The Effect of Empagliflozin Versus Placebo on the Rate of Arrhythmic Events in Heart Failure Patients
Phase: PHASE4
Conditions: Heart Failure, Diabetes Mellitus, Arrythmia
Sponsor: Rambam Health Care Campus

The effect of Empagliflozin versus placebo on the Rate of 
Arrhythmic events in Heart Failure patients
 
 
  
 
ERA-HF study
 
 
 
Principal Investigator:   
Oren Caspi MD PhD 
Department of Cardiology 
Rambam Health Care Campus 
2 Efron St., POB 9649, Haifa, 31096, Israel 
Tel: +972-4-7772180 
Fax:+972-4-7773364 
 
 
Date: 14/05/2017 
 
Version: 1.1 
Document status: Final 
Amendment: 
 
  

 
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PROTOCOL SIGNATURE PAGE 
 
Protocol Title 
The effect of Empagliflozin versus 
placebo on the Rate of Arrhythmic 
events in Heart Failure patients (ERA-
HF study) 
Protocol version and date 
Final version 1.1, 14/05/2017 
Study Phase 
IV 
Sponsor 
Oren Caspi MD PhD 
Sponsor representative 
 
 
By signing below, I, the investigator, approve the protocol and agree to 
conduct the clinical trial according to all stipulations of the protocol as 
specified in both the clinical and administrative sections. 
I agree to comply with the ICH-GCP, applicable Israeli MoH guidelines 
(2016) for the conduct of clinical trials, World Medical Association 
Declaration of Helsinki and applicable local regulations/guidelines. 
I agree to ensure that the confidential information contained in this 
document will not be used for any purpose other than the evaluation or 
conduct of the clinical investigation without the prior written consent of Dr 
Oren Caspi. 
 
__________________________________________________________ 
Investigator Signature                                                               Date 
 
__________________________________________________________ 
Name                          Institution                       City               Country 

 
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Table of content 
1 
Synopsis .................................................................................................. 8 
2 
Background Information ........................................................................ 16 
2.1 
Study Conduct .................................................................................... 16 
2.2 
Background ......................................................................................... 16 
2.3 
Investigational product ........................................................................ 19 
2.4 
Preclinical data .................................................................................... 19 
2.5 
Clinical data to date ............................................................................ 19 
2.6 
Known and potential risks and benefits .............................................. 21 
3 
Trial Objectives and Purpose ................................................................ 23 
3.1 
Primary Objective ................................................................................ 23 
3.2 
Secondary Objectives ......................................................................... 23 
4 
Trial Design ........................................................................................... 24 
4.1 
Primary and secondary endpoints ...................................................... 24 
4.1.1 
Primary Endpoint .......................................................................... 24 
4.1.2 
Secondary Endpoints .................................................................... 24 
4.2 
Overall study design ........................................................................... 25 
4.2.1 
Visit schedule and assessments ................................................... 28 
4.2.2 
Visit Procedures ............................................................................ 31 
4.3 
Trial treatment ..................................................................................... 36 
4.3.1 
Investigational therapy .................................................................. 36 
4.3.2 
Treatment assignment .................................................................. 36 
4.4 
Study drug interruption or discontinuation .......................................... 38 
4.4.1 
Discontinuation of study drug ........................................................ 38 
4.4.2 
Study drug interruption .................................................................. 39 
4.5 
Study Discontinuation ......................................................................... 39 
4.6 
Premature whole study termination .................................................... 40 
4.7 
Accountability procedures for the investigational products ................. 40 
5 
Selection and Withdrawal of Subjects ................................................... 42 
5.1 
Inclusion Criteria ................................................................................. 42 
5.2 
Exclusion Criteria ................................................................................ 42 
5.3 
Interruption or Discontinuation of Treatment ....................................... 43 
5.3.1 
Discontinuation of study drugs ...................................................... 43 
5.3.2 
Interruption of study drugs ............................................................ 44 
5.4 
Study Discontinuation ......................................................................... 44 

 
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6 
Treatment of Subjects ........................................................................... 45 
6.1 
Treatment regimen .............................................................................. 45 
6.1.1 
Treatment assignment .................................................................. 45 
6.2 
Concomitant therapy ........................................................................... 46 
6.3 
Treatment compliance ........................................................................ 46 
7 
Assessment of Efficacy ......................................................................... 47 
7.1 
PVCs Burden ...................................................................................... 47 
7.2 
Non-sustained ventricular tachycardia (NSVT) rate ............................ 48 
7.3 
A composite cumulative endpoint of ventricular arrhythmia load ........ 48 
7.4 
BNP ..................................................................................................... 49 
7.5 
Left ventricular end diastolic diameter ................................................ 49 
7.6 
Left ventricular ejection fraction (EF) .................................................. 49 
8 
Assessment of Safety ............................................................................ 50 
8.1 
Adverse events ................................................................................... 50 
8.1.1 
Definitions of adverse events ........................................................ 51 
8.1.2 
Adverse events of Special Interest (AESIs) .................................. 52 
8.1.3 
Adverse events grading ................................................................ 54 
8.1.4 
Adverse events outcome .............................................................. 55 
8.1.5 
Causality Assessment of Adverse events ..................................... 55 
8.2 
Adverse events reporting and monitoring requirements ..................... 57 
8.2.1 
General ......................................................................................... 57 
8.2.2 
SAE reporting ................................................................................ 57 
8.2.3 
Expedited Reporting ..................................................................... 59 
8.3 
Pregnancies ........................................................................................ 61 
8.4 
Laboratory evaluations ........................................................................ 61 
8.4.1 
Hematology ................................................................................... 62 
8.4.2 
Biochemistry.................................................................................. 62 
8.4.3 
Special tests: ................................................................................. 62 
8.4.4 
Urinalysis ....................................................................................... 63 
8.5 
Physical examinations/vital signs ........................................................ 63 
9 
Statistics ................................................................................................ 64 
9.1 
Sample size ........................................................................................ 64 
9.2 
Efficacy and Safety evaluation ............................................................ 65 
9.2.1 
Efficacy analysis: .......................................................................... 66 
9.2.2 
Safety Analysis: ............................................................................ 66 
10 
Direct Access to Source Data/Documents ............................................. 68 

 
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10.1 
Study monitoring ................................................................................. 68 
10.2 
Audits .................................................................................................. 68 
10.3 
IRB and regulatory inspections ........................................................... 69 
11 
Quality Control and Quality Assurance .................................................. 70 
12 
Ethics ..................................................................................................... 71 
12.1 
Institutional Review Board .................................................................. 71 
12.2 
Informed consent ................................................................................ 71 
12.3 
Declaration of Helsinki ........................................................................ 72 
13 
Data Handling and Record Keeping ...................................................... 73 
14 
Financing and Insurance ....................................................................... 74 
15 
Publication Policy .................................................................................. 75 
16 
Supplements ......................................................................................... 78 
 
List of Tables 
 
Table 1 ...................................................................................................................................... 20 
Table 2 visit schedule and assessments .......................................................... 28 
Table 3 Diagnostic criteria for DKA................................................................... 53 
 

 
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List of abbreviations 
 
  
Term 
Definition 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AESIS 
Adverse Events of Special Interest 
ATP 
ANTI-TACHYCARDIA PACING 
BI 
Boehringer Ingelheim 
BNP 
Brain Natriuretic Peptide 
CBC 
Complete Blood Count 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CRTDP 
Cardiac resynchronization Therapy Defibrillator 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
Electro Cardio Gram 
eCRF 
electronic Case Report File 
EF 
Ejection Fraction 
EOS 
End Of Study 
GFR 
Glomerular Filtration Rate 
FCBP 
Female of Child Bearing Potential 
HbA1c 
Glycated Hemoglobin A1c 
ICD 
Implantable Cardioverter Defibrillator 
ICH-GCP 
International Conference of Harmonization-Good 
Clinical Practice 
IRB 
Institutional Review Board 
MDS 
Myelo-Dysplastic-Syndrome 
MI 
Myocardial Infarction 
NSVT 
Non-Sustained ventricular Tachycardia 
NYHA 
New York Heart Association 
P.O. 
Per Os/ by mouth/orally 
PVCs 
Premature Ventricular Complexes 

 
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Q.D. 
Once a Day 
SAE 
Serious Adverse Event 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
ULN 
Upper Limit of Norm 
VT 
Ventricular Tachycardia 
WBC 
White Blood Cells 
WHO 
World Health Organization 
 
 
 
 
 

 
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1 Synopsis 
 
The effect of Empagliflozin versus placebo on the Rate of Arrhythmic 
)
F study
H
-
events in Heart Failure patients (ERA
PROTOCOL NUMBER: 
ERA_HF 
 
DATE PROTOCOL FINAL: 
16/03/2017 
STUDY DRUG:  
Empagliflozin 
INDICATION : 
Diabetes type 2 patients with 
heart failure and high arrhythmic 
burden 
 
STUDY PHASE: 
IV 
Background and 
  :
rationale
 
Empagliflozin is an orally available inhibitor of the sodium-
glucose co-transporter 2 (SGLT-2), that promotes enhanced 
glucose excretion in the urine, thereby lowering blood glucose 
concentrations in patients with type 2 diabetes mellitus (T2DM). 
The EMPA-REG OUTCOME study demonstrated a significant 
reduction in both heart failure hospitalization and cardiovascular 
death in type 2 diabetes patients with high risk for cardiovascular 
events. A potential mechanism underlying the pleotropic and 
explaining the remarkable early reduction in cardiovascular 
mortality may be related to the effect of empagliflozin on 
arrhythmic events. 
Multiple potential mechanisms have been suggested to mediate 
the positive cardiovascular effect of empagliflozin (altered 
cardiomyocyte metabolism, anti-arrhythmic effect, improved 
glycemic control, positive effect on myocardial contractility). 
Ventricular arrhythmias and the associated sudden cardiac 
death (SCD) is the leading cause of mortality in patients with 
heart failure. The risk for the occurrence of SCD in heart failure 
patients is closely related to the etiology (ischemic versus non-
ischemic) and the left ventricular EF. The introduction of 
defibrillation therapy for primary prevention of SCD in HF 
patients has revolutionized the field during the last 2 decades. 
Nevertheless, ventricular arrhythmias remain a major cause of 

 
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mortality for HF patients given the limited ability for risk 
stratification, and the dreadful prognosis associated with 
ventricular arrhythmias treated by defibrillation therapy. The 
burden of premature ventricular Complexes (PVCs) has been 
shown 
as 
an 
independent 
risk 
factor 
for 
ventricular 
tachyarrhythmia and SCD for healthy, ischemic and heart failure 
patients (with and without resynchronization and/or defibrillator 
therapy). 
Anti-arrhythmic 
drugs 
(AAD) 
are 
efficient 
in 
suppressing the occurrence of PVCs but for certain drugs, the 
associated with profile of adverse events and cardiotoxicity may 
paradoxically increase the rate of sudden cardiac death as 
learned by the remarkable CAST study. Be that as it may, easily 
suppressed PVC burden (without the associated adverse profile 
of AADs) has been suggested to correlate with reduction of the 
likelihood for SCD. Furthermore, the growing field of PVC 
ablation has been shown to have beneficial effect on cardiac 
function and the risk for ventricular arrhythmia. In summary, PVC 
suppression, a once neglected strategy, is now considered a 
promising strategy for evaluating the effect of therapeutic 
strategies on the risk for SCD. 
Empagliflozin treatment in high cardiovascular risk patients has 
been shown to have a relatively rapid powerful capability in 
reducing cardiovascular mortality. Among the suggested 
mechanisms mediating this effect of empagliflozin, anti-
arrhythmic effect (AAE) has the highest potential to translate into 
a rapid clinical beneficial effect on cardiovascular mortality, while 
other mechanisms are known to have a lag in their clinical effect 
based on data from previous studies. Based on this assumption, 
we hypothesize that the effect of empagliflozin on the rate of 
cardiovascular death may be mediated by a direct effect on the 
risk for arrhythmic events (via a direct or an indirect effect on the 
myocardium). The current study aims at assessing the effect of 
empagliflozin on arrhythmias in diabetic patients with HF with 
reduced EF and relatively high arrhythmic burden. 
Study Objectives 
The objective of the current study is to demonstrate the effect of 
empagliflozin compared to placebo on the rate of ventricular 
arrhythmic events in type 2 diabetes patients with heart failure 
with reduced ejection fraction and high risk arrhythmic profile. 
Primary endpoint:   
 
 
The primary endpoint is the burden of premature ventricular 
complexes, defined as the PVCs percentage of all beats in a 
pre-specified period captured on ICD or CRTD/P device. 
 

 
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Secondary endpoints: 
 
1. The number of non-sustained ventricular tachycardia (NSVT) 
episodes. 
2. A composite cumulative endpoint of ventricular arrhythmia 
load (number of: sustained ventricular tachycardia, ventricular 
fibrillation, antitachycardia pacing (ATP) or delivery of shock 
therapy episodes.  
3. The change in blood level of NT-Pro Brain Natriuretic peptide 
(BNP) from baseline to the end of any of the treatment periods. 
4. The change in Left ventricular end diastolic diameter on 
echocardiography from baseline to the end of any of the 
treatment periods. 
5. The change in left ventricular ejection fraction (EF) on 
echocardiography from baseline to the end of any of the 
treatment periods. 
6. Safety endpoints (as detailed bellow). 
 
