a major issue in subjects without diabetes, that are studied in this trial as well. 
When ertugliflozin is used together with sulfonylurea or insulin, hypoglycaemia might occur and therefore 
participants will be instructed to reduce concomitant antihyperglycemic medication accordingly.  
Fungal genital infections are the most common side effect of ertugliflozin and participants will be informed about 
this and instructed on prevention measures.  
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. AEs 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: 
There is no reasonable causal relationship between the investigational product administered and the AE. 
6.4 Abnormal Laboratory Test Results 
All clinically significant abnormal laboratory test results besides creatinkinase and NT-proBNP occurring during the 
study will be recorded as adverse events.  


 
 
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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 MSD 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 ≥ 3 fold ULN combined with an elevation of total bilirubin ≥ 2 fold ULN 
measured in the same blood sample 
- 
an isolated elevation of ALT and/or AST ≥ 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 ≥ 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, ertugliflozin may potentially 
modify the clinical presentation of DKA which may occur at lower plasma glucose levels than stated in the table 
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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 study sites shall report (i.e., from signing the informed consent onwards through the trial defined follow-up 
period) 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 the FDA Safety Information Form to the MSD Unique Entry Point 
immediately (within twenty four (24) hours or next business day whichever is shorter) 
Merck Sharp & Dohme Ges.m.b.H 
The ICON Vienna 
Wiedner Gürtel 9-13 
Fax: 0800 809 802 
The sponsor will report the SAE to the ethics committee and the local authorities. 
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 
The sample size calculations and the primary statistical method are based on the primary endpoint, which is the 
number of VT/VF episodes from randomization to week 52. The primary objective is to compare the rate of VT/VF 
episodes across the two experimental arms. The number of VT/VF episodes within 52 weeks can be considered as a 
discrete variable with relatively few possible values (0, 1, 2, 3 …) per patient. This fact prevent us from using the most 
common statistical methods in clinical trials that assume normality, such as Student’s t-test, linear regression or 


 
 
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analysis of variance.  We, instead, will use the negative binomial regression model, which is most appropriate in the 
case of recurrent events (the current situation), allows investigation of the treatment effect and confounding 
variables, and adjusts for variable follow-up times by using time at risk as the offset. For more details on the 
arguments to use the negative binomial models in this kind of research, please see: (18). Furthermore, the negative 
binomial will be used instead of the Poisson distribution (also used for modelling count data) due to expected over-
dispersion in the data.    
7.1 Sample size and power considerations 
Previous data showed that VT/VF episodes are decrease by two thirds within 6 months after initiation of 
sacubitril/valsartan in ICD±CRT patients (10). sVT/VF Episodes declined by 62.5% whereas nsVTs rate dropped by 
~70%.  Based on comparable effects on heart failure morbidity with either SGLT-2 inhibition or sacubitril/valsartan 
treatment we expect a profound reduction in sVT/VF in the treatment arm. Since data of the large SGLT2 outcome 
trials which did not focus on arrhythmias and their detection but only counted cases of sudden cardiac death have a 
signal of smaller effects we calculate with a decrease in the event rate of 30%. Moreover, the retrospective analysis 
by Martens et al provides a rather low event rate in their population. However, as pointed out in the Introduction 
other prospective randomized trials have considerably higher event rates. The sample size calculation is based on 
the mathematical formula provided by Zhu and Lakkis for comparing event rates of two negative binomial 
distributions (19). We used the function power.nb.test of the package MKmisc in R that implements the results of 
the paper cited above. According to that formula, the parameters needed to calculate the sample size are: The 
expected yearly rate of VT/VF episodes in the control group (r0),  The minimal clinical relevant effect (RR) defined 
here as the ratio of expected VT/VF episodes rates (RR = expected rate in treated/expected rate in control = r1/r0), 
the average follow-up or treatment duration (duration), the negative binomial dispersion parameter (k), the Type I 
error probability (α) and the power (1 - β).  To detect a 30% reduction in VT/VF episodes rate in the ertugliflozin 
group as compared to the placebo group (i.e. using RR =  0.70), with a power of 80% and an alpha-level of 0.05%, a 
sample size of 191  patients in each group is needed. In this sample size calculation, we assumed the dispersion 
parameter k to be 1.0, the expected yearly rate of VT/VF episodes in the control group (i.e. r0) to be 1.0 and an 
average follow-up of 11.4 months. To account for a dropout rate of about 5% in each group, we will need of 402 
patients in each arm. 
Out of the > 1000 patients with ICD±CRT being seen at our out-patients clinic >50% have experienced episodes of 
non-sustained VT within the last 12 months. In order to enrich the study population with higher risk patients at least 
on additional inclusion criterion has to be met (either nt-proBNP > 500pg/mL or LV-EF < 35% or hospitalization for 
heart failure within the last 12 months or >100nsVTs or > 1sVT/VF episode within the last 12 months). 
About 5-10% of our patients are currently treated with ARNI. Expecting similar numbers in the other participating 
centers we feel confident to recruit patients for this trial within 18 months. Moreover, the recent DAPA-HF trial with 
11% of patients on ARNI therapy revealed an unaltered benefit of SGLT-2 inhibition in these patients(2). 


 
 
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Taking into account that compared to the Martens-trial the expected reduction in the applied study is much lower, 
the observation period twice as long and the populations risk is enriched due to the inclusion criteria the calculation 
can be rated conservative. 
7.2 Data analysis 
Intention-to-treat (ITT) analyses will be applied as the primary analysis. Analysis of the primary endpoint is 
comparison of the number of sVT/VF episodes between treatment groups from randomization to week 52. The 
primary endpoint will be analysed using analysis of covariance (ANCOVA), with treatment as a fixed factor, the 
baseline number of sVT/VF episodes as a covariate and with adjustment for history of T2D and eGFR and site of 
randomization. 
Normally distributed variables will be presented as mean ± standard deviation (SD) and skewed distributed variables 
as median and interquartile range [IQR]. Comparisons between treatment and placebo group will be performed by 
an unpaired two sample t-test, Mann–Whitney test, or χ2 test as appropriate. 
A two-tailed p-value ≤0.05 will be considered statistically significant. 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 Cardiology 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. . 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 study will be monitored by qualified employees of the research group of cardiovascular 
Diabetology based on a specific monitoring plan.  
9. TREATMENT 
9.1 Study medication 
Ertugliflozin 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 5mg once daily in the morning, taken with or without food. Each tablet 
contains 5mg Ertugliflozin or Placebo. The pharmaceutical form is a 6.4 x 6.6 mm large triangular tablet debossed 
„701“ on one side Ertugliflozin has minor influence on the ability to drive and use machines. Patients should be 
advised to take precautions to avoid hypoglycaemia while driving and using machines, in particular when Ertugliflozin 
is used in combination with a sulfonylurea and/or insulin. Pharmacy (Anstaltsapotheke) at the University Hospital of 
Graz, Austria will pack the medication as 52 weeks supplies for study participants and label study medication 
according to current regulatory requirements. 


