Clinical trial NCT03200860
Conditions: Heart Failure Acute Heart Failure，Congestive Heart Failure; With Decompensation
Keywords: heart failure diuretic response empagliflozin
Sponsor: University Medical Center Groningen
Start date: 2017-12-18; Completion date: 2019-09-18
Enrollment: 80 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Acute decompensated heart failure is the fastest growing disease in the world and the leading cause of hospital admissions worldwide. Short term mortality and rehospitalization are extremely high (20-30% within 3-6 months) and there is no therapy available that improves clinical outcome in these patients. Empagliflozin is a selective inhibitor of sodium glucose co-transporter with diuretic and renal- protective properties. In patients with type 2 diabetes at high risk for cardiovascular events, empagliflozin reduced the risk of hospitalization for heart failure by 35%. Based on the promising pharmacological profile of empagliflozin in relation to the needs for treatment of acute decompensated heart failure, we hypothesize that empagliflozin exerts positive effects in acute decompensated heart failure, with or without diabetes,

This is a randomized, placebo-controlled, double-blind, parallel group, multicenter study in subjects admitted for acute decompensated heart failure. Eighty eligible subjects will be randomized in a 1:1 ratio to receive either empagliflozin 10 mg/day or matched placebo.

Detailed description:
This is a randomized, placebo-controlled, double-blind, parallel group, multicenter study in subjects admitted for acute decompensated heart failure. Eighty eligible subjects will be randomized in a 1:1 ratio to receive either empagliflozin 10 mg/day or matched placebo.

Treatment will be continued until 30 days after index event, and primary efficacy measurements will be carried out during hospitalization and safety events until 60 days after index hospitalisation.

Arms: arm 1: Empagliflozin 10 mg daily, oral, 30 days arm 2: Matching Placebo 10 mg daily, oral, 30 days
Interventions: intervention 1: Empagliflozin 10 MG intervention 2: Placebo Oral Tablet
Intervention descriptions: intervention 1: 10 mg daily, oral, 30 days intervention 2: Matching Placebo, 10 mg daily, oral, 30 days

Protocol documents:
Prot_000.pdf: 
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PROTOCOL TITLE : Randomized, double blind, placebo controlled, 
multicenter pilot study on the effects of empagliflozin on clinical 
outcomes in patients with acute decompensated heart failure 
(EMPA-RESPONSE-AHF) 
 
20 October 2017 
 
NCT03200860 
 
 


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PROTOCOL TITLE : Randomized, double blind, placebo controlled, 
multicenter pilot study on the effects of empagliflozin on clinical 
outcomes in patients with acute decompensated heart failure 
(EMPA-RESPONSE-AHF) 
 
Protocol ID 
UMCG-EMPA-1 
Short title 
Empagliflozin in acute decompensated heart 
failure 
EudraCT number  
2017-001679-22 
Version 
1.0 
Date 
July 19, 2017 
Coordinating investigator 1 
 
Prof. dr. Adriaan A. Voors, MD, PhD 
University Medical Center Groningen 
Department of Cardiology 
Hanzeplein 1, 9713 GZ  
Groningen, the Netherlands 
Email: a.a.voors@umcg.nl 
Coordinating investigator 2 
Prof. Dr. H.J. Lambers Heerspink 
University Medical Center Groningen 
Department of Clinical Pharmacology and 
Pharmacy 
Hanzeplein 1, 9713 GZ  
Groningen, the Netherlands 
Email: h.j.lambers.heerspink@umcg.nl 
Principal Investigtor UMCG 
Dr. K. Damman, Cardiologist 
University Medical Center Groningen 
Department of Cardiology 


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Hanzeplein 1, 9713 GZ  
Groningen, the Netherlands 
Email: k.damman@umcg.nl 
Sponsor (in Dutch: 
verrichter/opdrachtgever) 
University Medical Center Groningen 
Hanzeplein 1 
9713GZ Groningen 
The Netherlands 
 
 
Subsidising party 
Boehringer Ingelheim bv  
Independent expert (s) 
Dr. P.P. van Geel 
 
 
 
 
Laboratory sites  
Local labs 
 
 
Pharmacy  
Medication is obtained from Boehringer Ingelheim 
KG 
 
 


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PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
Sponsor or legal representative: 
Head of Department of Cardiology, 
UMCG: 
Prof. Dr. D.J. van Veldhuisen 
 
 
 
Coordinating Investigator: 
Prof dr. A.A.Voors, Cardiologist 
 
 
 
Coordinating Investigator: 
Prof. Dr. H.J. Lambers Heerspink, 
Clinical Pharmacologist 
 
 
 
 


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TABLE OF CONTENTS 
 
SUMMARY 
1. 
INTRODUCTION AND RATIONALE .............................................................................14 
2. 
OBJECTIVES ................................................................................................................14 
3. 
STUDY DESIGN ...........................................................................................................15 
4. 
STUDY POPULATION ..................................................................................................15 
4.1 
Population (base) ..................................................................................................15 
4.2 
Inclusion criteria ....................................................................................................15 
4.3 
Exclusion criteria ...................................................................................................15 
4.4 
Sample size calculation .........................................................................................16 
5. 
TREATMENT OF SUBJECTS .......................................................................................17 
5.1 
Investigational product/treatment ..........................................................................17 
5.2 
Use of co-intervention (if applicable) .....................................................................17 
5.3 
Escape medication (if applicable) ..........................................................................18 
6. 
INVESTIGATIONAL PRODUCT ....................................................................................18 
6.1 
Name and description of investigational  product(s) ..............................................18 
6.2 
Summary of findings from non-clinical studies.......................................................18 
6.3 
Summary of findings from clinical studies ..............................................................18 
6.4 
Summary of known and potential risks and benefits ..............................................19 
6.5 
Description and justification of route of administration and dosage .......................19 
6.6 
Dosages, dosage modifications and method of administration ..............................19 
6.7 
Preparation and labelling of Investigational Medicinal Product ..............................20 
6.8 
Drug accountability ...............................................................................................19 
7. 
NON-INVESTIGATIONAL PRODUCT ...........................................................................19 
8. 
METHODS ....................................................................................................................19 
8.1 
Study parameters/endpoints .................................................................................19 
8.1.1 
Main study parameter/endpoint .........................................................................19 
8.1.2 
Secondary study parameters/endpoints (if applicable) ......................................21 
8.1.3 
Other study parameters (if applicable) ...............................................................21 
8.2 
Randomisation, blinding and treatment allocation .................................................21 
8.3 
Study procedures ..................................................................................................22 
8.3.1 
Screening ..........................................................................................................28 
8.3.2 
Baseline ............................................................................................................28 
8.3.3 
Day 1 ................................................................................................................28 
8.3.4 
Day 2 ................................................................................................................28 
8.3.5 
Day 3 ................................................................................................................28 
8.3.6 
Day 4 ................................................................................................................28 
8.3.7 
Day 5 ................................................................................................................28 
8.3.8 
Day 30 ..............................................................................................................28 
8.3.9 
Day 60 ..............................................................................................................28 
 
Schedule of Event .............................................................................................28 
8.4 
Withdrawal of individual subjects...........................................................................28 