Study Design: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The present study is a randomized, prospective, controlled, 
double blind, cross-over, pairwise, add on standard therapy, 
event driven study, comparing empagliflozin versus placebo on 
the ventricular arrhythmia burden in a blocked randomization 
stratified by ischemic versus non-ischemic cardiomyopathy and 
PVC burden at screening of< or  to 4%. Potential study 
subjects will sign an informed consent prior to undergoing any 
study related procedure. Number of patients to be enrolled is 
128. 
This study encompass 4 periods for each study subject: 
screening period of 8 weeks, first treatment period of 8 weeks, 
washout period of 4 weeks and a second treatment period of 8 
weeks. Expected duration of subject participation is 6-7 months.  
Study assessments will be performed according the table of 
study procedures below. (Table 2) 
Screening period 
Patients will undergo screening for protocol eligibility within 56 
days (8 weeks) of recruitment. 
Subjects meeting all the inclusion criteria and without any 
exclusion criteria will be enrolled after signing an informed 
consent.  
Written informed consent must be obtained before any study 
specific medical procedures are performed. Evaluation consists 
of physical examination including vital signs, laboratory-

 
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screening assessments including urine pregnancy test for 
FCBP, HbA1c, device (ICD or CRTD/P) interrogation and 
echocardiography (if not done recently).    
First treatment period 
Randomization will take place after obtaining patient’s 
informed consent and after fulfilling the inclusion and exclusion 
criteria. Patients will be assigned to empagliflozin or placebo 
treatment for a period of 8 weeks by a central randomization 
process.  
Evaluations consists of vital signs, blood tests, device (ICD or 
CRTD/P) interrogation, 24h’ Holter ECG in case of ICD/CRTD/P 
malfunction as a backup arrhythmia assessment and 
echocardiography. Patient’s glucose level will be monitored by 
a home device 3 times a day in the first week and thereafter 
once a week or as needed. At visit 2, an endocrinologist 
consultant will give to the patient instructions for antidiabetic 
treatment titration according to appendix 1. 
Patients will be treated for 8 weeks with the study drug or 
placebo 10 mg/day every morning. 
Washout period 
Study subjects will stop study drug (empagliflozin/placebo) for 4 
weeks and will crossover to the second drug at the end of this 
period. During this period patient’s glucose level will be self 
monitored by a home device 3 times a day in the first week and 
thereafter once a week or as needed. Safety laboratory 
examinations, HbA1c, device interrogation and resetting, Holter 
ECG and echocardiography will be performed at the end of this 
period (visit 3). 
Second treatment period 
Patients will crossover to empagliflozin or placebo treatment 
for a period of 8 weeks.  
Evaluations consists of vital signs, laboratory assessments 
including pregnancy test for FCBP, patient’s glucose level will 
be monitored by a home device 3 times a day in the first week 
and thereafter once a week or as needed. Device (ICD or 
CRTD/P) interrogation and 24h’ Holter ECG in case of 
ICD/CRTD/P malfunction as a backup arrhythmia assessment 
and echocardiography.  
Patients will be treated for 8 weeks with the study drug 
or placebo 10 mg/day every morning. 

 
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Medication compliance will be performed during the 2 treatment 
periods by counting the returned study drug blisters. 
Duration of study:  
 
 
The duration of the treatment period is approximately 6 months. 
This time span is required for completing the therapy and 
determining the safety profile of the drug combination and the 
response rate.  
Estimated accrual duration: 12 months. Estimated total trial 
duration: 18 months 
 
Inclusion 
criteria: 
 
 
 
 
 
 
 
 
 
 
 Exclusion criteria: 
 
1. Heart failure patients with reduced ejection fraction 
(EF≤40%) assessed at least 6 months prior to recruitment 
and NYHA Class≥2 with ICD or CRTD/P. 
2. Patients implanted with ICD, CRTD/S or CRTP device that 
are capable of recording PVC burden and were implanted ≥2 
months prior to recruitment.  
3. High risk for arrhythmic events at baseline identified by 
either PVC burden ≥2%  or  >≥events of non sustained VT 
or ≥1 event of sustained ventricular tachycardia or need for 
anti-tachycardia pacing or defibrillation therapy, during a 
period of 2 months prior to recruitment. 
4. Diagnosis of type 2 diabetes mellitus prior to informed 
consent 
5. HbA1c≥7% and ≤12%. 
6. Signed and dated written informed consent by date of Visit 
1 in accordance with GCP legislation. 
1. Evidence of ICD malfunction. 
2. Antiarrhythmic treatment other than beta blockers. 
3. Past exposure to SGLT2 inhibitors. 
4. Uncontrolled diabetes with HbA1c>12% or glucose >240 
mg/dL after an overnight fast. 
5. Liver abnormalities defined by serum levels of alanine 
aminotransferase, aspartate aminotransferase, or alkaline 
phosphatase above 3 x upper limit of normal. 
6. Planned cardiac procedure within 3 months. 
7. Prior MI in the last 40 days. 
8. Calculated eGFR< 45ml/min/1.73m2 as determined by the 
MDRD formula GFR (mL/min/1.73 m2) = 175 × (Scr)-1.154 × (Age)-
0.203 × (0.742 if female) × (1.212 if African American) 

 
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9. BMI>50 
10. Medical History of active cancer in the past 2 years. 
11. History of recurrent UTIs or genital infections 
12. Systolic blood pressure <90 mmHg. 
13. Alcohol or drug abuse within 3 months of informed consent. 
14. Premenopausal women with planned preganancy or 
without adequate measures for birth-control. 
15.  Intake of an investigational drug in another trial within 30 
days prior to intake of study medication in this trial or 
participating in another trial involving an investigational 
drug and/or follow-up 
Assessments 
Efficacy:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The following evaluations will be conducted to judge the efficacy 
of the treatment regimen:  
Primary efficacy assessment is PVCs burden. PVCs burden will 
be evaluated as a part of the device interrogation on visit 1 to 
assess device integrity and proper function, in visit 2 to assess 
patient’s eligibility for the study according to in- and exclusion 
criteria. In visit 3 and 5 to assess for treatment efficacy.   
Assessment of the PVCs will be based on PVC counters for the 
various ICD/CRTD/P interrogated. Monitor counter reset will be 
conducted on visit 1,2,3,4 and 5. In the case of device 
malfunction, counter malfunction or any other cause of inability 
to readout the device PVC counter measurement, PVC burden 
will be calculated from a 12 Lead ECG Holter for 24 hours 
conducted at one of the last 7 days of the period assessed  
Secondary efficacy assessments are: 
NSVT rate: Non-sustained ventricular tachycardia rate is defined 
as the the number of NSVT events in a pre-specified period 
captured on ICD or CRTD/P device interrogation or as a backup 
information (in case of ICD or CRTD/P malfunction) on Holter 
ECG. The device will be activated along the whole study period 
and data will be captured on the CRF at visits 1 to 5. 
Composite endpoint of: sustained VT+VF, ATP or delivery of 
shock therapy: All the four parameters will be captured on ICD 
or CRTD/P device interrogation. Data from study device will be 
captured on the CRF at visits 1 to 5. 

 
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Safety:   
 
 
 
 
 
 
 
NT-Pro-BNP: NT-Pro-BNP Is a plasma level pf B-type Natriuretic 
Peptide used as a blood test for diagnosing and evaluation the 
presence/severity of heart failure. Plasma level will be performed 
at visits:2 to 5.  
Left ventricular end diastolic diameter: Left ventricular end 
diastolic diameter is defined as the cross-sectional diameter of 
the left ventricle, including the septum and the posterior 
thicknesses in diastole. The assessment is performed by 
echocardiography done at visits: 1 to 3 and 5. 
Ejection fraction: Ejection fraction is defined as the ratio of the 
stroke volume to the end-diastolic volume in the left ventricle as 
performed by echocardiography and expressed by percentage. 
The assessment is performed by echocardiography done at 
visits: 1 to 3 and 5. 
 
The following evaluations will be conducted to assess the 
safety of the treatment regimens: 
Adverse events 
Clinical laboratory evaluations (hematology, biochemistry, urine 
analysis) 
Complete physical examination including vital signs.  
Concomitant medication and procedures
 
Sample size 
consideration 
The planned sample size is 128 subjects, 64 in each study arm. 
When the sample size in each sequence group is 64, (a total 
sample size of 128) a 2 x 2 crossover design will have 80% 
power to detect a difference in Mean reduction of -10.0, 
assuming that the Crossover ANOVA MSE is 28.284 (the 
Standard deviation of differences, sd, is 40.0) using a two 
group T-test (Crossover ANOVA) with a 0.05 two-sided 
significance level.  
Efficacy analysis:
 
 
 
 
 
 
 
The primary efficacy is the percentage of PVCs during the 2 
months of empagliflozin treatment compared with the 
percentage of PVC on placebo. The two-sample T-test or Non-
parametric Wilcoxon-Mann-Whitney Rank sum test for 
independent samples (as is appropriate) will be applied for 
testing the carry-over effect in the primary endpoint between 
the two sequences. 
If no carry-over effect will be observed, then The Paired T-test 
or non-parametric Signed-rank test for two means (as is 
appropriate) will be applied for analyzing the difference in the 
above changes between the tested treatment and placebo. 

 
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Safety analysis:
 
 
Otherwise, if a carry-over effect will be found statistically 
significant, then the MMRM model (Mixed-effect model for 
repeated measures) will be applied for analyzing the difference 
in the above reduction between the tested treatment and the 
placebo. 
 
Data from all subjects who receive any study drug will be 
included in the safety analyses. The severity of the toxicities 
will be graded according to the NCI CTC whenever possible. In 
the by-subject analysis, a subject having the same event more 
than once will be counted only once. Adverse events will be 
summarized by the worst NCI CTC grade. Adverse events 
leading to death or to discontinuation from treatment, events 
classified as NCI CTC Grade 3 or Grade 4, study-drug-related 
events, and serious adverse events will be summarized 
separately. Laboratory data will be graded according to NCI 
CTC severity grade. 

 
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2 
Background Information 
2.1 Study Conduct 
This study will be conducted in compliance with the protocol approved by the 
Institutional Review Board, and according to Good Clinical Practice standards. 
No deviation from the protocol will be implemented without the prior review and 
approval of the IRB except where it may be necessary to eliminate an 
immediate hazard to a research subject. In such a case, the deviation will be 
reported to the IRB according to its policies and procedures. 
2.2 Background 
Empagliflozin is an orally available inhibitor of the sodium-glucose co-
transporter 2 (SGLT-2), that promotes enhanced glucose excretion in the 
urine, thereby lowering blood glucose concentrations in patients with type 2 
diabetes mellitus (T2DM). The EMPA-REG OUTCOME study1 demonstrated 
a significant reduction in both heart failure hospitalization and cardiovascular 
death in type 2 diabetes patients with high risk for cardiovascular events. A 
potential mechanism underlying the pleotropic and explaining the remarkable 
early reduction in cardiovascular mortality may be related to the effect of 
empagliflozin on arrhythmic events. 
T2DM is among the most common chronic diseases with increasing prevalence 
and incidence 2. T2DM is associated with profound cardiovascular disease 
(CVD) burden which is considered as a primary contributor to T2DM mortality 
in the setting of diabetes in the form of coronary artery disease (CAD), 
cerebrovascular disease, peripheral vascular disease (PVD), and heart failure 
(HF). T2DM is associated with 2-5-fold risk for heart failure with reduced or 
preserved left ventricular ejection fraction(EF). The key mechanisms 
contributing to this include: (1) Increased risk for CAD and a dreadful prognosis 
associated with the  T2DM-CAD duet; (2) Associated atherosclerosis and 
reduced vascular compliance leading to hypertension, afterload augmentation 
and impaired cardiac efficiency; (3) Abnormal metabolic response to adverse 

 
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stressors (i.e. ischemia) resulting in abnormal metabolism, lipotoxicity, cardiac 
steatosis, production of advanced glycation end products affecting diastolic 
function, and reduction of cardiac efficiency, all collectively known as “diabetic 
cardiomyopathy”. 
The recent introduction of renal sodium-glucose cotransporter 2 (SGLT2) 
inhibitors target a novel mechanism that affect glucose plasma levels. Briefly, 
SGLT2 receptors are responsible for absorbing glucose during normoglycemia 
and provide a buffering mechanism during hyperglycemia (allowing glucose 
urinary excretion) resulting in glycosuria. Importantly, In T2DM patients there is 
a paradoxical increase in SGLT2 expression and in the its thresholds for 
glucose urinary excretion. Empagliflozin, a member of the, recently introduced, 
clinically available, SGLT2 inhibitors was shown to effectively lower plasma 
glucose levels with a mean hemoglobin A1C (HbA1c) reduction of -0.7%3, 4 in 
both phase 2 and 3 clinical trials1, 5, 6. The EMPA-REG OUTCOME study, 
evaluated the cardiovascular effects of empagliflozin therapy in patients with 
high cardiovascular risk (Established significant coronary artery disease, recent 
unstable angina or myocardial infarction, recent stroke or peripheral artery 
disease). The study demonstrated a reduction in the primary composite 
outcome (that included death from cardiovascular causes, nonfatal myocardial 
infarction, or nonfatal stroke). Importantly, while the study did not show a 
significant effect of empagliflozin on the rate of myocardial infarction or stroke, 
empagliflozin therapy resulted in remarkable and significant reduction in 
cardiovascular mortality (38% relative risk reduction). Surprisingly, the effect of 
empagliflozin on the occurrence of cardiovascular events appeared very early 
within the course of the study (separation of curves started as early as less than 
1 month from treatment initiation). Multiple potential mechanisms have been 
suggested to mediate the positive cardiovascular effect of empagliflozin 
(altered cardiomyocyte metabolism, anti-arrhythmic effect, improved glycemic 
control, positive effect on myocardial contractility)3. 
Ventricular arrhythmias and the associated sudden cardiac death (SCD) is the 
leading cause of mortality in patients with heart failure. The risk for the 
occurrence of SCD in heart failure patients is closely related to the etiology 

 
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(ischemic versus non-ischemic) and the left ventricular EF 7. The introduction 
of defibrillation therapy for primary prevention of SCD in HF patients has 
revolutionized the field during the last 2 decades. Nevertheless, ventricular 
arrhythmias still remain a major cause of mortality for HF patients given the 
limited ability for risk stratification, and the dreadful prognosis associated with 
ventricular arrhythmias treated by defibrillation therapy8, 9. The burden of 
premature ventricular Complexes (PVCs) has been shown as an independent 
risk factor for ventricular tachyarrhythmia and SCD for healthy, ischemic and 
heart failure patients (with and without resynchronization and/or defibrillator 
therapy).10-19 Anti-arrhythmic drugs (AAD) are efficient in suppressing the 
occurrence of PVCs but for certain drugs, the associated with profile of 
adverse events and cardiotoxicity may paradoxically increase the rate of 
sudden cardiac death as learned by the remarkable CAST study.20 Be that as 
it may, easily suppressed  PVC burden (without the associated adverse profile 
of AADs) has been suggested to correlate with reduction of the likelihood for 
SCD21. Furthermore, the growing field of PVC ablation has been shown to 
have beneficial effect on cardiac function and the risk for ventricular 
arrhythmia22. In summary, PVC suppression, a once neglected strategy, is 
now considered a promising strategy for evaluating the effect of therapeutic 
strategies on the risk for SCD23. 
Empagliflozin treatment in high cardiovascular risk patients with diabetes has 
been shown to have a relatively rapid powerful capability in reducing 
cardiovascular mortality. Among the suggested mechanisms mediating this 
effect of empagliflozin, anti-arrhythmic effect (AAE) has the highest potential 
to translate into a rapid clinical beneficial effect on cardiovascular mortality, 
while other mechanisms are known to have a lag in their clinical effect based 
on data from previous studies. Based on this assumption, we hypothesize that 
the effect of empagliflozin on the rate of cardiovascular death may be 
mediated by a direct effect on the risk for arrhythmic events (via a direct or an 
indirect effect on the myocardium). The current study aims at assessing the 
effect of empagliflozin on arrhythmias in diabetes patients with HF with 
reduced EF and relatively high arrhythmic burden. 

