Conditions: Heart Failure
Keywords: heart failure empagliflozin Sodium-glucose Cotransporter-2 (SGLT2) Inhibitors
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 65
Healthy volunteers: no

Brief summary:
The primary purpose of this trial is to evaluate the impact of empagliflozin, as compared with placebo, on hemodynamic parameters (pulmonary artery diastolic pressure) in patients with heart failure (reduced or preserved ejection fraction, ischemic or non-ischemic etiology) who already have a CardioMEMs device (a wireless hemodynamic monitoring system) implanted for non-study related clinical reasons.

Detailed description:
A 12-week randomized, double-blind, placebo-controlled trial to explore the effects of once-daily empagliflozin 10 mg on hemodynamic parameters (pulmonary artery pressures) in patients with heart failure (reduced or preserved ejection fraction, ischemic or non-ischemic etiology) who already have a CardioMEMs device implanted for non-study related clinical reasons.

Arms:
arm 1: Empagliflozin 10 mg tab, once daily, for 12 weeks arm 2: Empagliflozin matching placebo oral tablet, once daily for 12 weeks

Interventions: intervention 1: Empagliflozin 10 mg Tab intervention 2: Placebo Oral Tablet
Intervention descriptions: intervention 1: Empagliflozin 10 mg Tab intervention 2: Empagliflozin matching placebo

Protocol document:
Prot_000.pdf: 
Protocol 
 
Protocol Title:  EMpagliflozin evaluation By measuRing 
ImpAct on HemodynamiCs in PatiEnts with Heart Failure 
(EMBRACE-HF) 
 
Protocol Number: 1245.129 
 
ClinicalTrials.gov registration:  NCT03030222 
 
Version:  
 
2 
 
Version Date:    September 24, 2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of 69 


EMBRACE-HF Protocol  v2.0                                                                                                         Page 2 of 69 
 
PROTOCOL SYNOPSIS 
A 12-week randomized, double-blind, placebo-controlled trial to explore the effects of empagliflozin on 
hemodynamic parameters (pulmonary artery pressures) in patients with heart failure (HF) (reduced or 
preserved ejection fraction, ischemic or non-ischemic etiology) who already have a CardioMEMs device 
implanted for non-study related clinical reasons. 
Study Hypothesis 
The trial will test a hypothesis that empagliflozin is superior to placebo in lowering pulmonary artery 
pressures in patients with HF.  
 
 
 
 
 
 
Study Centers and Number of Patients Proposed 
Up to 15 medical centers in the US will participate in the study, with competitive enrollment planned. 
Approximately 60 patients will be randomized over a target enrollment period of approximately 24 
months. 
 
Study Period 
 
Phase of Development 
Estimated date of first patient enrolled 
July 5th, 2017 
IV (post marketing) 
Estimated date of last patient completed 
May 31st, 2019 
IV (post marketing) 
 
Primary Objective 
To evaluate the effects of empagliflozin 10 mg daily on hemodynamic parameters (pulmonary artery 
diastolic pressure) in patients with heart failure (HF) (reduced or preserved ejection fraction, ischemic 
or non-ischemic etiology). 
 
Target Population 
Male and female patients with heart failure (HF) (reduced or preserved ejection fraction, ischemic or 
non-ischemic etiology) who already have a CardioMEMs implanted for non-study related clinical 
reasons. 
Investigational Product, Dosage, and Mode of Administration 
Empagliflozin 10 mg administered orally once daily for 12 weeks, in addition to standard of care for 
chronic heart failure. 
 


EMBRACE-HF Protocol  v2.0                                                                                                         Page 3 of 69 
 
Comparator, Dosage and Mode of Administration 
Matching placebo administered orally once daily for 12 weeks, in addition to standard of care for 
chronic heart failure. 
 
Study Duration 
Activation of all study sites is expected to take 6 months, followed by approximately 24 months to 
reach complete study enrollment. After randomization, empagliflozin or placebo will be administered 
for 12 weeks. At week 13 there will be a final study visit. Total study duration (after enrollment of the 
first patient) is approximately 33 months. 
 
Primary Endpoint 
Change in pulmonary artery diastolic pressure from baseline to end of treatment period (defined as average 
of pulmonary artery diastolic pressure measurements between weeks 8-12)  
 
Secondary Endpoints 
1. Change from baseline in pulmonary artery diastolic pressure at each interim time point (weeks 1, 
2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) 
2. Change in pulmonary artery systolic pressure from baseline to end of treatment period  
3. Change from baseline in pulmonary artery systolic pressure at each interim time point (weeks 1, 2, 
3, 4, 5, 6, 7, 8, 9, 10, 11 and 12)  
4. Change in mean pulmonary artery pressure from baseline to end of treatment period 
5. Change from baseline in mean pulmonary artery pressure at each interim time point (weeks 1, 2, 3, 
4, 5, 6, 7, 8, 9, 10, 11 and 12) 
6. Change in heart failure related quality of life using the Kansas City Cardiomyopathy Questionnaire 
(KCCQ) overall summary score from baseline to follow-up (defined as average of measurements at 6 
and 12 weeks).  
7. Proportion of patients with a ≥ 5pt increase from baseline in the Kansas City Cardiomyopathy 
Questionnaire (KCCQ) at either 6 weeks or 12 weeks of follow-up  
8. Change in 6-minute walk test from baseline to follow-up (defined as average of measurements at 6 
and 12 weeks) 
9. Change in NTproBNP from baseline to follow-up (defined as average of measurements at 6 and 12 
weeks) 
10. Change in BNP from baseline to follow-up (defined as average of measurements at 6 and 12 weeks) 
11. Proportion of patients with a ≥ 20% decrease from baseline in NTproBNP at either 6 weeks or 12 
weeks of follow-up. 


EMBRACE-HF Protocol  v2.0                                                                                                         Page 4 of 69 
 
12. Proportion of patients with a ≥ 20% decrease from baseline in BNP at either 6 weeks or 12 weeks 
of follow-up. 
13. Proportion of patients with both a ≥ 5pt increase from baseline in KCCQ and a ≥ 20% decrease from 
baseline in NTproBNP at either 6 weeks or 12 weeks of follow-up 
14. Number of diuretic medication adjustments during the treatment period (up-titration and down-
titration of diuretic doses to be evaluated separately) 
15. Change in Hemoglobin A1c from baseline to follow-up (defined as average of measurements at 6 and 
12 weeks), evaluated separately in patients with and without type 2 diabetes 
 
Exploratory Endpoints 
1. 
Change in pulmonary artery diastolic pressure between week 12 and week 13 
2. 
Change in mean pulmonary artery pressure between week 12 and week 13  
3. 
Change in pulmonary artery systolic pressure between week 12 and week 13 
4. 
Change in mean heart rate from baseline to end of treatment period 
5. 
Effects on average weekly loop diuretic dose (furosemide equivalent).  
6. 
Effects on hospitalizations for heart failure.  
7. 
Effects on urgent outpatient heart failure visits. 
8. 
Effects on hospitalizations for heart failure and urgent outpatient visits for heart failure 
9. 
Change in NYHA Class at 6 weeks from baseline and 12 weeks from baseline. 
10. 
Change in NTproBNP and KCCQ at 6 weeks from baseline and 12 weeks from baseline 
11. 
Number of medication adjustments other than diuretics (nitrates, hydralazine, ACE, ARB, b-
blockers, sacubitril/valsartan) during the treatment period 
12. 
Proportion of patients that progress to diabetes during the treatment period (within the 
subgroup of patients without diabetes at baseline only) 
 
Safety Variables 
1. 
All cause death 
2. 
Cardiovascular death 
3. 
Non-fatal myocardial infarction (MI) 
4. 
Stroke 
5. 
Acute kidney injury (defined as doubling of serum creatinine based on the modified RIFLE 
criteria) 
6. 
Adverse events (AEs) and serious adverse events (SAEs). AEs of special interest will include 
diabetic ketoacidosis (DKA), volume depletion (defined as hypotension, syncope, orthostatic 
hypotension or dehydration), non-traumatic lower limb amputations, and severe hypoglycemic 
events. 


EMBRACE-HF Protocol  v2.0                                                                                                         Page 5 of 69 
 
Statistical Methods 
Baseline demographic and clinical data will be described between treatment and placebo study arms as 
mean ± standard deviation for continuous variables and compared using Student’s T-test. Whereas discrete 
variables will be represented as a number and (%) and compared using the χ2 or Fisher’s exact test, as 
applicable.  
The time course of continuous variables will be presented using standard descriptive summary statistics 
calculated at each scheduled measuring time point and the last individual measuring time point. Moreover, 
standard descriptive summary statistics will be calculated for the change (absolute or percent) from 
baseline to each scheduled measuring time point after baseline and the last individual measuring time 
point. 
 
The primary endpoint of this study is the change in pulmonary artery diastolic pressure from baseline to end 
of treatment period (defined as average of pulmonary artery diastolic pressure measurements between 
weeks 8-12).  This will be analyzed using a repeated measures model incorporating a within-patient 
covariance structure to estimate the effect of treatment, and adjusted for diabetes status. 
A sample size of 28 patients for each group will achieve 80% power with α=0.05 to detect a 20% difference 
in pulmonary artery diastolic pressure between the empagliflozin 10 mg and placebo groups averaged over 
four repeated measures (weeks 8 through 12) assuming the following:  1) between-patient standard 
deviation = 6; 2) Within patient correlation between adjacent time points: 0.7; 3) PA diastolic pressure in 
the intervention arm of the trial will achieve a plateau by week 9 for the treatment group. Thus, the 
proposed sample size is 60 patients (30 per arm with 1:1 randomization ratio).  
Of note, participation of patients with and without Type 2 diabetes is allowed, but proportion of 
patients with diabetes may be capped at no more than 67% (40 patients) of the entire cohort. 
Statistical significance will be defined using two-sided tests with α=0.05, unless otherwise specified. All 
statistical analyses will be performed by the 
 Department of 
Biostatistics using SAS version 9.4 (SAS Institute, Cary, North Carolina). 
 
 
 


EMBRACE-HF Protocol  v2.0                                                                                                         Page 6 of 69 
 
Contents 
Protocol Synopsis………………………………………………………………………………………………..…………………………………..….2 
1 
INTRODUCTION ....................................................................................................................................... 12 
1.1 
Background and Significance .......................................................................................................... 12 
1.2 
Research Hypothesis ....................................................................................................................... 14 
1.3 
Rationale for conducting this study ................................................................................................ 14 
1.4 
Benefit/risk and ethical assessment ............................................................................................... 15 
1.4.1 
Risk Category .......................................................................................................................... 15 
1.4.2 
Potential Risks ......................................................................................................................... 15 
1.4.3 
Protection against Risks .......................................................................................................... 16 
1.4.4 
Benefit to Patients .................................................................................................................. 17 
1.4.5 
Informed Consent and Alternatives to Patients ..................................................................... 17 
1.4.6 
Conclusion ............................................................................................................................... 17 
2 
Study Objective ....................................................................................................................................... 17 
2.1 
Primary Objective ........................................................................................................................... 17 
2.1.1 
Secondary Objectives .............................................................................................................. 17 
2.1.2 
Exploratory objectives ............................................................................................................ 18 
2.1.3 
Safety topics ............................................................................................................................ 19 
3 
Study Plan and Procedures ..................................................................................................................... 19 
3.1 
Study Design ................................................................................................................................... 19 
3.2 
Study Procedures ............................................................................................................................ 19 
3.3 
Definition of Active Treatment ....................................................................................................... 22 
3.4 
Definition of Control Arm ............................................................................................................... 22 
3.5 
Overall Study Duration.................................................................................................................... 22 
4 
Study Population ..................................................................................................................................... 22 
4.1 
Inclusion criteria ............................................................................................................................. 22 


EMBRACE-HF Protocol  v2.0                                                                                                         Page 7 of 69 
 
4.2 
Exclusion criteria ............................................................................................................................. 23 
5 
Study Conduct ......................................................................................................................................... 24 
5.1 
Restrictions during the study .......................................................................................................... 24 
5.2 
Patient enrollment and randomization .......................................................................................... 25 
5.3 
Procedures for randomization ........................................................................................................ 25 
5.4 
Procedures for handling incorrectly enrolled or randomized patients .......................................... 25 
5.5 
Blinding and procedures for unblinding the study ......................................................................... 26 
5.5.1 
Methods for ensuring blinding ............................................................................................... 26 
5.5.2 
Methods for unblinding the study .......................................................................................... 26 
5.6 
Treatments ...................................................................................................................................... 27 
5.6.1 
Identity of study medication ................................................................................................... 27 
5.6.2 
Doses and treatment regimens .............................................................................................. 27 
5.6.3 
Drug Dispensing Scheme ........................................................................................................ 27 
5.6.4 
Duration of treatment ............................................................................................................ 27 
5.6.5 
Labeling ................................................................................................................................... 27 
5.6.6 
Storage .................................................................................................................................... 28 
5.6.7 
Medication Adjustment Protocol ........................................................................................... 28 
5.7 
Concomitant and post-study treatments ....................................................................................... 30 
5.7.1 
Recording of concomitant medication ................................................................................... 30 
5.8 
Treatment Compliance ................................................................................................................... 31 
5.8.1 
Accountability ......................................................................................................................... 31 
5.9 
Discontinuations of study medication ............................................................................................ 31 
5.9.1 
General discontinuation criteria ............................................................................................. 31 
5.9.2 
Study-specific discontinuation criteria ................................................................................... 31 
5.9.3 
Procedures for permanent discontinuation of a patient from study medication .................. 32 


EMBRACE-HF Protocol  v2.0                                                                                                         Page 8 of 69 
 
5.9.4 
Patient agrees to undergo the Premature Treatment Discontinuation Visit and then continue 
in-person study visits .............................................................................................................................. 32 
5.9.5 
Patient refuses to continue in-person study visits but agrees to undergo modified follow-
up………………………………………………………………………………………………………………………………………………………32 
5.9.6 
Patient refuses any form of follow-up .................................................................................... 32 
5.9.7 
Restart of study medication .................................................................................................... 32 
5.9.8 
Study Closure Visit .................................................................................................................. 32 
5.10 
Withdrawal from study ................................................................................................................... 33 
5.10.1 
Patients permanently discontinuing from study medication should be given conventional 
therapy, if applicable, and should always be asked to continue to attend protocol visits .................... 33 
5.11 
Study committees ........................................................................................................................... 33 
5.11.1 
Steering Committee ................................................................................................................ 33 
5.11.2 
Clinical Endpoint Adjudication Committee (CEC) ................................................................... 33 
5.11.3 
Independent Data and Safety Monitoring Committee (IDSMC) ............................................. 33 
6 
Collection of Study Variables .................................................................................................................. 34 
6.1 
Recording of data ............................................................................................................................ 34 
6.2 
Data Collection at enrollment and follow-up ................................................................................. 34 
6.2.1 
Screening Visit Procedures (Visit S) ........................................................................................ 35 
6.2.2 
Randomization Visit (Visit 1) ................................................................................................... 35 
6.2.3 
Daily after randomization for 12 weeks ................................................................................. 35 
6.2.4 
Visit 2, 3, 4 and 6 (phone visits) .............................................................................................. 35 
6.2.5 
Visit 5 and 7 (office visits) ....................................................................................................... 36 
6.2.6 
Visit 8 (Study Closure Visit) ..................................................................................................... 36 
6.2.7 
Premature Treatment Discontinuation Visit (PTDV)............................................................... 36 
6.3 
Patient Monitoring During Study Visits .......................................................................................... 37 
6.3.1 
Physical examination .............................................................................................................. 37 
6.3.2 
Phone Visits ............................................................................................................................. 37 


EMBRACE-HF Protocol  v2.0                                                                                                         Page 9 of 69 
 
6.4 
Vital signs ........................................................................................................................................ 38 
6.4.1 
Pulse and blood pressure ........................................................................................................ 38 
6.4.2 
Orthostatic blood pressure ..................................................................................................... 38 
6.4.3 
Supine BP and pulse ................................................................................................................ 38 
6.4.4 
Standing BP and pulse ............................................................................................................. 38 
6.5 
Six Minute Walk Test ...................................................................................................................... 38 
6.6 
Collection of Kansas City Cardiomyopathy Questionnaire (KCCQ) ................................................. 39 
6.7 
Laboratory assessments .................................................................................................................. 39 
7 
Biological Sampling Procedures .............................................................................................................. 39 
7.1 
Volume of blood ............................................................................................................................. 39 
7.2 
Handling, storage and destruction of biological samples ............................................................... 39 
8 
Safety ...................................................................................................................................................... 40 
8.1 
Definition of adverse events (AE) ................................................................................................... 40 
8.2 
Definitions of serious adverse event (SAE) ..................................................................................... 40 
8.2.1 
Classification of Death ............................................................................................................ 40 
8.2.2 
Universal classification of Myocardial Infarction (MI) ............................................................ 40 
8.2.3 
Definition of Stroke ................................................................................................................. 40 
8.2.4 
Primary ischemic stroke .......................................................................................................... 40 
8.2.5 
Primary hemorrhagic stroke ................................................................................................... 41 
8.2.6 
Unclassified stroke .................................................................................................................. 41 
8.2.7 
Hospitalizations for heart failure ............................................................................................ 41 
8.3 
Definitions of adverse events of special interest (AESI) ................................................................. 41 
8.3.1 
Acute kidney injury (Decreased renal function) ..................................................................... 41 
8.3.2 
Metabolic acidosis, ketoacidosis and diabetic ketoacidosis (DKA) ......................................... 41 
8.3.3 
Volume Depletion ................................................................................................................... 42 
8.3.4 
Severe Hypoglycemia .............................................................................................................. 43 


EMBRACE-HF Protocol  v2.0                                                                                                         Page 10 of 69 
 
8.3.5 
Non-Traumatic Lower limb Amputation ................................................................................. 43 
8.4 
Recording of adverse events........................................................................................................... 43 
8.4.1 
Collection of Adverse Events .................................................................................................. 43 
8.4.2 
Follow-up of unresolved Adverse Events ................................................................................ 43 
8.4.3 
Variables ................................................................................................................................. 43 
8.4.4 
Causal Relationship of Adverse Event ..................................................................................... 44 
8.4.5 
Adverse Events based on signs and symptoms ...................................................................... 45 
8.4.6 
Adverse Events based on examinations and tests .................................................................. 45 
8.5 
Reporting of serious adverse events .............................................................................................. 45 
8.5.1 
Reporting of serious adverse events to FDA and 
 .... 46 
9 
Ethical and Regulatory Requirements .................................................................................................... 47 
9.1 
Ethical conduct of the study ........................................................................................................... 47 
9.2 
Subject data protection .................................................................................................................. 47 
9.3 
Ethics and regulatory review .......................................................................................................... 47 
9.4 
Informed consent ........................................................................................................................... 47 
9.5 
Changes to the protocol and informed consent form .................................................................... 48 
9.6 
Audits and inspections .................................................................................................................... 48 
9.7 
Posting of information on clinicaltrials.gov .................................................................................... 48 
10 
Study Management by 
 .............................................................. 48 
10.1 
Pre-study activities.......................................................................................................................... 48 
10.2 
Training of study site personnel ..................................................................................................... 49 
10.3 
Monitoring of the study .................................................................................................................. 49 
10.4 
Source data ..................................................................................................................................... 49 
10.5 
Study agreements ........................................................................................................................... 49 
10.6 
Archiving of study documents ........................................................................................................ 49 
10.7 
Study timetable and end of study................................................................................................... 49 


EMBRACE-HF Protocol  v2.0                                                                                                         Page 11 of 69 
 
11 
Data Management by 
 ................................................................ 50 
12 
Statistical Methods and Sample Size Determination .......................................................................... 50 
12.1 
Description of analysis sets ............................................................................................................. 50 
12.1.1 
Efficacy analysis set ................................................................................................................. 50 
12.1.2 
Safety analysis set ................................................................................................................... 50 
12.2 
Methods of statistical analyses ....................................................................................................... 50 
12.2.1 
Primary endpoint .................................................................................................................... 51 
12.2.2 
Secondary endpoints .............................................................................................................. 51 
12.2.3 
Exploratory endpoints ............................................................................................................ 52 
12.2.4 
Safety variables ....................................................................................................................... 53 
12.2.5 
Analysis for safety ................................................................................................................... 53 
12.3 
Determination of sample size ......................................................................................................... 53 
13 
Important Medical Procedures to be Followed by the Investigator .................................................. 53 
13.1 
Medical emergencies and 
 Contacts .............................................................. 53 
13.2 
Overdose ......................................................................................................................................... 54 
13.3 
Pregnancy ....................................................................................................................................... 54 
14 
References .......................................................................................................................................... 54 
15 
Appendix A: Heart Failure hospitalization/URGENT outpatient visit ................................................. 57 
16 
Appendix B: Kansas city cardiomyopathy questionnaire (kccq) ......................................................... 59 
17     APPENDIX C: STORAGE CONDITIONS FOR THE TRIAL MEDICATION ................................. 63 
18     Appendix D: Principal investigator signature ................................................................................. 69 
 
 
 


EMBRACE-HF Protocol  v2.0                                                                                                         Page 12 of 69 
 
 
1 INTRODUCTION 
1.1 
Background and Significance 
The prevalence of both heart failure and type 2 diabetes or prediabetes are reaching epidemic proportions 
globally and in the United States.1 In a post hoc analysis of PARAGIDM-HF - a contemporary clinical trial of 
patients with heart failure and reduced ejection fraction (HFrEF), even among patients who reported no 
known history of T2DM, 49% had prediabetes, and 21% had unrecognized T2DM based on hemoglobin A1c 
(HbA1c) criteria.2  In recent clinical trials, HF has emerged as the most common cardiovascular (CV) 
complication of T2DM, exceeding the incidence of myocardial infraction or stroke.3  In addition to being 
common, incident HF is also arguably the most morbid cardiovascular complication of T2DM, with survival 
of less than 25% over 5 years among older T2D patients.4  
The intersection of T2DM, prediabetes and HF is quickly becoming a public health crisis, and despite these 
alarming statistics, remarkably little is known on the optimal strategies of managing patients with 
prediabetes, T2DM and HF. To date, no single class of glucose-lowering medications has been specifically 
tested for safety in heart failure patients. Furthermore, several existing classes of glucose-lowering 
medications present potential safety issues, specifically in terms of volume overload and hospitalizations 
for heart failure. Foremost among these classes are thiazolidinediones (TZDs)5-7 and, possibly, dipeptidyl 
peptidase (DPP-4), according to results of the SAVOR and EXAMINE clinical trials.8,9  Other classes of 
glucose-lowering medications (insulin and sulfonylureas) may lead to weight gain and hypoglycemic 
events10, which potentially impact heart failure symptoms. As a result, evidence-based recommendations 
are currently unavailable for optimal type 2 diabetes or prediabetes management in patients with heart 
failure. 
Sodium glucose cotransporter type 2 inhibitors (SGLT-2i) appear to be the most promising therapy to date 
for patients with HF. While they produce relatively modest HbA1c reduction, SGLT-2i exhibit a novel, 
entirely insulin-independent mode of action through increased urinary excretion of glucose.11 SGLT-2i may 
represent a transformational treatment for patients with HF and T2DM, as they are the first class of 
glucose-lowering agents ever to demonstrate a robust benefit for reducing HF hospitalizaions.11-13 The 
EMPA-REG OUTCOME trial randomized 7,020 patients with T2DM and established CV disease to 10 or 25 
mg of empagliflozin vs. placebo. After a median 3.1 years, significantly fewer patients in the empagliflozin 
group than in the placebo group experienced the primary outcome of MACE (10.5% vs. 12.1%), CV-related 
death (3.7% vs. 5.9%), or all-cause death (5.7% vs. 8.3%).13 There was no difference in outcomes between 
the10 and 25 mg doses of empagliflozin, with both dosage being statistically significantly superior to 
placebo for primary and secondary endpoints. 13 Though the trial was predominantly of diabetic patients 
with coronary artery disease (with only 10% of patients having known history of HF at baseline), the 
majority of the benefit appeared to be due to the highly significant reduction in hospitalizations for heart 
failure (a 35% relative risk reduction), and prevention of HF-related and arrhythmia-related deaths. The 
relative risk reduction in HHF was statistically similar between those with and without a history of HF; 
however, since overwhelming majority of patients did not have HF at baseline, this appeared to represent 
primarily a HF prevention effect.14 


EMBRACE-HF Protocol  v2.0                                                                                                         Page 13 of 69 
 
Supporting a class effect for SGLT-2i benefit on hospitalizations for HF, are similar results in the 
Canagliflozin Cardiovascular Assessment Study (CANVAS Program). The CANVAS Program was a 
combination of CANVAS, the original canagliflozin cardiovascular safety trial, which was used to gain FDA 
approval in 2013, and a separate CANVAS-R trial, which was combined with CANVAS for the purpose of 
demonstrating cardiovascular benefit. The CANVAS program enrolled a total of 10,142 patients with 
established CVD (65%) or at high risk of CV events (35%), randomized to canagliflozin (100 mg or 300 mg) 
or placebo.15 The primary outcome (nonfatal myocardial infarction or stroke, or CV-related death) occurred 
significantly less frequently with canagliflozin than with placebo (26.9 vs. 31.5 per 1000 patient-years).12 
While the reduction in CV and all-cause death with canagliflozin vs. placebo did not reach statistically 
significance, patients in the pooled canagliflozin arm experienced a significant  33% relative risk reduction 
in HHF.12 Real world data from a large multi-national non-interventional study, which combined data from 
well-established registries across 6 countries also supports the notion of a class benefit for SGLT-2i and HF 
outcomes. The CVD-REAL study analyzed over 300,000 T2DM patients and compared the HF outcomes in 
patients being newly initiated on SGLT-2is versus those being started on other glucose lowering 
medications. The main analysis (matched 1:1 using propensity score methodology), demonstrated a 39% 
relative risk reduction in HF hospitalizations associated with SGLT-2i use vs. other glucose-lowering drugs.16 
These reductions were also observed for the outcome of total HF events, and were consistent in patients 
with and without established HF.17  
While the excitement surrounding SGLT-2is as potential therapeutic class for the management of HF is 
warranted, many questions remain unanswered. It is unclear if the reduction in heart failure 
hospitalizations seen with SGLT-2is to date – which is primarily a signal for HF prevention, will also 
translate to a clinical benefit in patients with established HF, including patients with heart failure and 
reduced ejection fraction (HFrEF). Also given that patients without diabetes (including those with 
prediabetes) would also be expected to have some degree of glucosuria with SGLT-2i treatment, and that 
the CV benefits of SGLT-2i appear to be unrelated to either baseline HbA1c or change in HbA1c, it is 
possible that the potentially beneficial effects of SGLT-2i on reducing HHF may translate to those without 
T2DM.18Additionally, the mechanisms of action (MOA) through which SGLT-2 inhibitors may produce a 
benefit on HF remain unclear, and need further clarification.  
While the change in hemodynamic status (reflected by pulmonary artery pressures) is a critically important 
predictor of HF symptoms, HF hospitalizations and mortality19,20, no data currently exist in regards to the 
impact of SGLT2i on these parameters in patients with HF. One of the key reasons for this lack of data is the 
inability (until now) to reliably and non-invasively monitor pulmonary artery pressure in patients with 
T2DM and HF. CardioMEMS (Figure 1), a wireless hemodynamic monitoring system, approved in both U.S. 
and Europe for management of patients with symptomatic HF, is the first means to obtain hemodynamics 
wirelessly21. CardioMEMS is delivered through a catheter-based system and permanently implanted in the 
pulmonary artery. It is powered externally and has a pressure sensor (uses nanometer deflections) to 
provide continuous stream of hemodynamic data (Figure 2) through a wireless communication with a 
home receiver. The hemodynamic data is streamed to the physician through a secure database. 
Management using CardioMEMS hemodynamic data has been shown, in the CHAMPION trial22-24, to 
decrease hospitalizations for NYHA class III heart failure patients compared to management based on 
clinical information without CardioMEMS. Based on its effectiveness in decreasing hospitalizations in HF 


EMBRACE-HF Protocol  v2.0                                                                                                         Page 14 of 69 
 
patients and excellent safety profile, many patients have already had the CardioMEMS system implanted 
for HF management. Based on the existing epidemiologic data, and based on data from the CHAMPION 
trial, at least half of these HF patients likely have diabetes.  
This presents a unique and previously unavailable opportunity to better understand the impact of 
empagliflozin on the hemodynamic profile of patients (with or without T2DM) and HF, and provide key 
mechanistic insights into the empagliflozin effects on prevention of HF hospitalization and reduction in CV 
mortality seen in EMPA-REG Outcomes study13. Given the known link between filling pressures and risk of 
HF hospitalizations, further investigation in this field has substantial mechanistic and clinical importance. 
Therefore, we propose to perform a pilot randomized clinical trial to evaluate the effects of empagliflozin 
on filling pressures (pulmonary artery pressures) in patients (with or without type 2 diabetes) that have 
chronic heart failure. 
 