 
 
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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 secure area. 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 2 (week 52). 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. 
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. 


 
 
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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-
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. 


 
 
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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 3). 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.  
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 


 
 
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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 (HybridForms®). 
11.4 Electronic Recording of data 
This study will capture and process data using HybridForms® (electronic data capture) which will be built by Kapsch 
Business Com AG, Graz, Austria. HybridForms® 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 possible after the visit preferably within 7 working 
days. 
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 Chief investigator 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 


 
 
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- 
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 
evaluation of the clinical trial. 
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. 
 


 
 
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12. REFERENCES 
1. 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. The New England journal of medicine 2015;373:2117-2128 
2. McMurray JJV, Solomon SD, Inzucchi SE, Kober L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand 
IS, Belohlavek J, Bohm M, Chiang CE, Chopra VK, de Boer RA, Desai AS, Diez M, Drozdz J, Dukat A, Ge J, Howlett 
JG, Katova T, Kitakaze M, Ljungman CEA, Merkely B, Nicolau JC, O'Meara E, Petrie MC, Vinh PN, Schou M, 
Tereshchenko S, Verma S, Held C, DeMets DL, Docherty KF, Jhund PS, Bengtsson O, Sjostrand M, Langkilde AM, 
Committees D-HT, Investigators. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. The 
New England journal of medicine 2019; 
3. Liu J, Tarasenko L, Terra SG, Huyck S, Wu L, Pong A, Calle RA, Gallo S, Darekar A, Mancuso JP. Efficacy of ertugliflozin 
in monotherapy or combination therapy in patients with type 2 diabetes: A pooled analysis of placebo-controlled 
studies. Diabetes & vascular disease research 2019;16:415-423 
4. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, Falk V, Gonzalez-Juanatey JR, Harjola VP, 
Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GMC, Ruilope LM, 
Ruschitzka F, Rutten FH, van der Meer P, Group ESCSD. 2016 ESC Guidelines for the diagnosis and treatment of 
acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure 
of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure 
Association (HFA) of the ESC. European heart journal 2016;37:2129-2200 
5. Alvarez CK, Cronin E, Baker WL, Kluger J. Heart failure as a substrate and trigger for ventricular tachycardia. Journal 
of interventional cardiac electrophysiology : an international journal of arrhythmias and pacing 2019;56:229-247 
6. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive 
Heart Failure (MERIT-HF). Lancet 1999;353:2001-2007 
7. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J. The effect of spironolactone on 
morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study 
Investigators. The New England journal of medicine 1999;341:709-717 
8. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M, Eplerenone 
Post-Acute Myocardial Infarction Heart Failure E, Survival Study I. Eplerenone, a selective aldosterone blocker, in 
patients with left ventricular dysfunction after myocardial infarction. The New England journal of medicine 
2003;348:1309-1321 
9. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, 
Zile MR, Investigators P-H, Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. The 
New England journal of medicine 2014;371:993-1004 
10. Martens P, Nuyens D, Rivero-Ayerza M, Van Herendael H, Vercammen J, Ceyssens W, Luwel E, Dupont M, Mullens 
W. Sacubitril/valsartan reduces ventricular arrhythmias in parallel with left ventricular reverse remodeling in 
heart failure with reduced ejection fraction. Clinical research in cardiology : official journal of the German Cardiac 
Society 2019;108:1074-1082 
11. Investigators S, Yusuf S, Pitt B, Davis CE, Hood WB, Jr., Cohn JN. Effect of enalapril on mortality and the 
development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. The New 
England journal of medicine 1992;327:685-691 
12. Pfeffer MA, Braunwald E, Moye LA, Basta L, Brown EJ, Jr., Cuddy TE, Davis BR, Geltman EM, Goldman S, Flaker 
GC, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after 
myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. The New 
England journal of medicine 1992;327:669-677 
13. Webster MW, Fitzpatrick MA, Nicholls MG, Ikram H, Wells JE. Effect of enalapril on ventricular arrhythmias in 
congestive heart failure. The American journal of cardiology 1985;56:566-569 
14. Cannon CP, McGuire DK, Pratley R, Dagogo-Jack S, Mancuso J, Huyck S, Charbonnel B, Shih WJ, Gallo S, 
Masiukiewicz U, Golm G, Cosentino F, Lauring B, Terra SG, Investigators V-C. Design and baseline characteristics 


 
 
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of the eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes trial (VERTIS-CV). American heart 
journal 2018;206:11-23 
15. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Silverman MG, Zelniker TA, Kuder JF, Murphy SA, 
Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Ruff CT, Gause-Nilsson IAM, Fredriksson M, Johansson PA, Langkilde 
AM, Sabatine MS, Investigators D-T. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. The New 
England journal of medicine 2019;380:347-357 
16. Mahaffey KW, Neal B, Perkovic V, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Fabbrini E, Sun T, Li Q, Desai M, 
Matthews DR, Group CPC. Canagliflozin for Primary and Secondary Prevention of Cardiovascular Events: Results 
From the CANVAS Program (Canagliflozin Cardiovascular Assessment Study). Circulation 2018;137:323-334 
17. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR, 
Group CPC. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. The New England journal of 
medicine 2017; 
18. Robertson MC, Campbell AJ, Herbison P. Statistical analysis of efficacy in falls prevention trials. J Gerontol A Biol 
Sci Med Sci 2005;60:530-534 
19. Zhu H, Lakkis H. Sample size calculation for comparing two negative binomial rates. Stat Med 2014;33:376-387 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Appendix A Participating Study Centers  
 
➢ Study Center Universitätsklinikum Graz  
PI: Univ.-Prof. Dr. Daniel Scherr 
Universitätsklinik für Innere Medizin 
Klinische Abteilung für Kardiologie 
Auenbruggerplatz 15 
8036 Graz 
Tel.: +43 316 385 12544 
E-Mail: daniel.scherr@medunigraz.at  
 
 
Principal Investigator: 
Assoc.-Prof. Dr. Daniel Scherr: 
 