 
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2.3 Investigational product 
Empagliflozin (Jardiance®) is indicated as an adjunct to diet and exercise to 
improve glycemic control in adults with type 2 diabetes mellitus. 
Empagliflozin is an orally-active inhibitor of the sodium-glucose co-transporter 
2 (SGLT2).  
The chemical name of empagliflozin is D-Glucitol,1,5-anhydro-1-C-[4-chloro-
3-[[4- [[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-, (1S).  
Its molecular formula is C23H27ClO7 and the molecular weight is 450.91.  
Mechanism of action: Sodium-glucose co-transporter 2 (SGLT2) is the 
predominant transporter responsible for reabsorption of glucose from the 
glomerular filtrate back into the circulation. Empagliflozin is an inhibitor of 
SGLT2. By inhibiting SGLT2, empagliflozin reduces renal reabsorption of 
filtered glucose and lowers the renal threshold for glucose, and thereby 
increases urinary glucose excretion. 
2.4 Preclinical data 
Studies in rodents and non rodents animals evaluated carcinogenesis, 
mutagenesis and impairment of fertility. 
No increase in carcinogenesis (Renal tubule adenomas and carcinomas were 
observed in male mice at 1000 mg/kg/day, which is approximately 45 times the 
exposure of the maximum clinical dose of 25 mg.) 
Mutagenesis was not observed in in vitro mutagenicity assays. 
Empagliflozin had no effects on mating, fertility or early embryonic development 
in treated male or female rats up to the high dose of 700 mg/kg/day 
(approximately 155 times the 25 mg clinical dose in males and females, 
respectively).  
2.5 Clinical data to date 
Adverse reactions excluding hypoglycemia reported in ≥2% of patients treated 
with empagliflozin and greater than placebo in pooled placebo-controlled 

 
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clinical studies of empagliflozin monotherapy or combination therapy reflecting 
exposure of 1976 patients to empagliflozin: 
  Table 1 
 
Number (%) of patients 
 
Placebo 
N=995 
Empagliflozin 10 mg 
N=999 
Empagliflozin 25 mg 
N=977 
Urinary tract infection 
7.6% 
9.3% 
7.6% 
Female genital mycosis 
1.5% 
5.4% 
6.4% 
Upper respiratory tract infection 
3.8% 
3.1% 
4.0% 
Increased urination 
1.0% 
3.4% 
3.2% 
Dyslipidemia 
3.4% 
3.9% 
2.9% 
Arthralgia 
2.2% 
2.4% 
2.3% 
Male genital mycotic infections 
0.4% 
3.1% 
1.6% 
nausea 
1.4% 
2.3% 
1.1% 
 
Other adverse events observed in clinical studies: thirst was reported in 1.5% 
to 1.7% of patients treated by empagliflozin, most probably secondary to 
volume depletion due to osmotic diuresis properties of empagliflozin. Volume 
depletion caused by osmotic diuresis is the cause of: arterial hypotension, 
dehydration and orthostatic hypotension that were reported in 0.3% to 0.5% in 
clinical trials with empagliflozin. 
Mild impairment in renal function (increased serum creatinine or decrease in 
GFR) especially in persons with preexisting moderate renal impairment was 
noticed in clinical trials involving empagliflozin.  
Dose related increase in LDL cholesterol was observed in 4.6% to 6.5% versus 
2.3% in the placebo group. 
Hypoglycemia was observed in clinical trials when empagliflozin (10mg) was 
administrated as monotherapy in 0.4% of patients. Combination therapy with 
metformin resulted in hypoglycemia rate of 1.8% (versus 0.5% with placebo and 
metformin).  Combination therapy with insulin resulted in hypoglycemia rate of 

 
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19.5% (versus 20.6% with placebo and insulin). Combination theraphy with 
metformin and sulfonylura resulted in hypoglycemia rate of 16.1% (versus 8.4% 
with placebo and the baseline drugs). 
2.6 Known and potential risks and benefits 
Hypotension  
Empagliflozin 
causes 
intravascular 
volume 
contraction. 
Symptomatic 
hypotension may occur after initiating empagliflozin particularly in patients with 
renal impairment, the elderly, in patients with low systolic blood pressure, and 
in patients on diuretics. Before initiating empagliflozin, assess for volume 
contraction and correct volume status if indicated. Monitor for signs and 
symptoms of hypotension after initiating therapy and increase monitoring in 
clinical situations where volume contraction is expected  
Impairment in Renal Function  
Empagliflozin increases serum creatinine and decreases eGFR. The risk of 
impaired renal function with Empagliflozin is increased in elderly patients and 
patients with moderate renal impairment. More frequent monitoring of renal 
function is recommended in these patients renal function should be evaluated 
prior to initiating empagliflozin and periodically thereafter.  
Hypoglycemia with Concomitant Use with Insulin and Insulin 
Secretagogues  
Insulin and insulin secretagogues are known to cause hypoglycemia. The risk 
of hypoglycemia is increased when empagliflozin is used in combination with 
insulin secretagogues (e.g., sulfonylurea) or. Therefore, a lower dose of the 
insulin secretagogue or insulin may be required to reduce the risk of 
hypoglycemia when used in combination with empagliflozin.   
Genital Mycotic Infections  
Empagliflozin increases the risk for genital mycotic infections. Patients with a 
history of chronic or recurrent genital mycotic infections were more likely to 
develop mycotic genital infections. Risk for female genital infection is 5.4% 

 
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(versus 1.5% with placebo). Management includes monitoring and treatment  
as appropriate.  
Urinary Tract Infections  
Empagliflozin (10mg)  increases the risk for urinary tract infections (UTI) 
including pyelonephtritis and sepsis due to urinary tract infections. The risk for 
UTI increases with age and with female sex.  Risk for UTI is 9.3% (versus 7.6% 
with placebo). Management includes monitoring and treatment as appropriate.  
Increased Low-Density Lipoprotein Cholesterol (LDL-C)  
Increase in LDL-C can occur with empagliflozin. Monitor and treat as 
appropriate.  
Macrovascular Outcomes  
There have been no clinical studies establishing conclusive evidence of 
macrovascular risk reduction with empagliflozin or any other antidiabetic drug. 
 
 

 
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3 Trial Objectives and Purpose 
We hypothesize that the effect of empagliflozin on the rate of cardiovascular 
death may be mediated by a direct effect on the risk for arrhythmic events (via 
a direct or an indirect effect on the myocardium). The current study aims at 
assessing the effect of empagliflozin on arrhythmias in diabetic patients with 
heart failure with reduced EF and relatively high arrhythmic burden. 
3.1 Primary Objective 
The objective of the current study is to demonstrate the effect of empagliflozin 
compared to placebo on the rate of ventricular arrhythmic events in type 2 
diabetes patients with heart failure with reduced ejection fraction and high risk 
arrhythmic profile. 
3.2 Secondary Objectives 
To evaluate the effect of Empagliflozin on cardiac function,using 
molecular 
(NT-Pro_BNPlevels0, 
echocardiographic 
and 
physiological markers of myocardial function. 

 
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4 Trial Design                                                                                          
4.1     Primary and secondary endpoints 
4.1.1 Primary Endpoint 
The primary endpoint is the burden of premature ventricular complexes, 
defined as the PVCs percentage of all beats in a pre-specified period 
captured on ICD or CRTD/P device.  
PVC  burden will be calculated according to device interrogation. In case of 
device failure to appropriately monitor the PVC burden, 24hr 12 lead holter 
ECG recording will be used as a complimentary method for arrhythmia 
assessment. 
 
4.1.2 Secondary Endpoints 
1. The number of non-sustained ventricular tachycardia (NSVT) episoedes, 
defined as the NSVT number in a pre-specified period captured on ICD or 
CRTD/P device.  
2. A composite cumulative endpoint of ventricular arrhythmia load (number of: 
sustained ventricular tachycardia, ventricular fibrillation, antitachycardia 
pacing (ATP) or delivery of shock therapy episodes, defined as the 
arrhythmias number in a pre-specified period captured on ICD or CRTD/P 
device.  
3. The change in blood level of NT-Pro Brain Natriuretic peptide (BNP) from 
baseline to the end of any of the treatment periods 
4. The change in Left ventricular end diastolic diameter on echocardiography 
from baseline to the end of any of the treatment periods. 
5. The change in Left ventricular ejection fraction (EF) on echocardiography 
from baseline to the end of any of the treatment periods. 
6. Safety. 

 
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4.2 Overall study design  
The present study is a randomized, prospective, controlled, double blind, cross-
over, pairwise, add on standard therapy, event driven study, comparing 
empagliflozin versus placebo on the ventricular arrhythmia burden in a blocked 
randomization stratified by ischemic versus non-ischemic cardiomyopathy and 
PVC burden at screening of< or  to 4%. 
 
Patients will be recruited  from the congestive heart failure clinic of the study 
site and treated for up to 8 weeks with the study drug (or placebo) and then 
another 8 weeks with placebo (or study drug) with a washout period of 4 weeks 
between the two treatment periods. Potential study subjects will sign an 
informed consent prior to undergoing any study related procedure. Generally, 
study medications should be continued until intolerance. Treatment after 
completion of the study is at the discretion of the investigator.  
Up to 128 patients are planned to be enrolled. Enrollment time of the study is 
one year.  
This study encompass 4 periods for each study subject: screening period of 8 
weeks, first treatment period of 8 weeks, washout period of 4 weeks and a 
second treatment period of 8 weeks. Expected duration of subject participation 
is 6-7 months.  
Study assessments will be performed according the table of study procedures 
below. (Table 2)  
 
Screening / run in period 
Patients will undergo screening for protocol eligibility within 56 days (8 weeks) 
of recruitment. 
Subjects meeting all the inclusion criteria and do not meet any exclusion criteria 
will be enrolled after signing an informed consent. 
Written informed consent must be obtained before any study specific medical 
procedures are performed. Evaluation consists of physical examination 

 
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including vital signs, laboratory-screening assessments including urine 
pregnancy test for FCBP, HbA1c, device (ICD or CRTD/P) interrogation and 
echocardiography (if not done recently).   
  
First treatment period 
Randomization will take place after obtaining patient’s informed consent and 
after fulfilling the inclusion and exclusion criteria. Patients will be assigned to 
empagliflozin or placebo treatment for a period of 8 weeks by a central 
randomization process.  
Evaluations consists of vital signs, laboratory assessments blood examination, 
device (ICD or CRTD/P) interrogation, 24h’ Holter ECG in case of ICD/CRTD/P 
malfunction as a backup arrhythmia assessment and  echocardiography. 
Patient’s glucose level will be monitored by a home device 3 times a day in the 
first week and thereafter once a week or as needed. At visit 2, an 
endocrinologist consultant will give to the patient instructions for antidiabetic 
treatment titration according to appendix 1. 
Patients will be treated for up to 8 weeks with the study drug or placebo 10 
mg/day every morning. 
 
Washout period 
Study subjects will stop study drug (empagliflozin/placebo) of the first treatment 
period and will be given placebo for a washout period of 4 weeks and will 
crossover to the second drug at the end of this period at the beginning of the 
next treatment period. During this period, patient’s glucose level will be 
monitored by a home device 3 times a day in the first week and thereafter once 
a week or as needed. Safety laboratory examinations, HbA1c, device 
interrogation and resetting, Holter ECG and echocardiography will be 
performed at the end of this period (visit 3). In the case of abnormal glucose 
levels during the washout period, diabetes treatment will be changed according 
to appendix 1 aiming to maintain glucose levels at normal range.  

 
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Second treatment period 
Patients will crossover to empagliflozin or placebo treatment for a period of 8 
weeks.  
Evaluations consists of vital signs, laboratory assessments including pregnancy 
test for FCBP. Patient’s glucose level will be monitored by a home device 3 times 
a day in the first week and thereafter once a week or as needed. Device (ICD 
or CRTD/P) interrogation and 24h’ Holter ECG in case of ICD/CRTD/P 
malfunction as a backup arrhythmia assessment and echocardiography. In the 
case of abnormal glucose levels during the second treatment period, diabetes 
treatment will be changed according to appendix 1 aiming to maintain glucose 
levels at normal range.  
Patients will be treated for up to 8 weeks with the study drug or placebo 
10 mg/day every morning. 
Medication compliance will be performed during the two treatment periods by 
counting the returned study drug blisters.  
 