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8.4.1 
Specific criteria for withdrawal (if applicable) .....................................................28 
8.5 
Replacement of individual subjects after withdrawal .............................................28 
8.6 
Follow-up of subjects withdrawn from treatment ....................................................28 
8.7 
Premature termination of the study .......................................................................28 
9. 
SAFETY REPORTING ..................................................................................................28 
9.1 
Temporary halt for reasons of subject safety .........................................................28 
9.2 
AEs, SAEs and SUSARs ......................................................................................29 
9.2.1 
Adverse events (AEs) .......................................................................................29 
9.2.2 
Adverse events of special interest (AESI)..........................................................29 
9.2.3 
Serious adverse events (SAEs) .........................................................................29 
9.2.4 
Suspected unexpected serious adverse reactions (SUSARs) ...........................30 
9.3 
Annual safety report ..............................................................................................32 
9.4 
Follow-up of adverse events .................................................................................32 
9.5 
[Data Safety Monitoring Board (DSMB) / Safety Committee] .................................33 
10. 
STATISTICAL ANALYSIS .........................................................................................33 
10.1 
Primary study parameter(s) ...................................................................................33 
10.2 
Secondary study parameter(s) ..............................................................................34 
10.3 
Other study parameters ........................................................................................34 
10.4 
Interim analysis (if applicable) ...............................................................................33 
11. 
ETHICAL CONSIDERATIONS ..................................................................................34 
11.1 
Regulation statement ............................................................................................34 
11.2 
Recruitment and consent ......................................................................................34 
11.3 
Objection by minors or incapacitated subjects (if applicable) .................................35 
11.4 
Benefits and risks assessment, group relatedness ................................................35 
11.5 
Compensation for injury ........................................................................................35 
11.6 
Incentives (if applicable) ........................................................................................34 
12. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION ........................35 
12.1 
Handling and storage of data and documents .......................................................35 
12.2 
Monitoring and Quality Assurance.........................................................................36 
12.3 
Amendments .........................................................................................................36 
12.4 
Annual progress report ..........................................................................................35 
12.5 
Temporary halt and (prematurely) end of study report ...........................................35 
12.6 
Public disclosure and publication policy ................................................................36 
13. 
STRUCTURED RISK ANALYSIS ..............................................................................36 
13.1 
Synthesis ..............................................................................................................39 
14. 
REFERENCES .........................................................................................................39 


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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
ACE 
AHF 
ABR 
 Angiotensin-converting enzyme 
Acute Heart Failure 
ABR form, General Assessment and Registration form, is the application 
form that is required for submission to the accredited Ethics Committee 
(In Dutch, ABR = Algemene Beoordeling en Registratie) 
AE 
 Adverse Event 
AESI 
ARB 
AUC 
BNP 
Cmax 
 Adverse Events of Special Interest 
Angiotensin Receptor Blocker 
Area Under the Curve 
B-type Natriuretic Peptide 
Maximum observed concentration 
BI 
 Boehringer Ingelheim bv Netherlands 
BI KG 
 Boehringer Ingelheim GmbH & Co KG Germany 
CA 
 Competent Authority 
CCMO 
 Central Committee on Research Involving Human Subjects; in Dutch: 
Centrale Commissie Mensgebonden Onderzoek 
CV 
DKA 
 Curriculum Vitae 
Diabetic Ketoacidosis 
DSMB 
eGFR 
ECG 
 Data Safety Monitoring Board 
Estimated glomerular filtration rate 
Electrocardiogram 
EU 
 European Union 
EudraCT 
 European drug regulatory affairs Clinical Trials  
GCP 
HF 
 Good Clinical Practice 
Heart Failure 
IB 
 Investigator’s Brochure 
IC 
JVP 
 Informed Consent 
Jugular Venous Pressure 
IMP 
 Investigational Medicinal Product  
IMPD 
 Investigational Medicinal Product Dossier  
METC 
 
MRA 
NT-
 Medical research ethics committee (MREC); in Dutch: medisch ethische 
toetsing commissie (METC) 
Mineralocorticoid receptor antagonist 
n-terminal-prohormone brain natriuretic peptide 


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proBNP  
P-gp 
(S)AE 
 P-Glycoprotein 
(Serious) Adverse Event  
SGLT-2 
SPC 
 Sodium dependent Glucose Transporter –2 
Summary of Product Characteristics (in Dutch: officiële 
productinfomatie IB1-tekst) 
Sponsor 
 The sponsor is the party that commissions the organisation or 
performance of the research, for example a pharmaceutical 
company, academic hospital, scientific organisation or investigator. A 
party that provides funding for a study but does not commission it is not 
regarded as the sponsor, but referred to as a subsidising party. 
SUSAR 
UGT 
ULN 
VAS 
 Suspected Unexpected Serious Adverse Reaction 
UDP- Glycosyltransferase 
Upper Limit of Normal 
Visual Analogue Scale 
Wbp 
 Personal Data Protection Act (in Dutch: Wet Bescherming 
Persoonsgevens) 
WMO 
 Medical Research Involving Human Subjects Act (in Dutch: Wet 
Medisch-wetenschappelijk Onderzoek met Mensen 
 
 


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SUMMARY 
 
Rationale: Acute decompensated heart failure is the fastest growing disease in the world 
and the leading cause of hospital admissions worldwide. Short term mortality and 
rehospitalization are extremely high (20-30% within 3-6 months) and there is no therapy 
available that improves clinical outcome in these patients. Empagliflozin is a selective 
inhibitor of sodium glucose co-transporter with diuretic and renal-protective properties. In 
patients with type 2 diabetes at high risk for cardiovascular events, empagliflozin reduced the 
risk of hospitalization for heart failure by 35%. Based on the promising pharmacological 
profile of empagliflozin in relation to the needs for treatment of acute decompensated heart 
failure, we hypothesize that empagliflozin exerts positive effects in acute decompensated 
heart failure, with or without diabetes.  
 
Objectives:  
Primary Objective: 
The primary objective of this trial is to evaluate whether empagliflozin 10 mg/ day will relieve 
dyspnea, improves diuretic response, decreases length of initial hospital stay and plasma 
NT-proBNP levels compared to placebo in patients who are admitted for acute 
decompensated heart failure. 
Secondary Objectives:  
The secondary objectives of this trial are to evaluate the effects of empagliflozin on death 
and/or heart failure re-admission to Day 30 and on plasma and urinary markers of renal 
function and injury. 
Safety Objectives:  
The safety objectives of this trial are to evaluate whether empagliflozin is well tolerated, and 
does not cause an excess number of (serious) adverse events. Specific attention will be paid 
to hypotension, renal dysfunction, ketoacidosis and/ or hyperosmolar hyperglycemic 
syndrome. 
 
Study design:  This is a randomized, placebo-controlled, double-blind, parallel group, 
multicenter study in subjects admitted for acute decompensated heart failure. Eighty eligible 
subjects will be randomized in a 1:1 ratio to receive either empagliflozin 10 mg/day or 
matched placebo. 
 
 
 
 


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Study population:  
Inclusion Criteria: 
1. Male or female >18 years of age; Women of non-child-bearing potential must have a 
documentation of surgical sterilization (hysterectomy and/or bilateral oophorectomy) OR 
must have experienced menopause (no menses for >12 months). Women of child bearing 
potential must have a negative pregnancy test, AND must use highly effective methods of 
contraception during treatment with the investigational product plus 5 days after the end of 
study drug administration. 
2. Hospitalized for AHF; AHF is defined as including all of the followings measured at any 
time between presentation (including the emergency department) and the end of screening: 
a. Dyspnea at rest or with minimal exertion 
b. Signs of congestion, such as edema, rales, and/or congestion on chest radiograph 
c. BNP ≥350 pg/mL or NT-proBNP ≥1,400 pg/mL (for patients with atrial fibrillation: BNP≥500 
pg/mL or NT-proBNP ≥2,000 pg/mL) 
d. Treated with loop diuretics at screening  
3. Able to be randomized within 24 hours from presentation to the hospital 
4. Able and willing to provide freely given written informed consent 
5. eGFR (CKD-EPI) ≥30 ml/min/1.73m2 between presentation and randomization 
 
Exclusion Criteria: 
1. Diabetes Mellitus type 1  
2. Dyspnea primarily due to non-cardiac causes 
3.  Cardiogenic shock 
4.  Acute coronary syndrome within 30 days prior to randomization  
5.  Planned or recent percutaneous or surgical coronary intervention within 30 days prior to 
randomization 
6. Signs of keto-acidosis and/or hyperosmolar hyperglycemic syndrome (pH>7.30 and 
glucose >15 mmol/L and HCO3>18 mmol/L) 
7. Pregnant or nursing (lactating) women 
8. Current participation in any interventional study 
9.   Inability to follow instructions or comply with follow-up procedures 
10,   Any other medical conditions that may put the patient at risk or influence study results in 
the investigator’s opinion, or that the investigator deems unsuitable for the study 
 
 
 


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Intervention: In this study patients are randomized in a 1:1 ratio to receive an oral once daily 
dose of 10 mg empagliflozin or matching placebo tablet, both on top of standard of care. 
 