 
 
 
Signature 
Date 
I have read the attached protocol entitled "Ertugliflozin to Reduce Arrhythmic burden in ICD/CRT patientS (ERASe-
Trial)  – a phase III Study”, V 1.20 dated 22/12/21, and agree to abide by all provisions set forth therein.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
➢ Study Center Elisabethinen Linz 


 
 
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Protocol No: 
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37  
 
PI:  PD Dr. Martin Martinek 
Ordensklinikum Linz GmbH Elisabethinen 
Interne 2 – Kardiologie, Angiologie & Interne Intensivmedizin 
Fadingerstraße 1 
4020 Linz 
Tel.: +43 (0)732 7676 – 4900 
E-Mail: martin.martinek@ordensklinikum.at 
 
Principal Investigator: 
PD Dr. Martin Martinek: 
 
 
 
Signature 
Date 
 
I have read the attached protocol entitled "Ertugliflozin to Reduce Arrhythmic burden in ICD/CRT patientS (ERASe-
Trial)  – a phase III Study”, V V 1.20 dated 22/12/21, and agree to abide by all provisions set forth therein.  
 
 


 
 
Title: 
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Protocol No: 
Version 1.20 
 
22 December 2021 
 
 
38  
 
➢ Study Center Klinikum Klagenfurt  
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 
E-Mail: hannes.alber@kabeg.at  
 
 
Principal Investigator: 
Prim. PD Dr. Hannes Alber: 
 
 
 
Signature 
Date 
 
I have read the attached protocol entitled "Ertugliflozin to Reduce Arrhythmic burden in ICD/CRT patientS (ERASe-
Trial)  – a phase III Study”, V 1.20 dated 22/12/21, and agree to abide by all provisions set forth therein.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Title: 
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Protocol No: 
Version 1.20 
 
22 December 2021 
 
 
39  
 
➢ Study Center Wilhelminenspital  
PI: OA Dr. Michael Nürnberg 
3. Medizinische Abteilung mit Kardiologie mit Ambulanz 
Wilhelminenspital  
Montleartstraße 37, 1160 Wien, Österreich  
Tel.: +43 (0)1 49150 71003 
E-Mail: michael.nuernberg@wienkav.at  
 
 
Principal Investigator: 
OA Dr. Michael Nürnberg: 
 
 
 
Signature 
Date 
 
I have read the attached protocol entitled "Ertugliflozin to Reduce Arrhythmic burden in ICD/CRT patientS (ERASe-
Trial)  – a phase III Study”, V 1.20 dated 22/12/21, and agree to abide by all provisions set forth therein.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Title: 
ERASe–TRIAL 
 
Protocol No: 
Version 1.20 
 
22 December 2021 
 
 
40  
 
➢ Study Center Innsbruck 
PI: PD Dr. Markus Stühlinger 
Univ. Klinik für Innere Medizin III / Kardiologie und Angiologie 
Anichstraße 35 
6020 Innsbruck 
T: +43 (0) 50-504-22767 
E-Mail: markus.stuehlinger@tirol-kliniken.at   
 
 
Principal Investigator: 
PD Dr. Markus Stühlinger: 
 
 
 
Signature 
Date 
 
I have read the attached protocol entitled "Ertugliflozin to Reduce Arrhythmic burden in ICD/CRT patientS (ERASe-
Trial)  – a phase III Study”, V 1.20 dated 22/12/21, and agree to abide by all provisions set forth therein.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Title: 
ERASe–TRIAL 
 
Protocol No: 
Version 1.20 
 
22 December 2021 
 
 
41  
 
➢ Study Center Universitätsklinikum Wien 
PI: Univ.-Prof. Dr. Marianne Gwechenberger 
Univ. Klinik für Innere Medizin II /Klinische Abteilung für Kardiologie  
Währinger Gürtel 18-20 
1090 Wien  
T: +43 (0)  
E-Mail: Marianne.gwechenberger@meduniwien.ac.at 
 
 
Principal Investigator: 
Univ.-Prof. Dr. Marianne Gwechenberger: 
 
 
 
Signature 
Date 
 
I have read the attached protocol entitled "Ertugliflozin to Reduce Arrhythmic burden in ICD/CRT patientS (ERASe-
Trial)  – a phase III Study”, V 1.20 dated 22/12/21, and agree to abide by all provisions set forth therein.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Title: 
ERASe–TRIAL 
 
Protocol No: 
Version 1.20 
 
22 December 2021 
 
 
42  
 
➢ Study Center Landesklinikum Wiener Neustadt 
PI: Prim. Univ.-Doz. Dr. Franz Xaver Roithinger 
Landesklinikum Wiener Neustadt, 2. Medizinische Abteilung für Kardiologie, Nephrologie und 
Intensivmedizin,  
Corvinusring 3-5 
2700 Wiener Neustadt 
T: +43 2226 9004 12702 
                E-Mail: franzxaver.roithinger@wienerneustadt.lknoe.at  
 
Principal Investigator: 
Prim. Univ.-Doz. Dr. Franz Xaver Roithinger: 
 
 
 
Signature 
Date 
 
I have read the attached protocol entitled "Ertugliflozin to Reduce Arrhythmic burden in ICD/CRT patientS (ERASe-
Trial) – a phase III Study”, V 1.20 dated 22/12/21, and agree to abide by all provisions set forth therein.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Title: 
ERASe–TRIAL 
 
Protocol No: 
Version 1.20 
 
22 December 2021 
 
 
43  
 
➢ Study Center Kepler Universitätsklinikum Linz 
PI: Prim. PD Dr. Clemens Steinwender 
Kepler Universitätsklinikum Linz 
Med Campus III 
Krankenhausstraße 9 
4021 Linz  
T: +43 2226 9004 12702 
                E-Mail: Clemens.steinwender@kepleruniklinikum.at  
 
Principal Investigator: 
Prim. PD Dr. Clemens Steinwender: 
 
 
 
Signature 
Date 
 
I have read the attached protocol entitled "Ertugliflozin to Reduce Arrhythmic burden in ICD/CRT patientS (ERASe-
Trial) – a phase III Study”, V 1.20 dated 22/12/21, and agree to abide by all provisions set forth therein.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Title: 
ERASe–TRIAL 
 
Protocol No: 
Version 1.20 
 
22 December 2021 
 
 
44  
 
➢ Study Center Universitätsklinikum St. Pölten 
PI: OA PD Dr. Deddo Mörtl 
Universitätsklinikum St. Pölten 
Dunant-Platz 1 
3100 St. Pölten 
T: +43 2742/9004 - 0 
                E-Mail: deddo.moertl@stpoelten.lknoe.at   
 
Principal Investigator: 
OA PD Dr. Deddo Mörtl:  
 
 
 
Signature 
Date 
 
I have read the attached protocol entitled "Ertugliflozin to Reduce Arrhythmic burden in ICD/CRT patientS (ERASe-
Trial) – a phase III Study”, V 1.20 dated 22/12/21, and agree to abide by all provisions set forth therein.  
 