Figure 1: CardioMEMS device. 
 
 
Figure 2: Sample of CardioMEMS PA pressure continuous wave 
 
 
 
 
 
 
1.2 
Research Hypothesis 
Treatment with empagliflozin 10 mg daily for 12 weeks will produce greater reductions in pulmonary 
artery diastolic pressure as compared with placebo in patients with chronic heart failure. 
1.3 
Rationale for conducting this study 
This is a Phase IV study that will present a unique and previously unavailable opportunity to better 
understand the impact of empagliflozin on the hemodynamic profile of patients with HF, and provide 
key mechanistic insights into the empagliflozin effects on prevention of HF hospitalization and 
reduction in CV mortality seen in EMPA-REG Outcomes study. 
 


EMBRACE-HF Protocol  v2.0                                                                                                         Page 15 of 69 
 
1.4 
Benefit/risk and ethical assessment 
Empagliflozin is approved for the treatment of type 2 diabetes, therefore patients enrolled in the study 
that have type 2 diabetes will have an established indication for empagliflozin therapy. Although 
empagliflozin is currently not approved in patients without diabetes, when empagliflozin is used either 
as monotherapy or in addition to metformin, it does not cause excess hypoglycemia as compared with 
placebo. No additional safety issues (beyond those observed with empagliflozin in patients with Type 2 
diabetes) are anticipated in patients without diabetes treated with empagliflozin. Of note, several large 
cardiovascular outcome trials are currently evaluating various SGLT-2i as potential therapies for HF, 
and include patients with and without diabetes.25-27 
Moreover, we will target patients with previously implanted CardioMEMs pulmonary artery pressure 
monitor for a clinical indication unrelated to the study, thus avoiding exposure of patients to an 
invasive procedure for the purposes of the study. Accordingly, we consider the benefit/risk balance to 
patients enrolled in the study to be similar to that encountered in the usual clinical practice, with no 
additional ethical concerns. 
1.4.1 
Risk Category 
Considering empagliflozin‘s mechanism of action, the previous clinical experience with empagliflozin, 
the study’s design features (including the inclusion, exclusion, and discontinuation criteria), and the 
planned safety procedures, participation in this study presents a minimal and thus acceptable risk to 
the individual patients that will be included. 
1.4.2 
Potential Risks 
The potential risks associated with empagliflozin that have been identified based upon the mechanism 
of action, the preclinical results, and the clinical experience to date, as well as precautions included in 
the Phase III program to monitor and/or minimize these risks, are included in the empagliflozin 
prescribing information. 28 
In the overall pooled analysis in the phase III clinical studies, 17.3% of patients discontinued the drug 
due to adverse events. In clinical Phase III studies, events suggestive of genital fungal infections were 
reported in higher proportion of empagliflozin-treated patients than the placebo group and this can be 
explained by increased urinary glucose. Overall there were no imbalances of liver function test 
parameters between empagliflozin and placebo in Phase III studies.  
Due to the diuretic effect of empagliflozin, volume depletion (dehydration, hypovolemia and/or 
hypotension) is a potential concern. In the clinical program, from which subjects who in the judgment 
of investigator may be at risk of dehydration or volume depletion were excluded, very few serious 
events related to volume depletion were reported, and they were equally distributed between 
empagliflozin and placebo groups. In the EMPA-REG Trial – the largest large empagliflozin study to date 
- there was no difference in hypovolemia events between empagliflozin and placebo. Of note, all 
patients in this study will have symptomatic heart failure and elevated pulmonary artery pressures at 
baseline, which will further minimize the risk of hypovolemic adverse events. 
The U.S. Food and Drug Administration (FDA) on Dec 4th 2015 reported a warning for sodium-glucose 
cotransporter-2 (SGLT2) inhibitors which may lead to ketoacidosis, a serious condition where the body 
produces high levels of blood acids called ketones that may require hospitalization. At the time of this 
report there were 73 cases of acidosis reported as diabetic ketoacidosis (DKA), ketoacidosis, or ketosis 
in patients treated with SGLT2 inhibitors, only 4 patients were on empagliflozin.29 DKA, a subset of 
ketoacidosis or ketosis in diabetic patients, is a type of acidosis that usually develops when insulin 
levels are too low or during prolonged fasting. DKA most commonly occurs in patients with type 1 
diabetes and is usually accompanied by high blood sugar levels. The FDA reported cases were not 


EMBRACE-HF Protocol  v2.0                                                                                                         Page 16 of 69 
 
typical for DKA because most of the patients had type 2 diabetes and their blood sugar levels, when 
reported, were only slightly increased compared to typical cases of DKA. Factors identified in some 
reports as having potentially triggered the ketoacidosis included major illness, reduced food and fluid 
intake, and reduced insulin dose. The risk of euglycemic DKA is estimated to be very low in this study 
(given the small sample size, short duration of treatment, and the fact that patients without diabetes 
are likely not at risk for DKA) and provided that EMPA-REG study showed no difference in DKA 
incidence between the Empagliflozin and the placebo arms, and a recent meta analysis of all SGLT-2 
inhibitors in patients with type 2 DM, showed no significant increase in the risk of DKA.29  Nevertheless, 
out of an abundance of caution all patients will be provided with home urine ketone testing kits and 
patients will be monitored for symptoms of DKA during in-person visits and study-related phone calls. 
Patients will be instructed to self-test for urine ketones and directed to the closest emergency 
department if the urine ketone test is more than mildly positive. The instances of DKA (if any) will be 
closely monitored as AE of special interest by the study investigators, as well as the Independent Data 
and Safety Monitoring Committee. In addition, all patients that have T2D in this study will continue 
taking glucose-lowering medications (other than open-label SGLT-2 inhibitors) as background therapy. 
These drugs are widely used anti-hyperglycemic treatments and will be prescribed according to the 
approved label. 
Moreover, the FDA also reported a warning for SGLT2 inhibitors that might lead to serious urinary tract 
infections. However in the Phase III clinical studies, and in the more than 7000 patient EMPA-REG 
Outcome Trial,13 there was no difference in urinary tract infections overall - or complicated urinary 
tract infections specifically - between empagliflozin and placebo, both occurring at low rate.  
The US FDA has issued a more recent safety alert in regards to SGLT2-inihibtors and potential risk for 
acute kidney injury. However, in the large randomized EMPA-REG outcome trial, there was no 
difference in acute kidney injury between empagliflozin and placebo, and patients treated with 
empagliflozin experienced significantly better renal outcomes long term.  Similarly, data from other 
SGLT-2 inhibitor trials have confirmed no difference in acute kidney injury, and the long term 
nephroprotective benefits of SGLT-2 inhibitors in patients with type 2 DM.30 We plan to monitor renal 
function carefully in the EMBRACE-HF study, and doubling of serum creatinine is a safety variable that 
is being carefully ascertained; furthermore, all patients in EMBRACE-HF Trial are volume overloaded at 
baseline given the requirement for significantly elevated PA diastolic pressure, and therefore should be 
at low risk for hypovolemic events. Additionally all patients will have invasive hemodynamic 
monitoring as a part of their routine clinical care, which should decrease a possibility of significant 
volume depletion and acute kidney injury due to pre-renal etiology. The Independent Safety and Data 
Monitoring Committee will also be reviewing safety data continuously. 
Thus, the benefits and risks associated with the background medication and comparator treatment are 
well established and presented in their respective approved prescribing information. No study 
procedure will put patients at a risk beyond those ordinarily encountered during the performance of 
routine medical examinations or routine tests. 
1.4.3 
Protection against Risks 
This study has been designed with appropriate measures in place so as to monitor and minimize any of 
the potential health risks to participating patients. This includes careful monitoring of patient’s vital 
signs and laboratory values, and the temporary and if necessary permanent discontinuation of 
investigational product in individual patients in whom a potential health risk or a laboratory 
abnormality of clinical concern has been identified. Further, in order to ensure the safety of all patients 
participating in this study, an Independent Data and Safety Monitoring Committee (IDSMC)  will be 
formed that will continuously review safety data, including the incidence of serious adverse events 


EMBRACE-HF Protocol  v2.0                                                                                                         Page 17 of 69 
 
(SAEs), and conduct assessments to ensure the ongoing safety of study patients. The IDSMC 
responsibilities, authorities, and procedures will be documented in an IDSMC charter. The personnel 
involved in the clinical study at 
 will remain blinded to these 
analyses and will have no knowledge of the results presented to the IDSMC.  
1.4.4 
Benefit to Patients 
All patients will continue taking their active background therapy; although a direct benefit from 
randomized treatment cannot be assured as one half of patients will receive placebo, those with type 2 
diabetes randomized to empagliflozin may obtain better glucose control. In this study, the dose of 
empagliflozin 10 mg once daily was chosen to provide efficacy in improving heart failure symptoms and 
biomarkers, while mitigating the potential for AEs, based on previous clinical experience. In addition, 
among patients randomized to active drug, empagliflozin is expected to help maintain better glucose 
control (among those with type 2 diabetes), decrease body weight (or prevent weight gain) as well as 
help lower blood pressure especially in patients with elevated baseline blood pressure. All patients are 
also expected to receive some benefit in the form of increased medical care/attention when 
participating in study procedures, which includes at least 5 clinic visits with at least 5 physical 
examinations and at least 4 phone call visits over the 13-week study. 
1.4.5 
Informed Consent and Alternatives to Patients 
All prospective participants will be informed of the possible risks and benefits associated with this 
study, and their consent will be received prior to performing any study-related activity. When a 
prospective participant elects to not participate in the study or to withdraw from the study, other 
medications are available to treat their heart failure, and the patient will not be disadvantaged in any 
way. 
1.4.6 
Conclusion 
Considering the pre-clinical and clinical experience with empagliflozin and the precautions included in 
the study protocol, participation in this study presents a minimal and thus acceptable risk to patients 
who meet the inclusion/exclusion criteria and consent to take part in the study. 
 
For additional details on benefits and risk, please see the empagliflozin prescribing information. 
2 STUDY OBJECTIVE 
To evaluate the effects of empagliflozin 10 mg daily, as compared with placebo, on hemodynamic 
parameters (pulmonary artery diastolic pressure) in patients with heart failure (HF) (reduced or 
preserved ejection fraction, ischemic or non-ischemic etiology). 
 
2.1 
Primary Objective  
To compare the change in pulmonary artery diastolic pressure from baseline to end of treatment period 
(defined as average of pulmonary artery diastolic pressure measurements between weeks 8-12) between 
empagliflozin and placebo. 
 
2.1.1 
Secondary Objectives 
1. To compare change from baseline in pulmonary artery diastolic pressure between empagliflozin 
and placebo at each interim time point (weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) 


EMBRACE-HF Protocol  v2.0                                                                                                         Page 18 of 69 
 
2. To compare change in pulmonary artery systolic pressure from baseline to end of treatment period 
between empagliflozin and placebo 
3. To compare change from baseline in pulmonary artery systolic pressure between empagliflozin and 
placebo at each interim time point (weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) 
4. To compare change in mean pulmonary artery pressure from baseline to end of treatment period 
between empagliflozin and placebo 
5. To compare change from baseline in mean pulmonary artery pressure between empagliflozin and 
placebo at each interim time point (weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) 
6. To compare change from baseline to follow-up (defined as average of measurements at 6 and 12 
weeks) in heart failure related quality of life between empagliflozin and placebo, using the Kansas 
City Cardiomyopathy Questionnaire (KCCQ) overall summary score.  
7. To compare proportion of patients with a ≥ 5pts increase from baseline in the Kansas City 
Cardiomyopathy Questionnaire (KCCQ) at either 6 weeks or 12 weeks of follow-up between 
empagliflozin and placebo  
8. To compare change in 6 minute walk test from baseline to follow-up (defined as average of 
measurements at 6 and 12 weeks) between empagliflozin and placebo 
9. To compare change in NTproBNP from baseline to follow-up (defined as average of measurements at 
6 and 12 weeks) between empagliflozin and placebo 
10. To compare change in BNP from baseline to follow-up (defined as average of measurements at 6 and 
12 weeks) between empagliflozin and placebo 
11. To compare proportion of patients with a ≥ 20% decrease from baseline in NTproBNP at either 6 
weeks or 12 weeks of follow-up between empagliflozin and placebo. 
12. To compare proportion of patients with a ≥ 20% decrease from baseline in BNP at either 6 weeks 
or 12 weeks of follow-up between empagliflozin and placebo. 
13. To compare proportion of patients with both a ≥ 5pts increase from baseline in KCCQ and a ≥ 20% 
decrease from baseline in NTproBNP at either 6 weeks or 12 weeks of follow-up between 
empagliflozin and placebo 
14. To compare the number of diuretic medication adjustments during the treatment period (up-
titration and down-titration of diuretic doses to be evaluated separately) between empagliflozin 
and placebo 
15. To compare change in Hemoglobin A1c from baseline to follow-up (defined as average of 
measurements at 6 and 12 weeks) between empagliflozin and placebo (evaluated separately in patients 
with and without type 2 diabetes) 
 
2.1.2 
Exploratory objectives 
1. To compare change in pulmonary artery diastolic pressure between week 12 and week 13 
between patients originally randomized to empagliflozin or placebo 
2. To compare change in mean pulmonary artery pressure between week 12 and week 13 
between patients originally randomized to empagliflozin or placebo 
3. To compare change in pulmonary artery systolic pressure between week 12 and week 13 
between patients originally randomized to empagliflozin or placebo 


EMBRACE-HF Protocol  v2.0                                                                                                         Page 19 of 69 
 
4.  To compare change in mean heart rate from baseline to end of treatment period between 
empagliflozin and placebo 
5. To compare effects on average weekly loop diuretic dose (furosemide equivalent) between 
empagliflozin and placebo.  
6. To compare effects on hospitalizations for heart failure between empagliflozin and placebo.  
7. To compare effects on urgent outpatient heart failure visits between empagliflozin and 
placebo. 
8. To compare effects on hospitalizations for heart failure and urgent outpatient visits for heart 
failure between empagliflozin and placebo 
9. To compare change in NYHA Class at 6 weeks from baseline and 12 weeks from baseline 
between empagliflozin and placebo. 
10. To compare change in NTproBNP and KCCQ at 6 weeks from baseline and 12 weeks from 
baseline between empagliflozin and placebo 
11. To compare the number of medication adjustments other than diuretics (nitrates, hydralazine, 
ACE, ARB, b-blockers, sacubitril/valsartan) during the treatment period between empagliflozin 
and placebo 
12. Proportion of patients that progress to diabetes during the treatment period (within the subgroup 
of patients without diabetes at baseline only) 
 
2.1.3 
Safety topics 
Safety of empagliflozin will be monitored by assessment of SAEs, AEs of special interest and other 
parameters including mortality, non-fatal MI, stroke, acute kidney injury, volume depletion, severe 
hypoglycemic events, ketoacidosis, laboratory values, pulse, blood pressure, and physical examination 
findings. Patients with established type 2 diabetes will be encouraged to keep a diary and perform self-
monitoring of blood glucose and weight, as well as specifically test for symptoms of hypoglycemia and 
document severe hypoglycemic events, (a severe hypoglycemic event is defined as symptomatic event 
requiring external assistance due to severe impairment in consciousness or behavior with resolution 
of event with administration of glucose, glucagon or other corrective action and a capillary or 
plasma glucose value <54 mg/dL ). 
 
3 STUDY PLAN AND PROCEDURES 
3.1 
Study Design 
Randomized, double-blind, placebo-controlled trial. The control group will receive placebo 
administered orally once daily for 12 weeks plus standard of care. The treatment group will receive 
empagliflozin 10 mg administered orally once daily for 12 weeks plus standard of care. A follow-up visit 
at week 13 will be performed to evaluate filling pressures and markers of renal function. 
3.2 
Study Procedures 
At the screening visit, participants will undergo a physical exam (including vital signs and weight 
assessment) a laboratory panel, including HbA1c, BNP, NTproBNP, and a renal panel will be performed 
to determine study eligibility. CardioMEMs sensor readings will be obtained twice daily (in the morning 
and in the evening) for the 2 week period between screening and randomization visits to establish a 


EMBRACE-HF Protocol  v2.0                                                                                                         Page 20 of 69 
 
baseline for systolic, diastolic and mean PA pressure (Table 1). At the randomization visit, participants 
will be instructed to have a physical exam (including vital signs and weight assessment), laboratory 
testing, including HbA1c, BNP, NTproBNP, and a renal panel, complete the KCCQ and perform a 6 
minute walk test. CardioMEMs sensor readings will be taken by the patient at home twice a day for the 
12 weeks, once in the morning (when the patient wakes up) and once at night (before bedtime). 
Treatment or placebo will be administered for 12 weeks, with follow-up visits at 6 and 12 weeks during 
which a physical exam (including vital signs and weight assessment), labs, KCCQ, a 6 minute walk test 
will be performed and AEs/SAEs will be recorded. On days 2 and 7, as well as weeks 3 and 9 
participants will be contacted by phone to evaluate for AEs/SAEs, and encourage compliance with the 
study medication. One week after treatment ends, renal function at a follow-up office visit; 
CardioMEMs sensor readings will continue to be obtained twice daily between week 12 and week 13. 
PA diastolic, systolic and mean pressures will be assessed at weekly time points post-randomization 
(pulmonary pressures will be measured twice daily and averaged over each week for 12 weeks post- 
randomization, as well as between week 12 and week 13 post randomization). 
 
Table 1: Study Plan  
 
 
 
12 –week double-blind 
treatment period 
 
 
Screening 
Randomization 
 
 
 
 
 
 
 
Visit 
S 
1 
2 
3 
4 
5 
6 
7 
8 
Weekh) 
-2i) 
0 
2d 1 
3 
6 
9 
12 
PTDV 
13 
Patient obtains 
CardioMEMs 
pressure reading 
at home a) 
Twice daily between screening and 
randomization visits to establish baseline, 
then twice daily for 12 weeks following 
randomization visit, then twice daily 
during week 12 and week 13 
(immediately after treatment 
discontinuation). 
 
Office Visit 
X 
X 
 
 
 
X 
 
X 
X 
Phone Visitg) 
 
 
X 
X 
X 
 
X 
 
 
Physical Exam b) 
X 
X 
 
 
 
X 
 
X 
X 
Vital signs (BP, 
pulse) 
X 
X 
 
 
 
X 
 
X 
X 
Orthostatic BP, 
pulse 
X 
X 
 
 
 
X 
 
X 
X 


EMBRACE-HF Protocol  v2.0                                                                                                         Page 21 of 69 
 
NYHA Class 
X 
X 
 
 
 
X 
 
X 
X 
Weight 
X 
X 
 
 
 
X 
 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
Waist 
circumference 
X 
X 
 
 
 
X 
 
X 
X 
Medical History 
X 
 
 
 
 
 
 
 
 
Concomitant 
medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory 
assessments  
Xc) 
X d) 
 
 
 
X d) 
 
X d) 
X e) 
Urine pregnancy 
testf) 
X 
X 
 
 
 
X 
 
X 
X 
Urine albumin/ 
creatinine ratio 
test 
 
X 
 
 
 
X 
 
X 
X 
6 min walk test 
 
X 
 
 
 
X 
 
X 
X 
KCCQ 
 
X 
 
 
 
X 
 
X 
X 
AEs 
 
X 
X 
X 
X 
X 
X 
X 
X 
SAEs 
 
X 
X 
X 
X 
X 
X 
X 
X 
Hospitalizations 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
ER Visits 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Urgent outpatient  
heart failure visits 
 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense urine 
ketone strips 
 
X 
 
 
 
 
 
 
 
Dispense study 
medication 
 
X 
 
 
 
 
 
 
 
Return/redispense 
study medication 
 
 
 
 
 
X 
 
X 
 
Study medication 
accountability 
 
 
 
 
 
X 
 
X 
 
 
a) CardioMEMs sensor reading transmission occurs at home when patients lie down on a special pillow 
containing an antenna. It is a simple process that takes only a few minutes. In addition to the pillow, 
patients are usually equipped with an external unit. The external unit transmits the readings to a 
secure website where the data can be seen by providers.  
b) Physical Exam includes: complete physical examination consisting of general appearance, head, eyes, ears, 
nose, throat, neck, cardiovascular system, lungs, abdomen, lymph nodes, extremities, neurological system, 


EMBRACE-HF Protocol  v2.0                                                                                                         Page 22 of 69 
 
skin, musculoskeletal system, height (screening only), weight, pulse, blood pressure, monitoring for volume 
depletion, and assessment for ketoacidosis (difficulty breathing, nausea, vomiting, abdominal pain, 
confusion, and unusual fatigue or sleepiness). 
c) Screening laboratory assessment includes HbA1c, BNP, NTproBNP and renal panel. 
d) Randomization, Week 6 and Week 12 laboratory assessment includes HbA1c, Fasting Glucose, BNP, 
NTproBNP, CBC, renal panel, urine microalbumin/creatinine ration, and uric acid. 
e) Week 13 laboratory assessment includes only renal panel. 
f) Only for women with childbearing potential. 
g) Phone visits include recording any AE or SAE, self-monitoring of weight, self-monitoring of blood glucose 
(among patients with established T2D), and encouraging compliance with study medication. 
h) Visit Windows: There may be up to 2 weeks between the screening and randomization visits. Week 6, 12 and 
13 clinic visits have a +/- 2-day visit window.  Phone Visits have a +/-1-day visit window. 
  i) If a subject is a screen failure at the initial screening visit, they may be rescreened on three additional 
occasions at the discretion of the investigator. At the rescreening visit, the subject should be treated 
like a new subject and be assigned a new subject number and all screening visit procedures should be 
completed, including obtaining informed consent. 
 
3.3 
Definition of Active Treatment  
Empagliflozin 10 mg daily + Standard of Care (for heart failure) 
3.4 
Definition of Control Arm   
Matching Placebo + Standard of Care (for heart failure) 
3.5 
Overall Study Duration 
Subjects will participate for a total of 13 weeks. It is estimated that one subject will be enrolled per 
month (or every other month) at each site, with enrollment estimated to be complete within 24 
months and an approximate 5 months start-up time for all sites to be activated. Total estimated study 
duration is 33 months.  
 