Main study parameters/ endpoints:  
Primary endpoints: 
To estimate the mean response and associated variability for a) Dyspnea relief, assessed by 
VAS at baseline to Day 4 (or discharge if earlier); b) Diuretic response (defined as Δ weight 
kg/[(total i.v. dose)/40mg]+[(total oral dose)/80mg)] furosemide (or equivalent loop diuretic 
dose) up to Day 4); c) Length of initial hospital stay; d) Change in NT-proBNP from baseline 
to Day 4 (or discharge if earlier) 
 
Secondary endpoints: 
• Death and/or heart failure re-admission to Day 30 
• Change in  plasma values of renal function, including creatinine, eGFR, cystatin C, BUN, 
neutrophil gelatinase associated lipocalin (NGAL), kidney injury molecule (KIM-1), fibroblast 
growth factor 23 (FGF-23) and hemoglobin, hematocrit, albumin from baseline to Day 4 (or 
discharge if earlier)  
• Change in other plasma values of renal function, including creatinine, cystatin C, BUN, 
neutrophil gelatinase associated lipocalin (NGAL), kidney injury molecule (KIM-1), fibroblast 
growth factor 23 (FGF-23) and hemoglobin, hematocrit, albumin from baseline to Day 30 
• Change in urinary sodium excretion and urinary levels of markers of glomerular and tubular 
function, including urinary albumin excretion (UAE), N-acetyl-beta-D-glucosaminase (NAG), 
NGAL and KIM-1, from baseline to Day 4 (or discharge if earlier)  
• Change in urinary sodium excretion and urinary levels of markers of glomerular and tubular 
function, including urinary albumin excretion (UAE), N-acetyl-beta-D-glucosaminase (NAG), 
NGAL and KIM-1, from baseline to Day 30 
 
Safety endpoints: 
• Adverse events and serious adverse events 
 
One specific adverse event of special interest (AESI) will be a deterioration of eGFR to 
an absolute value below 20 mL/min/1.73m2 within the first 5 days of hospitalization. 
• Vital signs 
• ECGs 
• Laboratory evaluations 


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• Worsening heart failure to Day 5 post randomization (or discharge if earlier), defined as 
worsening signs and/or symptoms of heart failure that require an intensification of 
intravenous therapy for heart failure or mechanical ventilatory, renal or circulatory support. 
 
 
Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness:  
• 
Patients will visit the hospital more often than they would usually do (2 times per year 
instead of 1 time per year) 
• 
Patients will take extra medication, on top of their usual medication 
• 
Rare cases of diabetic ketoacidosis (DKA), some of which were life threatening, have 
been reported in patients treated with SGLT2 inhibitors, among which was empagliflozin. 
In some cases, only moderately elevated glucose levels, below 14 mmol/l, were reported. 
In case of non-specific symptoms like nausea, vomiting, anorexia, abdominal pain, 
excessive thirst, respiration difficulties, confusion, unusual fatigue or somnolence, 
diabetic ketoacidosis should be ruled out. In case of diabetic ketoacidosis, use of 
empagliflozin should be stopped immediately. 
• 
In patients hospitalized for surgery or acute severe medical conditions, empagliflozin 
treatment should be interrupted until the patient is stabilized again. 
• 
Although cases of liver damage were reported, causal relationship between empagliflozin 
and liver damage has not been shown. 
• 
Haematocrit elevations have been reported. 
• 
Elderly patients (older than 75 years) are at risk of dehydration as a result of 
empagliflozin treatment. Fluid intake should be monitored, notably in case of concomitant 
treatment with ACE inhibitors and diuretics. 
• 
Blood pressure may drop significantly. 
• 
In case of circumstances which may lead to fluid loss, careful monitoring of fluid status 
and electrolytes is warranted. 
  
Procedures:  
• Patient-reported AHF symptoms will be collected using a Visual Analog Scale (VAS) 
describing symptom severity at each point in time. These evaluations will be done daily from 
start of study drug administration up to Day 4 or discharge, if earlier.  
• Patients will have clinical evaluations, including AHF symptom assessments, fluid balance 
and recording of type and dose of diuretic drugs, fluid and sodium restrictive regiments, vital 
signs, physical examination emphasizing signs of HF, as well as an assessment of need for 


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further IV HF treatment and worsening HF events (for definition: see endpoints) at least daily 
to the earlier of Day 5 or discharge.  
• Blood will be collected for clinical chemistry and hematology assessments, and urine 
specimens will be collected daily during the first days of treatment for routine safety 
assessments and to evaluate renal function to the earlier of Day 5 or discharge and at the 
Day 30 visit.  
• The occurrence of adverse events and serious adverse events, mortality and hospital 
readmission for HF will be assessed at the Day 30 visit and Day 60 phone call.  
• Safety will be assessed by recording medical history, monitoring adverse events and vital 
signs, and performing physical examinations and routine clinical laboratory tests as per the 
protocol, as well as those felt to be clinically indicated by the investigator. Adverse events 
(AE) and serious adverse events (SAE) will be collected up to Day 60 from start of study 
drug administration. 
 
One specific AESI will be the deterioration of eGFR within the first 5 days of 
hospitalization (and randomized treatment) to an absolute value below (< ) 20 
mL/min/1.73m2.  
• Measurements of pH, Lactate, HCO3 and glucose will be performed daily up to Day 5 or 
discharge, if earlier to monitor for signs and symptoms of ketoacidosis and/or hyperosmolar 
hyperglycemic syndrome. In case keto-acidosis is suspected, further assessments will be 
done and diagnostic criteria as defined by the American Diabetes Association will be 
followed and safety stopping rules will be applied. 
• During the initial phase of hospitalization, patients will be continuously monitored for 
possible rhythm and/or conduction disorders at least during the first 24 hours of treatment.  


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1. INTRODUCTION AND RATIONALE 
Acute decompensated heart failure is one of the fastest growing diseases in the world and a  
leading cause of hospital admissions worldwide.(1) Short term mortality and rehospitalization  
are extremely high (20-30% within 3-6 months). There is no therapy available that improves  
clinical outcome of these patients.(2) Therefore, there is a very high unmet need to find  
effective treatments in patients with acute decompensated heart failure. Despite treatment  
with loop diuretics, many patients are discharged with residual congestion, which is related to  
a higher risk of early rehospitalization and death. Renal Failure and worsening renal function 
in patients with AHF is common and related to an impaired outcome. Empagliflozin is a  
selective inhibitor of sodium glucose co-transporter with diuretic and renal protective 
properties. Recently, empagliflozin reduced the risk of cardiovascular outcome and of  
death from any cause in patients with type 2 diabetes at high risk for cardiovascular  
events.(3) Interestingly, hospitalization for heart failure was reduced by 35% and risk of  
progression of nephropathy by 44%.(4) We hypothesize that the reduction in the risk of  
hospitalization for heart failure was caused by the diuretic and renal protective properties of  
empagliflozin and that empagliflozin is therefore beneficial for the treatment of patients who  
are hospitalized for acute decompensated heart failure.  
 