 
 
 
 
 

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Ettugliflozil io Reùrcc Anùyrhmic buden ín ICD/CRT prtieds (BRASe-Tlla$ - a pbose III
Sn¡dy
lfr¡s
lnstlüfüg¡rvc[hne
r(5
Koodlnlcrun¡rentrum ft r ldlnlrchr Sùdho
t"BBg
t¡ftbundle bnnchblo*
LDt
Lorv Denrlty Upoprcteln
tPw
Lsst P¡Ueñrâ$V¡Ct
MCI
Myocadlsl lnhrttlon
nsW
Non sustaltred wnulorlar todrycaÉb
nt proBNP
Èl't¡rmlnol pro b.type naùluredc pag$de
HÌlIâ
l,law Yorl Haalt As¡odallor
Él
Pondur ll¡¡drogenll
&L
Qu¡lltyof ll¡b
RR
sGtT-2
Sodlumdependent Bluco¡o €otronrporter 2
SJSÀR
Srsp¿cæd Une{p€Ged Se¡lou¡ Âdver¡e Reecüon
¡W
su¡tãlnd wnlrlsul8f tadryEtdh
TIOM
ms 2 Dlobctes MaÍ¡rur
TMF
TrlslMaster Flle
IMG
Tdrl ManagomeilGrcup
I9C
TtttlStærllB@mmlttee
utN
Upper Umlt of ilormst
un
UrlnúyTr0ct hlÞctlon
VF
Vonþlcular f lbilll¡tlon
V1
Venùlculart¡cÐsedh
ULN
Uppor Umftof florntl
un
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Ertuglifløin o Reô¡cs Aühythnic burdñ in ICD/CRT psdeotS (ERASaTrial) - a phæe t
sü¡dy
1 lntrodu¿don and radonale
Sodlum.dependentglucoee cotransportor2 (SGLllI l¡ malnlycpresed ln human kldnrys
and ¡mall lntestinel cells. ln the prc¡dmsltubule of the nephron SGtlì¿ ¡s responslble for the
rerbsorptlon of approxlmæely 9016 of the lTlbeted glucose. lnhlbltlon of SG[Tll was shown
to lncreate renal glucoce eraeüon snd to lower gluære. Subsequenüy, a nu¡rber of SGLT-2
inhibltors were developed and are armnüy approved for the hatm€nt of tyæ 2 dhbaes.
Cll outcome ùlaþ requfred by the Eumpean Medlclne¡ A¡ency {EMA! and Federal Drug
Admlnlstration (FoAf harc prwen addlüon¡l beneflclal efhcts on ærdlovascular outcome ln
various compounds of th¡t class. Empagllflorln could Even shor rlgntffcant poslüùe effects
on mortaltty(1). Mon corubtent and most pronounced un¡ the effect of reduclng heart
fallure hospl¡albdon. Mosrecantly, dota of dapanllfiorln uns publlshed IDAPA-HFIIZI
ertendlng these beneffdal cffests to nondlabeüc heart fallure padenB, slgnlflcantly
rcduclng the prlmary endpolnt of Cll death end worsenlng heart failure as well as CV-
rnortallty alone and even allcouße mortsll$. Ae doss-¡esponsc modelllng lndlcates that
ertugllllorln 5 mg rnd lli mg result ln near maxlmal urlnary glucose exoeüon (UGE) ln
paüents wlthtype 2 dlabates mellttu¡, provldlng8796 and 969iof ma¡dmal lnhlbhlon,
re¡pectfuely (product lnúomrüon Steglatrol, the lower dose can be expeced to be
comparably effrclent and wllltherefore be used ln thls study. Thls ls also mnfirmed by the
data of a rccent pooled analysls of prevlous phose lll trlals wlth erürglmorln showlng a
rcducüon ln HbAlc of only 0.1tú (31. Ventrlcular anhythmhs are s typlcalfeature of
advanced heart fallure wtth reduced eJectlon fracdon {HFTEF) or heert fallure wlth mld-
r¿nge elecüon fractlon {HFmrEFl, snd acæunt for a latre pmportlon of cardlac death ln thls
populadon. lmplantatlon of an ICD l¡ a slass lA recommendadon ln the ESC heart fallure
guldelhres both ln secondary prevenüon and prlmary prevendon llBfor DCxvl pðdentsll4l.
AddlüonalCRTfi¡nalon ls a dass lA recommendatlon ln allof these peüent¡ wlth Qß9
duntlon >150m¡ ln slnus rtrVthrn(4l. Slncs arrhythmle¡ ocanr lndependent of tñe type of
cardlomyopathv (lsdremlc, dllaüvg ldlopathlclthe unlfylng phenqtype of altered
conbactltlty and elewted dle¡toltc pressure and potenüallY lncreased systenr¡c
lnflammatlon ltself must be regprded as the tlgger of the¡e anhythmhsl5l. Thereforc,
lÂPr¡ürhì lJ¡ frûõ[&rlrlcn.duclArrlûtlÍÈhrùrblED/qtPÚ.rìÉGnÑôlddl-¡¡ltælll3¡d1.6¡ 
A 
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Errugtinøin to Redt¡ce ¡lnùythnlc bt¡¡dsr in ICD/CRT pali€als Gn ASe-Trial) - s Phsso III
Sü¡dy
cvery lmproyement of heart fallure should re¡ult ln a reductlon of wntrlcular arÌùYtñmlas'
Thls hæ been ¡hown extenslyely br beta-bloctent6l, aldo¡tercnÈanÞgoni¡B{7;8}, and
ARNtslg; 1Ol. t¡ne outcoms str¡dles wlth ACE lnhlblton dld only glve llmtted lnslght ln the
hrpe of aúvümlcevent¡, tlulr causes, and the ffi 
of the üeatments(ll; lill, whlle