4 STUDY POPULATION 
Voluntary participation will be sought from patients with chronic heart failure at specialized heart 
failure clinics for patients with previously implanted CardioMEMs for a clinical indication unrelated to 
the study. Informed consent will be obtained from potentially eligible participants prior to initiating 
screening visit procedures. 
4.1 
Inclusion criteria 
1. Age > 18 and <120 at the screening visit 
2. Established diagnosis of heart failure (for at least 16 weeks prior to the screening visit) with 
either preserved (LVEF>40%) or reduced systolic function (LVEF≤40%),  due to either ischemic 
or non-ischemic etiology, documented by an imaging modality (echocardiography, nuclear 
imaging, LV angiography, magnetic resonance imaging) within the past 24 months.  


EMBRACE-HF Protocol  v2.0                                                                                                         Page 23 of 69 
 
3. No major change in diuretic management for 48 hours prior to screening visit or 48  hours prior 
to randomization visit (major change defined by doubling of diuretic dose or addition of 
another diuretic medication) 
4. NYHA class II, III or IV heart failure symptoms at the screening and randomization visit 
5. Presence of previously (≥ 2 weeks prior to screening visit) implanted CardioMEMs pulmonary 
artery pressure monitor for a clinical indication unrelated to the study. 
6. PA diastolic pressure ≥ 12 mmHg at the time of the screening visit (last measurement available 
prior to the screening visit). 
7. Ability to provide informed consent prior to initiating screening visit procedures 
4.2 
Exclusion criteria 
1. Decompensated heart failure (hospitalization for heart failure within the 2 weeks prior to 
screening) or between screening and randomization 
2. History of type 1 diabetes 
3. Major change in diuretic management during 48 hours prior to screening visit or 48 hours prior 
to randomization visit. (major change defined by doubling of diuretic dose or addition of 
another diuretic medications) 
4. Significant variability in baseline PA diastolic pressures during screening period.  Defined as 
changes greater than  +/- 6 mmHg from average PA diastolic pressure during week 1 of the 
screening phase and average PA diastolic pressure during week 2 of the screening phase for 
those patients with an average baseline PA diastolic pressure during week 1 of the screening 
phase of <30 mmHg.   If the average baseline PA diastolic pressure during week 1 of the 
screening phase is ≥30 mmHg, then ≥20% relative change in average PA diastolic pressure 
between week 1 and week 2 of the screening phase will be used to define significant 
variability.  
5. Initiation of hydralazine, long-acting nitrates, beta blockers, ACEI/ARBs or Valsartan/sacubitril 
in the prior 4 weeks prior to screening 
6. Estimated glomerular filtration rate (eGFR) < 30  mL/min/1.73 m2 at the screening visit 
7. Admission for an acute coronary syndrome (ST-elevation MI, non-ST-elevation MI, or unstable 
angina), percutaneous coronary intervention, or cardiac surgery within 30 days prior to the 
screening visit.  
8. Implantation of cardiac resynchronization therapy (CRT) device within the previous 90 days. 
9. Implantation of the CardioMEMs device within the past 2 weeks.  
10. Planned cardiovascular revascularization (percutaneous intervention or surgical) or major 
cardiac surgery (coronary artery bypass grafting, valve replacement, ventricular assist device, 
cardiac transplantation, or any other surgery requiring thoracotomy), or planned implantation 
of CRT device within the 90 days after the screening visit. 
11.  Participation in any interventional clinical trial (with an investigational drug or device) that is 
not an observational registry within the 4 weeks prior to the screening visit.  
 
12. History of hypersensitivity to empagliflozin 


EMBRACE-HF Protocol  v2.0                                                                                                         Page 24 of 69 
 
13. For women of child-bearing potential: Current or planned pregnancy or currently lactating 
Women of childbearing potential are defined as any female who has experienced menarche 
and who is NOT permanently sterile or postmenopausal.  Post menopausal is defined as 12 
consecutive months with no menses without an alternative medical cause.  Women of child-
bearing potential, who are sexually active, must agree to use a medically-accepted method of 
birth control for the duration of the study.  Acceptable birth control methods include: (1) 
surgical sterilization (such as a hysterectomy or bilateral tubal ligation), (2) progesterone 
hormonal contraceptives (birth control pills or implants), (3) barrier methods (such as a 
condom or diaphragm) used with a spermicide, or (4) an intrauterine device (IUD). Women of 
child-bearing potential will have a urine pregnancy test at every clinic visit and it must be 
negative to continue study participation.   
 
14. Life expectancy <1 year at the screening visit 
15. Patients who are volume depleted based upon physical examination at the time of the 
screening or randomization visit 
16. PA diastolic pressure < 12 mmHg at the time of the screening visit (average of last four 
measurements available prior to the screening visit). 
17. Patients currently being treated with any SGLT-2 inhibitor (dapagliflozin, canagliflozin, 
empagliflozin) or having received treatment with any SGLT-2 inhibitor within the 8 weeks prior 
to the screening visit 
18. Average supine systolic BP <90 mmHg at the screening or randomization visit 
19. Current documented history of bladder cancer  
20. Active Gross Hematuria 
21. Heart failure due to restrictive cardiomyopathy, active myocarditis, constrictive pericarditis, 
severe stenotic valve disease, and HOCM (hypertrophic obstructive cardiomyopathy). 
22. History of heart transplant. 
23. Patients on heart transplant list as 1a and 1b status 
 
5 STUDY CONDUCT 
5.1 
Restrictions during the study 
For patients: 
Patients should be fasting from all food and beverages (except water) at least 6 hours before blood samples are 
taken for laboratory analysis at a clinic visit with the exception of the screening visit. Patients should not use 
alcohol for 24 hrs or use tobacco for 12 hrs prior to testing at a clinic visit. Patients with established type 2 
diabetes should not take any glucose-lowering medication when they are fasting.  On the day of a clinic visit, 
investigational product and other concomitant medications will be taken in the morning, after completion of 
certain required study procedures.  Patients shall not be allowed to use any prescribed SGLT-2 inhibitors 
(dapagliflozin, canagliflozin, empagliflozin), other than the investigational product, at any time during the study. 
Patients shall not be allowed to donate blood or bone marrow at any time during the study.  
 


EMBRACE-HF Protocol  v2.0                                                                                                         Page 25 of 69 
 
For physicians: 
Since the primary endpoint of the study is the change in pulmonary artery diastolic pressure, physicians will be 
encouraged to limit medication changes for the study patients. Changes of heart failure medications (and 
specifically diuretics) should directed by the medical needs of the patients, and patients safety is priority, 
however, we will encourage using clinical judgment and avoiding frequent medications changes during this 3-
month study. The recommended algorithm for medication adjustments is outlined in Section 5.6.7  
 
5.2 
Patient enrollment and randomization 
The Principal Investigator or delegate will: 
 
Obtain signed informed consent from the potential participants before any study specific procedures 
are performed 
 
Determine patient eligibility 
 
Assign potential patients a sequential enrollment number in the form of Site ID and enrollment number 
i.e.: XXX-XX 
 
Assign enrolled patient a unique randomization code using Sharp Clinical Interactive Voice and Web 
Response Systems (IVR/IWR). 
 
If a patient withdraws from participation in the study, then their enrollment number cannot be reused. 
Patients can only be randomized into the study once. 
 
5.3 
Procedures for randomization 
Sharp Clinical Services will provide a state-of-the-art Clinical Interactive Voice and Web Response 
Systems (IVR/IWR). Sharp Clinical IVR/IWR is an innovative value-based product for Subject enrollment, 
randomization, capturing clinical data, drug shipments, and managing drug supply. 
Sharp Clinical IVR/IWR Solutions are 21 CFR Part 11 compliant, user-friendly, and provide value to all 
users with big reductions in study start up times. The IVR/IWR System ensures data integrity, 
accelerates clinical site initiations, and can provide real-time metrics for subjects, sites and study 
inventory for approved users. 
Solutions and Services include: 
 
24/7 Operation 
 
Site Administration and Tracking 
 
Study Drug Distribution and Resupply Management 
Training and User-Materials: 
During system development, the Sharp PM creates a study-specific user manual and Quick Reference 
Guide for the IVR/IWR System. Site and client users are trained at investigator meetings or scheduled 
web-based training sessions conducted by the Sharp PM. 
 
 
5.4 
Procedures for handling incorrectly enrolled or randomized patients 
Patients who fail to meet the inclusion/exclusion criteria should not, under any circumstances, be 
enrolled or randomized. There can be no exceptions to this rule. 


EMBRACE-HF Protocol  v2.0                                                                                                         Page 26 of 69 
 
The following steps should be taken in the event that a patient, who does not meet inclusion/exclusion 
criteria, is found to have been inadvertently randomized in the study: 
 
The investigator should inform the 
 study team physician 
immediately. Ensuring patient safety must always be the number one priority. 
 
Study treatment must be discontinued in all cases where continued treatment is deemed to pose a 
safety risk to the patient. After a discussion between the study team physician and investigator, a 
decision may be reached that the patient should discontinue study medication. The rationale for 
discontinuing study medication must be clearly documented. The patient should remain in the 
study for follow-up in accordance with defined study procedures including follow-up on endpoints 
through the end of the study consistent with the FAS principle. 
 
In those cases where continuation of study therapy is judged not to present a concern related to 
safety and disease management, the rationale for continuing study therapy must be clearly 
documented. The patient should continue follow-up in accordance with defined study procedures. 
5.5 
Blinding and procedures for unblinding the study 
5.5.1 
Methods for ensuring blinding 
The treatment allocation in this study will be double blind. Empagliflozin (10 mg) tablets and matching 
empagliflozin placebo tablets will be provided, identical in appearance and with the same number, 
size, and packaging of tablets. Each bottle will be labeled with a unique bottle ID number that will be 
used to assign the treatment to the patient but will not indicate treatment allocation to the 
investigator. 
No member of the extended study team at 
, the CEC, or personnel 
at investigational centers will have access to the randomization scheme during the conduct of the 
study, with the exception of the Sharp Clinical Services, and the Biostatistics department at 
 
. 
The IDSMC will have access to the individual treatment codes and will be able to merge these with the 
collected study data while the study is ongoing. The IDSMC will review safety data on a periodic basis, 
including the incidence of AEs, and conduct safety assessments to ensure the ongoing safety of study 
patients. The IDSMC responsibilities, authorities, and procedures will be documented in a IDSMC 
charter. The personnel involved in the clinical study at 
 will remain 
blinded to these analyses and will have no knowledge of the results presented to the IDSMC. 
 
5.5.2 
Methods for unblinding the study 
Individual treatment codes, indicating the treatment allocation for each randomized patient, will be 
available to the investigator(s) or pharmacists from the Sharp Clinical IVR/IWR system. Routines for this 
will be described in the Sharp Clinical IVR/IWR system user manual that will be provided to each study 
site. 
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the patient requires knowledge of the treatment. The 
 
 physician 
 or delegate) should be consulted whenever possible prior to the 
investigator breaking the blind. The investigator documents and reports the action to 
 
, without revealing the treatment given to the patient to the 
 
staff. The number of individuals at the study site who become aware of the 


EMBRACE-HF Protocol  v2.0                                                                                                         Page 27 of 69 
 
treatment status should be kept to an absolute minimum including keeping the patient blinded if 
possible. Treatment with study medication should be continued if considered appropriate. 
 retains the right to break the code for SAEs that are unexpected 
and are suspected to be causally related to a study drug and that potentially require expedited 
reporting to regulatory authorities. Treatment codes will not be broken for the planned analyses of 
data until all decisions on the evaluability of the data from each individual patient have been made and 
documented. 
 
5.6 
Treatments 
5.6.1 
Identity of study medication 
Table 2 Identity of study medication 
Study Medication 
Dosage form and strength 
Manufacturer 
Empagliflozin 10 mg 
Biconvex, bevel-edged film-
coated, round shape, yellow 
tablet 10 mg (Size: 9.1 mm) 
 
 
Matching placebo for 
empagliflozin 10 mg 
Biconvex, bevel-edged film-
coated, round shape, yellow 
tablet 10 mg (Size: 9.1 mm) 
  
5.6.2 
Doses and treatment regimens 
At the randomization visit eligible patients will be randomly assigned to 1 of 2 treatments: 
 
Empagliflozin 10 mg, administered orally once daily for the 12 weeks. 
 
Matching placebo for empagliflozin 10 mg, administered orally once daily for the 12 weeks. 
The investigational product empagliflozin and matching placebo will be taken orally. The investigational 
product should be taken once daily in the morning and at approximately the same time of the day 
during the study period. Nevertheless prior to each office visit (except for the screening visit), patients 
with established type 2 diabetes should be instructed not to take any glucose-lowering medication in the 
morning and all patients should abstain from all food and beverages for 6 hours; however, drinking 
water is allowed. On the day of an office visit, investigational product and other concomitant 
medications will be taken in the morning, after completion of certain required study procedures. 
5.6.3 
Drug Dispensing Scheme 
At randomization, three (3) bottles of empagliflozin 10 mg or matching placebo will be dispensed, with 
each bottle containing 30 tablets. 
5.6.4 
Duration of treatment 
The control group will receive placebo administered orally once daily for 12 weeks plus standard of care. 
The treatment group will receive empagliflozin 10 mg administered orally once daily for 12 weeks plus 
standard of care. Subjects will participate for a total of 13 weeks.  
5.6.5 
Labeling 
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local regulatory 
guidelines. The labels will fulfill GMP Annex 13 and US FDA requirements for labeling. The label will include 
at least the following information: 


EMBRACE-HF Protocol  v2.0                                                                                                         Page 28 of 69 
 
 
Name of sponsor: 
 
 
Study drug(s) dosage form, route of administration, and quantity of dosage units 
 
Study code 
 
Enrollment code (will be added by the investigator when investigational product is dispensed) 
 
Kit ID 
 
Directions for use (For oral use) 
 
Storage conditions 
 
“for clinical trial use only” 
 
“keep out of reach of children” 
 
US caution statement 
5.6.6 
Storage  
All study drugs should be kept in a secure place under appropriate storage conditions and in the 
original container. The study medication label and empagliflozin prescribing information, which will be 
provided to sites by the study Sponsor as part of the study start-up package, specify appropriate 
storage, which is additionally outlined in Appendix C. 
5.6.7 
Medication Adjustment Protocol 
Since the medications used to treat heart failure (including diuretics, afterload reduction medication, 
etc.) can affect pulmonary artery pressures (the study’s primary endpoint), we encourage the 
investigators to only make changes in medical treatment when absolutely necessary for patient 
safety. To demonstrate the true effect of empagliflozin on pulmonary artery pressures, investigators 
are encouraged to adhere to the clinical pulmonary artery pressure monitoring protocol and 
medication adjustment protocol (detailed below) to avoid extreme variations in treatments across 
patients/investigators and sites. This protocol is adapted from the CHAMPION trial protocol20 and 
clinical experience: 
Pulmonary artery clinical monitoring protocol: Patients randomized in the EMBRACE-HF Trial will 
have pulmonary artery measured twice daily for 2 weeks between screening and randomization 
visits (to establish a pre-randomization baseline), twice daily during the 12 week treatment period, 
and twice daily during week 12 and week 13 (immediately after treatment discontinuation). 
Investigators are directed to clinically evaluate pulmonary artery pressures no more frequently than 
twice a week following randomization; and use pulmonary artery diastolic pressure averaged over 
the previous 7 calendar days (~14 previous measurements) to guide management; the only 
exception will be the first evaluation after randomization, which will use averaged pulmonary artery 
diastolic pressure over the previous 3-4 days. These averaged pulmonary artery diastolic pressure 
measurements will be compared with the patient’s pre-randomization baseline (itself an averaged 
measurement over the 2 weeks between screening and randomization), and the difference between 
these measurements will be used to guide clinical decision making as follows: 
 
 


EMBRACE-HF Protocol  v2.0                                                                                                         Page 29 of 69 
 
Hemodynamic-Guided Care Strategy  
Optivolemic patient 
Patients with minimal HF congestive symptoms, minimal evidence of poor perfusion, and no significant 
change in pulmonary artery diastolic pressure from pre-randomization baseline (defined as no increase or 
decrease in pulmonary artery diastolic pressure of >6 mmHg for those with pre-randomization average PA 
diastolic pressure of <30 mmHg; for those with pre-randomization average PA diastolic pressure of ≥30 
mmHg, no significant change in pulmonary artery diastolic pressure will be defined as no increase or 
decrease of ≥20%). 
For patients who meet the above guidelines, investigators are directed to make no changes in medical 
therapy. 
Hypervolemic  
Patients were considered to be hypervolemic if the pulmonary artery diastolic pressure increases by >6 
mmHg compared with pre-randomization baseline values (for those with pre-randomization baseline of 
<30 mmHg) or by ≥20% (for those with pre-randomization baseline of ≥30 mmHg) and/or if congestive 
symptoms are present. 
Hypervolemic Treatment Recommendations  
Investigators are instructed to add or increase diuretic (and appropriate electrolyte replacement) by an 
increase or addition of a loop diuretic, change to another loop diuretic, add a thiazide diuretic (with 
caution), or institute IV doses of loop diuretic in the office setting. Serum electrolyte evaluation with 
change in baseline medication is required for safety and reassessment of pulmonary artery pressure by 
using the HF pressure measurement system at least every 2-3 days until optivolemic status is restored. If 
diuretic strategies are not successful in restoring pressures to baseline, investigators are asked to add or 
increase nitrate therapy along with attempting to reeducate patients in salt intake and fluid restriction.  
If patients developed signs and symptoms of poor perfusion in addition to being hypervolemic the 
investigators are instructed to consider hospitalization if clinical evidence suggested need for IV diuretics, 
telemetry monitoring, or other IV therapeutic agents, such as inotropes. Investigators have the option to 
consider invasive hemodynamic monitoring for determination of cardiac output if indicated.  
Hypovolemic  
Patients are considered hypovolemic if pulmonary artery diastolic pressure decreases by > 6 mmHg 
compared with pre-randomization baseline values (for those with pre-randomization baseline of <30 
mmHg) or by ≥20% (for those with pre-randomization baseline of ≥30 mmHg) and/or those with evidence 
for poor perfusion in the absence of signs and symptoms of congestion.  
Hypovolemic Treatment Recommendations  
Patients with hypovolemia are treated by lowering or discontinuing diuretics or, if on a thiazide diuretic 
with loop diuretic, by lowering or discontinuing the dose of thiazide with adjustment of electrolyte 


EMBRACE-HF Protocol  v2.0                                                                                                         Page 30 of 69 
 
replacements. The investigator should also consider liberalization of oral fluid restriction and salt 
restriction. If the patient has postural hypotension, vasodilator dosage is to be held or lowered, especially if 
hypotensive when sitting or supine. If the patient has worsening renal function, the ACE/ARB dose should 
be held or lowered, especially if hypotensive while supine.  
If patients have signs and symptoms of poor perfusion in addition to being hypovolemic, the investigator 
should consider admission if clinical evidence suggests need for IV fluid repletion, telemetry monitoring, or 
the use of IV therapeutic agents. The investigator also has the option for invasive hemodynamic monitoring 
for determination of cardiac output if indicated.  
The detailed recommendations for hemodynamic-guided care strategy are outlined in the Figure below. 
 
 
Glucose-lowering medications adjustment protocol (only for patients with established T2D): 
For patients with established T2D and HbA1c if ≤ 7.0% and receiving insulin at baseline, it is recommended 
to reduce total daily insulin dose by 20%. For patients with established T2D and HbA1c if ≤ 7.0% and 
receiving sulfonylurea at baseline, it is recommended to reduce total daily sulfonylurea dose by 50%, or 
discontinue sulfonylurea in patients receiving the minimal dose of sulfonylurea at baseline. 
 
5.7 
Concomitant and post-study treatments 
5.7.1 
Recording of concomitant medication 
Detailed recording of all concomitant medications will be made at screening, randomization, and all 
subsequent visits. It will include all medication changes, but glucose lowering (in patients with 
established T2D) and heart failure medications (including every change in diuretic regimen) in 
particular.  


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5.8 
Treatment Compliance 
The administration of study medication should be recorded.  All stops re-starts of study medication 
prescribed by the investigator should be recorded. In addition, any non-prescribed temporary stops (>1 
week) of study medication should be recorded. 
Missed doses of empagliflozin or placebo blinded study medication should not be taken.  If a dose is 
missed the next regularly scheduled dose should be taken and should not be doubled. 
Patients are instructed to transmit CardioMEMs sensor readings twice a day per protocol. All missed 
opportunities to transmit data should be recorded and reviewed each phone and office visit. 
5.8.1 
Accountability 
The study medication provided for this study will be used only as directed in the study protocol. The 
study personnel will account for all study medication dispensed to and returned from the patient. 
Patients will be asked to bring all unused study medication and empty packages to the site at each 
office visit. The investigator or delegate will record the number of returned tablets and make an 
assessment regarding patient treatment compliance. Any patient found to be noncompliant would be 
counseled on the importance of taking their study medication as prescribed. 
Any study medication deliberately or accidentally destroyed must be recorded. Any discrepancy 
between dispensed and returned study medication should be explained. 
The investigator will retain the returned medication until the termination of the Clinical Study. Then 
the investigator will return any unused medication to Sharp Clinical Services for destruction of all 
unused study medication. 
 is responsible for confirming the 
investigator or delegate has recorded the quantities of returned and unused tablets at a patient level 
before medication is returned to Sharp Clinical Services.  
Patients who are transmitting CardioMEMs sensor readings as instructed will be counseled on the 
importance of transmitting this information. 
5.9 
Discontinuations of study medication 
Patients should be discontinued from study medication in the following situations: 
5.9.1 
General discontinuation criteria 
1. Patient decision. The patient is at any time free to discontinue treatment, without prejudice to 
further treatment. 
2. Adverse Events, i.e., any clinical AE, laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the best 
interest of the patient. 
3. Severe non-compliance to protocol as judged by the investigator and/or 
 
. 
4. Risk to patients as judged by the investigator. 
5. Incorrectly enrolled patients. 
6. Patient lost to follow-up. 
 
5.9.2 
Study-specific discontinuation criteria 
 
Doubling of serum creatinine above the baseline value confirmed by a repeated 
measurement within one week. 
 
Recurrent severe hypoglycemic events, defined as ≥2 severe events (a severe hypoglycemic 
event is defined as symptomatic event requiring external assistance due to severe impairment 
in consciousness or behavior with resolution of event with administration of glucose, 


EMBRACE-HF Protocol  v2.0                                                                                                         Page 32 of 69 
 
glucagon or other corrective action and a capillary or plasma glucose value <54 mg/dL ). 
This definition should be applied after possible contributing factors (eg, excessive physical 
activity, dietary and medication factors) have been excluded or addressed by the investigator. 
 
Occurrence of diabetic ketoacidosis (DKA) 
 
Pregnancy confirmed by a positive pregnancy test or otherwise verified. 
 
5.9.3 
Procedures for permanent discontinuation of a patient from study medication 
Patients permanently discontinuing study medication should be given conventional therapy, if 
applicable, and should continue routine care visits with their primary physician. 
A patient that decides to discontinue study medication will always be asked about the reason(s) for 
their desire to discontinue study medication and the presence of AEs (if any). These data will be 
ascertained and documented by the investigator.  AEs will be followed up and the patient should 
return all study medications. 
It is essential to collect as much data as possible for all patients throughout the study and especially all 
potential endpoint events. Discontinuation from study medication is not the same as complete 
withdrawal from the study (withdrawal of consent), which has a direct impact on the potential validity 
of all study data, and should be avoided wherever possible. 
5.9.4 
Patient agrees to undergo the Premature Treatment Discontinuation Visit and then continue in-
person study visits 
The patient agrees to undergo the Premature Treatment Discontinuation Visit (PTDV) and then 
continue in-person study visits according to plan. This is the preferred option and patients who 
discontinue study medication will always be asked if they agree to this approach. If agreed, as above, 
the patient will undergo their PTDV at the next scheduled office visit after the study medication is 
stopped. The patient will continue attending subsequent study visits according to schedule (Table 1).  
5.9.5 
Patient refuses to continue in-person study visits but agrees to undergo modified follow-up 
If the patient refuses to continue in-person study visits, but agrees to undergo modified follow-up, the 
in-person PTDV visit should be performed as soon as possible after the study medication is stopped. All 
subsequent visits until the end of study date will be done as modified follow-ups (eg, regular telephone 
contacts, a contact at study closure, or other means) in order to ascertain whether any endpoints or 
safety events had occurred. Such a patient has not withdrawn his/her consent or withdrawn from the 
study. 
5.9.6 
Patient refuses any form of follow-up 
If the patient refuses any form of follow-up, he/she officially withdraws from the study and may also 
decide to withdraw consent. This decision must be documented. At the end of the study, vital status on 
all such patients will be collected from publicly available sources, in accordance with local regulations. 
5.9.7 
Restart of study medication 
Whenever possible, restart of randomized study medication should be encouraged, even if a PTDV was 
previously completed. 
5.9.8 
Study Closure Visit 
All randomized patients should return for their study closure visit (visit 8) as soon as possible, but no 
later than 1 week after the previously scheduled visit 7. 
If a patient is unable to attend the study closure visit in person, telephone contact should be made to 
ascertain endpoint and AE information. At the study closure visit, physicians caring for the patient will 
decide which medication the patient should receive as part of his/her ongoing clinical care. 