Accompanying scientific program 
In order to gain a deeper insight into the mechanism of action of empagliflozin 
in individuals with diabetes with heart failure and arrhythmogenic risk, additional 
research projects will be performed based on urine and blood samples of 
patients participating in this trial. 
Additional samples will be drawn at different time points (visits 2-5) for the 
scientific projects, Furthermore, patients will be asked to agree, that the 
leftovers of the samples accompanying scientific program may be stored and 
used for other scientific analyses and projects. The following urine and blood 
examinations will be performed at the treatment periods: urine and blood 
biobank samples (This will require a separate IRB approval.), electrolytes urine 
examination, 24h urine collection, 6 minute walk distance and cardiopulmonary 
exercise test.  
 

 
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4.2.1  Visit schedule and assessments 
Table 2 visit schedule and assessments 
Trial Period 
Screening 
Treatment Period 
Visit 
1 
2 
3 
4 
5 
Study Week 
0 
8 
16 
20 
28 
Days from randomization 
-56 
0 
56 
84 
140 
Informed Consent 
X 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
Medical History 
X 
 
 
 
 
Concomitant therapy 
X 
X 
X 
X 
X 
Demographics 
X 
 
 
 
 
Physical Exam 
X 
X 
 
 
 
Vital Signs 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
Pregnancy test1 
X 
X 
 
X 
X 
Home Blood glucose monitoring2 
 
X 
X 
X 
X 
Safety blood samples3 
X 
X 
X 
 
X 
HbA1c 
X 
 
X 
 
X 
Device Interrogation 
X 
X 
X 
X 
X 
Monitor Counter Reset 
X 
X 
X 
X 
X 
12 Lead Holter ECG for 24hrs 
 
X 
X 
 
X 
Echocardiography 
X4 
X 
X 
 
X 
NT-Pro-BNP 
 
X 
X 
X 
X 
Medication Compliance check 
 
 
X 
 
X 
                                                          
 
1 For female patients with childbearing potential (Urine pregnancy test). 
2 Patients without means for daily home blood glucose monitoring will be given a device on visit 
2. Glucose level will be measured 3 times a day in the first week and thereafter once a week or 
as needed. Additional measurements are warranted in the case of hypo- or hyperglycemia signs 
or symptoms.  
3 Safety blood samples include: Fasting blood samples (8hr fasting), Liver and kidney 
functions, urine dipstick for signs of infection and ketoacidosis (if positive leukocyte esterase 
(WBC) or nitrites a midstream urine sample for urine culture will be taken. 
4 Echocardiography will be done if needed to verify patient suitability for inclusion criteria. 

 
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Trial Period 
Screening 
Treatment Period 
Visit 
1 
2 
3 
4 
5 
Study Week 
0 
8 
16 
20 
28 
Days from randomization 
-56 
0 
56 
84 
140 
Endocrinologist consult 
 
X 
 
 
 
Biobank samples 
 
X 
X 
X 
X 
Urine Analysis (Electrolytes) 
 
X 
X 
X 
X 
24hr Urine Sample collection 
 
X 
X 
X 
X 
CardioPulmonary Exercise Test & 
6 minute walk distance5 
 
X 
X 
 
X 
Adverse events 
 
X 
X 
X 
X 
 
  
 
 
 
 
Study scheme 
 
 
 
 
 
 
 
 
                                                          
 
5 In case of inability to perform cardiopulmonary exercise test according to clinical judgment , 
patient will have a 6 minute walk distance test). 
Visit 1 
Scree
ning 
Visit 2 
Baseline 
(Randomization) 
Empagliflozin 
Placebo      
2 months 
Empagliflozin 
Placebo 
 
2 months 
2 months 
     4 weeks 
(wash out) 
Visit 4 
(Cross-Over 
& Counter 
reset) 

 
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Visit 3 
Analysis 1 
  
Visit 5 
Analysis 2 

 
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4.2.2 Visit Procedures     
Screening visit (day -56 to 0)  
1. 
Obtain patient signed informed consent.    
Prior to a subject’s participation in the trial, an Informed Consent form will be 
signed and personally dated by the subject and by the person who conducted 
the Informed Consent discussion.  
If a subject is unable to read, an impartial witness should be present during 
the entire Informed Consent discussion. After the written Informed Consent, 
form is read and explained to the subject and after the subject has orally 
consented to participating in the trial if the subject is capable of doing so 
she/he should sign and personally date the Informed Consent form, the 
witness should sign and personally date the consent form. By signing the 
consent form if the subject is unable to sign, then the witness attests that the 
information in the consent form was accurately explained to, and apparently 
understood by the subject and that Informed Consent was freely given by the 
subject. 
Prior to participation in the trial, the subject will receive a copy of the signed 
and dated written Informed Consent form. During participation in the trial, the 
subject will receive a copy of the signed and dated consent form updates and 
a copy of any amendments to the written information provided to subjects.   
The investigator should document in the source data that the Informed 
Consent was signed prior to subject's participation in the study and 
according to the ICH guidelines, as described above. 
2. 
Review patient’s eligibility for the study according to in- and exclusion 
criteria.   
3. 
Demographic data will be recorded (sex, age, ethnic origin) 
4. 
Review and record relevant medical history. Participant's medical history 
should be fully documented at screening, to ensure compliance with study 
inclusion criteria and the absence of circumstances mentioned in the 
exclusion criteria. Medical history information must include, but not be limited 
to, past and present major illnesses, any previous surgery/operations and 
any current ongoing illness. 
5. 
Review and record current medical condition history (T2DM control, NYHA 
status, Heart failure therapy).  
6. 
Perform a complete physical examination. The treating investigator will 
conduct a complete physical examination and assess subject’s performance 

 
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status at screening in order to ensure compliance with study inclusion criteria 
and the absence of circumstance mentioned in the exclusion criteria.       
7. Measure vital signs at screening in order to ensure compliance with study 
criteria. Vital signs measurements will include systolic and diastolic blood 
pressure, pulse rate, respiratory rate, and body temperature. Body weight 
and height will also be measured. Measurements that may potentially 
constitute future adverse events (e.g. hypoglycemia, hypotension etc.) 
should be graded in the medical history form at baseline according to CTC 
as described in 8.1.3 below.  
8. 
Collect safety blood and urine samples. Including hematology and chemistry 
blood examinations and urine dipstick for signs of ketoacidosis or infection. 
Hematology: Testing of Complete Blood Counts (CBC) including differential 
and platelet count will be performed at screening, in order to ensure 
compliance with study inclusion criteria (5 ml blood per sample). Every out-
of-range value will be assessed by a physician and deemed as either 
clinically significant (S) or not significant (NS).  
Chemistry: Serum chemistry panel will consist of sodium, potassium, 
calcium, protein, albumin, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), bilirubin, alkaline phosphatase, blood urea 
nitrogen (BUN), creatinine, and fasting glucose. Chemistry will be 
performed at screening, in order to ensure compliance with study inclusion 
criteria (5-10 ml blood per sample). Every out-of-range value will be 
assessed by a physician and deemed as either clinically significant (S) or 
not significant (NS). 
11. 
Review menopausal status and in women of childbearing potential a 
urine pregnancy test (-HCG) will be performed. 
12. 
Collect venous blood will be drawn for HbA1c. 
13. 
Perform device interrogation by an electrophysiological technician for 
verification of arrhythmogenic risk according the eligibility criteria. 
14. 
Perform monitor counter reset by an electrophysiological technician. 
15. 
Perform echocardiography for verification of EF≤40% according to the 
eligibility criteria (if not done in the last 6 months). 
16. 
Review concomitant medications. All prior treatments (medications) 
received by the subject within 30 days of the initial screening visit and 
during the study will be recorded on the subject’s CRF including the 
name of the treatment, indication, total daily dose, frequency and the 
start and stop dates. Any medications (including prescription, over-
the-counter, herbal supplements and health store products) to be 
taken during the study will be documented. 

 
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Collection of information on standard of care treatment will be done as 
part of medications records during the study. 
17. 
Invite study subject to study site for Holter ECG installation in one of 
the 7 days before the next visit. 
 
Base line visit (2) (day 0 ±7 days) 
1. 
Patient’s enrollment.  Eligibility for the study according to inclusion and 
exclusion criteria will be rechecked but lab tests not repeated) if all 
criteria are fulfilled and there is no significant change in the subject’s 
health, he/she will be enrolled into the study to receive the first study 
drug. 
2. 
Get patient randomization number. 
3. 
Begin study drug treatment (active or placebo), provide patient 60 
tablets and give treatment instructions for home use.  
4. 
Perform a complete physical examination.  
5. 
Measure vital signs in order to ensure compliance with study criteria. Vital 
signs measurements will include systolic and diastolic blood pressure, pulse 
rate, respiratory rate, and body temperature. Body weight will also be 
measured. Measurements that may potentially constitute future adverse 
events (e.g. hypertension, fever etc.) should be graded in the medical history 
form at baseline according to CTC as described in 8.1.3 below 
6. 
Collect safety blood and urine samples. Including hematology and chemistry 
blood examinations and urine dipstick for signs of ketoacidosis or infection. 
7. 
Review menopausal status and in women of childbearing potential  perform 
a urine pregnancy test (-HCG). 
8. 
Collect home diary glucose results and provide a new diary for the 
following period. 
9. 
Provide home diary for daily blood glucose determination.  
10. 
Perform device interrogation. 
11. 
Perform Monitor counter reset. 
12. 
Collect Holter ECG device results and invite study subject to study site 
for Holter ECG installation in one of the 7 days days before the next 
visit. 
13. 
Perform echocardiography for determination of EF 
14. 
Consult endocrinologist for glucose lowering medication titration 
15. 
Collect blood examination for NT-Pro-BNP 
16. 
Collect urine and blood examination for biobank sample 
17. 
Collect urine for electrolyte concentration 

 
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18. 
Obtain 24 hours urine sample collection 
19. 
Perform cardiopulmonary exercise test (In case of inability to perform 
cardiopulmonary exercise test according to clinical judgment, patient 
will have a 6 minute walk distance test) 
20. 
Perform 6 minute walk distance 
21. 
Review concomitant medications. 
22. 
Document adverse events. 
 
Treatment washout visit (3) (day 56 ±7 days)  
1. 
Provide patient with 30 tablets of study drug for home use 
2. 
Collect study drug blisters returned by patient. 
3. 
Measure vital signs in order to ensure compliance with study criteria. 
Vital signs measurements will include systolic and diastolic blood 
pressure, pulse rate, respiratory rate, and body temperature. Body 
weight will also be measured.  
4. 
Collect safety blood and urine samples. Including hematology and 
chemistry blood examinations and urine dipstick for signs of 
ketoacidosis or infection. 
5. 
Remind patient to follow the endocrinologist intructions given on visit 2. 
6. 
Collect venous blood that will be drawn for HbA1c. 
7. 
Collect home diary glucose results and provide a new diary for the 
following period. 
8. 
Perform device interrogation. 
9. 
Perform Monitor counter reset. 
10. 
Collect Holter ECG device results and invite study subject to study site 
for Holter ECG installation in one of the 7 days days before the next 
visit. 
11. 
Perform echocardiography for determination of EF 
12. 
Collect blood examination for NT-Pro-BNP 
13. 
Collect urine and blood examination for biobank sample 
14. 
Collect urine for electrolyte concentration 
15. 
Obtain 24 hours urine sample collection 
16. 
Perform cardiopulmonary exercise test (In case of inability to perform 
cardiopulmonary exercise test according to clinical judgment , patient 
will have a 6 minute walk distance test) 

 
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17. 
Perform 6 minute walk distance 
18. 
Review concomitant medications. 
19. 
Document adverse events. 
Treatment visit (4) (day 84 ±7 days) 
1. 
Provide patient with 60 tablets of study drug for home use 
2. 
Collect study drug blisters returned by patient. 
3. 
Measure vital signs in order to ensure compliance with study criteria. Vital 
signs measurements will include systolic and diastolic blood pressure, pulse 
rate, respiratory rate, and body temperature. Body weight will also be 
measured.  
4. 
Review menopausal status and in women of childbearing potential perform 
a urine  pregnancy test (-HCG). 
5. 
Remind patient to follow the endocrinologist intructions given on visit 
2. 
6. 
Collect home diary glucose results and provide a new diary for the 
following period. 
7. 
Perform device interrogation. 
8. 
Perform Monitor counter reset. 
9. 
Collect blood examination for NT-Pro-BNP 
10. 
Collect urine and blood examination for biobank sample 
11. 
Collect urine for electrolyte concentration 
12. 
Obtain 24 hours urine sample collection 
13. 
Review concomitant medications 
14. 
Document adverse events. 
End of Study visit (5) (day 140 ±7 days) 
1. 
 
2. 
Collect study drug blisters returned by patient. 
3. 
Measure vital signs in order to ensure compliance with study criteria. Vital 
signs measurements will include systolic and diastolic blood pressure, pulse 
rate, respiratory rate, and body temperature. Body weight will also be 
measured.  
4. 
Collect safety blood and urine samples. Including hematology and chemistry 
blood examinations and urine dipstick for signs of ketoacidosis or infection. 
5. 
Review menopausal status and in women of childbearing potential perform 
a urine pregnancy test (-HCG). 
6. 
Collect venous blood that  will be drawn for HbA1c. 

 
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7. 
Collect home diary glucose results.  
8. 
Perform device interrogation. 
9. 
Perform Monitor counter reset. 
10. 
Collect Holter ECG device results. 
11. 
Perform echocardiography for determination of EF 
12. 
Collect blood examination for NT-Pro-BNP 
13. 
Collect urine and blood examination for biobank sample 
14. 
Collect urine for electrolyte concentration 
15. 
Obtain 24 hours urine sample collection 
16. 
Perform cardiopulmonary exercise test (In case of inability to perform 
cardiopulmonary exercise test according to clinical judgment , patient 
will have a 6 minute walk distance test) 
17. 
Perform 6 minute walk distance. 
18. 
Review concomitant medications. 
19. 
Document adverse events. 
4.3 Trial treatment   
4.3.1 Investigational therapy  
Empagliflozin and placebo is supplied to the study investigators by the 
Boehringer Ingelheim Company via the sponsor. Empagliflozin is supplied as 
10 mg tablets packaged in blister packs. 
Labels will comply with the legal requirements of Israel and be printed in 
Hebrew, Arabic and English. The storage conditions for study drug will be 
described on the medication label. Patients will receive study drug 10mg by the 
oral route q.d. if in the opinion of the investigator the patient is benefiting from 
treatment with this study drug, and in the absence of any safety concerns. 
Treatment will be withheld only in the case of limiting toxicities.  
4.3.2 Treatment assignment 
Treatment assignment will take place only after getting patients’ Informed 
consent and determining patient’s eligibility. Each patient will be assigned a 
unique patient number. Once assigned, numbers for any non-evaluable or 
discontinued patient will not be reused.  