 
2. OBJECTIVES 
 
Primary Objective:  
The primary objective of this trial is to evaluate whether empagliflozin 10mg/day will relieve 
dyspnea, improves diuretic response, decreases length of initial hospital stay and plasma 
NT-proBNP levels compared to placebo in patients who are admitted for acute 
decompensated heart failure. 
Secondary Objective:  
The secondary objectives of this trial are to evaluate the effects of empagliflozin on death 
and/or heart failure re-admission to Day 30 and on plasma and urinary markers of renal 
function and injury. 
Safety Objectives:  
The safety objectives of this trial are to evaluate whether empagliflozin is well tolerated, and 
does not cause an excess number of (serious) adverse events. Specific attention will be paid 
to hypotension, renal dysfunction, ketoacidosis and/ or hyperosmolar hyperglycemic 
syndrome. 
 


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3. STUDY DESIGN 
 
This is a randomized, placebo-controlled, double-blind, parallel group, multicenter study in 
subjects admitted for acute decompensated heart failure. Eighty eligible subjects will be 
randomized in a 1:1 ratio to receive either empagliflozin 10 mg/day or matched placebo. 
 
Duration and setting: Patients hospitalized for acute decompensated heart failure will be 
randomly assigned to empagliflozin or placebo (on top of standard of care treatment 
including loop diuretics) within 24 hours after admission. The intended duration of treatment 
will be 30 days after randomization. 
 
4. STUDY POPULATION 
4.1 Population (base) 
 
Patients with an acute hospital admission for decompensated heart failure. These patients 
will usually present at the emergency department and/or at the cardiac care unit.  
  
4.2 Inclusion Criteria 
 
1. Male or female >18 years of age; Women of non-child-bearing potential must have a 
documentation of surgical sterilization (hysterectomy and/or bilateral oophorectomy) OR 
must have experienced menopause (no menses for >12 months). Women of child bearing 
potential must have a negative pregnancy test, AND must use highly effective methods of 
contraception during treatment with the investigational product plus 5 days after the end of 
study drug administration. 
2. Hospitalized for AHF; AHF is defined as including all of the followings measured at any 
time between presentation (including the emergency department) and the end of screening: 
a. Dyspnea at rest or with minimal exertion 
b. Signs of congestion, such as edema, rales, and/or congestion on chest radiograph 
c. BNP ≥350 pg/mL or NT-proBNP ≥1,400 pg/mL (for patients with AF: BNP≥500 pg/mL or 
NT-proBNP ≥2,000 pg/mL) 
d. Treated with loop diuretics at screening  
3. Able to be randomized within 24 hours from presentation to the hospital 
4. Able and willing to provide freely given written informed consent 
5. eGFR (CKD-EPI) ≥30 ml/min/1.73m2 between presentation and randomization 
 


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4.3 Exclusion Criteria 
1. Diabetes Mellitus type 1  
2. Dyspnea primarily due to non-cardiac causes 
3  Cardiogenic shock 
4.  Acute coronary syndrome within 30 days prior to randomization  
5.  Planned or recent percutaneous or surgical coronary intervention within 30 days prior to 
randomization 
6.  Signs of ketoacidosis and/or hyperosmolar hyperglycemic syndrome (pH>7.30 and 
glucose >15 mmol/L and HCO3>18 mmol/L) 
7.  Pregnant or nursing (lactating) women 
8.   Current participation in any interventional study 
9.   Inability to follow instructions or comply with follow-up procedures 
10.   Any other medical conditions that may put the patient at risk or influence study results in 
the investigator’s opinion, or that the investigator deems unsuitable for the study 
 
4.4 Sample size calculation 
Sample size: n=80 (40 patients per study arm) 
 
With 40 patients in the control group, a given mean continuous response can be estimated 
within ± 0.2 Standard deviations (SD) with 80% confidence. We estimate the following mean 
responses for continuous outcome:  
 
1. Change in dyspnea VAS score: 1756±2353 mmxh,  
2. Diuretic response (of 0.56 ± 0.78 kg/40 mg Furosemide (or equivalent))  
3. Length of stay 9.6 to 10.5 days (± 9.1) 
4. Percentage change in NT-proBNP 24 (-1.0 – 88.7)% (SD 67% assuming normal 
distribution)  (all at 96 hours (day 4)) 
 
Binary outcomes, such as event rates of Death and/or HF re-admission at 60 days have 
occurred in approximately 10-15% of patients in AHF studies (RELAX-AHF and PROTECT 
studies).  A rate of 10% can be estimated within ± 6.1% and a rate of 15% within ± 7.2% with 
80% confidence.  
  
Treatment effect: 
As this is an exploratory analysis the overall power to establish small treatment effects is 
limited. Forty patients per group provides approximately 80% power to detect standardized 
mean treatment differences of approximately 0.48 SDs at the two-sided 20% significance 
level, which gives around the following differences: dyspnea VAS score of 1129 mmxh, 


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Diuretic response of 0.37 kg/40 mg Furosemide, Length of initial hospital stay of 4 days, and 
percentage change in NT-proBNP of 32%, with the above mentioned estimates of mean 
response in the control group.  
 
As an additional, exploratory analysis, and for graphical presentation, individual responses 
will be standardized (i.e., the difference from the overall mean divided by the overall SD) and 
aligned so that a bigger value represents a better outcome; log-rank scores for time-to-event 
outcomes will be thus standardized; and treatment effects presented as mean differences in 
standardized scores with 80% CIs.  As a measure of overall response to treatment, the 
average standardized score across the 4 outcomes will be computed for each patient, and 
the mean treatment difference and associated 95% CI for this average standardized score 
presented. 
 
 
5. TREATMENT OF SUBJECTS 
 
5.1 Investigational product/treatment 
Patients will be treated once daily with 10 mg empagliflozin tablets or matching placebo 
tablets. The tablets can be taken with or without food, swallowed whole with water. If a 
dose is missed, it should be taken as soon as the patient remembers. A double dose 
should not be taken on the same day. 
5.2 Use of co-intervention (if applicable) 
Simultaneous use of oral antidiabetics and heart failure treatment (diuretics, ACE 
inhibitors, ARBs, Betablockers, and MRA as per standard local practice) is allowed. 
Special attention should be paid to possible interactions for simultaneous use. 
Empagliflozin may add to the diuretic effect of thiazide and loop diuretics and may 
increase the risk of dehydration and hypotension. Insulin and insulin secretagogues, such 
as sulphonylureas, may increase the risk of hypoglycaemia. Therefore, a lower dose of 
insulin or an insulin secretagogue may be required to reduce the risk of 
hypoglycaemia when used in combination with empagliflozin.  
Co-medication with known inducers of UGT enzymes should be avoided due to a potential 
risk of decreased efficacy. An interaction study with gemfibrozil, an in vitro inhibitor of 
OAT3 and OATP1B1/1B3 transporters, showed that empagliflozin Cmax increased by 
15% and AUC increased by 59% following coadministration. These changes were not 
considered to be clinically meaningful. Inhibition of OATP1B1/1B3 transporters by co-
administration with rifampicin resulted in a 75% increase in Cmax and a 35% increase in 
AUC of empagliflozin. These changes were not considered to be clinically meaningful. 