EMBRACE-HF Protocol  v2.0                                                                                                         Page 33 of 69 
 
5.10 Withdrawal from study 
Patients are at any time free to withdraw from the study (i.e., discontinue study medication 
permanently and withdraw from visit assessments), without prejudice to further treatment 
(withdrawal of consent). Withdrawal of consent from the study must be ascertained and documented 
by the investigator. Such patients will always be asked about the reason(s) and the presence of any 
AEs. The reason for permanent discontinuation of treatment with the study medication and the date of 
the last intake of the study medication must be documented.  
5.10.1 Patients permanently discontinuing from study medication should be given conventional therapy, 
if applicable, and should always be asked to continue to attend protocol visits  
If the patient denies any additional protocol follow-up and officially withdraws consent from the 
study one of the alternatives a) to c) should be followed: 
 
At the time of discontinuation of treatment and withdrawal of consent from continued 
assessment the patient should, if possible, undergo the PTDV. The patient should return all 
study medication 
 
If the patient does not agree to this option (which must be documented), a modified PTDV (eg, 
a telephone contact) should be arranged. The approach taken should be documented. The 
patient should return all study medication 
 
If the patient does not agree to a) or b) this must be documented in the patient’s medical 
record. The patient should return all study medication. 
To ensure validity of study data, it is very important to collect as much data as possible throughout 
the study and especially vital status (dead or alive) at the SCV. The investigator or delegate will 
therefore attempt to collect information on all patients’ vital status from publicly available sources 
at the SCV, in accordance with local regulations, even if informed consent has been withdrawn 
completely. 
 
5.11 Study committees 
5.11.1 Steering Committee 
A steering committee will be formed and composed of PIs from each participating site. A publication 
plan will be developed with input from this committee. 
5.11.2 Clinical Endpoint Adjudication Committee (CEC) 
An independent CEC will be appointed and will adjudicate all heart failure hospitalizations. The 
committee members will not have access to individual treatment codes for any patient or clinical 
efficacy and safety event. The precise responsibilities and procedures applicable for the CEC will be 
detailed in a separate CEC charter. 
5.11.3 Independent Data and Safety Monitoring Committee (IDSMC) 
An independent DSMC will be appointed. 
The IDSMC will be responsible for safeguarding the interests of the patients in the study by assessing 
the safety of the intervention during the study, and for reviewing the overall conduct of the clinical 
study. The IDSMC will have access to the individual treatment codes and will be able to merge these 
with the collected study data while the study is ongoing. 


EMBRACE-HF Protocol  v2.0                                                                                                         Page 34 of 69 
 
The EC and 
 will not be made aware of the treatment codes until 
after clean file and database lock are declared. Similarly, all summary output reviewed at each IDSMC 
meeting will be held in confidence by the IDSMC members until the end of the study when clean file 
and database lock are declared. 
The IDSMC charter will be prepared to detail precise roles and responsibilities and procedures to 
ensure maintenance of the blinding and integrity of the study in the review of accumulating data and 
interactions with the Study PI.  
6 COLLECTION OF STUDY VARIABLES 
6.1 
Recording of data 
The REDCap Web Based Data Capture (WBDC) system will be used for data collection and query 
handling. The site Principal Investigator will ensure that data are recorded in the electronic Case Report 
Forms (eCRF) and will ensure the accuracy, completeness, and timeliness of the data recorded and of 
the provision of answers to data queries according to the Clinical Study Agreement (CSA). 
Data will be entered in the eCRF using the REDCap Web Based Data Capture (WBDC) system by trained 
personnel at the study site.  When data have been entered, reviewed, edited, and source data 
verification has been performed, as appropriate, by an 
 
representative, the data will be frozen to prevent further editing. The site Principal Investigator will be 
notified to sign the eCRF electronically. A copy of the eCRF data will be archived at the study site. 
6.2 
Data Collection at enrollment and follow-up 
TABLE 3 Laboratory variables 
Visit 
S 
1 2 
3 
4 5 
6 7 
8 
Week 
-2 
0 2d* 
1 
3 6 
9 12 13 
HbA1c 
X 
X  
 
 
X 
 
X 
 
Glucose** 
 
X  
 
 
X 
 
X 
 
BNP 
X 
X  
 
 
X 
 
X 
 
NTproBNP 
X 
X  
 
 
X 
 
X 
 
Urine albumin 
creatinine Ratio 
 
X  
 
 
X 
 
X 
 
Urine Pregnancy 
Test 
X 
X  
 
 
X 
 
X 
 
CBC 
 
X  
 
 
X 
 
X 
 
Renal Panel*** 
X 
X  
 
 
X 
 
X 
X 
 
 
      
                                  *days after randomization                
     **   included in the renal panel                
     *** the renal panel includes albumin, BUN/Creatinine Ratio (calculated), calcium,  
            carbon dioxide, chloride, creatinine, estimated glomerular filtration rate  
            (calculated), glucose, phosphate (as phosphorus), potassium, sodium, urea  
            nitrogen 


EMBRACE-HF Protocol  v2.0                                                                                                         Page 35 of 69 
 
6.2.1 
Screening Visit Procedures (Visit S) 
 
Informed consent 
 
Blood sampling for laboratory assessments 
 
Physical exam 
 
Vital Signs (seated pulse and BP and orthostatic pulse and BP) 
 
Weight 
 
Height 
 
Urine pregnancy test (only applicable for women of childbearing potential) 
 
Medical history 
 
Concomitant medications 
 
Eligibility criteria 
 
CardioMEMs pressure readings transmission (to be done twice daily at home between screening 
and randomization visits) 
 
6.2.2 
Randomization Visit (Visit 1)  
Patients that fulfill the eligibility criteria will undergo randomization procedures.  
 
Eligibility criteria 
 
Physical exam 
 
Vital Signs (seated pulse and BP and orthostatic pulse and BP) 
 
Weight 
 
Fasting blood sampling for laboratory assessments and biomarkers 
 
Urine pregnancy test (only for women of childbearing potential) 
 
Urine albumin/creatinine ratio 
 
Dispensed study medication 
 
Dispense Urine Ketone Strips 
 
Concomitant medications  
 
6 minute walk test  
 
KCCQ questionnaire  
 
CardioMEMs pressure readings transmission (to be done twice daily at home between screening 
and randomization visit) 
 
Adverse events 
 
Serious adverse events 
 
Hospitalizations, ER visits, urgent outpatient visits for heart failure 
 
Contact IVR/IWR for randomization 
 
Dispense study medication (three 30 count bottles of empagliflozin 10 mg. or matching placebo) 
 
6.2.3 
Daily after randomization for 12 weeks 
 
CardioMEMs pressure readings transmission twice a day for 12 weeks (once at awakening in the 
morning and once at night) 
 
6.2.4 
Visit 2, 3, 4 and 6 (phone visits) 
 
Concomitant medications  
 
Adverse events 
 
Serious adverse events 
 
Hospitalizations, ER visits, urgent outpatient visits for heart failure 


EMBRACE-HF Protocol  v2.0                                                                                                         Page 36 of 69 
 
 
Self-monitored weight 
 
Self-monitored Blood Glucose (in patients with established T2D only) 
 
Volume depletion monitoring 
 
Ketoacidosis monitoring 
 
Encourage compliance with study medication 
 
6.2.5 
Visit 5 and 7 (office visits) 
 
Physical exam  
 
Vital Signs (seated pulse and BP and orthostatic pulse and BP) 
 
Weight 
 
Fasting blood sampling for laboratory assessments and biomarkers 
 
Urine pregnancy test (only for women of childbearing potential) 
 
Urine albumin/creatinine ratio 
 
Concomitant medications 
 
6 minute walk test 
 
KCCQ questionnaire 
 
Concomitant medications  
 
Adverse events 
 
Serious adverse events 
 
Hospitalizations, ER visits, urgent outpatient visits for heart failure 
 
Volume depletion monitoring 
 
Ketoacidosis monitoring 
 
Study medication return (redispense at Visit 5) and accountability 
 
Contact IVR/IWR at Visit 7 for treatment completion 
 
6.2.6 
Visit 8 (Study Closure Visit) 
 
Physical exam 
 
Vital Signs (seated pulse and BP and orthostatic pulse and BP) 
 
Weight 
 
Fasting blood sampling for laboratory assessments (only for renal panel). 
 
Urine pregnancy test (only for women of childbearing potential) 
 
Urine albumin/creatinine ratio 
 
Concomitant medications 
 
Adverse events 
 
Serious adverse events 
 
Hospitalizations, ER visits, urgent outpatient visits for heart failure 
 
Volume depletion monitoring 
 
Ketoacidosis monitoring 
 
6.2.7 
Premature Treatment Discontinuation Visit (PTDV) 
 
Performed at next on-site visit or as soon as possible (see section 5.9) 
 
Physical exam 
 
Vital Signs (seated pulse and BP and orthostatic pulse and BP) 
 
Weight 
 
Fasting blood sampling for laboratory assessments 
 
Urine pregnancy test (only applicable for women of childbearing potential) 


EMBRACE-HF Protocol  v2.0                                                                                                         Page 37 of 69 
 
 
Urine albumin/creatinine ratio 
 
Concomitant medications 
 
6 minute walk test 
 
KCCQ questionnaire 
 
Concomitant medications Adverse events  
 
Serious adverse events 
 
Hospitalizations, ER visits, urgent outpatient visits for heart failure 
 
Volume status monitoring 
 
Ketoacidosis monitoring 
 
Study medication return and accountability 
 
Contact IVR/IWR for treatment discontinuation 
 
6.3 
Patient Monitoring During Study Visits 
6.3.1 
Physical examination 
A physical examination should be done according to schedule shown in Study Plan (Table 1). 
 
A complete physical examination should include general appearance, head, eyes, ears, nose, 
throat, neck, cardiovascular system, lungs, abdomen, lymph nodes, extremities, neurological 
system, skin, and musculoskeletal system. Collection of pulse and blood pressure should also be 
collected as described in section 7.5. The patient should always be evaluated for the presence of 
edema and other signs of volume overload (jugular venous distention, rales, ascites, etc).  
 
Evaluation of volume depletion, including orthostatic vital signs and other physical exam 
findings consistent with dehydration 
 
Evaluation for the presence of ketoacidosis, in patients experiencing signs or symptoms of 
ketoacidosis, such as tachypnea or hyperventilation, anorexia, abdominal pain, nausea, 
vomiting, lethargy, or mental status changes; administer appropriate testing for ketoacidosis 
and direct patients to the emergency department if ketoacidosis is confirmed. 
 
For patients with established T2D and HbA1c ≤ 7.0% and receiving insulin at baseline, it is 
recommended to reduce total daily insulin dose by 20%. For patients with established T2D and 
HbA1c ≤ 7.0% and receiving sulfonylurea at baseline, it is recommended to reduce total daily 
sulfonylurea dose by 50%, or discontinue sulfonylureas in patients receiving the minimal dose 
of sulfonylurea at baseline.    
 
Baseline data are collected at Visit 1 and any new or aggravated findings discovered on 
subsequent physical examinations should be recorded as AE if clinically relevant. 
 
It is recommend that self monitoring of blood glucose (SMBG) values is performed by the 
patients with established T2D, as per standard of care, and reviewed during the study visits. 
Investigators are strongly encouraged to not titrate glucose-lowering medications in patients 
with established T2D during the study, except if required for patient safety. 
 
Review of self-monitoring of weight, with adjustments in diuretic dose if appropriate for 
optimization of volume status  
6.3.2 
Phone Visits 
Phone visits should be done according to the schedule shown in Study Plan (Table 1). 
Evaluate possible AE and SAEs, medication usage, self-monitoring of weight, and self-monitoring of 
blood glucose (in patients with established type 2 diabetes only). 
Upon review of self-monitoring of weight, and self-monitoring of blood glucose (in patients with 
established type 2 diabetes only), consider adjustments in diuretics for optimization of volume 
status, and adjustments of glucose-lowering medications for optimization of glucose control (in 


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patients with established type 2 diabetes only) if required for patient safety. Remind patients 
about importance to transmit CardioMEMs pressures twice a day. 
6.4 
Vital signs 
6.4.1 
Pulse and blood pressure 
One pulse measurement will be taken after the patient has been sitting and resting for at least 5 
minutes and before blood samples are taken. The pulse measurement will be followed by three 
blood pressure (BP) measurements separated by at least 1 minute each. All three BP readings 
should be recorded. At screening, the seated BP will be recorded three times in both the left and 
the right arms. All three measurements should be made in one arm before transferring the cuff to 
the other arm. The arm with the highest mean seated BP readings will be the one used for all 
subsequent readings. The average of the three BP readings will be used for study analyses. BP 
readings should be taken while the patient is in a comfortable seated position with the arm 
supported at the level of the heart.  All readings should be recorded. Ideally, blood pressure should 
be measured with the same machine, at the same time of day, and by the same personnel at each 
visit. 
6.4.2 
Orthostatic blood pressure 
 
At visits where orthostatic BP and pulse are collected, supine and standing measurements should 
be made after the seated BP and pulse measurements have been made, using the same arm that 
was used for the seated BP measurements. All readings should be recorded. Ideally, blood pressure 
should be measured with the same machine, at the same time of day, and by the same personnel at 
each visit. 
6.4.3 
Supine BP and pulse 
 
The supine BP and pulse must be measured prior to the standing BP and pulse. After the patient 
rests in the supine position for at least 5 minutes, supine BP and pulse will be determined from 
three replicate measurements obtained at least 1 minute apart. All three readings must be 
recorded. For study analyses, the average of the three BP and pulse readings will be used. 
6.4.4 
Standing BP and pulse 
 
After the supine BP and pulse measurements are obtained, the patient will stand for 2 to 3 minutes. 
After this time, the BP will be measured with the arm supported at the level of the heart. Standing 
BP and pulse will be determined from three replicate measurements obtained at least 1 minute 
apart. All 3 readings must be recorded. For study analyses, the average of the three BP and pulse 
readings will be used. 
If a new occurrence of previously absent orthostatic hypotension is demonstrated, it should be 
recorded as AE. The investigator may consider reducing concomitant anti- hypertensive medication 
to alleviate signs and symptoms of orthostatic hypotension. 
6.5 
Six Minute Walk Test 
The 6MWT is a practical simple test that requires a 100-ft hallway but no exercise equipment or 
advanced training for technicians. Walking is an activity performed daily by all but the most severely 
impaired patients. This test measures the distance that a patient can quickly walk on a flat, hard 
surface in a period of 6 minutes (the 6MWD). It evaluates the global and integrated responses of all the 
systems involved during exercise, including the pulmonary and cardiovascular systems, systemic 
circulation, peripheral circulation, blood, neuromuscular units, and muscle metabolism. It does not 
provide specific information on the function of each of the different organs and systems involved in 


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exercise or the mechanism of exercise limitation, as is possible with maximal cardiopulmonary exercise 
testing. The self-paced 6MWT assesses the submaximal level of functional capacity. Most patients do 
not achieve maximal exercise capacity during the 6MWT; instead, they choose their own intensity of 
exercise and are allowed to stop and rest during the test. However, because most activities of daily 
living are performed at submaximal levels of exertion, the 6MWD may better reflect the functional 
exercise level for daily physical activities. 31 
6.6 
Collection of Kansas City Cardiomyopathy Questionnaire (KCCQ) 
The KCCQ (see appendix B) is a disease-specific health status instrument composed of 23 items that 
quantify the domains of physical limitation, symptoms, self-efficacy, social limitation, and quality of life 
limitation from heart failure. The overall summary score and all domains have been independently 
demonstrated to be valid, reliable, and responsive to clinical change. Scores range from 0 to 100. The 
KCCQ overall summary score, a small but clinically meaningful change is considered to be ≥ 5 points.32 
The patients will fill in PRO (KCCQ) paper form under the supervision of the site staff.  
6.7 
Laboratory assessments 
 
Blood and urine samples for determination of clinical chemistry, hematology and urinalysis testing will 
be taken at the times indicated in the Study Plan (see Table 1).  Any additional laboratory safety 
samples taken at the investigator’s discretion will be analyzed locally. 
7 BIOLOGICAL SAMPLING PROCEDURES 
7.1 
Volume of blood 
The total volume of blood that will be drawn from each patient for this study is listed in Table 4 below. 
The collection of additional samples is performed locally at the discretion of the investigator and 
recorded in the eCRF as appropriate, thus requiring additional sample volumes. 
 
Table 4  
Volume of blood to be drawn from each patient 
Assessment 
Sample volume 
(mL) 
Number of 
Samples 
Total Volume (mL) 
HbA1c 
4 mL whole blood 
4 
16 mL 
Glucose 
2 mL whole blood 
3 
6 mL 
BNP 
2 mL whole blood 
4 
8 mL 
NTproBNP 
2 mL whole blood  
4 
8 mL 
CBC 
4 mL whole blood 
3 
12 mL 
Renal Panel/Uric 
Acid 
 
4 mL whole blood 
5 
20 mL 
Total 
 
 
70 mL 
 
7.2 
Handling, storage and destruction of biological samples 
 Blood and urine samples will be processed by local staff for shipment to the central laboratory 
(Quest Diagnostics).  All samples should be taken by adequately trained study personnel and handled 
in accordance with instructions in the central laboratory manual. Up to date reference ranges will be 
provided during the study and laboratory results will be compared to the laboratory standard normal 


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ranges and flagged if they are outside the normal range. The Investigator should make an assessment 
of any clinically significant abnormalities in the laboratory reports. The laboratory reports should be 
signed, dated and retained at the study site as source data for laboratory variables. The clinical 
chemistry, hematology, and urinalysis samples will be disposed after analyses.  
 
8 SAFETY 
8.1 
Definition of adverse events (AE) 
An adverse event (AE) is defined as any untoward medical occurrence, including an exacerbation of a 
pre-existing condition, in a patient in a clinical investigation who received a pharmaceutical product. 
The event does not necessarily have to have a causal relationship with this treatment. 
8.2 
Definitions of serious adverse event (SAE) 
A serious adverse event (SAE) is defined as any AE which results in death, is immediately life-
threatening, results in persistent or significant disability / incapacity, requires or prolongs patient 
hospitalisation, is a congenital anomaly / birth defect, or is to be deemed serious for any other 
reason if it is an important medical event when based upon appropriate medical judgement which 
may jeopardise the patient and may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definitions. 
Patients may be hospitalized for administrative or social reasons during the study (e.g. days on which 
infusion takes place, long distance from home to site,). These and other hospitalizations planned at 
the beginning of the study do not need to be reported as a SAE in case they have been reported at 
screening visit in the source data and have been performed as planned. 
 
8.2.1 
Classification of Death 
Deaths will be sub-classified by CV and non-CV primary cause. CV death includes sudden cardiac 
death, death due to acute MI, death due to heart failure, death due to a cerebrovascular event, 
death due to other CV causes (e.g., pulmonary embolism, aortic disease, CV intervention), and 
deaths for which there was no clearly documented non-CV cause (presumed CV death). 
Additionally, CV deaths will be sub-classified by coronary heart diseases death (CHD death) and 
non-CHD death. CHD death includes Sudden Cardiac Death, Death due to Acute MI, and the subset 
of Death due to other CV Causes that are secondary to a coronary revascularization procedure. 
8.2.2 
Universal classification of Myocardial Infarction (MI) 
The Third Universal MI definition33 will be used as study specific MI criteria. 
8.2.3 
Definition of Stroke 
Stroke is defined as an acute episode of neurologic dysfunction attributed to a central nervous 
system vascular cause. Stroke should be documented by imaging (eg, CT scan or magnetic 
resonance imaging [MRI] scan). Evidence obtained from autopsy can also confirm the diagnosis. 
Stroke will be sub classified, when possible, as either: 
8.2.4 
Primary ischemic stroke 
Primary ischemic stroke is defined as an acute episode of focal brain, spinal, or retinal dysfunction 
caused by an infarction of central nervous system tissue and documented by imaging. A primary 
ischemic stroke may also undergo hemorrhagic transformation (i.e., no evidence of hemorrhage on 
an initial imaging study, but appearance on a subsequent scan). 


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8.2.5 
Primary hemorrhagic stroke 
Primary hemorrhagic stroke is defined as an acute episode of focal or global brain, spinal, or retinal 
dysfunction caused by non-traumatic intraparenchymal, intraventricular, or subarachnoid 
hemorrhage as documented by neuroimaging or autopsy. Microhemorrhages (<10 mm) evident 
only on MRI are not considered to be a hemorrhagic stroke. Subdural and epidural bleeding will be 
considered intracranial hemorrhage, but not strokes. 
8.2.6 
Unclassified stroke 
Stroke with unknown etiology will be classified as unclassified stroke if the type of stroke could not 
be determined by imaging or other means. 
8.2.7 
Hospitalizations for heart failure 
In the event that a patient is hospitalized for heart failure over the course of the study, source 
documents will be obtained to adjudicate events. See appendix A for detailed information. 
 
8.3 
Definitions of adverse events of special interest (AESI) 
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 
 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: 
               
8.3.1 
Acute kidney injury (Decreased renal function) 
Defined by a creatinine value showing a ≥ 2 fold increase from baseline and is above the ULN, 
consistent with the RIFLE criteria for stage 2 acute kidney injury. 
For the AESI “acute kidney injury” 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 judgment. 
 
 
8.3.2 
Metabolic acidosis, ketoacidosis and diabetic ketoacidosis (DKA) 
Postmarketing cases show an association between sodium-glucose cotransporter-2 (SGLT2) 
inhibitor use and the development of a high anion gap metabolic acidosis accompanied by 
elevation in urine or serum ketones, frequently in the setting of only mildly elevated glucose levels 
(euglycemic DKA). Investigators are strongly encouraged to instruct patients and caregivers about 
the signs and symptoms of ketoacidosis, such as tachypnea or hyperventilation, anorexia, 
abdominal pain, nausea, vomiting, lethargy, or mental status changes; evaluate for the presence of 
ketoacidosis in patients experiencing such signs or symptoms – using provided urine ketone testing 
kits; discontinue study medication and advice patients to go to the nearest emergency department 


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if ketoacidosis is confirmed; and take appropriate measures to correct the ketoacidosis and to 
monitor glucose levels. Investigators are also strongly encouraged to avoid concomitant risk factors 
potentially predisposing to DKA, including carbohydrate-restricted diets and marked reductions in 
insulin dose during the study among patients with established type 2 diabetes and receiving insulin 
at baseline (above and beyond reductions in insulin dose specified in the study protocol for 
patients with established type 2 diabetes)). Advise patients to alert you and seek medical attention 
immediately if they experience symptoms consistent with DKA such as:  nausea, vomiting, 
abdominal pain, confusion, change in breathing pattern and unusual fatigue or sleepiness. 
In case of metabolic acidosis ketoacidosis and DKA, further investigations should be done according 
to the medical judgement 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).34  
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.  
Diagnostic criteria for DKA: 
 
DKA 
 
Mild 
Moderate 
Severe 
Plasma glucose (mg/dL) 
>250 
>250 
>250 
Arterial pH 
7.25-7.30 
7.00-7.24 
<7.00 
Serum bicarbonate (mEq/L) 
15-18 
10 to <15 
<10 
Urine ketones* 
Positive 
Positive 
Positive 
Serum ketones* 
Positive 
Positive 
Positive 
Effective serum osmolality (mOsm/kg)** 
Variable 
Variable 
Variable 
Anion gap*** 
>10 
>12 
>12 
Alteration in sensoria or mental obtundation 
Alert 
Alert/drowsy 
Stupor/coma 
*             Nitroprusside reaction method 
**          Calculation: 2[measured Na (mEq/L) + glucose (mg/dL)/18 
***        Calculation: (Na+) – (Cl- + HCO3-) (mEq/L) 
 
8.3.3 
Volume Depletion 
Empagliflozin has a modest diuretic effect. The risk of volume depletion is enhanced when two 
diuretics are used in combination and in patients that otherwise are at risk for volume depletion. 
Therefore, caution should be exercised when administering to patients at risk for volume depletion 
due to co-existing conditions or concomitant medications, such as loop diuretics. These patients 
should be carefully monitored for volume status, electrolytes, and renal function, and encouraged 
to self-monitor weight during the study.  