sn¡dbs analysl4 the rap of vemrlcr¡tar anhythmlas dld ¡how a slSnlficant redudlon ln
thesa ewnts(lill. PreYlous date strowed thãt SGtr¿ lnhlbltor d¡pagliflo¡ln IDAPA+|FI
lmproræd prlrrary outcome tn a HFrEF populatlon comparable to sacr¡bibllÁnlsartan ln the
PARADIGM ùlal(91 (both Ùlals stlth a NNt of ã4. Thereforc, a conrparable lmpact on heert
fallure morbldþ and ventflcular anhythmlas ån be asumed br both dnt6s' Moreorer'
Martensetal.reportedonahlghlyslsntflcantreductlonofvenHn¡lerarrlrythmlasafter
lnltiatlon of sacubltrluvabartan ln ¡ retrosPectlve anaþsls of 151 paüents wttñ tn
observ¿tlon perlod of 6 months. The number of WVF €pltode¡ dedlned by mora than hñ'o
thlds (101.
Mortallty ln potlents on ¡CD theråpy ls hlgh desp¡te opdm¡l medlcal treatment' The study by
Marteru ls a retrospectfve anaþls of dsta of patients that were followed throughouttte
observadon perlod of3õ4 daYs.
Therefore, savtrely lll patlents and at lea¡t those who dled nfthln these 1il months wera not
analysed. Obvlousþ these patlents tend to have the hfhest burden of ventrlcular
anhythmlas. Therefore, event rate ln the M¡rtens study ls undereÛt¡mated'
It¡lore rell¡ble data on event rale¡ dedve fÏprn prospectve nndonrl¡ed Ulals suúr as the
RAFT study. They æport a rate of ws of -2 per yeer (11278 appmpdde lcD detectlons ln
5933.6 po$ent-years of Íollow-up) ln a cohort of padents wlth Seærely Educed left
ventrlcular elecdon frac{lon (<¡¡09ú1. Wthln another lncrea¡ed'rlsk populadon trcaed ln the
SHIE]O tflal 5896 dthe gl¡cebo'goup e¡¡p€rlenced "¡ll'c¡use shocl6 plus symptomatlc
tachy¡nhythm¡ås termlnåted by ATP¡. The overall number of eptsodes wæ 1595 ln 214
padents (arærage of -7.5/padent and yearl'
såprrnSn L¡: ¡rùCFbrtoR.düflAnùrrhúÊuíb lr|rqrcrp.ütfÉGn¡$'Tlldl-'9hæll¡sü¡Úf' 
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Erûrglillozin to Rsû¡c6 Ar¡byrhmic h¡rdsn in ICD/CRT pstimtS (ERASe-Tria$ - a pbase [It
Strdy
2 Südy ObfsctlYeû end Endpolnts
2.1 Prlnaryendc€€onderyobþcüYes
Tho primary objective ofûis etudy is to iwwligab lbe lnpact of Ertug¡ifiozin on iacident
suebined vcn¡igtltar tscbyc¡rdia or venticul¡r fibrill¡tion (sW\lF) ill psticûts wiü
ICD*CRT üempy. Sæondary objoctives inrcstigsts ltto iryact of Ertugli0ozin on thc
uumber of üruapeutic interveat¡on¡ of knpl¡¡æd dwiacq stiol fibtillstion, ud hert fh¡hr€
biomgúcrs,
2.2 Prlmary,socondory¡nd ¡afrtyendpolns
2J.l Prlneryerdpolnl
Ths primary eúdpoint is úemmb€rof i¡rsideot $¡sf¡ined (>30 sec@ds) ventier¡l¡¡
ucþcardia or veoficr¡lar ûhittdion (sVT/\tr) Êrom ra¡rdo'uiz¡tim to wæl¡ 52
L7-2 SsrordsryendpolnB
Secondary cndpoinb u'e as follors:
- The number ofincident nou.s¡¡t¡hsd wrriculartcåycudia (n¡W) ûom ¡¡ndomiz¡$on
toweo¡( 52
- Tbe uunb€r of ¡pprop¡iaCI lÇÞt€glncút opírodes ûom r¡ndomization to week 52
- Ttc nt¡mber of bocpiUlization dr¡e to hea¡t f¡ilrne ñom roAoniz¡fioa ¡o wæk 52
- The rotBl numberofbo¡pit¡liz¡tioo daya fmm rurdoú¡zst¡on to a,æk 52
- Tte cåange inNTproBNP û0m nndoüizatim to wæk 52.
'The chango i¡ tfbAlc þrßls ûon nndo¡¡ization ¡o wcek 52.
- Co¡diovsscu¡ar mortality fmn n¡domiz¡don o week 52.
?";2,l S¡þtyendPolnr¡
- All.car¡se mortalif
-N¡¡nbe¡ of ¡eríous advsr¡e evenb
- Nr¡nber sf hypog¡ycssmio oùEnb
- Numbcr of gooit¡l infectio¡s
- Nr¡mber of kcto¡cidotio wfib
- Cbanges in liver fü¡gtion pnrametert (AST' ALT, GGT)
3¡pr¡rr¡.rl L*crü$flohtoirdrr¡rMryrlurdcbudt||ürlcD/tßl'|ltüüsFF¡A¡!.fddl-lpùall$dl.D¡tr
rgruf¡O¡l 
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Brürgl¡fl@in o Rsduce A¡rbÊhío hrdeû in ICD/CRT prtioots (gRASo'Tthl) - a pha.no llf
Shdy
- Chengee in reo¡l ftnction poranclerc (cr¡dinine, eGFR)
3 Study Methods 
- .,.
3,1 6enênl $þdï Dg¡lgn ¡nd Plon
Th¡s is a two su¡ rmdoaized Conmlled rnulti+r¡m, ps¡¡üst-gup. .bubl€'blínd€d fisl'
Tte oon¡ol go$ ls a p¡coüo and üre acated groç iB Ert¡gliflozin 'lbe ain of the hi¡l i¡ to
¡bow sup€riority ofErtrglifløin oærPlacebo in HFrEF a¡rd HFn¡ßF peiienf wftb
ICtlrCR'I thea¡y.
3.2 lnch¡slo¡rE¡rcluslon Otterla ond Genenl Strdy Populatlon
3¿t lnd¡doncrllsrb