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Empagliflozin exposure was similar with and without co-administration with verapamil, a 
P-gp inhibitor, indicating that inhibition of P-gp does not have any clinically relevant effect 
on empagliflozin. Interaction studies conducted in healthy volunteers suggest that the 
pharmacokinetics of empagliflozin were not influenced by co-administration with 
metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, verapamil, ramipril, 
simvastatin, torasemide and hydrochlorothiazide. Drug-drug interactions involving the 
major CYP450 and UGT isoforms with empagliflozin and concomitantly administered 
substrates of these enzymes are considered unlikely. Empagliflozin does not inhibit P-gp 
at therapeutic doses. Based on in vitro studies, empagliflozin is considered unlikely to 
cause interactions with drugs that are P-gp substrates. Interaction studies conducted in 
healthy volunteers suggest that empagliflozin had no clinically relevant effect on the 
pharmacokinetics of metformin, glimepiride, pioglitazone, sitagliptin linagliptin, simvastatin, 
warfarin, ramipril, digoxin, diuretics and oral contraceptives. 
5.3 Escape medication (if applicable) 
Not applicable 
 
6. INVESTIGATIONAL PRODUCT  
 
6.1 Name and description of investigational product(s) 
Active study medication: 
Film coated tablets, containing 10 mg empagliflozin and lactose monohydrate, 
equivalent to 154,3 mg water free lactose. Other ingredients are: micro crystalline 
cellulose, hydroxypropylcelluloase, croscarmellose sodium, colloid water free 
siliciumdioxide, magnesium stearate, hypromellose, titanium dioxide (E171), talk, 
macrogol 400, and ferric oxide yellow (E172). 
Placebo matching 10 mg empagliflozin tablets contain the same ingredients, except 
empagliflozin. 
Study medication will be provided by Boehringer Ingelheim Pharma GmbH & Co. 
KG (BI KG). 
 
6.2 Summary of findings from non-clinical studies 
Please refer to the SPC of empagliflozin. 
 
6.3 Summary of findings from clinical studies 
 
Please refer to IMPD of empagliflozin. 


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6.4 Summary of known and potential risks and benefits 
• 
Rare cases of diabetic ketoacidosis (DKA), some of which were life threatening, 
have been reported in patients treated with SGLT2 inhibitors, among which was 
empagliflozin. In some cases, only moderately elevated glucose levels, below 
14 mmol/l, were reported. In case of non-specific symptoms like nausea, 
vomiting, anorexia, abdominal pain, excessive thirst, respiration difficulties, 
confusion, unusual fatigue or somnolence, diabetic ketoacidosis should be ruled 
out. In case of diabetic ketoacidosis, use of empagliflozin should be stopped 
immediately. 
• 
In patients hospitalized for surgery or acute severe medical conditions, 
empagliflozin treatment should be interrupted until the patient is stabilized 
again. 
• 
Diabetes Type I patients should not be treated with empagliflozin 
• 
Although cases of liver damage were reported, causal relationship between 
empagliflozin and liver damage has not been shown. 
• 
Haematocrit elevations have been reported. 
• 
Elderly patients (older than 75 years) are at risk of dehydration as a result of 
empagliflozin treatment. Fluid intake should be monitored, notably in case of 
concomitant treatment with ACE inhibitors and diuretics. 
• 
Blood pressure may drop significantly. 
• 
In case of circumstances which may lead to fluid loss, careful monitoring of fluid 
status and electrolytes is warranted. 
 
6.5 Description and justification of route of administration and dosage 
The 10 mg oral tablets are the registered formulation of empagliflozin (JardianceR). 
 
6.6 Dosages, dosage modifications and method of administration 
Patients will receive one 10 mg tablet empagliflozin/placebo once daily during 30 
days. 
 
 
   6.6.1. Stopping rules and discontinuation criteria 
The administration of study drug will need to be discontinued if a patient experiences any of 
the following events during study drug administration: 
• 
A drop in systolic blood pressure below 90 mmHg OR a symptomatic systolic blood 
pressure decrease between 90 and 100 mmHg accompanied by signs and/or 
symptoms related to hypotension. 
• 
Signs of ketoacidosis and/or hyperosmolar hyperglycemic syndrome (pH>7.30 and 
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nausea, vomiting, anorexia, abdominal pain, excessive thirst, respiration difficulties, 
confusion, unusual fatigue or somnolence, diabetic ketoacidosis should be ruled out.  
• 
Any increase of serum creatinine >50%. 
 
6.7 Preparation and labelling of Investigational Medicinal Product 
Study medication will be prepared and labelled by BI KG and delivered to the 
participating sites. 
 
6.8 Drug accountability 
Study medication will be ordered by TCC and shipped in tranches o the participating 
sites. Batches will be decided upon based on inclusion rate, in order to avoid an 
excess number of study medication reaching the expiry date. Shipments will be 
documented by Boehringer Ingelheim. Study medication is stored under the 
requested storage conditions in the hospital pharmacy. Study drug kits are assigned 
to the patient by using the IVRS system, made available by TCC. 
Study medication will be released by the respective hospital pharmacies on an 
individual patient basis and every release is documented. Dispensing and collection 
of returned study medication will be executed and documented by the investigators 
and used medication is stored in the hospital pharmacies. 
Upon closure of the study, used and unused study medication is documented by the 
sites and returned to the local hospital pharmacy , who will document receipt and 
who will destroy the study medication. Destruction will be documented as well. 
 
7. NON-INVESTIGATIONAL PRODUCT 
 
Not Applicable. 
  
8. METHODS 
8.1 Study parameters/endpoints 
8.1.1 Main study parameter/endpoint 
 
Primary endpoints: 
To estimate the mean response and associated variability for a) Dyspnea relief, assessed by 
VAS at baseline to Day 4 (or discharge if earlier); b) Diuretic response (defined as Δ weight 
kg/[(total i.v. dose)/40mg]+[(total oral dose)/80mg)] furosemide (or equivalent loop diuretic 
dose) up to day ;c) Length of initial hospital stay; d) Change in NT-proBNP from baseline to 
Day 4 (or discharge if earlier) 


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8.1.2 Secondary study parameters/endpoints (if applicable) 
 
Secondary endpoints: 
• Death and/or heart failure re-admission to Day 30 
• Change in  plasma values of renal function, including creatinine, eGFR, cystatin C, BUN, 
neutrophil gelatinase associated lipocalin (NGAL), kidney injury molecule (KIM-1), fibroblast 
growth factor 23 (FGF-23) and hemoglobin, hematocrit, albumin from baseline to Day 4 (or 
discharge if earlier)  
• Change in other plasma values of renal function, including creatinine, cystatin C, BUN, 
neutrophil gelatinase associated lipocalin (NGAL), kidney injury molecule (KIM-1), fibroblast 
growth factor 23 (FGF-23) and hemoglobin, hematocrit, albumin from baseline to Day 30 
• Change in urinary sodium excretion and urinary levels of markers of glomerular and tubular 
function, including urinary albumin excretion (UAE), N-acetyl-beta-D-glucosaminase (NAG), 
NGAL and KIM-1, from baseline to Day 4 (or discharge if earlier).  
• Change in urinary sodium excretion and urinary levels of markers of glomerular and tubular 
function, including urinary albumin excretion (UAE), N-acetyl-beta-D-glucosaminase (NAG), 
NGAL and KIM-1, from baseline to day 30 
 
8.1.3 Other study parameters (if applicable) 
 
Safety endpoints: 
• Adverse events and serious adverse events 
 
One specific AESI will be a deterioration of eGFR to an absolute value below 20 
mL/min/1.73m2 within the first 5 days of hospitalization. 
• Vital signs 
• ECGs 
• Laboratory evaluations 
• Worsening heart failure to Day 5 post randomization (or discharge if earlier), defined as 
worsening signs and/or symptoms of heart failure that require an intensification of 
intravenous therapy for heart failure or mechanical ventilatory, renal or circulatory support. 
 