 
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A central randomization based on a 1:1 basis, of a pre-determined 
randomization schedule prepared by the data management of the CRO will 
provide the investigator treatment allocation to empagliflozin or placebo by fax 
or email. Treatment allocation and a unique randomization number will be sent 
by the CRO to the investigator soon after a copy of the inclusion and exclusion 
criteria will be fulfilled and signed by the investigator in the appropriate CRF 
form and sent by fax or email to the data management of the study CRO. Email 
address: rmarilus@netvision.net.il. Fax number: 972-9-9540-457. 
Blinding                                                                                                          
The investigators, the Sponsor, and any personnel involved in patients’ 
assessment, monitoring and data management will be blinded to the patient 
assignment.    
The active study drug and placebo will be packaged and labeled by Boehringer 
Ingelheim Company.  
All study drugs blisters and tablets will appear identical to ensure blinding.  
Study drugs will be dispensed by the site pharmacy, in accordance with the 
randomization code system and the blinded study team will have no access to study 
drug or placebo, or randomization information.  
Emergency Identification of Study drug   
In case of a medical emergency, when the study drug assignment is needed 
to make treatment decisions for the patient, the investigator may unblind the 
patient's drug assignment. The Sponsor and medical monitor should be 
notified of the event prior to breaking of the code, if possible. If this is not 
possible, the Sponsor should be notified immediately afterwards, and the 
patient's drug code assignment should not be revealed. The circumstances 
leading to the breaking of the code should be fully documented, in the 
investigator’s study files and in the patient’s source documentation. Treatment 
assignment should not be recorded in any study documents. 
The reason for breaking the blind must be documented in the patient’s CRF 
and in the patient’s medical records. 

 
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Documentation of contact or attempted contact with the clinical research 
physician prior to breaking the blind must also be documented in the patient’s 
medical records. 
4.4 Study drug interruption or discontinuation                                             
4.4.1 
Discontinuation of study drug 
The following events will be considered as reasons for drug discontinuation: 
 
Subject’s request 
 
Intolerable grade 3/4 adverse drug reaction that is judged by the 
investigator to be either physically or psychologically detrimental to the 
patient. 
 
Any study drug interruption that exceeds 14 consecutive days. 
 
Patient’s non-compliance with study procedures as evaluated by PI and/or 
sponsor as warranting therapy discontinuation. 
 
Other reasons regarded by the PI as warranting therapy discontinuation. 
 
Premature study termination as described below. 
 
Pregnancy. If a woman becomes pregnant during the treatment period of 
the study, she will immediately be withdrawn from the study and will be 
followed up until delivery. 
The investigator should contact the subject either by telephone or through a 
personal visit or a responsible relative must be contacted to determine as 
completely as possible the reason for the withdrawal. A complete final 
evaluation at the time of the patient’s withdrawal should be made with an 
explanation of why the patient is withdrawing. If the reason for removal of a 
patient from the study treatment is an adverse event or an abnormal 
laboratory test result, the principal specific event or test will be recorded on 
the case report form.  
The section for “Study Completion” in the CRF must be completed for all 
patients. The reason for early discontinuation should be given, even if the 
patient refused to return for a final visit. Patients whose treatment is 

 
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discontinued prematurely due to significant adverse events (AEs) should 
continue to be followed until resolution of the AE, and the relevant sections of 
the CRF should be completed as appropriate. Patients who are discontinued 
due to clinically significant abnormalities in clinical laboratory results should 
continue to be evaluated until the abnormality resolves or is judged permanent.  
Patients lost to follow up should be recorded as such on the CRF. If patients 
refuse to return for these visits or are unable to do so, the patient should be 
considered off-study. 
Subjects withdrawn from the study will not be replaced. 
4.4.2 
Study drug interruption 
No study drug interruption is allowed unless for safety reasons. 
4.5 Study Discontinuation  
The patient or the investigator can decide to discontinue subject participation 
on study. 
Possible reasons of premature study termination include: 
 Death 
 Participation in another investigational drug trial 
 Loss to follow-up 
 Patient withdrawal of  consent 
 Malfunction of CRTD/ICD. 
 Clinical need to begin antiarrhythmic drug excluding beta blockers. 
 Occurance of myocardial infarction. 
 Sepsis as a consequence of UTI or genital infection. 
 Administrative problems (of the whole study) 
 
Patient of investigator not compliant with study protocol. 
 

 
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 Occurrence of an AE which makes discontinuation desirable or necessary 
in the investigators’ and/or the patients’ opinion  
 
In those cases, no patient follow-up will be recorded. 
The section for “Study Completion” in the CRF must be completed for all 
patients. The reason for early discontinuation should be given, even if the 
patient refused to return for a final visit. Patients who discontinue prematurely 
due to significant adverse events (AEs) should continue to be followed until 
resolution of the AE, and the relevant sections of the CRF should be completed 
as appropriate. Patients who are discontinued due to clinically significant 
abnormalities in clinical laboratory results should continue to be evaluated until 
the abnormality resolves or is judged permanent.  
4.6 Premature whole study termination 
 
Administrative problems e.g.: recurrent serious or severe ADR clinically 
evaluated by PI and/or sponsor as warranting whole study termination. 
 A decision made by the sponsor and/or IRB/EC and/or local regulatory 
agency to terminate the study 
4.7 
Accountability 
procedures 
for 
the 
investigational 
products 
Study drug will be dispensed by the pharmacy at the investigator’s institution.  
The patient may be dispensed up to an 8 weeks supply of medication. The 
pharmacy must maintain an individual record of the patient. Drug dose, number 
of tablets received and returned must be recorded. 
 
 
 
 
 

 
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5 Selection and Withdrawal of Subjects                           
5.1 Inclusion Criteria 
1. Heart failure patients with reduced ejection fraction (EF≤40%) as assessed 
by echocardiographyat least 6 months prior to recruitment and NYHA 
Class≥2  
2. Patients implanted with ICD, CRTD/S or CRTP devices that are capable of 
recording the PVC burden and implanted ≥ 2 months prior to recruitment. 
3. High risk for arrhythmic events at baseline identified by either PVC burden 
≥2%  or  ≥2 events of non sustained VT or ≥1 event of sustained 
ventricular tachycardia or need for anti-tachycardia pacing or defibrillation 
therapy, during a period of 2 months prior to recruitment. 
4. Diagnosis of type 2 diabetes mellitus prior to informed consent 
5. HbA1c≥7% and ≤12%. 
6. Signed and dated written informed consent by date of Visit 1 in accordance 
with GCP legislation.  
5.2 Exclusion Criteria 
1. Evidence of ICD malfunction. 
2. Antiarrhythmic treatment other than beta blockers. 
3. Past exposure to SGLT2 inhibitors. 
4. Uncontrolled diabetes with HbA1c>12% or glucose >240 mg/dL after an 
overnight fast. 
5. Liver abnormalities defined by serum levels of alanine aminotransferase, 
aspartate aminotransferase, or alkaline phosphatase above 3 x upper limit 
of normal. 
6. Planned cardiac procedure within 3 months. 
7. Prior MI in the last 40 days. 

 
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8. Calculated eGFR< 45ml/min/1.73m2 as determined by the MDRD formula 
GFR (mL/min/1.73 m2) = 175 × (Scr)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if African 
American) 
9. BMI>50 
10. Medical History of active cancer in the last 2 years. Exceptions include the 
following: Basal cell carcinoma of the skin, Squamous cell carcinoma of 
the skin, Carcinoma in situ of the cervix, Carcinoma in situ of the breast, 
Incidental histologic finding of prostate cancer (TNM stage of T1a or T1b). 
11. 
History of recurrent UTIs or genital infections 
12. 
Systolic blood pressure<90mmHg. 
13. 
Alcohol or drug abuse within 3 months of informed consent. 
14. Pre-menopausal women (last menstruation <+ 1 year prior to informed 
consent) who: 
·         - are nursing or pregnant or 
·         - are of child-bearing potential and are not practicing an acceptable 
method of birth control, or do not plan to continue using this method 
throughout the study and do not agree to submit to periodic pregnancy 
testing during participation in the trial. Acceptable methods of birth control 
include tubal ligation, transdermal patch, intra uterine devices/systems, 
oral, implantable or injectable contraceptives, sexual abstinence, double 
barrier method and vasectomised partner. 
 
15. Intake of an investigational drug in another trial within 30 days prior to 
intake of study medication in this trial or participating in another trial 
involving an investigational drug and/or follow-up                      
5.3 Interruption or Discontinuation of Treatment 
5.3.1 Discontinuation of study drugs 
See section 4.4.1 

 
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5.3.2 Interruption of study drugs 
No study drug interruption is allowed unless for safety reasons. 
5.4 Study Discontinuation  
See section 4.5 

 
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6 Treatment of Subjects                                                       
6.1 Treatment regimen 
Patients will receive study drug: empagliflozin or placebo for an exposure period 
of up to 16 weeks - at the two treatment periods in a crossover design. Dosage, 
dosage regimen and route of administration are detailed in 4.3.1 
6.1.1 Treatment assignment  
This study will be double blind.  At the Baseline/randomization visit, qualified 
patients will be randomly assigned in a 1:1 ratio to either empagliflozin at a dose 
of 10 mg/day or placebo (study drug packages will be identical for all 
treatments).   
Each patient’s treatment will be assigned manually on the basis of a pre-
determined randomization schedule prepared by the data management of the 
study CRO (_____________). The randomization code will be generated and 
stored under secure and blinded conditions. The randomization will include 
stratification logarithm by ischemic versus non-ischemic cardiomyopathy and 
PVC burden at screening of< or  to 4% 
Each subject will be assigned a subject screening number.   
The screening number will be structured so that each subject participating in 
the study will have a unique number. Screening number must not be re-used 
for different subjects. In case a subject is re-screened, the initial screening 
number should be retained and used. 
Once subject’s eligibility is confirmed, a subject will be assigned with a unique 
randomization number and will be randomized to treatment arm according to 
the randomization list Randomization number which will start with an RND or 
ENR followed by the site number and 3 digit subject number (for example – 
RND/ENR01-001, RND/ENR01-002 etc. for site number 1, etc.) 

 
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A dedicated "Subject Identification Log" will be kept at site. This log will include 
the subject's identifying details (e.g. name, ID number, telephone number) 
together with the screening and randomization number (if applicable).  
The "Subject Identification Log" will be kept only at the investigational site and 
will not be taken out of the site. 
6.2 Concomitant therapy  
In general, concomitant medications and therapies deemed necessary for the 
supportive care and safety of the patient are allowed, provided their use is 
documented in the patient records and on the appropriate Case Report Form. 
The administration of antiarrhythmic treatment other than beta blockers 
 is NOT permitted. Similarly, the use of other concurrent investigational drugs 
is not allowed. The use of any of the prohibited medications or drugs/illegal 
substances within the prohibited time period will be considered a protocol 
deviation, which must be recorded on the appropriate CRF(s) or deviation 
violation form. Subjects with repeated protocol deviations may be discontinued 
from the study at the discretion of the investigator and/or sponsor. 
6.3 Treatment compliance 
Number of study drug tablets administrated orally to every subject at home, will 
be evaluated by blister check up by the study coordinator/investigator and 
accounted on CRF.  
 
 
 

 
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7 Assessment of Efficacy  
Efficacy assessments will be evaluated by: PVCs burden, NSVT number, 
Composite endpoint of: number of sustained VT+VF, ATP or delivery of shock 
therapy, BNP, End diastolic diameter and ejection fraction.  
7.1 PVCs Burden 
The primary efficacy parameter to be assessed will be PVCs burden. 
PVCs burden is defined as the PVCs percentage of all beats in a pre-specified 
period captured on ICD or CRTD/P device. 
PVCs burden will be evaluated as a part of the device interrogation on visit 1 to 
assess device integrity and proper function, in visit 2 to assess patient’s 
eligibility for the study according to in- and exclusion criteria. In visits 3 and 5 to 
assess for treatment efficacy.   
Assessment of the PVCs will be based on PVC counters for the various 
ICD/CRTD/P interrogated (from Medtroinic, St. Jude, Guidant – Boston 
Scientific, Biotronik). Monitor counter reset will be conducted on visit 1,2,3,4 
and 5. The equation for calculating the PVC burden for monitoring providing the 
PVC number per period will be: 
𝑃𝑉𝐶 𝐵𝑢𝑟𝑑𝑒𝑛(%) =
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑃𝑉𝐶𝑠
𝐴𝑣𝑒𝑟𝑎𝑔𝑒 𝐻𝑅 ( 𝑏𝑒𝑎𝑡𝑠
𝑚𝑖𝑛𝑢𝑡𝑒) ∗60 ∗24 ∗(#𝑑𝑎𝑦𝑠 𝑖𝑛 𝑡ℎ𝑒 𝑝𝑒𝑟𝑖𝑜𝑑 𝑎𝑠𝑠𝑒𝑠𝑠𝑒𝑑)
 
 
For monitors providing the PVC burden per hour the calculation will be: 
 
𝑃𝑉𝐶 𝐵𝑢𝑟𝑑𝑒𝑛(%) =
𝐴𝑣𝑒𝑟𝑎𝑔𝑒𝑃𝑉𝐶
ℎ𝑜𝑢𝑟
𝐴𝑣𝑒𝑟𝑎𝑔𝑒 𝐻𝑒𝑎𝑟𝑡 𝑅𝑎𝑡𝑒( 𝐵𝑒𝑎𝑡𝑠
𝑀𝑖𝑛𝑢𝑡𝑒) ∗60
 
  
In  case of device malfunction, counter malfunction or any other cause of 
inability to readout the device PVC counter measurement, PVC burden will be 