l) HfrEf or HFnTEF o¡d ICIITCRT tl¡erapy > 3 months
2) At l€0st l0 documcoted noæ$¡stsin8d ws wiùin ths lEd 12 mothr pluo
- nt.proBNP> 500pglmL or
-LV-EF<35%or
- botpita[zaion for hest faihæ within lhe last 12 molh¡ or
- >lül¡sVT6 wilhin th lÉt 12 moalhs
3) hformod co¡sent hst !o bo giveo i¡ writt¡n fom.
Ð€GIIR> 30 mVmin/1.73m2
5) Blood prcsnrru boforo firs dn¡g dosing: RRryunlic >100mllHg
Q Blood pæesnrebefo¡o ñrrtdtr¡g doein$ Rnd¡astolic >dlunHg
Ð l8 - t0 yeslÊ ofsgp
t¿¿ E¡cluCon crhtls
t) Aûy otù6 form of diabcroc r¡elllh¡s ü¡¡ t!?e 2 diúeæs mcll¡üs, history of diabetic
ketosEidogig
2) Ongoi$ væùiculr ¡nt¡íümi¡
3) Ihowu allerry !o SGLT-2 inhibiton
a) Hsnodyn¡¡¡io irstability ar dcfined by i¡brv¡oor¡s adninisrnt¡o'n of c¡techol¡mine'
s¡lcirtm-s€ositizcñ or phoephodicstøase inlibiors
sîpËÈñ ¡¡: t üündn .o n¿Å ¡,fi fra. hn¡,t ¡, lcg/Émr.¡ít5 (3n stfí¡û-rrùst m5df' 0¡E ol
t /@,tE,l - 
P¡lt9olr¡
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Ftr¡t|noøa b'n¡ùso.túytü¡¡fo ttrdä¡ h l@rcHf prürrils FnASÞTlf al) - ¡ ph¡¡c III
$ury
5) >1 çsirods of aaur fu¡poghrc@ir sith¡n fu f¡ú ó møù¡ rpld¡rlnqtud wt .Ê ¡Dslfil
oruúhrylm
ú) ptmd úri¡h ¡bldæ fin vuüfculr lú¡thmiÊ
7) plrm¡dcryh¡dgion ofltD, upl¡u¡ôrptalo sndohlûun CItI;Þ d*ic¡.
l¡3 nm¡CamHon
Atu m¡æfug ¡It qtÍgüþ¡@ frrturdst wilt ü¡rú¡dddinlc os oflhc twt 8nã
dfûË@rlrneËmlry r¡ql[FlnsüdÊftlfdellffimrfic*üldållímu¿
I¡ommwdtn¡ rrcdml m¡¡tr¡S orrgns' ¡ry/erns"ffie'üb *hilch witt bs
tr$FtlEd"/i&:¡mdFrûIdþtr¡ù¡ihlanrovtd¡iltr ofudrymtutsüü¡üdüt ThË
r¡¡dod¡gon *ilt:bs¡re[firû]y ¡lb W æ ã d¡abffi ¡¡d ty !trR< 60 w ä 60"
gnlv tg'aüxt¡mbæ*tlttar¡aa¡tr i¡th¡ c¡¡s ¡rnortfu (cffl' Tt¡cfurËd8$ûr ìflilt
mdoüin r¡nt¡ø¡l'güF.=t{ii¡rqffi6El[,ot¡ ti6 (q¡hitrtruútûE wle tu concrpmdïng
snbtc*lr@ls ø¡tilófÉllrù e h fib0üfrÈd.
t¡ S$dyâüürrn.nt3
Dü b sûllocbd'cæltd¡sgto'tlc fttlowhq ¡obcúrla:
cflüúrt
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tâtffir¡¡¡-tûffinrorr¡rrüüffiËhn¡r[rttÌtf_Ë|n*rffi¡þr|q-rËbns¡ü.0üt I 
tJl|{ct
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Ert¡gliflozin to Redr¡ce Arbythic burdsn in I@/CRT psrticols (ERASe'tial) - a phnre III
Sturiy
Hdsht
Wclttrt
x
T
x
II
I
.t
I
t
x
x
x
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lCDmno8¡don
nt pro8t¡P llocail
t
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t'
I 6mlnsalttst
Sood¡anChg
t¡lnr fun¡tlon peramet¡n (45[,
Ilrr,aarl
t 
....-.--
Renallunalon prllmsteÉ
lcrcadnlne, e€Fil
Adìrerse Eventi
otlponß m"di¡cad
orul¡äiffiútt{tt- * 
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s¡fsv¡¡¡e3tfnêntüdûrc
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4 SampleShe
Previor¡s drb showod th¡t lff/W cpi,eodor a¡o desr€ase by tro tbird¡ wilhiû 6 mouthe aftsr
initisüot ofssflblúlt/wlsaftrn ln tGDrúIfT pudcuu (10). s\/T/\/F þiædca dcclincd by
625%wùof€tsnsvT¡'æelFpcdby-lWo.Basedoncøprrableefrcg{sonhea¡tÈiltre
norbirlþ wiù either SOLT-2 i¡hibition or ¡¡sub¡liUvslsurttrl Eedlmcnt wo cpec't a
p¡ofor¡¡d ¡cdustion in s\ftlVF iu the üe¡he¡t ¡ro" Sine rhtr of Üe lslgs SGLTz outsome
ui¡ls uåioh did ¡ot foc¡t¡ on aúythmiac and their detectios bül @ly cou¡ted cases of
$ddeú cs¡d¡as dealh bsve a ¡igDd of cmslter sffesls we crlsr¡lde wilb s dcc¡æ¡¡o ln the weot
r*e of 3Øo. Mo¡sovcn, fho rüocpoc{fue malysir by Martmr ot al prrovidee s rttbä lolt e'vcrû
rato in &oir popularioa" Eowwer, as poinÞd out i¡ the htroû¡ction other prcrpeAivo
randou¡zcd ü¡8¡s h¡ys cotrsid€ñbly higtlr evenl tür. Tñe ranple ¡izs c¡lcrrlatioa b b¡sd
3lP!f,ttoñ tl:ttû[[lÈ!l¡ûBú¡llntrl¡bh¡fuiln lcglËfÎtoüttúGnA¡È'frl4-ttàæl[$rtf'or¡ d 
t'oilltr
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Enryliflozin lo Reduce Anùylhic br¡rdsn in ICD/CRT pr¡ÍÊDfi (ERAS*Tríal) - a phasc Itr
Study
on the m8lhermticat formuta prcvided by Zhu a¡d l¿kki¡ for oomparing weut rates of trro
negairæ binomial distrrtütion¡ (l l). we t¡¡ed the finc'tion powermb.Est of the pactnge
MKmiec i¡ R lbat iñplemefltl lhc r6dls of the prper cÍtcd sbove. According to thnr formulg