 
8.2 Randomisation, blinding and treatment allocation 
Subjects will be randomised 1:1 to active or placebo treatment. Randomisation will be 
executed byusing the IVRS system. Treatment assignment will take place by the Trial 
Coordination Center, University Medical Center Groningen, the Netherlands. Patients will 
maintain this randomisation number throughout the study. Randomisation will be executed in 
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8.3 Study procedures 
8.3.1 Screening 
At screening, the following assessments will be executed: 
- 
Written informed consent 
- 
Demographic data 
- 
Medical history by chart review and interviewing of the patient  
- 
Supine vital signs after 5 minutes rest (systolic and diastolic blood pressure, heart 
rate, respiratory rate) 
- 
Physical examination, including weight, height (only at screening), edema, rales, 
JVP, orthopnea assessment 
- 
12-lead electrocardiogram (ECG) 
- 
NYHA class assessment 
- 
Screening BNP/NT-proBNP and pregnancy test (local lab) 
- 
Clinical lab chemistry panel (Na, K, BUN, creatinine, haemoglobin, Ht, lactate, 
glucose, HCO3-, pH), haematology and urinalysis  
- 
Concomitant medication 
- 
Adverse eventsIn- and exclusion criteria 
8.3.2 Baseline (0 hours) 
After having confirmed eligibility by confirming all inclusion criteria and by ruling out 
either one of the exclusion criteria, the following assessments will be executed: 
- 
Randomization 
- 
Supine vital signs after 5 minutes rest (systolic and diastolic blood pressure, heart 
rate, respiratory rate) 
- 
Physical examination, including weight, edema, rales, JVP, orthopnea 
assessment 
- 
NYHA class assessment 
- 
Clinical lab chemistry panel (Na, K, BUN, creatinine, haemoglobin, Ht, lactate, 
glucose, HCO3-, pH, NT-proBNP ), haematology and urinalysis at local lab 
- 
Collection of two EDTA blood samples for biomarker analysis and buffy coat for 
genetic analysis 
- 
Collection of one Urine sample for biomarker analysis 
- 
Dyspnea VAS 
- 
Fluid balance by measuring ingested and excreted fluid volumes 
- 
Start of 24 hour continuous Holter ECG monitoring 


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- 
Study drug dispensing and administration 
- 
Concomitant medication 
- 
Adverse events 
 
8.3.3 Day 1 (24 hours) 
On Day 1, the following assessments will be executed: 
- 
Supine vital signs after 5 minutes rest (systolic and diastolic blood pressure, heart 
rate, respiratory rate) 
- 
Physical examination, including weight, edema, rales, JVP, orthopnea 
assessment 
- 
NYHA class assessment 
- 
Clinical lab chemistry panel(Na, K, BUN, creatinine, haemoglobin, Ht, lactate, 
glucose, HCO3-, pH, NT-proBNP), haematology and urinalysis at local lab 
- 
Collection of two EDTA blood samples for biomarker analysis 
- 
Collection of one Urine sample for biomarker analysis  
- 
Dyspnea VAS 
- 
Fluid balance by measuring ingested and excreted fluid volumes 
- 
End of 24 hour continuous Holter ECG monitoring 
- 
Study drug dispensing and administration 
- 
Concomitant medication 
- 
Adverse events 
- 
AESI, including drop in eGFR below 20 mL/min/1.73m2 
 
8.3.4 Day 2 (48 hours) 
On Day 2, the following assessments will be executed: 
- 
Supine vital signs after 5 minutes rest (systolic and diastolic blood pressure, heart 
rate, respiratory rate) 
- 
Physical examination, including weight, edema, rales, JVP, orthopnea 
assessment 
- 
NYHA class assessment 
- 
Clinical lab chemistry panel (Na, K, BUN, creatinine, haemoglobin, Ht, lactate, 
glucose, HCO3-, pH, NT-proBNP), haematology and urinalysis at local lab 
- 
Collection of two EDTA blood samples for biomarker analysis 
- 
Collection of one Urine sample for biomarker analysis  
- 
Dyspnea VAS 


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- 
Fluid balance by measuring ingested and excreted fluid volumes 
- 
Study drug dispensing and administration 
- 
Concomitant medication 
- 
Adverse events 
- 
AESI, including drop in eGFR below 20 mL/min/1.73m2 
 
8.3.5 Day 3 (72 hours) 
On Day 3, the following assessments will be executed: 
- 
Supine vital signs after 5 minutes rest (systolic and diastolic blood pressure, heart 
rate, respiratory rate) 
- 
Physical examination, including weight, edema, rales, JVP, orthopnea 
assessment 
- 
NYHA class assessment 
- 
Clinical lab chemistry panel (Na, K, BUN, creatinine, haemoglobin, Ht, lactate, 
glucose, HCO3-, pH, NT-proBNP) , haematology and urinalysis at local lab 
- 
Dyspnea VAS 
- 
Fluid balance by measuring ingested and excreted fluid volumes 
- 
Study drug dispensing and administration 
- 
Concomitant medication 
- 
Adverse events 
- 
AESI including drop in eGFR below 20 mL/min/1.73m2 
- 
2 Blood samples (EDTA) for biomarker analysis  
- 
Collection of one Urine sample for biomarker analysis 
 
8.3.6 Day 4 (96 hours) 
On Day 4, the following assessments will be executed: 
- 
Supine vital signs after 5 minutes rest (systolic and diastolic blood pressure, heart 
rate, respiratory rate) 
- 
Physical examination, including weight, edema, rales, JVP, orthopnea 
assessment 
- 
including NYHA class assessment 
- 
Clinical lab chemistry panel (Na, K, BUN, creatinine, haemoglobin, Ht, lactate, 
glucose, HCO3-, pH, NT-proBNP), haematology and urinalysis at local lab 
- 
Dyspnea VAS 
- 
Fluid balance by measuring ingested and excreted fluid volumes 
- 
Study drug dispensing and administration 


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- 
Concomitant medication 
- 
Adverse events 
- 
AESI including drop in eGFR below 20 mL/min/1.73m2 
- 
2 Blood samples (EDTA) for biomarker analysis  
- 
Collection of one Urine sample for biomarker analysis 
 
8.3.7 Day 5 (120 hours) 
On Day 5, the following assessments will be executed: 
- 
Supine vital signs after 5 minutes rest (systolic and diastolic blood pressure, heart 
rate, respiratory rate) 
- 
Physical examination, including edema, rales, JVP, orthopnea assessment 
- 
NYHA class assessment 
- 
Clinical lab chemistry panel (Na, K, BUN, creatinine, haemoglobin, Ht, lactate, 
glucose, HCO3-, pH, NT-proBNP), haematology and urinalysis at local lab 
- 
Study drug dispensing and administration 
- 
Concomitant medication 
- 
Adverse events 
- 
AESI, including drop in eGFR below 20 mL/min/1.73m2 
 
8.3.8 Day 30 (+ 3 days) On site visit 
On Day 30, the following assessments will be executed: 
- 
Supine vital signs after 5 minutes rest (systolic and diastolic blood pressure, heart 
rate, respiratory rate) 
- 
Physical examination, including edema, rales, JVP, orthopnea assessment 
- 
NYHA class assessment  
- 
Abbreviated clinical lab chemistry panel (Na, K, BUN, and creatinine, NT-
proBNP), urinalysis measured at local lab 
- 
EDTA Blood sample for biomarker analysis  
- 
Collection of one Urine sample for biomarker analysis 
- 
Study drug return/ tablet count 
- 
Concomitant medication 
- 
Adverse events 
 
8.3.9 Day 60 (+ 5 days) Phone call 
On Day 60, the following assessments will be executed: 


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- 
Telephone contact with patient in which the occurrence of Adverse events will be 
questioned 
 
 
 
 