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8.3.4 
Severe Hypoglycemia 
All severe hypoglycemic events, (defined as symptomatic event requiring external assistance due to 
severe impairment in consciousness or behavior with resolution of event with administration of 
glucose, glucagon or other corrective action and a capillary or plasma glucose value <54 mg/dL), 
must be documented and reported.  
8.3.5 
Non-Traumatic Lower limb Amputation 
There is no evidence to date that use of empagliflozin impacts the risk of non-traumatic lower limb 
amputations. This AESI is being collected for surveillance of non-traumatic lower limb amputation 
events across the current clinical trials of empagliflozin. 
8.4 
Recording of adverse events 
8.4.1 
Collection of Adverse Events 
 
 AEs and SAEs (including hospitalizations for heart failure) will be recorded from Screening 
throughout the treatment period and including the follow-up period (Visit 8). 
All AEs/SAEs are to be recorded by the site.  SAEs, DAEs, AEs of Special Interest and non-serious 
AEs will be captured in the e-CRF.  Worsening of the underlying disease or of other pre-existing 
conditions will be recorded as an (S)AE in the e-CRF.  Changes in vital signs, ECG, physical 
examination and laboratory test results will be recorded as an (S)AE in the e-CRF , if they are 
judged clinically relevant by the investigator. 
SAEs and AESI are defined in section 8. 
A drug adverse event (DAE) is an adverse event which leads to premature and permanent 
discontinuation of study medication.   
Information about all urgent outpatient heart failure visits will also be recorded by the site and 
captured in the e-CRF. 
8.4.2 
Follow-up of unresolved Adverse Events 
 
Any AEs that are unresolved at the patient’s last visit in the study are followed up by the 
investigator for as long as medically indicated. 
 retains the right to request 
additional information for any patient with ongoing AE(s)/SAE(s) at the end of the study, if judged 
necessary. The requirement to follow-up is not intended to delay database lock or production of 
the clinical study report. Both these activities should proceed as planned with ongoing AEs if 
necessary. 
Any follow-up of ongoing AEs/SAEs after database lock will be reported to 
, 
who will notify the appropriate regulatory authorities of 
 and study drug 
manufacturer. 
8.4.3 
Variables 
 
The following variables will be collected for each AE; 
 
AE (verbatim) 
 
Date when the AE started and stopped 
 
Maximum intensity 
 
Whether the AE is serious or not 
 
Investigator causality rating against the Investigational Product (yes or no) 


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 
Action taken with regard to investigational product 
 
Outcome 
 
In addition, the following variables will be collected for SAEs: 
 
Date AE met criteria for serious AE 
 
Date Investigator became aware of serious AE 
 
AE is serious due to 
 
Date of hospitalization 
 
Date of discharge 
 
Probable cause of death 
 
Date of death 
 
Autopsy performed 
 
Causality assessment in relation to Study procedure(s) 
 
Causality assessment in relation to Other medication 
 
Description of AE 
 
The intensity of the AE should be judged based on the following: 
 
Mild: Awareness of sign(s) or symptom(s) which is/are easily tolerated 
 
Moderate: Enough discomfort to cause interference with usual activity 
 
Severe:  Incapacitating or causing inability to work or perform usual activities 
 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity. An 
AE of severe intensity need not necessarily be considered serious. For example, nausea that 
persists for several hours may be considered severe nausea, but not a SAE. On the other hand, a 
stroke that results in only a limited degree of disability may be considered a mild stroke but would 
be a SAE. 
8.4.4 
Causal Relationship of Adverse Event 
 
The Investigator will assess causal relationship between Investigational Product and each Adverse 
Event, and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable 
possibility that the event may have been caused by the investigational product?’ 
Medical judgment should be used to determine the relationship, considering all relevant factors, 
including pattern of reaction, temporal relationship, de-challenge or re-challenge, confounding 
factors such as concomitant medication, concomitant diseases and relevant history. Assessment of 
causal relationship should be recorded in the case report forms.  
Yes: 
There is a reasonable causal relationship between the investigational product 
 
administered and the AE.  
No: 
There is no reasonable causal relationship between the investigational product 
 
administered and the AE.  
For SAEs causal relationship will also be assessed for other medication and study procedures. Note 
that for SAEs that could be associated with any study procedure the causal relationship is implied as 
‘yes’. 
 
 


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8.4.5 
Adverse Events based on signs and symptoms 
 
All AEs spontaneously reported by the patient or reported in response to the open question from 
the study personnel: ‘Have you had any health problems since the previous visit/you were last 
asked?’, or revealed by observation will be collected.  When collecting AEs, the recording of 
diagnoses is preferred (when possible) to recording a list of signs and symptoms. However, if a 
diagnosis is known and there are other signs or symptoms that are not generally part of the 
diagnosis, the diagnosis and each sign or symptom will be recorded separately. 
8.4.6 
Adverse Events based on examinations and tests 
 
The results from protocol mandated laboratory test and vital signs will be summarized in the clinical 
study report. Deterioration as compared to baseline in protocol-mandated laboratory values and 
vital signs will only be reported as AEs if they are clinically significant, fulfill any of the SAE criteria or 
are the reason for discontinuation of treatment with the investigational product, or require the 
patient to receive specific corrective therapy. 
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, the 
sign/symptom will be reported as an AE and the associated laboratory result/vital sign will be 
considered as additional information. Wherever possible the reporting investigator uses the clinical, 
rather than the laboratory term (e.g., anemia versus low hemoglobin value). In the absence of 
clinical signs or symptoms, clinically relevant deteriorations in non-mandated measurements will be 
reported as AE(s). 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination as 
compared with the baseline assessment will be reported as an AE. 
8.5 
Reporting of serious adverse events 
All AEs/SAEs have to be reported to 
, whether or not considered causally related 
to the investigational product. The site investigator is responsible for informing their local IRB as per 
local requirements. 
Investigators and other center personnel must inform appropriate 
 
representatives via the web based data capture (WBDC) system of any SAE that occurs in the course of 
the study within 1 day (i.e., immediately but no later than the end of the next business day) of when he 
or she becomes aware of it. Follow-up information on SAEs must also be reported by the Investigator 
within the same time frame. 
An automated email alert will be sent to the designated 
 representative, when the 
page with SAE information is saved in WBDC system by the Investigators or other site personnel. If the 
WBDC system is not available, then the Investigator or other study site personnel reports by fax an SAE 
to the appropriate 
 representative. A paper back- up SAE report is used for this 
purpose. The same reporting time frames still apply. The investigator is responsible for completing the 
eCRF as soon as the system becomes available again.  
The 
 representative will work with the Investigator to compile all the necessary 
information and ensure that all the necessary information is provided to 
 within 
one calendar day of initial receipt for fatal and life threatening events and within five calendar days of 
initial receipt for all other SAEs. 
 
 


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8.5.1 
Reporting of serious adverse events to FDA and Boehringer Ingelheim Pharmaceuticals  
 
The Sponsor (
 will inform the FDA, via a MedWatch/AdEERs form, 
of any serious or unexpected adverse events that occur in accordance with the reporting obligations of 
21 CFR 312.32, and will concurrently forward all such reports to 
 
. It is the responsibility of the Sponsor to compile all necessary information and ensure that the FDA 
receives a report according to the FDA reporting requirement timelines and to ensure that these 
reports are also submitted to  at the same time. The Sponsor shall report (i.e., from signing the 
informed consent onwards through the trial defined follow-up period) all SAEs and non-serious AEs 
which are relevant for a reported SAE and Adverse Events of Special Interest (AESI) by fax or other 
secure method using  MedWatch/AdEERs form to the  Unique Entry Point in accordance with 
timeline specified below: 
 
within five (5) calendar days upon receipt of initial and follow-up SAEs containing at least one 
fatal or immediately life-threatening event;  
 
within ten (10) calendar days upon receipt of any other initial and follow-up SAEs.  
 
  
  
  
 
 
 
 
For each adverse event, the investigator will provide the onset date, end date, intensity,treatment 
required, outcome, seriousness, and action taken with the investigational drug. The investigator will 
determine the expectedness of the investigational drug to the AEs as defined in the Listed Adverse 
Events section of the 
 Investigator Brochure for the Productor 
 Drug 
Information e.g. Summary of Product Characteristics (SmPC) or Product Information (PI) for the 
authorised Study Drug provided by  
 
The investigator does not need to actively monitor patients for adverse events once the clinical trial 
has ended. However, if the investigator becomes aware of an SAE(s) that occurred after the patient has 
completed the clinical trial (including any protocol specified follow-up period), it should be reported to 
the Sponsor if investigator considers it as relevant to the study drug. 
 
 


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9 ETHICAL AND REGULATORY REQUIREMENTS 
9.1 
Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice (GCP), applicable regulatory 
requirements and the 
 policy on Bioethics. 
9.2 
Subject data protection 
The Informed Consent Form will incorporate (or, in some cases, be accompanied by a separate 
document incorporating) wording that complies with relevant data protection and privacy legislation. 
9.3 
Ethics and regulatory review 
An Ethics Committee/Institutional Review Board (IRB) should approve the final study protocol, 
including the final version of the Informed Consent Form and any other written information and/or 
materials to be provided to the patient. The investigator/Head of the study site will ensure the 
distribution of these documents to the applicable Ethics Committee/IRB, and to the study site staff. 
The opinion of the Ethics Committee should be received in writing. The investigator should submit a 
notification of direction/determination as well as a copy of the IRB written approval to 
 
before enrolment of any patient into the study. 
The Ethics Committee/IRB should approve all advertising used to recruit patients for the study. 
 should approve any modifications to the Informed Consent Form 
that are needed to meet local requirements. 
If required by local regulations, the protocol should be re-approved by the Ethics Committee annually. 
Before enrolment of any patient into the study, the final study protocol, including the final version of 
the Informed Consent Form, is approved by the national regulatory authority or a notification to the 
national regulatory authority is done, according to local regulations. 
 will handle the distribution of any of these documents to the 
national regulatory authorities. 
 will provide Regulatory Authorities, Ethics Committees/IRB and 
Principal Investigators with safety updates/reports according to local requirements, including SUSARs 
(Suspected Unexpected Serious Adverse Reactions), where relevant. 
Each Principal Investigator is responsible for providing the Ethics Committees/IRB with reports of any 
serious and unexpected adverse drug reactions that occur with the study medication during the study, 
according to their local Ethics Committee/IRB regulations.  
9.4 
Informed consent 
The Principal Investigator or delegate at each center will: 
 
Ensure each patient is given full and adequate oral and written information about the nature, 
purpose, possible risk and benefit of the study 
 
Ensure each patient is notified that they are free to discontinue from the study at any time 
 
Ensure that each patient is given the opportunity to ask questions and allowed time to consider the 
information provided 
 
Ensure each patient provides signed and dated informed consent before conducting any study 
specific procedure 


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 
Ensure the original, signed Informed Consent Form(s) is/are stored in the 
 
Investigator’s Study File 
 
Ensure a copy of the signed Informed Consent Form is given to the patient 
 
Ensure that any incentives for patients who participate in the study as well as any provisions for 
patients harmed as a consequence of study participation are described in the informed consent 
form that is approved by an Ethics Committee. 
9.5 
Changes to the protocol and informed consent form 
If there are any substantial changes to the study protocol, then these changes will be documented in a 
study protocol amendment and where required in a new version of the study protocol (Revised Clinical 
Study Protocol). 
 will distribute any subsequent amendments and new versions of 
the protocol to each Principal Investigator(s). If a protocol amendment requires a change to a center’s 
Informed Consent Form, 
 and the center’s IRB are to approve the 
revised Informed Consent Form before the revised form is used. 
 
9.6 
Audits and inspections 
Authorized representatives of 
, a regulatory authority, or an Ethics 
Committee may perform audits or inspections at the center, including source data verification. The 
purpose of an audit or inspection is to systematically and independently examine all study- related 
activities and documents, to determine whether these activities were conducted, and data were 
recorded, analyzed, and accurately reported according to the protocol, GCP, guidelines of the 
International Conference on Harmonization (ICH), and any applicable regulatory requirements. The 
investigator will contact 
 immediately if contacted by a regulatory 
agency about an inspection at the center. 
 
9.7 
Posting of information on clinicaltrials.gov 
Study information from this protocol will be posted on clinicaltrials.gov before enrollment of patients 
begins. 
 
10 STUDY MANAGEMENT BY 
 
10.1 Pre-study activities 
Before the first patient is entered into the study, it is necessary for a representative of 
 
 to evaluate the investigational study site to: 
 
Determine the adequacy of the facilities 
 
Determine availability of appropriate patients for the study 
 
Discuss with the investigator(s) (and other personnel involved with the study) their responsibilities 
with regard to protocol adherence, and the responsibilities of 
 
or its representatives. This will be documented in a Clinical Study Agreement between 
 
and the investigator. 


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10.2 Training of study site personnel 
Before the first patient is entered into the study, a 
 representative 
will review and discuss the requirements of the Clinical Study Protocol and related documents with the 
investigational staff and also train them in any study specific procedures and the WBDC system(s) 
utilized. 
The Principal Investigator will ensure that appropriate training relevant to the study is given to all of 
these staff, and that any new information relevant to the performance of this study is forwarded to the 
staff involved. 
The Principal Investigator will maintain a record of all individuals involved in the study (medical, 
nursing and other staff). 
10.3 Monitoring of the study 
During the study, a 
 representative will conduct regular monitoring 
visits with the study site. The monitoring visits may be conducted by phone, e-mail or by in-person 
visits to the study site. The monitoring visits will: 
1. Provide information and support to the investigator(s) 
2. Confirm that facilities remain acceptable 
3. Confirm that the investigational team is adhering to the protocol, that data are being accurately 
and timely recorded in the eCRF and that study drug accountability checks are being performed 
4. Perform source data verification (a comparison of the data in the eCRF with the patient’s medical 
records at the hospital or practice, and other records relevant to the study) including verification of 
informed consent of participating patients.  
 
The 
 representative will be available between visits if the 
investigator(s) or other study site personnel need information and advice about the study conduct. 
10.4 Source data 
The Clinical Study Agreement (CSA) will specify the location of source data. Access to source 
documents and source data is essential to inspection and review of clinical studies by the Food and 
Drug Administration (FDA). 
10.5 Study agreements 
The Principal Investigator at each center should comply with all the terms, conditions, and obligations 
of the CSA, or equivalent, for this study. In the event of any inconsistency between this Clinical Study 
Protocol and the CSA, the terms of Clinical Study Protocol shall prevail with respect to the conduct of 
the study and the treatment of patients and in all other respects, not relating to study conduct or 
treatment of patients, the terms of the CSA shall prevail. 
Agreements between 
 and the Principal Investigator should be in 
place before any study-related procedures can take place, or patients are enrolled. 
10.6 Archiving of study documents 
The Investigator follows the principles outlined in the CSA. 
10.7 Study timetable and end of study 
The study is expected to start in December 2016 and to end in June 2018. Planned treatment duration 
in the study is 12 weeks. 
 will notify investigators when recruitment 


EMBRACE-HF Protocol  v2.0                                                                                                         Page 50 of 69 
 
is complete. The end of the entire study is defined as ‘the last visit of the last patient undergoing the 
study’. 
The study may be terminated at individual centers if the study procedures are not being performed 
according to GCP, or if recruitment is slow. 
 may also terminate the 
entire study prematurely if concerns for safety arise within this study or in any other study with 
empagliflozin. 
 
11 DATA MANAGEMENT BY 
 
Data management will be performed by 
 Data Management Center 
staff. Data will be entered in the WBDC system at the study site. Trained site staff will be responsible 
for entering data on the observations, tests and assessments specified in the protocol into the WBDC 
system. Data entered in the WBDC system will be immediately saved to a central database and 
changes tracked to provide an audit trail. The data will then be source data verified, reviewed/queried 
and updated as needed. The Principal Investigator is responsible for electronically signing the eCRF. 
Data queries will be raised for inconsistent, improbable or missing data. All entries to the study 
database will be available in an audit trail. The data will be frozen and then locked to prevent further 
editing. When all data have been coded, validated, signed, and locked, a clean file will be declared. Any 
treatment revealing data may thereafter be added and the final database will be locked. A copy of the 
eCRF will be archived at the study site when the study has been locked. 
 
12 STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION 
12.1 Description of analysis sets 
12.1.1 Efficacy analysis set 
Intention to treat (ITT) is defined as all patients who have been randomized to study treatment, 
received at least one dose of study medication and completed at least one CardioMeMs 
transmission after randomization. The ITT data set will be used for the primary and secondary 
efficacy endpoints and exploratory endpoints. 
12.1.2 Safety analysis set 
All patients who received at least 1 dose of randomized empagliflozin or placebo, and for whom 
post-dose data are available, will be included in the safety analysis set. Throughout the safety 
results sections, erroneously treated patients (eg, those randomized to empagliflozin but actually 
given placebo) will be accounted for in the actual treatment group. If a patient received study drug 
from the wrong kit for only a part of the treatment duration and then switched to another, the 
associated actual treatment group for that patient will be the treatment group the patient had the 
longest exposure to. 
12.2 Methods of statistical analyses 
Randomization will be stratified by diabetes status (diabetes vs. no-diabetes). All analyses will be on 
the ITT unless otherwise specified. Baseline demographic and clinical data will be described between 
treatment and placebo study arms as mean ± standard deviation for continuous variables and 
compared using Student’s T-test. Whereas discrete variables will be represented as a number and (%) 
and compared using the χ2 or Fisher’s exact test, as applicable.  


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The time course of continuous variables will be presented using standard descriptive summary 
statistics calculated at each scheduled measuring time point and the last individual measuring time 
point. Moreover, standard descriptive summary statistics will be calculated for the change (absolute or 
percent) from baseline to each scheduled measuring time point after baseline and the last individual 
measuring time point. 
 
Due to the large number of study sites and the expected low number of patients per site it will not be 
appropriate to explore site effects.  
 
Statistical significance will be defined using two-sided tests with α=0.05, unless otherwise specified. All 
statistical analyses will be performed by the 
 Department of 
Biostatistics using SAS version 9.4 (SAS Institute, Cary, North Carolina). 
 
12.2.1 Primary endpoint 
 
The primary endpoint of this study is the change in pulmonary artery diastolic pressure from baseline to end 
of treatment period (defined as average of pulmonary artery diastolic pressure measurements between 
weeks 8-12).  This will be analyzed using a repeated measures model incorporating a within-patient 
covariance structure to estimate the effect of treatment. 
Primary endpoint will be analyzed in the entire patient cohort, and then within the subgroups of patients 
with and without diabetes (as pre-specified subgroup analyses). 
 
12.2.2 Secondary endpoints 
The following secondary endpoints have been identified: 
1. Change from baseline in pulmonary artery diastolic pressure at each interim time point (weeks 1, 
2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) 
2. Change in pulmonary artery systolic pressure from baseline to end of treatment period  
3. Change from baseline in pulmonary artery systolic pressure at each interim time point (weeks 1, 2, 
3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) 
4. Change in mean pulmonary artery pressure from baseline to end of treatment period 
5. Change from baseline in mean pulmonary artery pressure at each interim time point (weeks 1, 2, 3, 
4, 5, 6, 7, 8, 9, 10, 11 and 12) 
6. Change in heart failure related quality of life using the Kansas City Cardiomyopathy Questionnaire 
(KCCQ) overall summary score from baseline to follow-up (defined as average of measurements at 6 
and 12 weeks).  
7. Proportion of patients with a ≥ 5pts increase from baseline in the Kansas City Cardiomyopathy 
Questionnaire (KCCQ) at either 6 weeks or 12 weeks of follow-up  
8. Change in 6 minute walk test from baseline to follow-up (defined as average of measurements at 6 
and 12 weeks) 
9. Change in NTproBNP from baseline to follow-up (defined as average of measurements at 6 and 12 
weeks) 


EMBRACE-HF Protocol  v2.0                                                                                                         Page 52 of 69 
 
10. Change in BNP from baseline to follow-up (defined as average of measurements at 6 and 12 weeks) 
11. Proportion of patients with a ≥ 20% decrease from baseline in NTproBNP at either 6 weeks or 12 
weeks of follow-up. 
12. Proportion of patients with a ≥ 20% decrease from baseline in BNP at either 6 weeks or 12 weeks 
of follow-up. 
13. Proportion of patients with both a ≥ 5pts increase from baseline in KCCQ and a ≥ 20% decrease 
from baseline in NTproBNP at either 6 weeks or 12 weeks of follow-up 
14. Number of diuretic medication adjustments during the treatment period (up-titration and down-
titration of diuretic doses to be evaluated separately) 
15. Change in Hemoglobin A1c from baseline to follow-up (defined as average of measurements at 6 and 
12 weeks), evaluated separately in patient with and without type 2 diabetes 
 
Continuous variable comparisons will be analyzed using the same repeated measures method as the 
primary analyses. Treatment and time interaction will be included to model the effect patterns. The 
mean change within each treatment group will be calculated with corresponding 95% confidence 
intervals for each time point.  Dichotomous outcomes will be analyzed using logistic regression 
including a fixed effect for treatment; odds ratios and 95% confidence intervals will be reported.  
Secondary endpoints will be analyzed in the entire patient cohort, and then within the subgroups of 
patients with and without diabetes (as pre-specified subgroup analyses). 
12.2.3 Exploratory endpoints 
The following exploratory endpoints have been identified: 
1. Change in pulmonary artery diastolic pressure between week 12 and week 13 
2. Change in mean pulmonary artery pressure between week 12 and week 13  
3. Change in pulmonary artery systolic pressure between week 12 and week 13 
4. Change in mean heart rate from baseline to end of treatment period 
5. Effects on average weekly loop diuretic dose (furosemide equivalent).  
6. Effects on hospitalizations for heart failure.  
7. Effects on urgent outpatient heart failure visits. 
8. Effects on hospitalizations for heart failure and urgent outpatient visits for heart failure 
9. Change in NYHA Class at 6 weeks from baseline and 12 weeks from baseline. 
10. Change in NTproBNP and KCCQ at 6 weeks from baseline and 12 weeks from baseline 
11. Number of medication adjustments other than diuretics (nitrates, hydralazine, ACE, ARB, b-
blockers, sacubitril/valsartan) during the treatment period 
12. Proportion of patients that progress to diabetes during the treatment period (within the 
subgroup of patients without diabetes at baseline only) 
 


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Exploratory data will be summarized descriptively and presented by treatment group.  
Exploratory endpoints will be analyzed in the entire patient cohort, and then within the subgroups of 
patients with and without diabetes (as pre-specified subgroup analyses). 
12.2.4 Safety variables 
The safety evaluations will include the analyses of all AEs and SAEs, however the following safety 
variables have been identified a priori: 
1. 
All cause death 
2. 
Cardiovascular death 
3. 
Non-fatal myocardial infarction (MI) 
4. 
Stroke 
5. 
Acute kidney injury (defined as doubling of serum creatinine based on the RIFLE criteria) 
6. 
Adverse events (AEs) and serious adverse events (SAEs). AEs of special interest will include diabetic 
ketoacidosis (DKA), volume depletion (defined as hypotension, syncope, orthostatic hypotension or 
dehydration), severe hypoglycemic events, and non-traumatic lower limb amputations. 
Safety data will be summarized descriptively and presented by treatment group. 
 
12.2.5 Analysis for safety 
Safety analyses will be done periodically during the study and reported to the IDSMC. A formal IDSMC 
charter will be developed along with the possible stopping rules. 
 
12.3 Determination of sample size 
A sample size of 28 patients for each group will achieve 80% power with α=0.05 to detect a 20% 
difference in mean pulmonary artery pressure between the empagliflozin 10 mg and placebo groups 
over the treatment period. 
The assumptions for this calculation were: 1) between-patient standard deviation = 6, 2) Within patient 
correlation between adjacent time points: 0.7, 3) Mean PA pressure in the intervention arm of the trial 
will achieve a plateau at the 9th time point for treatment group. 
  
13 IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED BY THE INVESTIGATOR 
13.1 Medical emergencies and 
 Contacts 
The Principal Investigator is responsible for ensuring that procedures and expertise are available to 
handle medical emergencies during the study. A medical emergency usually constitutes an SAE and is 
to be reported as such. 
In the case of a medical emergency the investigator may contact the Study Team Physician at 
 
. 


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Name 
Role in the study 
Address & telephone number 
 
Lead Study Team Physician 
responsible for the protocol 
 
 
 
 
 
 
 Study Manager 
 
 
 
  
 
 
 
13.2 Overdose 
Overdose is defined as the accidental or intentional ingestion of any dose of investigational product 
that is considered both excessive and medically important. Empagliflozin has been well tolerated at 
doses of up to 800 mg/day in single dose testing in healthy volunteers35 and up to 100 mg/day in 
repeat dose testing for 8 days in healthy volunteers and patients with type 2 diabetes36.  If an overdose 
is suspected, monitoring of vital functions as well as treatment, as appropriate, should be performed. If 
an overdose occurrence meets the criteria for a Serious Adverse Event, then it must be reported as 
Serious Adverse Event. 
13.3 Pregnancy 
Any pregnancy during the course of this study should be recorded.  Pregnancy itself is not regarded as 
an Adverse Event unless there is a suspicion that the investigational product under study may have 
interfered with the effectiveness of a contraceptive medication. 
 If any pregnancy occurs in the course of the study, the patient should be discontinued, the 
investigational product should be stopped and then investigators or other site personnel must inform 
appropriate 
 immediately but no later than the end of the next 
business day of when he or she becomes aware of it. 
 
14 REFERENCES 
1. 
Go, A. S. et al. Heart disease and stroke statistics--2014 update: a report from the American 
Heart Association. Circulation 129, e28-e292, doi:01.cir.0000441139.02102.80 [pii] 
10.1161/01.cir.0000441139.02102.80 (2014). 
2. 
McMurray, J. J. et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J 
Med 371, 993-1004, doi:10.1056/NEJMoa1409077 (2014). 
3. 
Parving, H.-H. et al. Cardiorenal End Points in a Trial of Aliskiren for Type 2 Diabetes. New 
England Journal of Medicine 367, 2204-2213, doi:10.1056/NEJMoa1208799 (2012). 
4. 
Bertoni, A. G. et al. Heart failure prevalence, incidence, and mortality in the elderly with 
diabetes. Diabetes Care 27, 699-703 (2004). 