the parameten neðded o calcu¡8t€ the oemplc ¡izs r¡ü The erpected yssrly rate of WVF
episoilæ in lhe conbol grcup (r0), The nrininnl qlin¡csl rstev¡nt etreü (RR) dof¡ned heæ ¡s
lhe ntio of oxpocted VrryF epirodos rater (RR = orpectod rato in t!f,tad/ecç€cûed rato in
conüul =r1û0), the avelage frllow-up orüestment duradon (únation), the negrtive binomial
d¡¡p€rÊ¡ori pa¡amctr (k), üre [ae I erru probabi¡¡ty (s) ¡nd tho powcr (l . F). To derest E
3070 rcducûion in VTAtr episodos raÞ in tùe ertrgli0ozin gfoup æ compared to tbe placebo
gFoW (i.c, ruing RR :0.70), wilh a power ol SW/oand m alpba-levol of 0.05%, a sample size
of l9l patients in each g¡oup ¡s needed" ln lhir sanple sizs calcrrlstion, wo ¡ssumed üo
dispcrsioa pannrctcr k ûo bs 1.0, the eoçecæd yeuþ r¡ts of VÎ/VF ep¡sodcs ln ths contol
¡roup (Le. ú) to be 1.3 and En svtra8e foltow-up of I1.4 month¡. To acco¡¡nt for adropout
rate of abortr 5% in ea¡h gmup, we will nccd of¡t02 puíeor in ûobl.
5 Statbücal analyslg
Tbe Negotivo Binoü¡al Regressim model will ba üsed to alelyse rhe primry cndpoinr
(rumberofsVT/vFcpisortss ñon randomization loweok 52). Thcscmodels ue¡u¡tableuåeo
comprring resuritût eìrsntrstes in diffsmnt Foups.Thry ¡ttow ínvestigntion ofths tmtment
eFect üd confonnding vuiablc, and adJuS fsr vüísble fotlow-up timos þ rsing timc at risk
a¡ the offiettt. Tbe,y ale a geooraliz¡tiou of the more comuronly rued Poi¡son regression
oodel¡ (in case of over-dirycrsiou) and ¡¡e ¡lso ruperior to difi€rñt Cox*ogession
notho.t¡12. We çrill nodel ths orßpeated nr¡Dbsr of e\¡I'll/P cpiaodcc a¡ fottor¡vrl .
los(r¿U) = loe( ¿rl) * Ps* p¡x¡1
lVboto tij. ts tho erpoerne tine of patient i i¡ ¡fow j 0 = I if conuoh tsz if ucarcd), Fij i¡ rbc
cxpoclcd nrmber of sVT/\lF opirodee ofpaûient i Ín grcupj during the sxnoí¡re perlod tij a¡d
xij is the teaûrent indicator ofpaient i in gror¡pj (xlj = 0 ifj=l (conüol) and I ifj - 2 (Eeated)).
It ca¡ bs shwn from the eqr¡¡tion above ths¡ tbe yerty rae ¡atio bsûs,€eo üeated aad mn¡ols
i¡ a dircct firnction of the paremeter pl a¡d csn bo døÍvcd as
3âPrüúrr Ltúù¡lñüJnþß.drEár¡ùr¡nlsb¡¡d¡nlntco/tf,lpüñÉ{EnÁ¡È?tdl-.Fhæ 
t!Sü¡úy. grb
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Ertugliftozin to Rsú¡ce Áú¡hn¡s brudeo in ICD/CRT psticûlft (ERASe-IllaD - a phaco III
Stdy
RR = eFr. Tbè cñicary of ttre dnrg, coúps¡Ed to placaþ will tben bs investigded þ testiag
úe following null and sltcroriw lrypothes€s:
ll¡:P1= Q 6 H,u0t+0
The ñ¡nd¡or glmnb from the IvfASS pa¡kags in R wilt be used for üis sson urd for Etting
tbo negative binomial regrcssim model. The nodsl will also sdjust for ths basoline number of
sVTAlF. S€ns¡l¡yity s¡s¡ysi¡ wilt be caried out by usiug melhods ¡oh¡st ¡ ouüicrg.
The aoalyris of secmdary onsoinb will bo a¡ follows: Ibc nuurbc of i¡cidefi nsVf, lho
numberofapprogiate lClLüatmenf cpisodes. the tot¡l numberofhocpiulizntion ùletoheart
ftilrue w¡ll be urelysod udng a bcta binonial model. Tho change ln ìÙflroBNP and the chanç
in IIbAlc twels from ratrdomlzst¡m to wecL 52 will be uutyred uring a mulliplo linear
regression model Eospiblizadon day¡ ftrom rudomization to week 52 will be compaed
bchrc¡rr rbe þo grûrps using oem and SD. Cardiovasct¡lar mortality will be ¡n¡lys€d by
cmparing popotlions ¡¡ros üte two gfot¡ps.
5.1 Covarl¡tes and subgroup¡
All aoalyres, including the p¡inrry en¡lysis, w¡U be a4iusted fur the vci¡bles u¡od whoo
rtr*i$ing rhe ¡udomiz¡tion if the uamplc cize pcrmits. Analysir mey also be ¡djt¡sted for
ba¡sline level¡ of üe d€p€rrdmr vüiables if svå¡lsble. No subgrotp analyrec aro plrnned"
5,2 Mlcsln¡ DatÐ
Missingdstawittbsimpuredforlheprinr¡'aoatyseiftherrylos¡zs8l|ow8.Mirsing
v¡tuæ witl bo itrrputed ruing Mulüple Impulatioawith CbsitdEquaion (MICE) appmach.
Teo in¡nrted dst¡ sëtc with qíll bo gcocraled. Ttc ¡¡sly¡is will ba porfonned oa each of lhe
l0 inrputed d¡bsets, which will pmduce e¡tim¡tcs oftreatnoût offecn and the str¡düd er¡or
of th¡t est¡losþ. FÍnally, úe sêt of Ësl¡matcs sad sbnd¡rd enon will bo o¡¡¡yrsd by lbe mlce