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Schedule of Events 
Timepoint
Screen
Baseline
D1
D2
D3
D4
D5
D30 (+ 3d)
visit
D60 (+ 5d)
phone call
ICF
x
Medical history
x
Vital signs (BP, HR, RR)
x
x
x
x
x
x
x
x
Physical exam incl. HF assessment a, b
x
x
x
x
x
x
x
x
Weight
x
x
x
x
x
x
x
ConMed
x
x
x
x
x
x
x
x
Adverse Events 
x
x
x
x
x
x
x
x
x
ECG
x
Incl/Excl criteria
x
Randomization
x
Dyspnea VAS
x
x
x
x
x
NYHA assessment 
x
x
x
x
x
x
x
x
Fluid balance
x
x
x
x
x
Study drug administration
x
x
x
x
x
x
xd
Holter ECG monitoring c
x
x
Screening BNP/NT-proBNP
x
Serum pregnancy
x
Chemistry, Hematology, Urinalysis e
x
x
x
x
x
x
x
xf
Biomarkers
x
x
x
x
x
x
a) HF assessments: Edema, rales, JVP, orthopnea
b) Height to be measured at screening
d) Final study drug administration if visit occurs on Day 30, study drug return and tablet count
f ) Abbreviated Chemistry panel on Day 30 (Sodium, Potassium, BUN and creatinine), urinalysis
Procedures/ Assessments
Local Lab
Central Lab
c) To be perform during the first 24 hours of study drug administration
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8.4 Withdrawal of individual subjects 
 
Subjects can leave the study at any time for any reason if they wish to do so without any 
consequences. The investigator can decide to withdraw a subject from the study for 
urgent medical reasons. 
8.4.1 Specific criteria for withdrawal (if applicable) 
 
Not applicable 
 
8.5 Replacement of individual subjects after withdrawal 
 
Withdrawn subjects will not be replaced. 
 
8.6 Follow-up of subjects withdrawn from treatment 
Subjects withdrawn from treatment will be asked whether the investigator will be allowed 
to contact the patient regularly during the study in order to collect information regarding 
vital status and eventual (serious) adverse events. Investigators will be urged to have 
subjects consent to them gathering follow-up information of each withdrawn subject. 
 
8.7 Premature termination of the study 
The study may be prematurely terminated if either one or more of the following criteria 
apply: 
• 
Request by the independent Data Safety Monitoring Board to prematurely terminate 
the study because of safety or futility reasons 
• 
Apparent inability to include sufficient subjects  
• 
Bankruptcy of the sponsor 
 
9. SAFETY REPORTING 
9.1 Temporary halt for reasons of subject safety 
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the 
study if there is sufficient ground that continuation of the study will jeopardise subject 
health or safety.  The sponsor will notify the accredited METC without undue delay of a 
temporary halt including the reason for such an action. The study will be suspended 
pending a further positive decision by the accredited METC. The investigator will take 
care that all subjects are kept informed.  
 


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9.2 AEs, SAEs and SUSARs 
9.2.1 Adverse events (AEs) 
Adverse events are defined as any undesirable experience occurring to a subject 
during the study, whether or not considered related to the investigational product. All 
adverse events reported spontaneously by the subject or observed by the investigator 
or his staff will be recorded. Adverse events (AE) will be recorded from randomization 
to Day 30. Serious adverse events (SAE) and adverse events of special interest 
(AESI) are to be reported from randomization up to the Day 60 phone call. 
 
9.2.2 Adverse Events of Special Interest (AESI) 
According to Boehringer Ingelheim standard requirements, Adverse Events of Special 
Interest (AESI) will be collected throughout the study, simultaneously with the 
collection of Adverse Events. 
The following AESI will be collected: 
 
Hepatic injury 
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters after randomisation: 
- An elevation of AST and/or ALT > 3 fold ULN combined with an elevation of 
total bilirubin > 2 fold ULN measured in the same blood sample 
- An isolated elevation of ALT and/or AST > 5 fold ULN 
These laboratory findings constitute a hepatic injury alert and the patients 
showing these abnormalities need to be followed up according to medical 
abnormalities need to be followed up according to medical judgement. 
In case of clinical symptoms of hepatic injury (icterus, unexplained 
encephalopathy, unexplained coagulopathy, right upper quadrant abdominal 
pain, etc.) without laboratory results (ALT, AST, total bilirubin) available, the 
investigator should make sure these parameters are analysed, if necessary in an 
unscheduled blood test 
 
Worsening Renal Function 
either defined by: 
 
 
 
drop in eGFR below (<) 20 mL/min/1.73m2 in the first 5 days of  
 
 
 
randomized treatment 
 
 
or 
 


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A serum creatinine value showing > 2 fold increase from baseline and is above 
the ULN. 
For the AESI “Worsening renal function” the Investigator shall collect an 
unscheduled laboratory sample for creatinine as soon as judged clinically 
necessary and initiate follow-up laboratory test of creatinine according to medical 
judgement. Additionally, the Investigator shall provide information on the medical 
handling of the AESI, including changes in concomitant treatment.  
 
Metabolic acidosis, ketoacidosis and diabetic ketoacidosis (DKA) 
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). 
Investigators should note that not all criteria in the table below need to apply for 
the diagnosis of DKA, and clinical judgement should also be taken into 
consideration. Due to its mechanism of action, empagliflozin may potentially 
modify the clinical presentation of DKA which may occur at lower plasma glucose 
levels than stated in the table below. 
 
Table: 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) 
 
9.2.3 Serious adverse events (SAEs) 
A serious adverse event is any untoward medical occurrence or effect that  
- 
results in death; 
- 
is life threatening (at the time of the event); 


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- 
requires hospitalisation or prolongation of existing inpatients’ hospitalisation; 
- 
results in persistent or significant disability or incapacity; 
- 
is a congenital anomaly or birth defect; or 
- 
any other important medical event that did not result in any of the outcomes listed 
above due to medical or surgical intervention but could have been based upon 
appropriate judgement by the investigator. 
An elective hospital admission will not be considered as a serious adverse event. 
 
The investigator will report all SAEs to the sponsor without undue delay after 
obtaining knowledge of the events.  
 
The sponsor will report the SAEs through the web portal ToetsingOnline to the 
accredited METC that approved the protocol, within 7 days of first knowledge for 
SAEs that result in death or are life threatening followed by a period of maximum of 8 
days to complete the initial preliminary report. All other SAEs will be reported within a 
period of maximum 15 days after the sponsor has first knowledge of the serious 
adverse events. 
9.2.4 Suspected unexpected serious adverse reactions (SUSARs) 
 
Adverse reactions are all untoward and unintended responses to an investigational 
product related to any dose administered. 
 
Unexpected adverse reactions are SUSARs if the following three conditions are met: 
1. the event must be serious (see chapter 9.2.2); 
2. there must be a certain degree of probability that the event is a harmful and an 
undesirable reaction to the medicinal product under investigation, regardless of 
the administered dose; 
3. the adverse reaction must be unexpected, that is to say, the nature and severity 
of the adverse reaction are not in agreement with the product information as 
recorded in: 
- 
Summary of Product Characteristics (SPC) for an authorised medicinal 
product; 
The sponsor will report expedited the following SUSARs through the web portal 
ToetsingOnline to the METC : 
 SUSARs that have arisen in the clinical trial that was assessed by the METC; 


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 SUSARs that have arisen in other clinical trials of the same sponsor and with the 
same medicinal product, and that could have consequences for the safety of the 
subjects involved in the clinical trial that was assessed by the METC. 
The remaining SUSARs are recorded in an overview list (line-listing) that will be 
submitted once every half year to the METC. This line-listing provides an overview 
of all SUSARs from the study medicine, accompanied by a brief report highlighting 
the main points of concern.  
The expedited reporting of SUSARs through the web portal Eudravigilance or 
ToetsingOnline is sufficient as notification to the competent authority. 
 