 
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calculated from a 12 Lead ECG Holter for 24 hours conducted at one of the last 
7 days of the period assessed and will be calculated as: 
𝑃𝑉𝐶 𝐵𝑢𝑟𝑑𝑒𝑛(%) =
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑃𝑉𝐶𝑠
𝐴𝑣𝑒𝑟𝑎𝑔𝑒 𝐻𝑒𝑎𝑟𝑡 𝑅𝑎𝑡𝑒 ( 𝑏𝑒𝑎𝑡𝑠
𝑚𝑖𝑛𝑢𝑡𝑒) ∗60 ∗24
 
 
Monitor 
counter 
readout 
and 
resetting 
will 
be 
performed 
by 
an 
electrophysiologist technician; data will be entered into the CRF by the study 
coordinator after approval of the principal investigator. 
7.2 Non-sustained ventricular tachycardia (NSVT)  
Non-sustained ventricular tachycardia number is defined as the NSVT number 
in a pre-specified period captured on ICD or CRTD/P device interrogation, or 
as a backup information (in case of ICD or CRTD/P malfunction) on Holter ECG. 
The device will be activated during the whole study period and data will be 
captured on the CRF at visits 1 to 5. The Holter ECG device of 24 h’ will be 
performed in  case of device malfunction, counter malfunction or any other 
cause of inability to readout the device PVC counter measurement. Holter 
assessment will be conducted at one of the last 7 days of the period assessed. 
Data from study device/Holter will be captured on the CRF at visits 2, 3 and 5. 
. 
7.3 
A 
composite 
cumulative 
endpoint 
of 
ventricular 
arrhythmia load  
This is defined as the number of sustained ventricular tachycardia, and/or 
ventricular fibrillation, and/or tachycardia pacing (ATP) and/or delivery of shock 
therapy. All the four parameters will be captured on ICD or CRTD/P device 
interrogation. Sustained VT and NSVT will be captured as a backup information 
(in case of ICD or CRTD/P malfunction) on Holter ECG. The device will be 
activated during the whole study period. The Holter ECG device of 24 h’ will be 
performed In the case of device malfunction, counter malfunction or any other 
cause of inability to readout the device PVC counter measurement. Holter 

 
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assessment will be conducted at one of the last 7 days of the period assessed. 
Data from study device/Holter will be captured on the CRF at visits 2, 3 and 5. 
7.4 
NT-Pro-BNP 
NT-Pro-BNP Is a plasma level of B-type Natriuretic Peptide used as a blood 
test for diagnosing and evaluation the presence/severity of heart failure. Plasma 
level will be performed at visits:2 to 5. 
7.5 
Left ventricular end diastolic diameter  
End diastolic diameter is defined as the cross-sectional diameter of the left 
ventricle, including the septum and the posterior thicknesses in diastole. The 
assessment is performed by echocardiography done at visits: 1 to 3 and 5. 
7.6 Left ventricular ejection fraction (EF)  
Ejection fraction is defined as the ratio of the stroke volume to the end-diastolic 
volume in the left ventricle as performed by echocardiography and expressed 
by percentage. The assessment is performed by echocardiography done at 
visits: 1 to 3 and 5. 
 
 
 
 
 
 
 
 
 
 

 
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8 Assessment of Safety   
Safety assessments will consist of evaluating adverse events and serious 
adverse events, adverse events of special interest, laboratory parameters 
including hematology, chemistry & urine analysis, vital signs, physical 
examinations, monitoring compliance, and documentation of all concomitant 
medications and/or therapies. 
8.1 Adverse events 
The information obtained during study visit subject questioning, review of 
subject's compliance record, physical examinations, vital signs 
measurements, blood testing, and by any other means will be evaluated in 
light of baseline medical data and thus provide the basis for adverse events 
identification and grading. The adverse events reported during the trial will be 
graded (see 8.1.3 below), documented and assessed in light of their clinical 
significance and relation to investigational product. In addition, the following 
information regarding the AE must be obtained: start date, end date (if 
applicable), outcome (resolved / unresolved), and action taken (e.g. dose 
adjustment, therapy discontinuation, concomitant medication). Adverse event 
monitoring will be conducted throughout subject's participation. 
Information about all adverse events, whether volunteered by the patient, 
discovered by investigator questioning, or detected through physical 
examination, laboratory test or other means, will be collected and recorded on 
the Adverse Event Case Report Form and followed as appropriate.  
Medical conditions/diseases present before starting study treatment are only 
considered adverse events if they worsen after starting study treatment. 
Clinical events occurring before starting study treatment but after signing the 
informed consent form are recorded on the Medical History/Current Medical 
Conditions Case Report Form. Abnormal laboratory values or test results 
constitute adverse events only if they induce clinical signs or symptoms 
leading to a premature control of the abnormal value before the next 
scheduled laboratory test, leading to a change in study medication (e.g. dose 

 
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modification, interruption or permanent discontinuation), requires a change in 
concomitant therapy (e.g. addition or change in a concomitant medication, 
therapy or treatment) or require therapy. 
Any Adverse Event occurring by the time of study completion (within four weeks 
of last drug intake) must be recorded on the Adverse Event CRF page. 
Any adverse event term needs to be provided for each event; preferably using 
the short name based on the CTCAE ver. 4.0 or preferred term on the 
MedDRA. 
8.1.1  Definitions of adverse events 
Adverse event 
An adverse event is defined as any untoward medical occurrence or effect in a 
patient treated on a study protocol, which does not necessarily have a causal 
relationship with the study treatment. An AE is therefore described as any 
unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom or disease temporally associated with the use of the study treatment, 
whether or not considered related to the study treatment. This definition 
includes any abnormalities or anomalies that were not seen at baseline or which 
worsened during the course of the study, if present at baseline. 
Adverse Reaction (AR) 
This is defined as all untoward and unintended responses to a study 
treatment related to any dose administered. A causal relationship between 
the study treatment and an AE is at least a reasonable possibility (probably or 
possibly related), i.e. the relationship cannot be ruled out. 
Serious Adverse Event 
A serious AE (SAE) is defined as any AE occurring at any dose that results in 
any of the following outcomes:  
■ 
death 
■ 
a life-threatening AE, as defined below 
■ 
patient hospitalization or prolongation of existing hospitalization 
■ 
a persistent or significant disability/incapacity 

 
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■ 
a congenital anomaly/birth defect 
■ 
important medical event, as defined below 
A life-threatening AE is any AE that places the subject, in the view of the 
investigator, at immediate risk of death from the reaction as it occurred 
(i.e. it does not include a reaction that, had it occurred in a more severe 
form, might have caused death).
 
An important medical event is an AE that may not result in death, be life-
threatening, or require hospitalization but may be considered a serious AE 
when, based upon appropriate medical judgment, may jeopardize the subject 
and may require medical or surgical intervention to prevent one of the 
outcomes listed above. It can also include AEs otherwise judged to be serious 
by either the investigator or the sponsor. 
8.1.2 
Adverse events of Special Interest (AESIs) 
 
The term AESI relates to any specific AE that has been identified at the 
project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on 
knowledge from other compounds in the same class.  AESIs need to be 
reported to the Pharmacovigilance Department of Boehringer Ingelheim within 
the same timeframe that applies to SAEs. 
Patients with AESIs need to be followed up appropriately, regardless of the 
origin of the laboratory data (e.g. central, local etc.). The Investigator should 
consider which, if any, concomitant therapies should not be taken during 
evaluation.  Discontinued treatments can be reintroduced per Investigator 
discretion. 
The following are considered as AESIs: 
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 

 
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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.   
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. 
Metabolic acidosis, ketoacidosis and diabetic ketoacidosis (DKA) 
In case of metabolic acidosis, ketoacidosis and DKA further investigations 
should be done according to the medical judgment and the clinical course 
until a diagnosis is made and/or the patient is recovered. 
DKA is defined by the diagnostic criteria in the table below, and as defined by 
the American Diabetes Association (ADA). 
Investigators should note that not all criteria in the table below need to apply 
for the diagnosis of DKA, and clinical judgment should also be taken into 
consideration. Due to its mechanism of action, empagliflozin may potentially 
modify the clinical presentation of DKA which may occur at lower plasma 
glucose levels than stated in the table below. 
Table 3 Diagnostic criteria for DKA 
Table 3 Diagnostic criteria for DKA 
 
DKA 
 
Mild 
Moderate 
Severe 

 
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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 
* 
Nitroprusside reaction method 
** Calculation: 2[measured Na (mEq/L) + gluc 
Contact details of the local pharmacovigilance unit/LVPM: E-mail: PV_local 
Israel@boehringer_ingelheim.com 
 
Suspected Unexpected Serious Adverse Reaction (SUSAR) This is 
defined as an adverse reaction, the nature or severity of which is not 
consistent with the known study treatment information.  
8.1.3 Adverse events grading 
AE will be documented and graded according to the International Common 
Toxicity Criteria (CTCAE) version 4.0  
AE that do not appear in the CTC will be graded as follows:  
■ Mild (Grade 1): Sign or symptom, usually transient, requiring no special 
treatment and generally not interfering with usual activities  
■ Moderate (Grade 2): Sign or symptom, which may be ameliorated by 
simple therapeutic measures, may interfere with usual activity.  
■ Severe (Grade 3): Sign or symptom that is intense or debilitating and 
that interferes with usual activities and/or requires hospitalization. 
Recovery is usually aided by therapeutic measures and the 
discontinuation of the study product may be required. 

 
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■ Life threatening or disabling (Grade 4): Sign or symptom that is Life 
threatening or disabling. 
■ Death (Grade 5): Death related to AE 
8.1.4 Adverse events outcome 
Outcome is classified as follows: 
1. Recovered – The subject has fully recovered from the AE with no residual 
effects observable. 
2. Recovered with sequelae – The subject has fully recovered from the AE with 
residual effects.  
3. Ongoing – AE is still ongoing by the end of study. 
4. Unknown. 
5. Death. 
8.1.5 Causality Assessment of Adverse events 
All AEs will be evaluated by the investigator and assigned an estimated 
relationship to the investigational product. As empagliflozin safety profile is 
well established, the investigator should consider it when evaluating AE 
relationship to empagliflozin. The terms "probable", "possible", "remote", or 
"unrelated" refer to the association with the use of the investigational product, 
as defined below.  
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 directly in participant 
CRF. 
AEs associated with the use of investigational product 
AEs associated with the use of investigational product (i.e. probably or 
possibly related to treatment as defined below) are also termed Adverse Drug 
Reactions (ADRs). 

 
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Probable: AE that are considered with a high degree of certainty to be related 
to the investigational drug. An AE is considered probably related if: 
 It follows a reasonable temporal sequence to the administration of the drug. 
 It cannot be reasonably explained by the known characteristics of the 
patient subject’s clinical state, environmental factors, or other modes of 
therapy administered to the subject.  
 It follows a known pattern of response to the drug. 
Possible: AE in which the connection between the investigational drugs 
appears unlikely but cannot be ruled out with certainty. An AE may be 
considered possibly related if: 
 It follows a reasonable temporal sequence to the administration of the drug. 
 It may have been produced by the patient’s clinical state, environmental 
factors, or other modes of therapy administered to the patient. 
 
It follows a known pattern of response to the drug. 
AEs not associated with the use of investigational product 
Remote: AE that meet the following criteria: 
 It does not follow a reasonable temporal sequence to the administration of 
the drug. 
 It may readily have been produced by the subject’s clinical state, 
environmental factors, or other modes of therapy administered to the 
subject. 
 It does not follow a known pattern of response to the drug. 
Unrelated: AE that are judged to be clearly and incontrovertibly due only to 
extraneous causes, and do not meet the criteria for Probable, Possible, or 
Remote defined above. 

 
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8.2 Adverse events reporting and monitoring requirements 
8.2.1 General 
All adverse events, serious and non-serious, will be fully documented in both 
source documents and CRF, and each AE will be assessed in light of its 
clinical significance. For each adverse event, the investigator will provide the 
onset, end, intensity, treatment required, outcome, seriousness and action 
taken with the investigational drug. The investigator will determine the 
relationship to the investigational drug, i.e. causality assessment, for each AE. 
Events occurring prior to initiation of first dose should be recorded on the 
Medical History page of the CRF. Any AE occurring after initiation of the first 
dose and/or during any point throughout the study should be recorded on the 
Adverse Event page of the CRF. All adverse events occurring up to 30 days 
after the last dose of study drug administration should be captured in the 
CRF. AEs should be recorded in the CRF using the CTC AE terminology 
(short name). Whenever possible, diagnoses should be given when signs and 
symptoms are due to a common etiology. 
Occurrence of any grade 4 AE must warrant clinical evaluation by the treating 
investigator to decide whether it is considered an SAE. If it is an SAE the 
investigator should report it to the sponsor within 24 hours (see section 8.2.2 
SAE Reporting). Grade 4 AEs, which were not considered SAEs by the 
investigator, should be reviewed by the monitor who will forward them to the 
sponsor's medical monitor to approve that none of the AEs are SAEs. 
8.2.2 SAE reporting 
The PI or his designee must report to the sponsor any SAE or AESIs 
independent from their seriousness, if applicable occurring after first dose of 
study drug and up to 30 days after last dose of study drug, regardless of their 
relationship to the investigational product.  
Sponsor contact details for SAE reporting:  
______________________________________________________________ 