R packa¡¡e t¡¡ pmdr¡cs overell (pooled) esdnstes, confiilsncs intsYslq rnd pvaluer for tbs
Eeatmeûf efrecl
5.3 lntcrlm Anaþ¡og snd Daür Monlorlng (e¡ appllcablel
No intgrin dnat¡nee arc plsmsd for thir ûrdy
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l. ZiD¡nsB B, \Ãfaonor C, t-scJtin JM. Filahctt D, Bluhtrld E, llrntul S, Maühaur Àã. Dcvins T.
Johanscn OE, Wocrle lfr, Broedl UC, trã¡cohi $8, fnre¡üg¡¡on E.RO. Empag¡iflozir,
Cardisv¡tcul¡r Outcomcs, qnd Mort¡lity ln Type 2 DiÊbûtÊs. ThcNcw England journd of
medisine 201 5;3?3 :21 I 7 -2128
2. McMunay JW, Solomon SD, Inzrrcchi SE, Kobcr L, Kosiborod MN,Ivfartínc¿ FA,
Ponikow¡ki P, SrbstinÊ lyt9, Ar¡nd lS. Bclohluvck t, Bobm M, Cbjang CE, Chopn \lI( de
Bocr Rd Dæei A$, DiczM, Dm¿dz t, Ddrst A, Ge J, Howleûl JG, KslotË T, ¡çita!¡gre M,
Lj,mgrnrl CEA, Mcrkoly B, Nicolcu JC, O'Meüa 4 Peilric MC, Vtnh PN, Schou M,
Tsrcshqhsnlß S, Vcrm¡ S, HËld C, D Msb DI- DocbErty Ktr, Jhurd PS, BcngEeon O,
Sjosüud M, LangkÍldo Alttf, Committ¡æ D-!IT,Invertigators, D¡pasliflozb in Petieols with
Heart'Fsit¡¡c aod Reduced Ejocdon Eraction. Tho N¡w Englsud jot¡md of mcdlcino 2019;
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Eü¡diÍq¿in to Rcduc€ Arrhytlunic bu¡dm b ICD/CRT pstientS (ERASe-TriaD - n phrrc Itr
Study
lt Lio ¡, Tar¡scoko I" Tera SG, Hu¡,ck S, tüu t , Pong À C¡lle RÀ Gallo S, lM¡ A,
Muta¡¡o JP. Efficscy of ertrgllflozin in uonoürorapy orconnin¡rion úqtpy in prtieob wilh
t¡ço 2 dirbetæ: A pooled m¡btsis ofptacobo.contolled ¡ttdiæ. Diabete¡ &-v¡scr¡l¡r ¿iseasc
rEseûcb 201 9¡ t 6:4 I 5423
4. Psníkow¡ki P, Voo¡s AA Ankcr 8D, Bueno H, Clel¡¡d JOn CodB AJS. Fs¡k V,
Gonzlez¡_l¡¡snaþy J& E¡rjole vP, Irnlcon'eta EA, Jessup M, Lindo G Nihoya¡nopoulos p,
P¡rissí¡ JT, PiGskB B, R¡lsy JP, Ro¡¡¡o GMC, Ruilopo IJvf, Ruschitdo r, Ruüeû Fh van der
Meer P, Gmup ESCSD. 2016 ESC Guidclinec for thc diegno¡i¡ urd teahe¡¡t of asute snd
chmnio heart ftiluro: The T¡s& Fo¡sE for ths dlrgnosis md bcsheot of acr¡ûs urd chmnic
hea¡t f¡¡hrg of lhe Eumpea Sociery of Cardiologgr (BsC)Dovelopcd wrlh rhe epcciel
conribudon of tbs llearr Faitu¡o Arsocidiol (ttFA) sf tbc ESC. E ¡rûpee boarl jorroâl
2016,þ7t2129-22t0
5. Ahrarc¿ CK Clonin 4 Bstcr nI. Kluger J. Heart ftilrro ¡s a subsæ urd tigger for
venEiodnr tac,h¡rcardi4 Jor¡rn¡t ofiuteivcntion¡l tüsÊ elect¡@bysiologr: u inæmstioîsl
journal of ant¡lhraíu ead pcing 20 lg:5622i19-247
6. Effcct of metryrolol CR/)(L in cb¡onic hea¡t hih¡o: Mctoprolol CR/J(L R¡odomi¡cd
Inlcvention Tll¡l in Cong€stivg E€art Faihæ (tuERr+Ð.I^mcer 1999;353:2ü)l-2Ð7
7. Piü. B, Znmnd p, Røne W¡, Cody & Casbig¡e A Psrtz, ¡r.Pglcosky J, Wittæ J. The
eftct ofepirooolactono oamcbidity mdnort¡lity ln patients wilh seveÉ hea¡t fhilu¡r.
R¡¡tdomiæd Aldaôno Br¡ah¡ation Strdy Investígatore. The New Eogland journat of
nediclne I 9Ð9i!41 :7 t9-7 t7
E. Pitl B, Remme W, Zannad F, N€ston J, M¡¡tinsz F, RøikerB, B¡ümm R, Hr¡rley S,
Klclmaa J, C¡all¡n M Eplerrnone Poot-Acrúe Myocad¡Bl tnÊ¡sî¡otr H€ari F¡ih¡re'4 Sr¡rvival
Sûdy t Eplercoonq a ælectiw aldode¡oae blockor, i¡ pøiros wiú lefr veouicr¡la¡
dygfimstion aftm myocudial ioemiou The New EnglandJonmal ofmediche
2003;348:l3(Þ-I321
9. MoMuray JI, Packs M, Deca¡ AS, Oong J, læfkowiu MP, Ridoh AR" Roulea¡ IL Sh¡
VC, Sobmsn SD, Snredberg K, Zile !vl& twætigrton P-H, Conmittæ Angiotqruin
nepr¡lysn iltibfion vo¡n¡s cn¡lspril ¡tr hoùl faituß. The Nerr nnghd jo¡msl ofmediciue
2fll4S7l:993-lfXl4
t0. M¡¡teria P, Nuyeas D, RivæAyerza M, Va¡ Henndacl H, Vqc¡rnea J, Coyssenr W
Luwsl E IhpontM, MullcDBW. Sasubidllv¡l¡st¡¡¡edræeevenùícularanùythmias in
parallel wilh lcfr wnriqdû rwcrso ruodêliry in he¡rt ñilr¡æ wi¡h rrdûcgd ejecrion
ftaction Clinicsl r€sea¡Eh in cardiology : ofñcial joumal ofthc Gcrmm Cardiac Socidy
20t*108:10?4-1082
ll. Zbu If, I¡kkfu It Sample ¡ize cslsrtsdon for conparing tnn nogntivu binonisl rÊtc&
St¡tinics iu Medicinc. 201 aÉ3(3):37 ñ4
sltr+rùrLLE r,qËbhÞß.úElnillunbhrdlnh t€O/Cßl p¡ËüEl¡nâSlÏttfl-r¡hesailt$t¡.oa;lr
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