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5. 
Erdmann, E. et al. Pioglitazone use and heart failure in patients with type 2 diabetes and 
preexisting cardiovascular disease: data from the PROactive study (PROactive 08). Diabetes 
Care 30, 2773-2778, doi:dc07-0717 [pii] 
10.2337/dc07-0717 (2007). 
6. 
Komajda, M. et al. Heart failure events with rosiglitazone in type 2 diabetes: data from the 
RECORD clinical trial. Eur Heart J 31, 824-831, doi:ehp604 [pii] 
10.1093/eurheartj/ehp604 (2010). 
7. 
Ryden, L., Thrainsdottir, I. & Swedberg, K. Adjudication of serious heart failure in patients from 
PROactive. Lancet 369, 189-190, doi:S0140-6736(07)60106-8 [pii] 
10.1016/S0140-6736(07)60106-8 (2007). 
8. 
Scirica, B. M. et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes 
mellitus. N Engl J Med 369, 1317-1326, doi:10.1056/NEJMoa1307684 (2013). 
9. 
White, W. B. et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N 
Engl J Med 369, 1327-1335, doi:10.1056/NEJMoa1305889 (2013). 
10. 
Gerstein, H. C. et al. Long-term effects of intensive glucose lowering on cardiovascular 
outcomes. N Engl J Med 364, 818-828, doi:10.1056/NEJMoa1006524 (2011). 
11. 
Inzucchi, S. E. et al. SGLT-2 inhibitors and cardiovascular risk: proposed pathways and review 
of ongoing outcome trials. Diab Vasc Dis Res 12, 90-100, doi:10.1177/1479164114559852 
(2015). 
12. 
Neal, B. et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. New 
England Journal of Medicine 0, null, doi:10.1056/NEJMoa1611925. 
13. 
Zinman, B. et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N 
Engl J Med, doi:10.1056/NEJMoa1504720 (2015). 
14. 
Fitchett, D. et al. <div xmlns="http://www.w3.org/1999/xhtml failure outcomes with 
empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-
REG OUTCOME<sup>®</sup> trial</div>. European Heart Journal, 
doi:10.1093/eurheartj/ehv728 (2016). 
15. 
Neal, B. et al. Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular 
Assessment Study (CANVAS)—a randomized placebo-controlled trial. Am Heart J 166, 
doi:10.1016/j.ahj.2013.05.007 (2013). 
16. 
Kosiborod, M. et al. Lower Risk of Heart Failure and Death in Patients Initiated on SGLT-2 
Inhibitors Versus Other Glucose-Lowering Drugs: The CVD-REAL Study. Circulation, 
CIRCULATIONAHA. 117.029190 (2017). 
17. 
Scheerer, M. et al. Gesamtereignisraten für die Hospitalisierung bei Herzinsuffizienz (HHI) bei 
Neueinstellung auf SGLT-2-Hemmer im Vergleich zu anderen Antidiabetika–Daten aus dem 
klinischen Alltag aus Deutschland, Schweden und Norwegen mit mehr als 45.000 Typ 2 
Diabetes Patienten (CVD-Real). Diabetologie und Stoffwechsel 12, LB12* (2017). 
18. 
Inzucchi, S. E. et al. SGLT-2 inhibitors and cardiovascular risk: proposed pathways and review 
of ongoing outcome trials. Diab Vasc Dis Res 12, doi:10.1177/1479164114559852 (2015). 
19. 
Zile MR, Bourge RC, Bennett TD, et al. Application of implantable hemodynamic monitoring in the 
management of patients with diastolic heart failure: a subgroup analysis of the COMPASS-HF trial. 
Journal of cardiac failure. Dec 2008;14(10):816-823. 
20. 
Stevenson LW, Zile M, Bennett TD, et al. Chronic ambulatory intracardiac pressures and future 
heart failure events. Circulation. Heart failure. Sep 2010;3(5):580-587. 
21. 
Medical SJ.  https://health.sjm.com/heart-failure-answers/treatment-options/pulmonary-artery-
pressure-monitoring/cardiomems. Available at: https://health.sjm.com/heart-failure-
answers/treatment-options/pulmonary-artery-pressure-monitoring/cardiomems. Accessed 
10/29/2015, 2015. 


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22. 
Adamson PB, Abraham WT, Aaron M, et al. CHAMPION trial rationale and design: the long-term 
safety and clinical efficacy of a wireless pulmonary artery pressure monitoring system. J Card Fail. 
Jan 2011;17(1):3-10. 
23. 
Abraham WT, Adamson PB, Bourge RC, et al. Wireless pulmonary artery haemodynamic 
monitoring in chronic heart failure: a randomised controlled trial. Lancet. Feb 19 
2011;377(9766):658-666. 
24. 
Abraham WT, Stevenson LW, Bourge RC, et al. Sustained efficacy of pulmonary artery pressure to 
guide adjustment of chronic heart failure therapy: complete follow-up results from the CHAMPION 
randomised trial. Lancet. Nov 6 2015. 
25. 
 EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction 
(EMPEROR-Reduced). ClinicalTrials.gov 2017; 
https://clinicaltrials.gov/ct2/show/NCT03057977?term=03057977&rank=1  
26.   
EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection 
Fraction (EMPEROR-Preserved). ClinicalTrials.gov 2017; 
https://clinicaltrials.gov/ct2/show/NCT03057951?term=03057951&rank=1  
27.   
Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or 
Cardiovascular Death in Patients With Chronic Heart Failure (Dapa-HF). ClinicalTrials.gov 2017; 
https://clinicaltrials.gov/ct2/show/NCT03036124?term=03036124&rank=1 
28. 
Boehringer Ingelheim Pharmaceuticals I. Jardiance Prescribing Information - Boehringer Ingelheim. 
2016; Jardiance Prescribing Information. Available at: http://docs.boehringer-
ingelheim.com/Prescribing Information/PIs/Jardiance/jardiance.pdf. Accessed August 11th, 2016. 
29. 
Tang H, Li D, Wang T, Zhai S, Song Y.  Effect of Sodium-Glucose Cotransporter 2 Inhibitors on 
Diabetic Ketoacidosis Among Patients With Type 2 Diabetes: A Meta-analysis of Randomized 
Controlled Trials. Diabetes Care. 2016 Aug;39(8):e123-4 
30. 
Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, 
Matthews DR, CANVAS Program Collborative Group. The New England Journal of Medicine. 2017 
Aug 17;377(7):644-657.   
31. 
Guyatt GH, Sullivan MJ, Thompson PJ, et al. The 6-minute walk: a new measure of exercise capacity 
in patients with chronic heart failure. Can Med Assoc J. Apr 15 1985;132(8):919-923. 
32. 
Hauptman PJ, Masoudi FA, Weintraub WS, Pina I, Jones PG, Spertus JA. Variability in the clinical 
status of patients with advanced heart failure. J Card Fail. Oct 2004;10(5):397-402. 
33. 
Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. Circulation. 
Oct 16 2012;126(16):2020-2035 
34. 
Kitabchi AE, Umpierrez GE, Murphy MB, et al. Hyperglycemic crises in diabetes. Diabetes care. Jan 
2004;27 Suppl 1:S94-102. 
35. 
Seman L MS, Nehmiz G, Simons G, Ren B, Pinnetti S, Woerle H and Dugi K. Empagliflozin (BI 10773), 
a Potent and Selective SGLT2 Inhibitor, Induces Dose-Dependent Glucosuria in Healthy Subjects. 
Clinical Pharmacology in Drug Development. April 2013 2013;2(2):152-161. 
36. 
Heise T, Seman L, Macha S, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of 
multiple rising doses of empagliflozin in patients with type 2 diabetes mellitus. Diabetes therapy : 
research, treatment and education of diabetes and related disorders. Dec 2013;4(2):331-345. 
 
 
 
 
 


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15 APPENDIX A: HEART FAILURE HOSPITALIZATION/URGENT OUTPATIENT VISIT 
A Heart Failure Event includes hospitalization for heart failure and may include urgent outpatient visits. 
Heart failure hospitalizations should remain delineated from urgent visits. 
 
A Heart Failure Hospitalization is defined as an event that meets ALL of the following criteria: 
 
 
The patient is admitted to the hospital with a primary diagnosis of heart failure 
 
The patient’s length-of-stay in hospital extends for at least 24 hours (or a change in calendar date if 
the hospital admission and discharge times are unavailable) 
 
The patient exhibits documented new or worsening symptoms due to heart failure on 
presentation, including at least ONE of the following: 
 
o Dyspnea (dyspnea with exertion, dyspnea at rest, orthopnea, paroxysmal nocturnal 
dyspnea) 
o Decreased exercise tolerance  
o Fatigue 
o Other symptoms of worsened end-organ perfusion or volume overload 
 
 
The patient has objective evidence of new or worsening heart failure, consisting of at least TWO 
physical examination findings OR one physical examination finding and at least ONE laboratory 
criterion), including: 
 
o Physical examination findings considered to be due to heart failure, including new or 
worsened: 
 
Peripheral edema 
 
Increasing abdominal distention or ascites (in the absence of primary hepatic 
disease) 
 
Pulmonary rales/crackles/crepitations 
 
Increased jugular venous pressure and/or hepatojugular reflux 
 
S3 gallop 
 
Clinically significant or rapid weight gain thought to be related to fluid retention 
 
o Laboratory evidence of new or worsening heart failure, if obtained within 24 hours of 
presentation, including: 
 
Increased B-type natriuretic peptide (BNP)/ N-terminal pro-BNP (NT- proBNP) 
concentrations consistent with decompensation of heart failure (such as BNP > 500 
pg/mL or NT-proBNP > 2,000 pg/mL). In patients with chronically elevated 
natriuretic peptides, a significant increase should be noted above baseline. 
 
Radiological evidence of pulmonary congestion 
 
Non-invasive or invasive diagnostic evidence of clinically significant elevated left- 
or right-sided ventricular filling pressure or low cardiac output. For example, 
echocardiographic criteria could include: E/e’ > 15 or D-dominant pulmonary 
venous inflow pattern, plethoric inferior vena cava with minimal collapse on 
inspiration 
OR 


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 
Invasive diagnostic evidence with right heart catheterization showing a pulmonary 
capillary wedge pressure (pulmonary artery occlusion pressure) • ≥18 mmHg, 
central venous pressure ≥ 12 mmHg, or a cardiac index < 2.2 L/min/m2 
 
 
The patient receives initiation or intensification of treatment specifically for heart failure, including 
at least ONE of the following: 
 
o Augmentation in oral diuretic therapy 
o Intravenous diuretic, inotrope, or vasodilator therapy 
o Mechanical or surgical intervention, including: 
 
Mechanical circulatory support (e.g., intra-aortic balloon pump, ventricular assist 
device) 
 
Mechanical fluid removal (e.g., ultrafiltration, hemofiltration, dialysis) Using 
available information, Heart Failure will be categorized based on the following: 
 
Left ventricular ejection fraction (LVEF) 
 
Type 
 
Etiology 
 
 
An Urgent Heart Failure Visit is defined as an event that meets all of the following: 
 
 
The patient has an urgent, unscheduled office/practice or emergency department 
visit for a primary diagnosis of heart failure, but not meeting the criteria for a heart 
failure hospitalization. 
 
All signs and symptoms for heart failure hospitalization (i.e., 3) symptoms; 4) 
physical examination findings/laboratory evidence of new or worsening heart 
failure, as indicated above) must be met 
 
The patient receives initiation or intensification of treatment specifically for heart 
failure, as detailed in the above section with the exception of oral diuretic therapy, 
which will not be sufficient. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16 APPENDIX B: KANSAS CITY CARDIOMYOPATHY QUESTIONNAIRE (KCCQ) 
 
Kansas City Cardiomyopathy Questionnaire (KCCQ) 
 
The following questions refer to your heart failure and how it may affect your life. Please read and 
complete the following questions.  There are no right or wrong answers.  Please mark the answer that best 
applies to you. 
Heart failure affects different people in different ways.  Some feel shortness of breath while others feel 
fatigue.  Please indicate how much you are limited by heart failure (shortness of breath or fatigue) in your 
ability to do the following activities over the past 2 weeks. 
 
Activity 
Extremely 
Limited 
Quite a bit 
Limited 
Moderately 
Limited 
Slightly 
Limited 
Not at all 
Limited 
Limited for other 
reasons or did not 
do the activity 
Dressing yourself 
 
 
 
 
 
 
Showering/Bathing 
 
 
 
 
 
 
Walking 1 block on 
level ground  
 
 
 
 
 
 
Doing yardwork, 
housework or 
carrying groceries 
 
 
 
 
 
 
Climbing a flight of 
stairs without 
stopping 
 
 
 
 
 
 
Hurrying or jogging 
(as if to catch a bus) 
 
 
 
 
 
 
 
2.  Compared with 2 weeks ago, have your symptoms of heart failure (shortness of breath, fatigue, 
or ankle swelling) changed?   
 
 
My symptoms of heart failure have become…  
Much worse  
Slightly 
worse  
Not changed 
Slightly better Much better 
I’ve had no symptoms 
over the last 2 weeks 
 
 
 
 
 
 
 


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3.  Over the past 2 weeks, how many times did you have swelling in your feet, ankles or legs when 
you woke up in the morning? 
 
Every morning 
3 or more times 
a week, but not 
every day 
1-2 times a week Less than once a 
week 
Never over the 
past 2 weeks 
 
 
 
 
 
 
 
4.  Over the past 2 weeks, how much has swelling in your feet, ankles or legs bothered you? 
 
It has been ... 
Extremely 
bothersome 
Quite a bit 
bothersome 
Moderately 
bothersome 
Slightly 
bothersome 
Not at all 
bothersome 
I’ve had no 
swelling 
 
 
 
 
 
 
 
 
5.  Over the past 2 weeks, on average, how many times has fatigue limited your ability to do what 
you  want?  
All of the 
time 
Several times 
per day 
At least once 
a day 
3 or more times 
per week but not 
every day 
1-2 times 
per week 
Less than once a 
week 
Never over 
the past 2 
weeks 
 
 
 
 
 
 
 
 
 
Over the past 2 weeks, how much has your fatigue bothered you? 
 
It has been ... 
Extremely 
bothersome 
Quite a bit 
bothersome 
Moderately 
bothersome 
Slightly 
bothersome 
Not at all 
bothersome  
I’ve had 
no fatigue 
 
 
 
 
 
 
 
7. Over the past 2 weeks, on average, how many times has shortness of breath limited your ability 
to do what you wanted?  
All of the 
time 
Several times 
per day 
At least once 
a day 
3 or more times 
per week but not 
every day 
1-2 times 
per week 
Less than once a 
week 
Never over 
the past 2 
weeks 
 
 
 
 
 
 
 
 


EMBRACE-HF Protocol  v2.0                                                                                                         Page 61 of 69 
 
8.  Over the past 2 weeks,  how much has your shortness of breath bothered you? 
 
It has been ... 
Extremely 
bothersome 
Quite a bit 
bothersome 
Moderately 
bothersome 
Slightly 
bothersome 
Not at all 
bothersome 
I’ve had no 
shortness of breath 
 
 
 
 
 
 
 
9.  Over the past 2 weeks, on average, how many times have you been forced to sleep sitting up in a 
chair or with at least 3 pillows to prop you up because of shortness of breath? 
 
Every night 
3 or more times a 
week, but not every day 
1-2 times a 
week 
Less than once 
a week 
Never over the 
past 2 weeks 
 
 
 
 
 
 
10.  Heart failure symptoms can worsen for a number of reasons.  How sure are you that you know what to 
do, or whom to call, if your heart failure gets worse? 
 
Not at all sure  
Not very sure 
Somewhat sure 
Mostly sure 
Completely sure 
 
 
 
 
 
 
 
11.  How well do you understand what things you are able to do to keep your heart failure symptoms from 
getting worse? (for example, weighing yourself, eating a low salt diet etc.) 
 
Do not understand  
at all 
Do not understand 
very well 
Somewhat 
understand 
Mostly 
understand 
Completely 
understand 
 
12.  Over the past 2 weeks, how much has your heart failure limited your enjoyment of life? 
 
It has extremely 
limited my 
enjoyment of life 
It has limited my 
enjoyment of life 
quite a bit 
It has moderately 
limited my 
enjoyment of life 
It has slightly 
limited my 
enjoyment of life 
It has not limited 
my enjoyment of 
life at all  
 
 
 
 
 
 


EMBRACE-HF Protocol  v2.0                                                                                                         Page 62 of 69 
 
13.  If you had to spend the rest of your life with your heart failure the way it is right now, how 
would you feel about this? 
Not at all 
satisfied  
Mostly 
dissatisfied 
Somewhat 
satisfied 
Mostly 
satisfied 
Completely 
satisfied 
 
 
 
 
 
 
 
14.  Over the past 2 weeks, how often have you felt discouraged or down in the dumps because of 
your heart failure? 
I felt that way 
all of the time 
I felt that way 
most of the time 
I occasionally 
felt that way 
I rarely felt that 
way 
I never felt that 
way 
 
 
 
 
 
 
15.  How much does your heart failure affect your lifestyle?  Please indicate how your heart failure 
may have limited your participation in the following activities over the past 2 weeks. 
Please place an X in one box on each line 
 
Activity 
 
Severely 
limited 
 
Limited quite a 
bit 
 
Moderately 
limited 
 
Slightly 
limited 
 
Did not limit 
at all 
Does not apply 
or did not do for 
other reasons 
Hobbies, 
recreational 
activities 
 
 
 
 
 
 
 
 
 
 
 
 
Working or doing 
household chores 
 
 
 
 
 
 
 
 
 
 
 
 
Visiting  family or 
friends out of your 
home 
 
 
 
 
 
 
 
 
 
 
Intimate 
relationships with 
loved ones  
 
 
 
 
 
 
 
 
 
 
 
 
Place an X in one box on each line 
 




EMBRACE-HF Protocol  v2.0                                                                                                         Page 64 of 69 
 
(Part A) 
 
1. 
Products included in trial medication: 
 
Medication kit type * 1 
 
Storage conditions labeled by CTSU/Vendor 
Storage conditions not labeled by CTSU/Vendor 
blinded 
open label 
open label commercial product 
Product, Formulation, Dosage strength 
Packaging material 
(for comparators incl. INN, trade name and manufacturer name; EU or US) 
 
Empagliflozin 
 Film-coated tablets 10 mg or placebo 
PP Bottle 
Medication kit type * 2 
Storage conditions labeled by CTSU/Vendor 
Storage conditions not labeled by CTSU/Vendor 
blinded 
open label 
open label commercial product 
Product, Formulation, Dosage strength 
Packaging material 
(for comparators incl. INN, trade name and manufacturer name; EU or US) 
Empagliflozin
 Film-coated tablets 25 mg or placebo 
PP Bottle 
 
*table might be adopted or multiplicated due to study design 


EMBRACE-HF Protocol  v2.0                                                                                                         Page 65 of 69 
 
(Part B) 
 
2. 
Storage conditions based on current SPI for included products: 
 
Medication kit type(s) * 1 + 2 
(requiring identical storage statement) 
Product, Formulation, Dosage strength 
SPI no. incl version 
Either released or in preparation 
Empagliflozin 
 Film-coated tablets 10 mg or placebo 
007-SPI-1264-ABCD-01 
( 11.0 ) 
Empagliflozin 
 Film-coated tablets 25 mg or placebo 
007-SPI-1264-ABCD-01 
( 11.0 ) 
Storage conditions: 
EU / ROW 
This medicinal product does not require any special 
(outer carton**) 
CZ I/II (except 
storage conditions. 
for KR)***: 
ROW CZ III/IV 
Do not store above 30°C. 
and KR 
US/CA: 
Store at 25°C (77°F); excursions permitted to 15-30°C 
(59-86°F). 
Stability of 
EU/ROW: 
--- 
reconstituted/diluted/ 
mixed solution / 
US/CA: 
--- 
In-Use-Stability: 
Shipping conditions: 
No temperature relevance 


EMBRACE-HF Protocol  v2.0                                                                                                         Page 66 of 69 
 
Alert settings for 
--- 
temperature loggers: 
Remarks: 
--- 
* Tables might be adopted or multiplicated due to study design 
 
** Text on immediate containers may be shortened or omitted by CTSU in accordance with applicable 
regulations 
*** Storage conditions might be tightened due to country specific requirements 







SAP_001.pdf: 
Statistical Analysis Plan  
 
Protocol Title:  EMpagliflozin evaluation By measuRing 
ImpAct on HemodynamiCs in PatiEnts with Heart Failure 
(EMBRACE-HF) 
 
Protocol Number: 1245.129 
 
ClinicalTrials.gov registration:  NCT03030222 
 
Version Number:    Final 
 
Version Date:     
March 8, 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Page 1 of 36 


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Page 2 of 36
Abbreviation or 
special term 
Explanation 
AE 
AFib 
Adverse Event  
Atrial fibrillation 
BMI 
Body mass index 
BNP 
B-type natriuretic peptide 
CRF 
Case Report Form (electronic/paper) 
DBP 
Diastolic Blood Pressure 
DM 
Diabetes mellitus 
EPS 
GFR 
Enrolled Patients Set 
Glomerular filtration rate 
HbA1c 
Hemoglobin A1c 
HDL 
High-Density Lipoprotein 
HF 
Heart failure 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
LVEF 
Left Ventricular Ejection Fraction 
ITTS 
Intention to treat set 
IP 
MCAR 
MDRD 
NSVT 
NTproBNP 
NYHA 
Investigational Product 
Missing completely at random 
Modification of Diet in Renal Disease 
Nonsustained ventricular tachycardia 
N-terminal (NT)-pro hormone BNP 
New York Heart Association 
PPS 
PAC 
PTDV 
PVC 
Per protocol set 
Premature atrial contractions 
Premature treatment discontinuation visit 
Premature ventricular contractions 
SAE 
Severe Adverse Event 
SAFS 
Safety Analysis Set 
SAS 
Statistical Analysis Software 
SBP 
Systolic Blood Pressure 
SD 
Standard deviation 
SE 
Standard error 


Embrace-HF SAP 
Page 3 of 36
Abbreviation or 
special term 
Explanation 
SGLT-2 
Sodium-glucose cotransporter 2 
T2DM 
VF 
VT 
Type 2 Diabetes Mellitus 
Ventricular fibrillation 
Ventricular tachycardia 


Embrace-HF SAP 
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Contents 
1  INTRODUCTION................................................................................................................................................ 6 
1.1 Study Objectives ........................................................................................................................................ 6 
1.2 Study Design .............................................................................................................................................. 8 
1.3 Sample Size and Power ............................................................................................................................ 10 
2 GENERAL CONSIDERATIONS FOR DATA ANALYSES ........................................................................................ 10 
2.1 Analysis Data Sets .................................................................................................................................... 10 
2.2 Protocol Deviations and Major Eligibility Violations ............................................................................... 12 
2.3 Strata, Covariates, and pre-specified subgroup analyses........................................................................ 12 
2.4 Endpoints Definitions .............................................................................................................................. 13 
2.5 Multiple Testing ....................................................................................................................................... 15 
2.6 Missing Data ............................................................................................................................................ 15 
2.7 Data Handling Conventions and Transformations .................................................................................. 15 
3 Analyses of Baseline Characteristics ............................................................................................................... 16 
3.1 Demographics and Baseline Characteristics ............................................................................................ 16 
3.2 Medical History .................................................................................................................................... 16 
3.2.1 Diabetes History ............................................................................................................................... 16 
3.2.2 Other Medical History ...................................................................................................................... 16 
3.3 Physical examination ............................................................................................................................... 17 
3.4 Lab results ................................................................................................................................................ 17 
4 SUBJECT DISPOSITION .................................................................................................................................... 18 
4.1 Subject Enrollment .................................................................................................................................. 18 
4.2 Disposition of Subjects ............................................................................................................................ 18 
4.3 Extent of Exposure ................................................................................................................................... 18 
4.3.1 Duration of Exposure to Study Drug ................................................................................................. 18 
4.3.2 Adherence with Study Drug.............................................................................................................. 19 
5 EFFICACY ANALYSES ........................................................................................................................................ 19 
5.1 Analysis of the Primary Efficacy Endpoint ............................................................................................... 19 
5.2 Secondary outcome variables ................................................................................................................. 20 
5.3 Exploratory outcome variables ................................................................................................................ 23 
5.4 Supplemental pre-specified analyses. ..................................................................................................... 24 
6 SAFETY ANALYSES ........................................................................................................................................... 24 


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7 REFERENCES....................................................................................................................................................25
8 SOFTWARE ...................................................................................................................................................... 25 
9 APPENDICES .................................................................................................................................................... 25 
9.1 Scoring and Interpreting the KCCQ.......................................................................................................... 25 
9.2 Protocol deviations .................................................................................................................................. 29 


Embrace-HF SAP 
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Primary Study 
Objectives 
To compare pulmonary artery diastolic pressure at the end of 
treatment period (defined as average of pulmonary artery diastolic 
pressure measurements between weeks 8-12) between empagliflozin 
and placebo. 
Secondary Study 
Objectives 
1. To compare pulmonary artery diastolic pressure between 
empagliflozin and placebo at each interim time point (weeks 1, 2, 3, 4, 
5, 6, 7, 8, 9, 10, 11 and 12) 
2. To compare pulmonary artery systolic pressure at the end of treatment 
period between empagliflozin and placebo 
3. To compare pulmonary artery systolic pressure between empagliflozin 
and placebo at each interim time point (weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 
10, 11 and 12) 
4. To compare mean pulmonary artery pressure at the end of treatment 
period between empagliflozin and placebo 
5. To compare mean pulmonary artery pressure between empagliflozin 
and placebo at each interim time point (weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 
10, 11 and 12) 
6. To compare the average of measurements at 6 and 12 weeks in heart 
failure related health status between empagliflozin and placebo, using 
the Kansas City Cardiomyopathy Questionnaire (KCCQ) overall 
summary score.  
7.
in the Kansas City Cardiomyopathy Questionnaire (KCCQ) overall 
summary score at 6 and 12 weeks between empagliflozin and placebo  
8. To compare 6-minute walk test at follow-up (defined as average of 
measurements at 6 and 12 weeks) between empagliflozin and placebo 
9. To compare NTproBNP at follow-up (defined as average of 
measurements at 6 and 12 weeks) between empagliflozin and placebo 
10. To compare BNP at follow-up (defined as average of measurements at 
6 and 12 weeks) between empagliflozin and placebo 
11.
baseline in NTproBNP at 6 and 12 weeks between empagliflozin and 
placebo. 
12. To compar
baseline in BNP at 6 and 12 weeks between empagliflozin and 
placebo. 