 
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Reports concerning SAEs and AESIs, if applicable, and pregnancy reports 
shall be forwarded to the BI Unique Entry Point in accordance with the 
following timelines: 
(i) Initial and follow-up reports concerning SAEs and AESIs, if applicable 
containing at least one (1) fatal or immediately life-threatening event within 
five (1) calendar days upon receipt, 
(ii) Initial and follow-up reports of any other SAE and AESI, if applicable 
within ten (1) calendar days upon receipt. 
(iii) Pregnancy report and outcome of pregnancy within seven (3) calendar 
days upon receipt.  
The SAE reports shall include all SAEs, AESIs (if applicable) and non-serious 
AEs which are relevant for the reported SAE or AESI and, in particular, the 
following information: 
(i) the listedness of the reported events based on BI Investigator’s Brochure 
for the Study Drug or BI Drug Information e.g. Summary of Product 
Characteristics (SmPC) or Product Information (PI) for the authorized Study 
Drug provided by BI, 
(ii) Investigator’s causal assessment as to whether the event(s) is/are related 
to the use of the Study Drug, and 
(iii) the seriousness of each AE. 
An initial report shall be completed in a  Serious Adverse Event form provided 
by the sponsor and must be faxed or emailed to rmarilus@netvision.net.il, fax: 
972-9-9540457 within 24 hours of the investigator becoming aware of the 
event, and must include SAE general description, start date, end date (if 
applicable), the reason for evaluation as a SAE, basic patient information, 
assessment of the relationship to the investigational product, expectedness, 
and study therapy information.  
When new, updated, or corrected information about a previously reported 
SAE is obtained, the SC should fill out a follow-up report and fax or email it to 

 
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the sponsor within 48 hours of receiving the FU information. Relevant 
concomitant medication and medical history CRF pages shall be included in 
the Follow-up report. Source documents to support the SAE (e.g. discharge 
summary, test results) shall be included as well.  
The SAE form used to document an SAE FU is the same form used to 
document an SAE. 
A complete SAE report (i.e. With no missing information) must be sent to the 
sponsor at the first possible date and no later than 7 calendar days after SAE 
end date.  
SAE will be recorded on designated CRF forms in a timely manner and no 
later than 7 calendar days after its end date. 
Where a SAE is followed by reports of recurrent episodes, re-exposure, 
complications or progression of the initial SAE, all such reports must be 
reported as follow-up to the original episode. If a new SAE occurring at a 
different time interval is considered completely non-associated to a previously 
reported one, a new SAE form should be submitted as an initial report.  
The PI or his designee will submit the SAE report to IRB/EC according to 
applicable local regulations. 
8.2.3 Expedited Reporting 
Expedited reporting by PI to IRB/EC is warranted for all Suspected 
Unexpected Serious Adverse Reactions (SUSAR), i.e. unexpected SAEs that 
are considered related to study product as defined in Section 8.1.5. Additional 
cases will be communicated by PI to IRB/EC via expedited reporting when 
required by local regulation. 
Any SAE, irrespective of causality, occurring in a patient after providing 
informed consent and until four weeks after ending study participation / study 
drug administration must be reported. SAEs occurring afterwards should only 
be reported if considered by the investigator attributable to the sponsor 
investigational drug(s).  
 

 
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8.2.3.1 Sponsor Reporting SUSARs to PI 
The sponsor should report all Suspected Unexpected Serious Adverse 
Reactions (SUSARs), i.e. unexpected SAEs that are considered related to 
study product as defined in Section 8.1.1, to the PI in the following timelines: 
death and other life threatening events will be reported within 7 days of the date 
the event was reported to sponsor and the rest of the SUSARs will be reported 
to the PI within 15 days. The sponsor should provide the PI with the list of 
SUSARs that occurred in all of the sites periodically, at least once every 6 
months. The report will include a summary of the main safety issues of the study 
product that came up during the reporting period.  
8.2.3.2  Reporting SUSAR to the Israeli MOH 
The sponsor should report SUSARs to the Israeli MOH in an annual 
Development Safety Update Report (DSUR), which describes all of the new 
safety information accumulated during the year. The report should include a 
summary and conclusions of the main safety issues of the study product. 
The DSUR should be sent to dsur@moh.health.gov.il within 60 days of the data 
lock. In addition, the sponsor should send the MOH the DSUR on a CD with an 
accompanying letter. The sponsor should inform the PI and the MOH of the 
following information within 7 days of receiving it:  
a. Decisions of regulatory authorities regarding the continuation of the study  
b. Any decision to discontinue the study for any reason, temporarily or 
permanently.  
All notifications to the MOH should be sent to:  
clinicaltrials.pharm@moh.health.gov.il  
Any pregnancy of a study subject or a partner of a male subject after the first 
dosing is considered an immediately reportable event. 
Such events must be reported within one (1) working day of the investigator 
becoming aware of the event. Pregnancies shall be followed for the duration of 
the pregnancy. It is the PI’s responsibility to provide to the sponsor follow-up 

 
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information on the outcome of the pregnancy including information about any 
sequelae. 
Information about all serious adverse events will be collected and recorded on 
the Serious Adverse Event Report Form.  
Additional safety examinations and procedures 
If any unclear clinical event, including symptoms, signs, or other observations 
or abnormalities, should occur, the Investigator, or any other physician in 
charge, may perform additional clinical examinations and procedures (other 
than outlined in this protocol), including any clinical, laboratory, imaging 
and/or technical testing, in order to clarify and establish the etiology and 
diagnosis of this clinical event. 
8.3 Pregnancies  
Any pregnancy of patient or patient’s spouse that occurs during study 
participation should be reported using a Clinical Trial Pregnancy Form. To 
ensure patient safety each pregnancy must also be reported to the sponsor and 
BI within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary 
termination, details of birth, and the presence or absence of any birth defects 
or congenital abnormalities or maternal and newborn complications.  
8.4 Laboratory evaluations 
Laboratory results will be reported to the investigator who will review abnormal 
laboratory findings for clinical significance. The investigator will document any 
laboratory test results that are clinically significant on the lab report and provide 
details of the relationship to investigational product and the action taken. If a 
change in a laboratory value represents a medical condition, the medical 
condition will be listed in the AE record unless this is a pre-existing medical 
condition allowed under the inclusion criteria. If no correlation is possible, the 
direction of change (increase or decrease) and the actual value will be 
recorded. 

 
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The institution will perform laboratory analyses according to the Visit Schedule 
(see Table 2). The sponsor must be provided with a copy of the laboratory’s 
certification, and a tabulation of the normal ranges for each parameter required. 
Additionally, if at any time a patient has laboratory parameters obtained from a 
different outside laboratory, the sponsor must be provided with a copy of the 
certification and a tabulation of the normal ranges for that laboratory.     
At any time during the study, abnormal laboratory parameters which are 
clinically relevant (e.g. require dose modification and/or interruption of study 
drug, lead to clinical symptoms or signs or require therapeutic intervention), 
whether specifically requested in the protocol or not, must be recorded on the 
appropriate Comment CRF page in addition to the appropriate laboratory CRF 
page. When abnormal laboratory values or test results constitute an adverse 
event (i.e., induces clinical signs/symptoms or requires therapy) they must be 
recorded on the Adverse Events CRF. 
8.4.1 Hematology 
Hematology includes assessment of Complete Blood Count (CBC) including: 
hemoglobin, white blood cell count, platelet count, and a differential count 
including: neutrophils, lymphocytes, monocytes, eosinophils, and basophils. 
Hematological evaluations (CBC) should be collected according to the Visit 
Schedule (see Table 2). 
8.4.2 Biochemistry 
The following blood chemistry results should therefore be collected according 
to the Visit Schedule (see Table 2). 
Serum Creatinine, Bun, Glucose, Sodium, Potassium, Total Protein, Albumin, 
SGOT (AST), SGPT (ALT), Alkaline Phosphatase, and Total Bilirubin. 
When, in the opinion of the investigator, other clinical laboratory evaluations 
may be relevant for assessing the patient’s status, they will be completed and 
entered into the database as appropriate.  
8.4.3 Special tests: 
N/A 

 
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8.4.4 Urinalysis  
Urinalysis will be performed according to the visit schedule (see Table 2). 
Specific gravity, pH, semi-quantitative “dipstick” evaluation of glucose, protein, 
bilirubin, ketones, leukocytes and blood. In case of findings on the urinary 
dipstick, such as leukocytes, nitrites or blood (except during menstruation for 
the female subjects), a microscopic examination including RBC/HPF, 
WBC/HPF and casts/LPF will be performed. If casts are noted, the type is to be 
specified on the relevant comments page in the CRF. A midstream urine 
sample (~ 30 mL) will be obtained, in order to avoid contamination and allow a 
proper assessment. 
8.5 Physical examinations/vital signs 
A physical examination including vital signs will be performed according to the 
Visit Schedule (see Table 2). Information about the physical examination and 
vital signs must be present in the source documentation at the study site. 
Significant findings present prior to the start of study drug must be included in 
the Relevant Medical History/Current Medical Conditions CRF. Significant 
findings made after the start of study drug, which meet the definition of an 
adverse event, must be recorded on the Adverse Event Case Report Form. 
There are no Case Report Forms to capture routine normal findings from 
physical examinations and vital signs assessments. Vital signs will include body 
temperature (°C), respiratory rate (breaths/min), pulse rate (beats/min), systolic 
and diastolic blood pressure (mmHg). 
 
 
 
 

 
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9 Statistics 
9.1 Sample size 
The primary endpoint is the percentage of PVCs during the 2 months of 
empagliflozin treatment compared with the percentage of PVC on placebo. A 
sample size of 128 patients was selected based on the estimated effect of 10% 
reduction in the rate of arrhythmic events assuming a standard deviation of 40% 
in measured values, with alpha of 0.05 and power of 0.8 (2-sided test). The 
efficacy analysis will be conducted using an as treated approach and will be 
performed using the Wilcoxon signed-rank test, p value≤0.05 will be considered 
significant. 
The rationale for sample size calculation was based on detecting a difference  
of at least 10% in the reduction in rate of arrhythmic events from baseline  
between study treatments with 80% power and 5% significance level.   
Sample size justification 
When the sample size in each sequence group is 64, (a total sample size of  
128) a 2 x 2 crossover design will have 80% power to detect a difference in  
Mean reduction of -10.0, assuming that the Crossover ANOVA MSE is 28.284  
(the Standard deviation of differences, sd, is 40.0) using a two group T-test  
(Crossover ANOVA) with a 0.05 two-sided significance level.  
Reference: 
Senn, Stephen Cross-over Trials in Clinical Research (2nd Edition) Wiley  
(2002).  
 
 

 
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9.2 Efficacy and Safety evaluation 
General 
All measured variables and derived parameters will be listed individually and, if 
appropriate, tabulated by descriptive statistics.  
For categorical variables, summary tables will be provided giving sample size, 
absolute and relative frequency and 95% CI (Confidence Interval) for 
proportions by study treatment. 
For continuous variables, summary tables will be provided giving sample size, 
arithmetic mean, standard deviation, median, minimum and maximum and 95% 
CI (Confidence Interval) for means of variables by study treatment.  
All tests will be two-tailed, and a p value of 5% or less will be considered 
statistically significant. 
The data will be analyzed using the SAS ® version 9.3 (SAS Institute, Cary 
North Carolina). 
Analysis Populations 
Safety Population: will include all randomized subjects who received any study 
drug. 
Intention-to-Treat (ITT) Population: will include all subjects included in the 
safety population who provided at least one post-baseline assessment for the 
primary endpoint. 
Per-Protocol Population: will include all subjects in the ITT population who 
complete the study in compliance with the protocol and have no major protocol 
violations. 
 
  

 
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9.2.1 Efficacy analysis:  
The primary endpoint is the percentage of PVCs during the 2 months of 
empagliflozin treatment compared with the percentage of PVC on placebo.  
The two-sample T-test or Non-parametric Wilcoxon-Mann-Whitney Rank sum 
test for independent samples (as is appropriate) will be applied for testing the 
carry-over effect in the primary endpoint between the two sequences. 
If no carry-over effect will be observed, then The Paired T-test or non-
parametric Signed-rank test for two means (as is appropriate) will be applied 
for analyzing the difference in the above changes between the tested treatment 
and placebo. 
Otherwise, if a carry-over effect will be found statistically significant, then the 
MMRM model (Mixed-effect model for repeated measures) will be applied for 
analyzing the difference in the above reduction between the tested treatment 
and the placebo. The model will included terms for study arm (sequence), 
treatment and period as fixed effects, and subject nested within study arm as a 
random effect. Other covariates (such as age and baseline measures) will be 
included if they will be found different between the groups and affecting the 
outcome.  
Secondary Endpoints: 
Frequency of non-sustained ventricular tachycardia (NSVT) episoedes and 
composite cumulative ventricular arrhythmia load will be summarized by 
treatment. 
Changes in blood level of NT-Pro Brain Natriuretic peptide (BNP), Left 
ventricular end diastolic diameter and Left ventricular ejection fraction (EF) from 
baseline will be summarized in appropriate tables by treatment.  
9.2.2 Safety Analysis: 
Data from all subjects who receive any study drug will be included in the safety 
analyses.  

 
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All adverse events will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA, most updated Version) terminology and presented in 
tables by System Organ Class (SOC) and Preferred Term (PT).  
AE data will be listed individually and summarized by SOC and by PT within a 
system organ class under each treatment. 
The severity of the toxicities will be graded according to the NCI CTCAE 
(Ver4.0) whenever possible. In the by-subject analysis, a subject having the 
same event more than once will be counted only once. Adverse events will be 
summarized by worst NCI CTC grade. Adverse events leading to death or to 
discontinuation from treatment, events classified as NCI CTCAE Grade 3 or 
Grade 4, study-drug-related events, and serious adverse events will be 
summarized separately.  
Laboratory data will be graded according to NCI CTCAE severity grade.  
Any deviations from the previously described statistical plan will be described 
and justified in a protocol amendment. 
Other safety parameters including vital signs and physical examination will be 
summarized in appropriate tables. 
Concomitant medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the 
Anatomical Therapeutic Chemical classification system.  
 
 

 
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10 Direct Access to Source Data/Documents 
Access to the subject’s source data and study documents will occur only with 
the subject’s acknowledgement and agreement by signing an informed 
consent. The investigator will permit study-related monitoring, audits, 
Institutional Review Board (IRB) review and regulatory inspection(s), providing 
direct access to source data and documents. 
10.1 Study monitoring 
The monitoring visits will enable the sponsor or the monitor acting on his behalf, 
to assess the study’s progress status, to verify the exactness and degree of 
completeness of the CRFs, to ensure that protocol as well as local regulations 
are being followed and that the investigator is fulfilling his obligations. 
Monitoring visits will also enable to correct errors in the CRFs compared to the 
source documents. The investigator will authorize the monitor, at a mutually 
convenient time during the study and after its end, to periodically review all of 
the CRFs and the related parts of administrative, medical and laboratory files 
of each participant in the study. The CRFs must be filled out before the 
monitoring visits. 
10.2 Audits 
During the study, people belonging to the sponsor quality assurance group may 
visit the investigator site in order to audit the study. The purpose of this visit is 
to check that the study is carried out according to Good Clinical Practices. 
Before conducting an audit, the monitor will contact the investigator in order to 
agree upon a mutually suitable date. The investigator and his team are required 
to cooperate with the auditors and to grant them access to the patients’ medical 
files and to the study documents (CRFs and investigator’s binders). 
 

 
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10.3 IRB and regulatory inspections 
 A regulatory authority may also wish to conduct an inspection (during the 
study or even after its completion). If an inspection is requested by a 
regulatory authority, the investigator must inform the sponsor and BI 
immediately that this request has been made. 
The Principal Investigator must obtain IRB approval for the investigation.  
Initial IRB approval, and all materials approved by the IRB for this study 
including the subject consent form and recruitment materials must be 
maintained by the Investigator and made available for inspection. 
 

 
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11 Quality Control and Quality Assurance 
Data from the CRFs are entered into the study database by Contract Research 
Organization staff following their own internal standard operating procedures 
that have been reviewed and approved by the sponsor. 
Subsequently, the entered data are systematically checked by Data 
Management staff, using error messages printed from validation programs and 
database listings.  Obvious errors are corrected by Data Management 
personnel.  Other errors or omissions are entered on Data Query Forms, which 
are returned to the investigational site for resolution.  The signed original and 
resolved Data Query Forms are kept with the CRFs at the investigator site, and 
a copy is sent to the sponsor so the resolutions can be entered into the 
database.  Quality control audits of all key safety and efficacy data in the 
database are made prior to locking the database. 

 
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12 Ethics 
12.1 Institutional Review Board 
Before implementing this study, the protocol, the proposed informed consent 
form and other information to subjects, must be reviewed by a properly 
constituted Institutional Review Board (IRB). A signed and dated statement that 
the protocol and informed consent have been approved by the IRB must be 
given to the sponsor before study initiation. The name and occupation of the 
chairman and the members of the IRB must be supplied to the sponsor. Any 
amendments to the protocol, other than administrative ones, must be approved 
by this committee. 
12.2 Informed consent 
The investigator must explain to each subject (or legally authorized 
representative) the nature of the study, its purpose, the procedures involved, 
the expected duration, the potential risks and benefits involved and any 
discomfort it may entail. Each subject must be informed that participation in the 
study is voluntary and that he/she may withdraw from the study at any time and 
that withdrawal of consent will not affect his/her subsequent medical treatment 
or relationship with the treating physician. 
This informed consent should be given by means of a standard written 
statement, written in non-technical language. The subject should read and 
consider the statement before signing and dating it, and should be given a copy 
of the signed document. If the subject cannot read or sign the documents, oral 
presentation may be made or signature given by the subject’s legally appointed 
representative, if witnessed by a person not involved in the study, mentioning 
that the patient could not read or sign the documents. No patient can enter the 
study before his/her informed consent has been obtained. 
The informed consent form is considered part of the protocol, and must be 
submitted by the investigator with it for IRB approval.  

 
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12.3 Declaration of Helsinki 
The investigator must conduct the trial in accordance with the principles of the 
Declaration of Helsinki, which can be accessed via the website of the World 
Medical Association at http://www.wma.net/e/policy/17-c_e.html. 

 
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13 Data Handling and Record Keeping  
The information resulting from the execution of the protocol will be coded into 
the eCRFs database. 
The eCRFs must be filled out on a timely basis. The data will be monitored and 
verified.  
Each eCRF will be signed and dated by the investigator or a co-investigator 
named by the former in each site and clinically responsible for the patient during 
the study. 
Access to the eCRF will be by individual passwords & according to GCP 
recommendations. 
The completed eCRFs data will be transferred by the eCRF operator to the 
sponsor & will be kept by them for at least 15 years. 
     
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 

 
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14 Financing and Insurance 
Financing and insurance will be addressed in the future in a separate 
agreement. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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15 Publication Policy 
Any formal presentation or publication of data from this trial will be considered 
as a joint publication by the investigator(s) and appropriate sponsor’s 
personnel. Authorship will be determined by mutual agreement. It is a 
multicenter study, it is mandatory that the first publication is based on data from 
all centers, analyzed as stipulated in the protocol, by the sponsor statisticians, 
and not by the investigators. Investigators participating in multicenter studies 
agree not to present data gathered from one center or a small group of centers 
before the full publication, unless formally agreed to by all other investigators 
and the sponsor. 
The investigator may be required to sign the clinical study report, if it is to be 
used in a registration submission to the health authorities of some countries. 
For multicenter studies, only the coordinating (principle) investigator nominated 
by the sponsor at the start of the trial would provide any needed signature.  
 
 

 
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References 
1. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. 
Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. The 
New England journal of medicine. 2015;373:2117-2128 
2. Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of 
diabetes for 2010 and 2030. Diabetes research and clinical practice. 
2010;87:4-14 
3. Heerspink HJ, Perkins BA, Fitchett DH, Husain M, Cherney DZ. Sodium 
glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: 
Cardiovascular and kidney effects, potential mechanisms, and clinical 
applications. Circulation. 2016;134:752-772 
4. Vasilakou D, Karagiannis T, Athanasiadou E, Mainou M, Liakos A, Bekiari E, 
et al. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: A 
systematic review and meta-analysis. Annals of internal medicine. 
2013;159:262-274 
5. Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, 
et al. Empagliflozin and progression of kidney disease in type 2 diabetes. The 
New England journal of medicine. 2016;375:323-334 
6. Ferrannini E, Seman L, Seewaldt-Becker E, Hantel S, Pinnetti S, Woerle HJ. 
A phase iib, randomized, placebo-controlled study of the sglt2 inhibitor 
empagliflozin in patients with type 2 diabetes. Diabetes, obesity & 
metabolism. 2013;15:721-728 
7. Cleland JG, Chattopadhyay S, Khand A, Houghton T, Kaye GC. Prevalence 
and incidence of arrhythmias and sudden death in heart failure. Heart failure 
reviews. 2002;7:229-242 
8. Poole JE, Johnson GW, Hellkamp AS, Anderson J, Callans DJ, Raitt MH, et 
al. Prognostic importance of defibrillator shocks in patients with heart failure. 
The New England journal of medicine. 2008;359:1009-1017 
9. Mark DB, Anstrom KJ, Sun JL, Clapp-Channing NE, Tsiatis AA, Davidson-
Ray L, et al. Quality of life with defibrillator therapy or amiodarone in heart 
failure. The New England journal of medicine. 2008;359:999-1008 
10. Aktas MK, Mittal S, Kutyifa V, McNitt S, Polonsky B, Steinberg J, et al. The 
burden and morphology of premature ventricular contractions and their impact 
on clinical outcomes in patients receiving biventricular pacing in the 
multicenter automatic defibrillator implantation trial-cardiac resynchronization 
therapy (madit-crt). Annals of noninvasive electrocardiology : the official 
journal of the International Society for Holter and Noninvasive 
Electrocardiology, Inc. 2016;21:41-48 
11. Ataklte F, Erqou S, Laukkanen J, Kaptoge S. Meta-analysis of ventricular 
premature complexes and their relation to cardiac mortality in general 
populations. The American journal of cardiology. 2013;112:1263-1270 
12. Cheriyath P, He F, Peters I, Li X, Alagona P, Jr., Wu C, et al. Relation of atrial 
and/or ventricular premature complexes on a two-minute rhythm strip to the 
risk of sudden cardiac death (the atherosclerosis risk in communities [aric] 
study). The American journal of cardiology. 2011;107:151-155 

 
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13. Kostis JB, Byington R, Friedman LM, Goldstein S, Furberg C. Prognostic 
significance of ventricular ectopic activity in survivors of acute myocardial 
infarction. Journal of the American College of Cardiology. 1987;10:231-242 
14. Lee V, Hemingway H, Harb R, Crake T, Lambiase P. The prognostic 
significance of premature ventricular complexes in adults without clinically 
apparent heart disease: A meta-analysis and systematic review. Heart (British 
Cardiac Society). 2012;98:1290-1298 
15. Lerma C, Gorelick A, Ghanem RN, Glass L, Huikuri HV. Patterns of ectopy 
leading to increased risk of fatal or near-fatal cardiac arrhythmia in patients 
with depressed left ventricular function after an acute myocardial infarction. 
Europace : European pacing, arrhythmias, and cardiac electrophysiology : 
journal of the working groups on cardiac pacing, arrhythmias, and cardiac 
cellular electrophysiology of the European Society of Cardiology. 
2013;15:1304-1312 
16. Martinez-Alanis M, Ruiz-Velasco S, Lerma C. Quantitative analysis of 
ventricular ectopic beats in short-term rr interval recordings to predict 
imminent ventricular tachyarrhythmia. International journal of cardiology. 
2016;225:226-233 
17. Mittal S, Aktas MK, Moss AJ, McNitt S, Kutyifa V, Steinberg JS, et al. The 
impact of nonsustained ventricular tachycardia on reverse remodeling, heart 
failure, and treated ventricular tachyarrhythmias in madit-crt. Journal of 
cardiovascular electrophysiology. 2014;25:1082-1087 
18. Ruwald MH, Mittal S, Ruwald AC, Aktas MK, Daubert JP, McNitt S, et al. 
Association between frequency of atrial and ventricular ectopic beats and 
biventricular pacing percentage and outcomes in patients with cardiac 
resynchronization therapy. Journal of the American College of Cardiology. 
2014;64:971-981 
19. Dukes JW, Dewland TA, Vittinghoff E, Mandyam MC, Heckbert SR, Siscovick 
DS, et al. Ventricular ectopy as a predictor of heart failure and death. Journal 
of the American College of Cardiology. 2015;66:101-109 
20. Ruskin JN. The cardiac arrhythmia suppression trial (cast). The New England 
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21. Goldstein S, Brooks MM, Ledingham R, Kennedy HL, Epstein AE, Pawitan Y, 
et al. Association between ease of suppression of ventricular arrhythmia and 
survival. Circulation. 1995;91:79-83 
22. Zang M, Zhang T, Mao J, Zhou S, He B. Beneficial effects of catheter ablation 
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(British Cardiac Society). 2014;100:787-793 
23. Santangeli P, Marchlinski FE. Ventricular ectopy as a modifiable risk factor for 
heart failure and death: "Deja vu all over again" may be a good thing. Journal 
of the American College of Cardiology. 2015;66:110-112 
 

 
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16 Supplements 
Appendix 1   Diabetes medication titration 
Researches will make an effort to prevent hypoglycemia events and 
worsening hyperglycemia at all stages of the study. All patients will receive an 
endocrinology consultation on diabetes medication titration prior to starting 
any study medication. Any changes in the diabetes treatment regimen are 
allowed apart from initiating SGLT2 inhibitors. 
The consultation will include instruction to monitor fasting glucose closely on 
the first week of each period of the study, to make changes in medication 
doses upon initiation of each study period (including a specific 
recommendation for the washout period) and in any case that glucose is over 
150 for 3 consecutive days (see details on specific medication below). This 
instruction will be repeated by the cardiologist on subsequent visits at the 
beginning of washout and at the beginning of the second treatment period.  
If at any point of the study fasting glucose is over 180 for 7 days despite 
taking the following measures – schedule emergency endocrinology 
consultation within a week.  
 
Decision to titrate depends on patient glycemic control prior to study:  
A. Patients with HbA1c over 7.5% and fasting glucose usually over 150 
with no hypoglycemia events or glucose measurements under 90 – no 
change in diabetes medications or insulin. 
  
B. Patients with fasting glucose usually under 150 or HbA1c under 7.5% - 
when oral medication (empagliflozin or placebo) is started reduce 
insulin by 20%, stop sulfonylurea and repaglinide, titrate as indicated 
below according to glucose measurements. 
 
Basal insulin 
If fasting glucose usually under 150 or HbA1c  under 7.5% - reduce by 20% 
upon initiation of study medication. Otherwise no change. 

 
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Further titration by the patient throughout study: 
If fasting glucose for 3 days is:        Basal insulin should be changed by: 
>180 mg/dL         
  increase by 4 units 
>140 mg/dL      
 
 
  increase by 2 units 
<110 mg/dL ->   
 
  decrease by 2 units 
<100mg/dL      
 
 
  decrease by 4 units 
 
If fasting glucose in even one measurement is low, reduce basal insulin: 
<90mg/dL        decrease by 4 units 
< 80 mg/dL      decrease by 6 units 
 
Prandial insulin or insulin mixes 
If preprandial noon/evening/bedtime glucose is under 100 - decrease all 
doses by 20% 
If noon+evening+bedtime glucose is over 150 for 3 days – increase dose by 
10% 
 
Sulfonylurea 
If fasting glucose under 150 mg/dL or HbA1c under 7.5%  -  stop 
Then: 
If fasting glucose over 150 for 7 days restart at half dose 
If under half dose fasting glucose over 150 for 7 days -   return to full dose 
If anytime during study glucose under 90+symptoms or under 70 without 
symptoms – stop 
 
Acarbose, DPP4 inhibitors, short acting GLP1 agonits 
No initial changes 
If hypoglycemia occurs (glucose under 90+symptoms or under 70 without 
symptoms)  stop  one medication in the following  order: GLP1 agonist/DPP4 
inhibitor, acarbose 
 
Metformin , 
No initial changes. 

 
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If hypoglycemia only on Metformin and study drug – reduce Metformin to half 
the dose