Embrace-HF SAP 
Page 7 of 36
13.
at  6 and 12 weeks between empagliflozin and placebo 
14. To compare the number of diuretic medication adjustments during the 
treatment period (up-titration and down-titration of diuretic doses to be 
evaluated separately) between empagliflozin and placebo 
15. To compare Hemoglobin A1c at follow-up (defined as average of 
measurements at 6 and 12 weeks) between empagliflozin and placebo 
(evaluated separately in patients with and without type 2 diabetes) 
Exploratory 
objectives 
1. To compare change in pulmonary artery diastolic pressure between 
week 12 and week 13 between patients originally randomized to 
empagliflozin or placebo 
2. To compare change in mean pulmonary artery pressure between week 
12 and week 13 between patients originally randomized to 
empagliflozin or placebo 
3. To compare change in pulmonary artery systolic pressure between 
week 12 and week 13 between patients originally randomized to 
empagliflozin or placebo 
4.  To compare heart rate at the end of treatment period (defined as 
average measurements between weeks 8-12) between empagliflozin 
and placebo  
5. To compare effects on average weekly loop diuretic dose (furosemide 
equivalent) between empagliflozin and placebo.  
6. To compare effects on hospitalizations for heart failure between 
empagliflozin and placebo.  
7. To compare effects on urgent outpatient heart failure visits between 
empagliflozin and placebo. 
8. To compare effects on hospitalizations for heart failure or urgent 
outpatient visits for heart failure between empagliflozin and placebo 
9. To compare change in NYHA Class at 6 weeks from baseline and 12 
weeks from baseline between empagliflozin and placebo. 
10. To compare NTproBNP, BNP, 6-minute walk test, Hemoglobin A1c,
and KCCQ Overall summary Score, at 6 weeks and 12 weeks 
separately, between empagliflozin and placebo 
11. To compare the number of medication adjustments other than diuretics 
(nitrates, hydralazine, ACE, ARB, b-blockers, sacubitril/valsartan) 
during the treatment period between empagliflozin and placebo 
12. Proportion of patients that progress to diabetes during the treatment 
period (within the subgroup of patients without diabetes at baseline 
only) 


Embrace-HF SAP 
Page 8 of 36
Design Configuration 
and Subject 
Population 
Randomized, double-blind, placebo-controlled trial. The control group 
will receive placebo administered orally once daily for 12 weeks plus 
standard of care. The treatment group will receive empagliflozin 10 mg 
administered orally once daily for 12 weeks plus standard of care. A 
follow-up visit at week 13 will be performed to evaluate filling 
pressures and markers of renal function. 
Treatment Groups 
Empagliflozin 10 mg administered orally vs. placebo  
Inclusion criteria 
1. Age > 18 and <120 at the screening visit 
2. Established diagnosis of heart failure (for at least 16 weeks prior to the 
screening visit) with either preserved (LVEF>40%) or reduced systolic 
-ischemic 
etiology, documented by an imaging modality (echocardiography, 
nuclear imaging, LV angiography, magnetic resonance imaging) within 
the past 24 months.  
3. No major change in diuretic management for 48 hours prior to 
screening visit or 48  hours prior to randomization visit (major change 
defined by doubling of diuretic dose or addition of another diuretic 
medication) 
4. NYHA class II, III or IV heart failure symptoms at the screening and 
randomization visit 
5.
ted 
CardioMEMs pulmonary artery pressure monitor for a clinical 
indication unrelated to the study. 
6.
of the screening visit (last 
measurement available prior to the screening visit). 
7. Ability to provide informed consent prior to initiating screening visit 
procedures 
Exclusion 
criteria 
1. Decompensated heart failure (hospitalization for heart failure within the 
2 weeks prior to screening) or between screening and randomization 
2. History of type 1 diabetes 
3. Major change in diuretic management during 48 hours prior to 
screening visit or 48 hours prior to randomization visit. (major change 
defined by doubling of diuretic dose or addition of another diuretic 
medications) 
4. Significant variability in baseline PA diastolic pressures during 
screening period.  Defined as changes greater than  +/- 6 mmHg from 
average PA diastolic pressure during week 1 of the screening phase and 
average PA diastolic pressure during week 2 of the screening phase for 
those patients with an average baseline PA diastolic pressure during 


Embrace-HF SAP 
Page 9 of 36
week 1 of the screening phase of <30 mmHg.   If the average baseline 
PA diastolic pressure during week 
between week 1 and week 2 of the screening phase will be used to 
define significant variability.  
5. Initiation of hydralazine, long-acting nitrates, beta blockers, 
ACEI/ARBs or Valsartan/sacubitril in the prior 4 weeks prior to 
screening 
6. Estimated glomerular filtration rate (eGFR) < 30  mL/min/1.73 m2 at 
the screening visit 
7. Admission for an acute coronary syndrome (ST-elevation MI, non-ST-
elevation MI, or unstable angina), percutaneous coronary intervention, 
or cardiac surgery within 30 days prior to the screening visit.  
8. Implantation of cardiac resynchronization therapy (CRT) device within 
the previous 90 days. 
9. Implantation of the CardioMEMs device within the past 2 weeks.  
10. Planned cardiovascular revascularization (percutaneous intervention or 
surgical) or major cardiac surgery (coronary artery bypass grafting, 
valve replacement, ventricular assist device, cardiac transplantation, or 
any other surgery requiring thoracotomy), or planned implantation of 
CRT device within the 90 days after the screening visit. 
11. Participation in any interventional clinical trial (with an investigational 
drug or device) that is not an observational registry within the 4 weeks 
prior to the screening visit.  
12. History of hypersensitivity to empagliflozin 
13. For women of child-bearing potential: Current or planned pregnancy or 
currently lactating 
14. Women of childbearing potential are defined as any female who has 
experienced menarche and who is NOT permanently sterile or 
postmenopausal.  Post menopausal is defined as 12 consecutive months 
with no menses without an alternative medical cause.  Women of child-
bearing potential, who are sexually active, must agree to use a 
medically-accepted method of birth control for the duration of the 
study.  Acceptable birth control methods include: (1) surgical 
sterilization (such as a hysterectomy or bilateral tubal ligation), (2) 
progesterone hormonal contraceptives (birth control pills or implants), 
(3) barrier methods (such as a condom or diaphragm) used with a 
spermicide, or (4) an intrauterine device (IUD). Women of child-
bearing potential will have a urine pregnancy test at every clinic visit 
and it must be negative to continue study participation.   
15. Life expectancy <1 year at the screening visit 


Embrace-HF SAP 
Page 10 of 36
16. Patients who are volume depleted based upon physical examination at 
the time of the screening or randomization visit 
17. PA diastolic pressure < 12 mmHg at the time of the screening visit 
(average of last four measurements available prior to the screening 
visit). 
18. Patients currently being treated with any SGLT-2 inhibitor 
(dapagliflozin, canagliflozin, empagliflozin) or having received 
treatment with any SGLT-2 inhibitor within the 8 weeks prior to the 
screening visit 
19. Average supine systolic BP <90 mmHg at the screening or 
randomization visit 
20. Current documented history of bladder cancer  
21. Active Gross Hematuria 
22. Heart failure due to restrictive cardiomyopathy, active myocarditis, 
constrictive pericarditis, severe stenotic valve disease, and HOCM 
(hypertrophic obstructive cardiomyopathy). 
23. History of heart transplant. 
24. Patients on heart transplant list as 1a and 1b status 
Planned Sample Size 
Approximately 30 patients will be enrolled in each arm.  
Power Statement 
A sample size of 28 patients for each group will achieve 80% power with 
diastolic pulmonary artery pressure 
between the empagliflozin 10 mg and placebo groups over the treatment 
period. 
The assumptions for this calculation were: 1) difference in diastolic 
pulmonary artery is 4, 2) between-patient standard deviation = 6, 3) Within 
patient correlation: 0.7, 4) diastolic PA pressure in the intervention arm of 
the trial will achieve a plateau at the 9th time point for treatment group. 
Efficacy and safety analyses will be performed on data from the following analysis sets: 


Embrace-HF SAP 
Page 11 of 36
Enrolled patients set (EPS) will consist of all patients who signed the informed consent. This 
data set will be used to summarize the patient disposition data. 
Modified intention to treat set (modified ITTS) is defined as all patients who have been 
randomized to study treatment, have received at least one dose of study medication, and have 
sufficient evaluable data for endpoint ascertainment during follow up. For clarity, patients 
with no evaluable data for a particular outcome during follow up will be excluded from the 
analyses of these respective endpoints. For example, for the CardioMems endpoints, patients 
with no measurements between 8 and12 weeks will be excluded from the analyses.  In 
patients who undergo initiation of intravenous home inotropic support and/or receive left 
ventricular assist device or heart transplant during the study or who are started on a 
prohibited medication (open label SGLT-2is), for efficacy analyses, the data point(s) prior to 
these events will be used. Subjects will be analyzed according to the randomization group. 
The modified ITTS data set will be used for the primary, secondary, and selected exploratory 
efficacy endpoints.  
On-treatment set (OTS) includes all subjects in the modified ITTS. Primary and secondary 
endpoint measurements will be excluded for the follow-up time point(s) when subjects were 
temporarily or permanently off the study drug at the time the corresponding measurements 
were obtained. The OTS data set will be used for a sensitivity analyses for the primary, 
secondary, and selected exploratory efficacy endpoints. 
The per protocol set (PPS) includes all subjects in the modified ITTS who did not have any 
major protocol deviations. Major protocol deviations, which are detailed in section 2.2, will 
be determined prior to unblinding of treatment groups. Subjects will be summarized 
according to actual treatment received regardless of the allocated treatment. This will be used 
for a sensitivity analysis for the primary efficacy endpoints only. 
The safety analysis set (SAFS) includes all patients who received at least 1 dose of study 
medication. Throughout the safety results sections, erroneously treated patients (eg, those 
randomized to empagliflozin but actually given placebo) will be accounted for in the actual 
treatment group. If a patient received study drug from the wrong kit for only a part of the 
treatment duration and then switched to another, the associated actual treatment group for 
that patient will be the treatment group the patient had the longest exposure to. The main 
safety analyses will be restricted to adverse events that occurred between randomization and 
the 12-week visit. Adverse events that occurred between 12 weeks and 13 weeks (after 
discontinuation of study treatment) will be collected, and presented in a separate, 
supplemental analysis. The safety analysis set will be used to summarize safety data and 
patient demography and their baseline characteristics, and to analyze selected exploratory 
endpoints (heart failure hospitalizations, urgent heart failure visits, and a composite of heart 
failure hospitalizations or urgent heart failure visits).  If there is a difference between the 
SAFS and modified ITTS, baseline and demography data will also be presented for the IITS.   


Embrace-HF SAP 
Page 12 of 36
Important Protocol Deviations (IPDs) are defined as those important deviations from the protocol 
that are likely to have an impact on the efficacy and/or safety of study treatments.  
Protocol deviations will be reviewed in a blinded fashion by the study team prior to database lock. 
All decisions to exclude patients and/or data from the modified ITTS or PPS will be made prior to 
the unblinding of the study and agreed by the study team.  
Error! Reference source not found.9.2 specifies the criteria for IPDs Patients having IPDs will be 
summarized and listed by treatment group and overall. The list of protocol deviations (including 
IPDs) will be compiled separately and finalized prior to database lock. 
2.3 Strata, Covariates,
pre-
group analyses
All efficacy and safety endpoints will be analyzed in the entire cohort, and then within the subgroups 
of patients with and without diabetes. Analyses for the primary and secondary endpoints will be 
adjusted for the corresponding baseline measurements as well as history of diabetes (DM), eGFR, 
and age. A sensitivity analysis will be conducted for each endpoint adjusting for the following 
additional baseline covariates:  AFib type (No AFib, persistent/permanent AFib, paroxysmal AFib) 
and LVEF (as continuous variable). Restricted cubic splines will be used for continuous variables to 
accommodate non-linear effects.  
Additional sensitivity analysis will use the same model as the primary analysis, but adjust only for 
the corresponding baseline measurements, without additional covariates. 
Additionally, the following pre-specified subgroup analyses will be performed for the primary 
endpoints (stratified by the baseline variables below):  
Baseline LVEF ( 40%, > 40%) 
Atrial fibrillation type (No AFib, permanent/persistent AFib, paroxysmal AFib) 
Age (<65
65) 
Sex (male, female)  
Race (white, black, other)  
Baseline RAASi type (ARNI, ACE/ ARB, neither) 
Loop diuretic dose (Furosemide equivalent mean daily dose: 
40 mg, >40 mg) 
Subgroup analyses will be carried out by augmenting the primary analysis model with terms for 
subgroup and a subgroup-by-treatment interaction. Adjusted point estimates and 95% confidence 
intervals will be calculated for the effect of empagliflozin compared with placebo within each 
subgroup. An interaction p-value will be provided.  
Due to low number of patients per site, site effects will not be explored.  


Embrace-HF SAP 
Page 13 of 36
2.4 Endpoints Definitions 
Primary endpoints:  
Average pulmonary artery diastolic pressure at the end of treatment period (defined as 
average of weekly average pulmonary artery diastolic pressure measurements between weeks 
8-12) 
Secondary endpoints:  
1. Weekly average pulmonary artery diastolic pressure at each interim time point (weeks 1, 2, 3, 
4, 5, 6, 7, 8, 9, 10, 11 and 12) 
2. Average pulmonary artery systolic pressure at the end of treatment period (defined as 
average of weekly average pulmonary artery systolic pressure measurements between weeks 
8-12) 
3. Weekly average pulmonary artery systolic pressure at each interim time point (weeks 1, 2, 3, 
4, 5, 6, 7, 8, 9, 10, 11 and 12) 
4. Average mean pulmonary artery pressure at the end of treatment period (defined as average 
of weekly average mean pulmonary artery pressure measurements between weeks 8-12) 
5. Weekly average mean pulmonary artery pressure at each interim time point (weeks 1, 2, 3, 4, 
5, 6, 7, 8, 9, 10, 11 and 12) 
6. Heart failure related health status using the Kansas City Cardiomyopathy Questionnaire 
(KCCQ) overall summary score at follow-up (defined as average of measurements at 6 and 
12 weeks).  
7.
Cardiomyopathy Questionnaire (KCCQ) at 6 and 12 weeks. 
8. 6-minute walk test at follow-up (defined as average of measurements at 6 and 12 weeks) 
9. NTproBNP at follow-up (defined as average of measurements at 6 and 12 weeks) 
10. BNP at follow-up (defined as average of measurements at 6 and 12 weeks). 
11.
6 and 12 weeks. 
12. Proportion of patients with 
aseline in BNP at 6 and 12 weeks. 
13.
decrease from baseline in NTproBNP at 6 and 12 weeks. 
14. Number of diuretic medication adjustments during the treatment period (up-titration and 
down-titration of diuretic doses to be evaluated separately) 
15. Hemoglobin A1c at follow-up (defined as average of measurements at 6 and 12 weeks), 
evaluated separately in patient with and without type 2 diabetes 
Exploratory Outcome Variables  


Embrace-HF SAP 
Page 14 of 36
1. Change in pulmonary artery diastolic pressure between week 12 and week 13 
2. Change in mean pulmonary artery pressure between week 12 and week 13  
3. Change in pulmonary artery systolic pressure between week 12 and week 13 
4. Average heart rate from at the end of treatment period 
5. Effects on average weekly loop diuretic dose (furosemide equivalent). 
The following equations will be used to convert doses to Furosemide equivalent:  
40 mg Furosemide = 20 mg Torsemide = 2 mg Bumetanide = 50 mg Ethacrynic Acid 
When patient is not on a loop diuretic, dose = 0 mg. 
week dosing regimen for loop diuretic at the recorded dose.  
In addition to comparing daily loop diuretic dose between treatment arms, we will also 
compare the proportion of patients who had their loop diuretic dose reduced or discontinued 
during the treatment period.  
6. Effects on hospitalizations for heart failure.  
Only events positively adjudicated by the clinical event committee will be included. Events 
that occurred between screening and randomization, and between 12 weeks and 13 weeks 
will be excluded from this analysis. Events that occurred between the week 12 and week 13 
study visits will be reported in a separate, supplemental analysis. 
7. Effects on urgent outpatient heart failure visits. 
Only events positively adjudicated by the clinical event committee will be included. Events 
that occurred between screening and randomization, and between 12 weeks and 13 weeks 
will be excluded from this analysis. Events that occurred between the week 12 and week 13 
study visits will be reported in a separate, supplemental analysis. 
8. Effects on hospitalizations for heart failure and urgent outpatient visits for heart failure 
Only events positively adjudicated by the clinical event committee will be included. Events 
that occurred between screening and randomization, and between 12 weeks and 13 weeks 
will be excluded from this analysis. Events that occurred between the week 12 and week 13 
study visits will be reported in a separate, supplemental analysis. 
9. Change in NYHA Class at 6 weeks from baseline and 12 weeks from baseline. 
Change in NYHA class is defined as a 3-level categorical variable: 1) Decrease, 2) No 
change, 3) Increase. For patients missing NYHA class at 12 weeks, value at 6 weeks will be 
used.  
10. Effect on NTproBNP, BNP, 6-minute walk test, Hemoglobin A1c, and KCCQ overall 
summary score  at 6 and 12 weeks 
11. Number of medication adjustments other than diuretics (nitrates, hydralazine, ACE, ARB, b-
blockers, sacubitril/valsartan) during the treatment period 
12. Proportion of patients that progress to diabetes during the treatment period (within the 
subgroup of patients without diabetes at baseline only) 


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2.5 Multiple Testing   
The primary hypothesis will be tested at the 2-sided 5% significance level. No adjustments for 
multiplicity will be made for secondary and exploratory endpoints.  
2.6 Missing Data  
For CardioMEMS sensor data (pulmonary artery diastolic pressure, pulmonary artery systolic 
pressure, and mean pulmonary artery pressure), patients with no measurements in the two weeks 
between screening and randomization and patients with no measurements at the end of the study (8-
12 weeks) will be excluded from analyses. In addition, CardioMEMS sensor data (pulmonary artery 
diastolic pressure, pulmonary artery systolic pressure, and mean pulmonary artery pressure), will be 
examined by data coordinating center staff in a blinded manner prior to data lock, and measurements 
confirmed to be erroneous (e.g., non-physiologic), will be excluded from analyses. Repeated 
measure models using maximum likelihood will be used to accommodate missed measurements 
under the assumption that data are missing at random conditional on the covariates and on the 
observed sensor data.   
For other endpoints that are measured at 6-week and 12-week follow-up visits (e.g. NT pro-BNP, 
KCCQ, etc.), a premature treatment discontinuation visit (PTDV) will be scheduled for patient who 
drop out of the study prematurely, whenever possible, to get the last assessment. The PTDV 
assessment will be carried forward to the next follow-up time point. Analyses will be conducted 
among patients with a baseline assessment and with at least one follow-up assessment (including the 
PTDV measurements) using repeated measure models. 
For partially completed KCCQs, the scoring algorithm accommodates a limited number of skipped 
responses.  
Missing data due to deaths is expected to be very low (fewer than 5 patients) because of the short 
follow-up period and will be ignored in the primary analysis.  
2.7 Data Handling Conventions and Transformations  
Diabetes duration will be calculated as (Consent date  DM diagnosis date) / 365.25. It will be 
rounded to the whole year.  
Body mass index (BMI) will be calculated as weight (kg) / [height (m)]2. It will be displayed to 1 
decimal place in listings, but will not be rounded or truncated prior to summarization 
Estimated glomerular filtration rate (eGFR) will be calculated using the MDRD-4 equation: GFR in 
mL/min per 1.73 m2 = 175 x SerumCr-1.154 x age-0.203 x 1.212 (if patient is African American) x 
0.742 (if female). Patients with missing data in Creatinine Serum, age, race, or gender will not have 
eGFR calculated.  


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If urine microalbumin value is reported as being too high for the laboratory to calculate a UACR, 
5000 mg value for UACR will be used. 
e
Patient demographics, baseline clinical characteristics, medical histories, and baseline labs will be 
described overall and by treatment group. Continuous measures will be summarized by mean 
-tests.  Categorical variables will be summarized 
by frequency and percent and compared using 
s, as appropriate. 
Age 
Sex 
Race/Ethnicity 
Diabetes duration 
History of diabetic peripheral neuropathy 
History of diabetic autonomic neuropathy 
History of diabetic retinopathy 
History of diabetic ketoacidosis (DKA) event 
History of hyperosmolar hyperglycemic syndrome (HHS) event 
History of severe hypoglycemic event(s) 
History of amputation 
History of heart failure 
NYHA Class 
Most Recent LVEF Assessment 
History of PAD 
History of hypertension 
History of coronary artery disease 
History of dyslipidemia 
History of angina 
History of atrial fibrillation 
History of atrial flutter 
History of MI 


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History of PCI 
History of CABG 
History of ventricular tachycardia 
ICD implanted 
Permanent pacemaker implanted 
History of valve disease 
Body Mass Index 
Sitting Pulse and Blood Pressure 
Supine Pulse and Blood Pressure 
Standing Pulse and Blood Pressure 
3.4 La
s
HbA1c 
BNP 
NT pro-BNP 
Glucose (mg/dL) 
BUN - urea nitrogen (mg/dL) 
Creatinine (mg/dL) 
Estimated Glomerular Filtration Rate (eGFR) 
Sodium (mmol/L) 
Potassium (mmol/L) 
Chloride (mmol/L) 
Carbon Dioxide (mmol/L) 
Calcium (mg/dL) 
Phosphate - as phosphorus (mg/dL) 
Albumin (g/dL) 
Random Urine Creatinine (mg/dL) 
Random Urine Microalbumin < 0.2 mg/dL 
Random Urine Microalbumin (mg/dL) 
Enter Urine Albumin result, if measurable. 
Random Urine Albumin/Creatinine Ratio (mcg/mg creat) 


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The number and percent of subjects randomized for each site will be summarized overall and by 
treatment group.  The denominator for the percent calculation will be number of subjects screened. 
A summary of subject disposition will be provided overall and by treatment group, as appropriate. 
This summary will present the number of subjects screened, randomized, included in the safety 
analysis set, and the number and percent of subjects meeting the following criteria: 
Completed the study drug treatment, 
Did not complete the study drug treatment (with summary of reasons for not completing the 
study treatment) 
Completed the study (includes the study treatment period and any post treatment follow up 
period), and 
Did not complete the study, (with summary of reasons for not completing the study).  
The denominator for the percent of subjects in each category will be the number of subjects in the 
safety analysis set.  
No inferential statistics will be generated. A data listing of reasons for premature study 
treatment/study discontinuation will be provided. 
Duration of exposure to study drug will be defined as (last dose date  first dose date of double-blind 
treatment phase + 1), regardless of temporary interruptions in study drug administration, and will be 
expressed in weeks (shown to one decimal place, e.g., 4.5 weeks).  
Duration of exposure to study drug will be summarized using descriptive statistics (sample size, 
mean, standard deviation, median, first quartile (Q1), third quartile (Q3), minimum, and maximum). 
Summaries will be provided by treatment group for the safety analysis set. 


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The actual number of tablets ingested will be calculated using the Study Drug Accountability 
CRF:  
             Total number of tablets dispensed - total number of tablets returned. 
The expected number of tablets ingested will be calculated based on the Study Drug 
Dispensed CRF and Study Drug Accountability CRF:  
          Total number of days supposed on study drug ([date of last dose of study drug - start date + 1]) 
Adherence rate  
100(total number of tablets ingested) / (expected number of tablets ingested). 
Adherence will be capped at 100% for summarization. Patients with unreturned bottles will be 
excluded from adherence calculations.  
Descriptive statistics for adherence (sample size, mean, standard deviation, median, Q1, Q3, 
minimum, and maximum) will be provided by treatment group and overall for the safety analysis set.  
Analysis of the primary efficacy endpoints will be performed on the modified ITT data set, first on 
the entire cohort, then within the subgroups of subjects with and without diabetes, and then within 
other subgroups as specified in section 2.3. Several sensitivity analyses will be performed as outlined 
in section 2.3 for the primary efficacy endpoint; in addition, supportive analyses will be repeated 
using the same models on the on-treatment set (OTS) and per-protocol set (PPS). 
Mean, standard deviation, median, and interquartile range (IQR) will be reported for weekly average 
pulmonary artery diastolic pressure at each week (weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) and 
the average of measurements between weeks 8 and 12, for the entire cohort and by treatment group. 
A generalized linear mixed model with identity link and Normal distribution will be used to estimate 
the effect of treatment on the average of pulmonary artery diastolic pressure between week 8 and 12, 
adjusting for baseline measurement, history of DM, eGFR, and age. Assessment time t (in weeks), 
defined as number of days since randomization divided by 7, will be included as restricted cubic 
splines with 4 knots to capture the nonlinear trajectories.  Random intercept and random coefficients 
for cubic splines will be included for subjects. The model is as follows:  


Embrace-HF SAP 
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where,  
 denotes the diastolic pressure for subject  at week t, 
 is a 0/1 variable denoting 
treatment group (empagliflozin vs. placebo), t indicates the follow-up assessment time (t, a real 
number between 1 and 14) and 
 is a vector of spline basis functions, and
 is the design matrix for 
baseline measurement, age,  DM,  and baseline eGFR.  are subject random intercepts 
 are subject 
random coefficient for cubic spline function 
. With this parameterization, the quantity 
represents the expected effect of empagliflozin vs. placebo on pulmonary artery diastolic 
pressure at week t, and the quantity 
represents the expected effect on average diastolic 
pressure between 8 and 12 weeks. Appropriate simplification might be necessary to ensure model  
convergence. 
A sensitivity analysis will be performed using the same model additionally adjusting for AFib type 
(No AFib, persistent/permanent AFib, paroxysmal AFib) and baseline LVEF.  
Additional sensitivity analysis will use the same model as the primary analysis, but adjust only for 
the corresponding baseline measurements, without additional covariates. 
Finally, another sensitivity analysis will repeat the primary analysis on the on-treatment set (OTS). 
The following secondary outcomes will be analyzed on the intention to treat (modified ITT) data set, 
first on entire subject cohort and then within subgroups of subject with or without diabetes.  
1. Weekly average pulmonary artery diastolic pressure at each interim time point (weeks 
1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) 
Using the same model as that of the primary endpoint, the effect of empagliflozin vs. placebo 
at each interim time point will be estimated by 
. The estimated average 
pulmonary artery diastolic pressure at each time point will be obtained using Least Square 
Means for empagliflozin and placebo separately.  
2. Weekly average pulmonary artery systolic pressure at the end of treatment period 
(defined as average of pulmonary artery systolic pressure measurements between weeks 
8-12) 
3. Weekly average pulmonary artery systolic pressure at each interim time point (weeks 1, 
2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) 


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4. Weekly average mean pulmonary artery pressure at the end of treatment period 
(defined as average of mean pulmonary artery pressure measurements between weeks 
8-12) 
5. Weekly average mean pulmonary artery pressure at each interim time point (weeks 1, 
2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) 
Pulmonary artery systolic pressure and mean pulmonary artery systolic pressure will be 
analyzed in a manner analogous to that of pulmonary artery diastolic pressure.  
6. Heart failure related health status using the Kansas City Cardiomyopathy 
Questionnaire (KCCQ) overall summary score at follow-up (defined as average of 
measurements at 6 and 12 weeks).  
Mean, standard deviation, median, and interquartile range (IQR) will be reported for KCCQ 
overall summary score and its change from baseline at 6 and 12 weeks.  
A generalized linear mixed model with identity link and Normal distribution will be used to 
estimate the effect of treatment on average KCCQ overall summary score at 6 and 12 weeks, 
adjusting for baseline measurement, history of DM, eGFR, and age. Random intercept will 
be included for subjects. The model is as follows:  
,  
where,  
 denotes the expected KCCQ overall summary score for subject  at week , 
 is 
a 0/1 variable denoting treatment group (empagliflozin vs. placebo),  indicates the follow-up 
assessment time (week 6, t =0; week 12, t = 1), and  is the design matrix for baseline 
measurement, age,  DM,  and baseline eGFR.  are subject random intercepts with variance 
. With this parameterization, effect of empagliflozin vs. placebo is estimated by 
 at 6 
weeks and 
 at 12 weeks. The quantity 
 represents the expected average 
effect of empagliflozin vs. placebo on KCCQ summary score at 6 and 12 weeks. 
Similar analyses will be repeated for KCCQ clinical summary score. 
7. Proportion of subject
Cardiomyopathy Questionnaire (KCCQ) at 6 and 12 weeks separately. 
Unadjusted proportions of subjects with a  5 pts increase from baseline in KCCQ overall 
score at 6 and 12 weeks, will be reported for the treatment group and placebo group. A 
logistic regression model will be used to assess the effect of treatment on the proportion of 
subjects with a 
5 pts increase. Models will be adjusted for baseline KCCQ overall 
summary score, history of DM, eGFR, and age. The model is specified as follows:  


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where  
denotes the expected probability for subject
with a 
pts increase in KCCQ 
overall score, 
is a 0/1 variable denoting treatment group (empagliflozin vs. placebo),  
is the design matrix for log baseline NT pro-BNP, baseline KCCQ summary score, history of 
DM, eGFR, and age. With this parameterization, the quantity 
 represents the odds 
ratio of achieving a 
 pts increase in the treatment group vs. the placebo group.  
Additionally, responder analysis will be conducted to report proportion of patients with 
deterioration (5 points or greater decrease), no change (change between -5 to 5 points), small-
moderate improvement (5 to 9 points increase), moderate-large improvement (10 to 19  
points increase), and very large improvement (20 points or greater increase) in KCCQ overall 
summary score at 6 and 12 weeks. Similar analyses will be repeated for KCCQ clinical 
summary score. 
8. 6 minute walk test at follow-up (defined as average of measurements at 6 and 12 weeks) 
6 minute walk test will be analyzed in a manner analogous to that of secondary outcome 6. 
Effect of empagliflozin vs. placebo is estimated by 
 at 6 weeks and 
 at 12 weeks. 
The quantity 
 represents the expected average effect of empagliflozin vs. placebo 
on KCCQ summary score at 6 and 12 weeks 
9. NTproBNP at follow-up (defined as average of measurements at 6 and 12 weeks) 
NTproBNP will be analyzed in a manner analogous to that of secondary outcome 6. 
Although Gama distribution and log link will be used to account for the skewed nature of 
NTproBNP.  
10. BNP at follow-up (defined as average of measurements at 6 and 12 weeks). 
BNP will be analyzed in a manner analogous to that of NTproBNP.  
11. Proportion of subject
6 and 12 
weeks separately. 
12. Proportion of subject
6 and 12 weeks 
separately. 
13. Proportion of subject
 20% 
decrease from baseline in NTproBNP at 6 and 12 weeks separately. 
Outcome 11, 12, and 13 will be analyzed in a manner analogous to that of secondary 
outcome 7.  
14. Number of diuretic medication adjustments during the treatment period (up-titration 
and down-titration of diuretic doses to be evaluated separately) 
Number of diuretic medication adjustments, up-titrations, and down-titrations will be 
reported using mean, standard deviation, median, and interquartile range (IQR), and will be 
compared using Poison regression between the treatment and placebo group.  
Proportion of patients with no diuretic medication adjustments, up-titrations, and down-
titrations will be reported using mean and standard deviation, and will be compared using 
-test between the treatment and placebo group.  


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15. Hemoglobin A1c at follow-up (defined as average of measurements at 6 and 12 weeks), 
evaluated separately in subject with and without type 2 diabetes 
HbA1c will be analyzed in a manner analogous to that of secondary outcome 6. 
In addition, proportion of patients with HbA1c 
6.5 at 6 weeks, 12 weeks, and at both 6 and 
12 weeks will be reported within the subgroups of patients with and without Diabetes.  
1. Change in pulmonary artery diastolic pressure between week 12 and week 13 
Using the same model for the primary endpoint, the effect of empagliflozin vs. placebo on 
change between week 12 and week 13 will be estimated by 
2. Change in mean pulmonary artery pressure between week 12 and week 13  
Will be analyzed in a manner analogous to that of pulmonary artery diastolic pressure.  
3. Change in mean pulmonary artery systolic pressure between week 12 and week 13 
Will be analyzed in a manner analogous to that of pulmonary artery diastolic pressure.  
4. Change in average heart rate from at the end of treatment period 
Will be analyzed in a manner analogous to that of pulmonary artery diastolic pressure.  
5. Effects on average weekly loop diuretic dose (furosemide equivalent).  
6.
Daily loop diuretic dose will be analyzed in a manner analogous to that of secondary outcome 6, 
although appropriate distributions and link functions will be chosen for the given outcomes. 
Additionally, among patients who were on loop diuretic at randomization, we will also compare the 
proportion of patients who had loop diuretic dose reduced or discontinued (using the average 
reported dose at 6 weeks and 12 weeks). Effects on hospitalizations for heart failure.  
7. Effects on urgent outpatient heart failure visits. 
8. Effects on hospitalizations for heart failure and urgent outpatient visits for heart failure 
A Cox proportional hazard model will be used to assess the effect of treatment vs. placebo on 
the time to the first occurrence for outcomes 5, 6, and 7, adjusting for history of DM, eGFR, 
and age. A sensitivity analysis will be conducted additionally adjusting for AFib type (No 
AFib, persistent/permanent AFib, paroxysmal AFib) and baseline LVEF. A second 
sensitivity analysis will be performed using the same approach, but without adjustment for 
covariates 
9. Change in NYHA Class at 6 weeks from baseline and 12 weeks from baseline. 
10. Effect on NTproBNP, BNP, 6-minute walk test, Hemoglobin A1c, and KCCQ overall 
summary score at 6 weeks and 12 weeks between empagliflozin and placebo. 


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NTproBNP, BNP, 6-minute walk test, Hemoglobin A1c, and KCCQ overall summary score 
will be analysed in a manner analogous to that of secondary outcome 6. Effect of 
empagliflozin vs. placebo is estimated by 
 at 6 weeks and 
 at 12 weeks. 
11. Number of medication adjustments other than diuretics (nitrates, hydralazine, ACE, 
ARB, b-blockers, sacubitril/valsartan) during the treatment period 
12. Proportion of subjects that progress to diabetes during the treatment period (within the 
subgroup of subjects without diabetes at baseline only) 
Subjects that progress to diabetes will be summarized by frequency and percent and 
compared using 
-specified
For all outcomes that include assessment of KCCQ overall summary score, additional sensitivity 
analyses will be performed using KCCQ Clinical Summary Score, Social Limitation, Total 
Symptom Score, Physical Limitation, Quality of Life, in a manner analogous to that of the KCCQ 
overall summary score.  
In addition, additional subgroup analyses (in addition to stratification by DM status, using strata 
specified in section 2.3) may be repeated for all secondary efficacy outcomes.  
Furthermore, as a supportive analysis, distributional regressions may be conducted to assess the 
effect of empagliflozin on variability of pulmonary diastolic and systolic pressure. 
Safety analyses will be performed on the safety analysis set (SAF). Total number of adverse events 
as well as number and proportion of subjects developing adverse event(s) will be compared by 
treatment group. For subject level analyses multiple events will be counted once only per subject in 
each summary. The following safety variables will be included:  
1. All cause death 
2. Cardiovascular death 
3. Non-fatal myocardial infarction (MI) 
4. Stroke 
5. Acute kidney injury (defined as doubling of serum creatinine based on the modified RIFLE 
criteria) 
6. Adverse events (AEs).  
Adverse events of special interest 
o
Diabetic Ketoacidosis 
o
Volume Depletion Event (defined as hypotension, syncope, orthostatic 
hypotension or dehydration) 
o
Severe Hypoglycemic Event 
o
Acute Kidney Injury 


Embrace-HF SAP 
Page 25 of 36
o
Non-traumatic Lower Limb Amputations 
Drug Adverse Event 
Serious Adverse event 
o
Resulted in death 
o
In-patient hospitalization or prolonging of existing in-patient hospitalization 
o
Persistent or significant disability 
o
Life-threatening  
o
Congenital anomaly/birth defect 
o
Important medical event 
Other adverse events 
o
Urgent outpatient heart failure visits 
Safety analyses will be restricted to adverse events that occurred between randomization and 12 
weeks. Adverse events occurred between 12 weeks and 13 weeks will be presented separately in a 
supplemental analysis. 
1. Green CP1, Porter CB, Bresnahan DR, Spertus JA., Development and Evaluation of the Kansas 
City Cardiomyopathy Questionnaire: A New Health Status Measure for Heart Failure, J Am Coll 
Cardiol. 2000 Apr;35(5):1245-55 
2. Hunger,M et all, Longtitudinal beta regression models for analyzing health-related quality of life 
scores over time Medical Research Methodology, 2012; 12:144 
All analyses will be performed using SAS 9.4 or higher.  
There are 10 summary scores within the KCCQ, which are calculated as follows: 
A. Physical Limitation 
The Physical Limitation score corresponds to questions 1a through 1f. Responses to questions 1a 
through 1f should be coded numerically as follows: 
1 = Extremely Limited 
2 = Quite a bit Limited 
3 = Moderately Limited 
4 = Slightly Limited 


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Page 26 of 36
5 = Not at all Limited 
6 = Limited for other reasons or did not do the activity 
If the responses to questions 1a through 1f are not values 1, 2, 3, 4 or 5 then the response is set to 
missing. Note that a response of 6 (Limited for other reasons or did not do the activity) is treated as a 
missing value. If at least three responses to questions 1a-1f are not missing, then the physical 
limitation score is computed by calculating the mean response and standardizing the result as 
follows:  
Physical Limitation = 100*(Mean Response  1)/4 
B. Symptom Stability  
The Symptom Stability score corresponds to question 2. Responses to question 2 should be coded 
numerically as follows: 
1 = Much Worse 
2 = Slightly Worse 
3 = Not Changed 
4 = Slightly Better 
5 = Much Better 
If the response is 6 (no symptoms over last 2 weeks) then set the response to 3 (not changed). If 
question 2 is not missing then the symptom stability score is computed by standardizing the result as 
follows: 
Symptom Stability = 100*(Response  1)/4 
C. Symptom Frequency 
The Symptom Frequency score corresponds to questions 3, 5, 7 and 9. The responses should be 
coded sequentially (1, 2, 
Question 3 
1 = Every Morning 
2 = 3 or more times per week, but not every day 
3 = 1-2 times a week 
4 = Less than once a week 
5 = Never over the past 2 weeks 
Questions 5 and 7 


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1 = All of the time 
2 = Several times per day 
3 = At least once a day 
4 = 3 or more times per week, but not every day 
5 = 1-2 times per week 
6 = Less than once a week 
7 = Never over the past 2 weeks 
Question 9 
1 = Every night 
2 = 3 or more times a week, but not every day 
3 = 1-2 times a week 
4 = Less than once a week 
5 = Never over the past 2 weeks 
If two or more responses are missing then symptom frequency cannot be computed and will be 
missing. Otherwise, the symptom frequency is computed by calculating the mean of the standardized 
responses and multiplying by 100 as follows: 
Symptom Frequency = 100*Mean((Q3  1)/4, (Q5  1)/6, (Q7  1)/6, (Q9  1)/4) 
D. Symptom Burden 
The Symptom Burden score corresponds to questions 4, 6 and 8. The responses should be coded 
numerically as follows: 
1 = Extremely Bothersome 
2 = Quite a bit Bothersome 
3 = Moderately Bothersome 
4 = Slightly Bothersome 
5 = Not at all Bothersome 
ath) 
If a response is 6 (none) then set the response to 5 (not at all). If at least one response is present then 
symptom burden score is computed by calculating the mean response and standardizing the result as 
follows: 
Symptom Burden = 100*(Mean Response  1)/4 
E. Total Symptom Score 


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The total symptom score is calculated as the mean of the symptom frequency score and symptom 
burden score. 
F. Self-Efficacy 
The Self-Efficacy score corresponds to questions 10 and 11. Responses to questions 10 and 11 
should be coded sequentially (1, 2, 3, 4, 5) in order of increasing health status, with 1 denoting the 
response associated with the lowest health status. If at least one question response is present then the 
self-efficacy score may be computed by standardizing the mean response as follows: 
Self-Efficacy = 100*(Mean Response  1)/4 
G. Quality of Life 
The Quality of Life score corresponds to questions 12, 13 and 14. Responses to questions 12, 13 and 
14 should be coded sequentially (1, 2, 3, 4, 5) in order of increasing health status, with 1 denoting 
the response associated with the lowest health status. If at least one question response is present then 
the quality of life score may be computed by standardizing the mean response as follows: 
Quality of Life = 100*(Mean Response  1)/4 
H. Social Limitation  
The Social Limitation score corresponds to questions 15a through 15d. These responses should be 
coded numerically as follows: 
1 = Severely Limited 
2 = Limited Quite a bit 
3 = Moderately Limited 
4 = Slightly Limited 
5 = Did Not Limit at All 
6 = Does not apply or did not do for other reasons 
If the responses to questions 15a through 15d are not values 1, 2, 3, 4 or 5 then the response is set to 
missing. Note that a response of 6 is treated as a missing value. If at least two question responses are 
present then the social limitation score may be computed by standardizing the mean response as 
follows: 


Embrace-HF SAP 
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Social Limitation = 100*(Mean Response  1)/4 
I.
Clinical Summary Score 
The clinical summary score is calculated as the mean of the physical limitation score and total 
symptom score. 
J. Overall Summary Score 
The overall summary score is calculated as the mean of the physical limitation score, total symptom 
score, quality of life score and social limitation score. 
Number 
Important Protocol Deviations Criteria 
Major 
Impact on 
Analysis 
(MIA)/Other 
Exclusion level 
1. Did not fulfil eligibility criteria  inclusion criteria: 
1.1 
Ability to provide informed consent prior to 
initiating screening visit procedures 
MIA 
Complete exclusion from PPS and 
MODIFIED ITTS 
1.2 
Age > 18 and < 120 at the screening visit  
Other 
No exclusion  
1.3 
Established diagnosis of heart failure  
Other 
To be decided on a case by case 
basis 
1.4 
No major change in diuretic management for 
48 hours prior to screening visit or 48  hours 
prior to randomization visit (major change 
defined by doubling of diuretic dose or 
addition of another diuretic medication) 
Other 
To be decided on a case by case 
basis 


Embrace-HF SAP 
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Number
Important Protocol Deviations Criteria
Major 
Impact on 
Analysis 
(MIA)/Other 
Exclusion level
1.5 
NYHA class II or III heart failure symptoms at 
the screening and randomization visit  
Other 
To be decided on a case by case 
basis 
1.6 
eeks prior to 
screening visit) implanted CardioMEMs 
pulmonary artery pressure monitor for a 
clinical indication unrelated to the study. 
Other 
To be decided on a case by case 
basis 
1.7 
me 
of the screening visit (last measurement 
available prior to the screening visit). 
Other 
To be decided on a case by case 
basis 
2. Did not fulfil eligibility criteria  exclusion criteria: 
2.0 
Decompensated heart failure (hospitalization 
for heart failure within the 2 weeks prior to 
screening) or between screening and 
randomization 
Other 
To be decided on a case by case 
basis 
2.1 
History of type 1 diabetes  
Other 
To be decided on a case by case 
basis 
2.2 
Major change in diuretic management during 
48 hours prior to screening visit or 48 hours 
prior to randomization visit. (major change 
defined by doubling of diuretic dose or 
addition of another diuretic medications) 
Other 
To be decided on a case by case 
basis 
2.3 
Significant variability in baseline PA diastolic 
pressures during screening period.   
Other 
To be decided on a case by case 
basis 
2.4 
Initiation of hydralazine, long-acting nitrates, 
beta blockers, ACEI/ARBs or 
Valsartan/sacubitril in the prior 4 weeks prior 
to screening 
Other 
To be decided on a case by case 
basis 


Embrace-HF SAP 
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Number
Important Protocol Deviations Criteria
Major 
Impact on 
Analysis 
(MIA)/Other 
Exclusion level
2.5 
Estimated glomerular filtration rate (eGFR) < 
30  mL/min/1.73 m2 at the screening visit 
Other 
To be decided on a case by case 
basis 
2.6 
Admission for an acute coronary syndrome 
(ST-elevation MI, non-ST-elevation MI, or 
unstable angina), percutaneous coronary 
intervention, or cardiac surgery within 30 days 
prior to the screening visit  
Other 
To be decided on a case by case 
basis 
2.7 
Implantation of cardiac resynchronization 
therapy (CRT) device within the previous 90 
days. 
Other 
To be decided on a case by case 
basis 
2.8 
Implantation of the CardioMEMs device 
within the past 2 weeks.  
Other 
To be decided on a case by case 
basis 
2.9 
Planned cardiovascular revascularization 
(percutaneous intervention or surgical) or 
major cardiac surgery (coronary artery bypass 
grafting, valve replacement, ventricular assist 
device, cardiac transplantation, or any other 
surgery requiring thoracotomy), or planned 
implantation of CRT device within the 90 days 
after the screening visit. 
Other 
To be decided on a case by case 
basis 
2.10
Participation in any interventional clinical trial 
(with an investigational drug or device) that is 
not an observational registry within the 4 
weeks prior to the screening visit.  
Other 
To be decided on a case by case 
basis 
2.11
History of hypersensitivity to empagliflozin 
Other 
To be decided on a case by case 
basis 


Embrace-HF SAP 
Page 32 of 36
Number
Important Protocol Deviations Criteria
Major 
Impact on 
Analysis 
(MIA)/Other 
Exclusion level
2.12
For women of child-bearing potential: Current 
or planned pregnancy or currently lactating.  
Other 
To be decided on a case by case 
basis 
2.13
Life expectancy <1 year at the screening visit  
Other 
To be decided on a case by case 
basis 
2.14
Patients who are volume depleted based upon 
physical examination at the time of the 
screening or randomization visit 
Other 
To be decided on a case by case 
basis 
2.15
PA diastolic pressure < 12 mmHg at the time 
of the screening visit (average of last four 
measurements available prior to the screening 
visit). 
Other 
To be decided on a case by case 
basis 
2.16
Patients currently being treated with any 
SGLT-2 inhibitor (dapagliflozin, canagliflozin, 
empagliflozin) or having received treatment 
with any SGLT-2 inhibitor within the 8 weeks 
prior to the screening visit 
Other 
To be decided on a case by case 
basis 
2.17
Average supine systolic BP <90 mmHg at the 
screening or randomization visit 
Other 
To be decided on a case by case 
basis 
2.18
Current documented history of bladder cancer  
Other 
To be decided on a case by case 
basis 
2.19
Active Gross Hematuria 
Other 
To be decided on a case by case 
basis 


Embrace-HF SAP 
Page 33 of 36
Number
Important Protocol Deviations Criteria
Major 
Impact on 
Analysis 
(MIA)/Other 
Exclusion level
2.20
Heart failure due to restrictive 
cardiomyopathy, active myocarditis, 
constrictive pericarditis, severe stenotic valve 
disease, and HOCM (hypertrophic obstructive 
cardiomyopathy).  
Other 
To be decided on a case by case 
basis 
2.21
History of heart transplant. 
Other 
To be decided on a case by case 
basis 
2.22
Patients on heart transplant list as 1a and 1b 
status 
Other 
To be decided on a case by case 
basis 


Embrace-HF SAP 
Page 34 of 36
3. Subject developed discontinuation of investigational product criteria but dosing continued
3.0
Subject experienced an Adverse Event which in the 
opinion of the Investigator, contraindicated 
further dosing 
Other
To be reviewed on the 
case by case basis 
3.1
Pregnancy confirmed by a positive pregnancy test 
or other examinations 
Other
Complete exclusion 
from PPS 
3.2
Donation of blood or bone marrow during the 
study period  
Other
To be decided on a 
case by case basis 
3.3
Admission for an acute coronary syndrome (ST-
elevation MI, non-ST-elevation MI, or unstable 
angina), percutaneous coronary intervention, or 
cardiac surgery during the study period.  
Other
To be decided on a 
case by case basis 
4. Subject received prohibited concomitant medication but study treatment not discontinued: 
4.4.1
SGLT2
Other 
Only the efficacy 
endpoints before the 
start of SGLT2 will be 
included in modified 
IITS, OTS, and PPS 
5. Subject received incorrect investigational treatment/dose  
5.0 
Subject took incorrect treatment or damaged 
Investigational Drug Kit 
MIA 
To be decided on a 
case by case basis 
5.1 
Major compliance issues <80% or >120% 
compliance with IP dosing in double blind 
treatment period 
MIA 
To be decided on a 
case by case basis 
5.3 
Subject randomized but never took IP 
MIA 
To be decided on a 
case by case basis 
5.4 
Subject randomized and stopped taking IP for a 
long period of time after the initial dose, and then 
resumed IP  
MIA 
To be decided on a 
case by case basis 


Embrace-HF SAP 
Page 35 of 36
5.5 
Overdose 
MIA 
To be decided on the 
case by case basis 
6. Protocol-required procedure not adhered to: 
6.0
Study data collection has not been stopped when 
subject decided to withdraw their consent from 
the study completely 
Other 
No exclusion from PPS
Data collected after 
consent withdrawal to 
be excluded from data 
base 
6.1
Subjects with absence of NT-proBNP data at 
randomization visit and having values at Screening 
visit.   
Other 
No exclusion from PPS
Values from screening 
visit will be used to 
impute the values at 
randomization visit. 
6.2
Subjects with absence of baseline NT-proBNP data
at both screening and randomization visits  
Other
Excluded from the NT-
proBNP analyses 
6.3
Subjects with no NT-proBNP values after 
randomization 
Other
Excluded from the NT-
proBNP analyses 
6.4
Subjects with absence of baseline KCCQ summary 
score at randomization visit 
Other
Excluded from the 
KCCQ analyses  
6.5 
Subjects with no KCCQ overall summary score 
after randomization 
Other 
Excluded from KCCQ 
analyses  
6.6 
Subjects with absence of baseline 6-minute walk 
assessment at randomization visit 
Other 
Excluded from the 6-
minute walk analyses 
6.7 
Subjects with no 6-minute walk assessment after 
randomization 
Other 
Excluded from 6-
minute walk analyses  
6.8 
Subjects with missing values in the covariates: age, 
gender, Hx AFib, AFib type, Hx DM, eGFR at 
randomization, lvef at randomization  
Other 
No exclusion from PPS 
Excluded from the first 
and second primary 
analysis 


Embrace-HF SAP 
Page 36 of 36
6.9
Subject with absence of CardioMEMS sensor 
measurements (pulmonary artery diastolic 
pressure, pulmonary artery systolic pressure, 
and mean pulmonary artery pressure) in the 
two weeks between screening and 
randomization and/or at the end of the study 
(8-12 weeks)
Excluded from the 
corresponding analyses