The sponsor will report expedited all SUSARs to the competent authorities in other 
Member States, according to the requirements of the Member States.  
 
The expedited reporting will occur not later than 15 days after the sponsor has first 
knowledge of the adverse reactions. For fatal or life threatening cases the term will be 
maximal 7 days for a preliminary report with another 8 days for completion of the report.  
 
9.3 Annual safety report 
 
In addition to the expedited reporting of SUSARs, the sponsor will submit, once a year 
throughout the clinical trial, a safety report to the accredited METC, competent authority, 
and competent authorities of the concerned Member States. 
This safety report consists of: 
 a list of all suspected (unexpected or expected) serious adverse reactions, along with 
an aggregated summary table of all reported serious adverse reactions, ordered by 
organ system, per study; 
 a report concerning the safety of the subjects, consisting of a complete safety analysis 
and an evaluation of the balance between the efficacy and the harmfulness of the 
medicine under investigation. 
 
9.4 Follow-up of adverse events 
All AEs will be followed until they have abated, or until a stable situation has been 
reached. Depending on the event, follow up may require additional tests or medical 
procedures as indicated, and/or referral to the general physician or a medical specialist. 
SAEs need to be reported till end of study, as defined in the protocol.  
 


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9.5 Data Safety Monitoring Board (DSMB) 
In this trial, an independent DSMB will be established to perform ongoing safety 
surveillance. The composition, working routines and responsibilities of the DSMB are 
described in a separate DSMB charter. The independent DSMB will be established before 
the first subject is included into the study. 
The advice(s) of the DSMB will only be sent to the sponsor of the study. Should the 
sponsor decide not to fully implement the advice of the DSMB, the sponsor will send the 
advice to the reviewing METC, including a note to substantiate why (part of) the advice of 
the DSMB will not be followed. 
 
10. STATISTICAL ANALYSIS 
 
The primary endpoints will be assessed in the intention to treat (ITT) population. This 
population consists of the population of patients that were actually randomized to one to 
the two treatment arms and received at least one dose of study medication.  
 
The first assessment will be the calculation of the mentioned response variables in the 
placebo population including change in dyspnea VAS score at Day 4, diuretic response at 
Day 4, percentage change in plasma NTproBNP at Day 4 and length of hospital stay. 
These response variables will be calculated and presented as mean +/- SD if normal 
distributed or median (25th and 75th percentile) in the case non normal distribution is 
found. For the presentation of baseline characteristics in both treatment arms, continuous 
variables will be presented as mean  +/- standard deviation, non-normally distributed 
variables as median (25th-75th percentile), and categorical variables as count 
(percentages).  
 
10.1 
Primary study parameter(s) 
 
The primary analysis of the treatment effect of the randomized treatment will be carried 
out in the ITT population. For each individual response variable for the primary 
continuous outcome measure we estimate a treatment effect of 0.48 standard deviations, 
at the two sided 20% significance level (P value 0.2), with 80% power. The difference in 
the continuous response variables between the two treatment groups will be analysed 
using a t-test, assuming normality of these continuous variables. Since this primary 
outcome measure consists of an exploratory analysis, a conservative P value of 0.2 for 
significance will be used, and no correction for multiplicity will be adopted. 


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As exploratory analysis, individual responses (for the continuous response variables) will 
be standardized, and log rank scores for time to event outcomes will be standardized. 
Using this approach the standardized mean difference between treatment groups will be 
calculated. Furthermore, these standardized responses will be averaged across the 
primary outcome response variables, resulting in a mean standardized response score, 
from which a mean standardized response score difference may be estimated between 
treatments and assessed using t-test. 
 
10.2 
Secondary study parameter(s)  
Secondary response variable include death and/or heart failure re-admission through Day 
30 which will be assessed using logistic regression analysis for the between treatment 
difference. Changes in biomarkers and the difference in change between treatment 
groups, including plasma or urinary biomarkers will be assessed using t-test for normal 
distributed variables and Wilcoxon rank sum test if non-normally distributed.  
 
10.3 
Other study parameters 
Adverse event rates between treatment groups will be analysed using Fisher’s exact 
tests, and presented as counts (percentages). 
 
11. ETHICAL CONSIDERATIONS 
11.1 
Regulation statement 
The study will be conducted according to the principles of the Declaration of Helsinki (64th 
WMA General Assembly, October 2013), and in accordance with the Medical Research 
Involving Human Subjects Act (WMO) and other guidelines, regulations and Acts (GCP, 
GMP). 
 
11.2 
Recruitment and consent 
Recruitment of patients will take place through continuous monitoring of the Emergency 
Room admissions. Once a potentially eligible patient is admitted to the Emergency Room, 
and the diagnosis acute heart failure has been established, the Principal Investigator or a 
sub-investigator (physician) will verify eligibility based on hospital charts. Once eligibility 
has been established, the supervising cardiologist will be asked for permission to ask the 
patient for consent to participation in the study. After approval by the supervising 
cardiologist, the Principal Investigator or sub-Investigator will approach the patient, and 


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ask whether he/she is potentially interested in participation in the study. Interested 
patients will be provided with the patient information leaflet and they will be given verbal 
information about the study. Patients will be adequate time to consider their decision and 
to ask questions. Once a patient remains interested in participation, the Principal 
Investigator or sub-Investigator will go through all study details once again and then the 
patient signs and dates the informed consent form first, after which the Principal 
Investigator or sub-Investigator will sign and date the informed consent form, too. Before 
having obtained written informed consent from the patient, no study related assessments 
will be performed.  
 
11.3 
Objection by minors or incapacitated subjects (if applicable) 
Not Applicable 
 
11.4 
Benefits and risks assessment, group relatedness 
Empagliflozin has been shown to be relatively safe and well tolerated by patients with 
Diabetes Mellitus Type 2, and in heart failure patients with NYHA II-III heart failure it 
proved to reduce overall mortality. Based on these finding, the relative risk is estimated to 
be relatively low, while potential benefit may be expected.  
 
11.5 
Compensation for injury 
The sponsor/investigator has a liability insurance which is in accordance with article 7 of 
the WMO. 
  
The sponsor (also) has an insurance which is in accordance with the legal requirements 
in the Netherlands (Article 7 WMO). This insurance provides cover for damage to 
research subjects through injury or death caused by the study. 
The insurance applies to the damage that becomes apparent during the study or within 4 
years after the end of the study. 
 
12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
12.1 
Handling and storage of data and documents 
A subject identification code list will be made to link the data to the subject in order to be 
able to trace data to an individual subject. This code will not be based on the patient 
initials and birth-date. The key to the code will be safeguarded by the investigator since 
the data will be kept for a period of 15 years. The handling of personal data will comply 


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with privacy laws, legislation, codes and/or guidelines that apply in the applicable 
jurisdictions the study is conducted. 
 
12.2 
Monitoring and Quality Assurance  
Independent monitors will monitor the study in each country according to a pre-specified 
monitoring plan.  The monitors are trained in GCP and will be trained on study specific 
tasks and processes.  As part of the UMCG Quality Management Strategy monitor 
oversight will be implemented through regular documentation reviews and co-monitoring 
activities. 
 
12.3 
Amendments  
A ‘substantial amendment’ is defined as an amendment to the terms of the METC 
application, or to the protocol or any other supporting documentation, that is likely to 
affect to a significant degree: 
- the safety or physical or mental integrity of the subjects of the trial; 
- the scientific value of the trial; 
- the conduct or management of the trial; or 
- the quality or safety of any intervention used in the trial. 
 
All substantial amendments will be notified to the METC and to the competent authority. 
 
Non-substantial amendments will not be notified to the accredited METC and the 
competent authority, but will be recorded and filed by the sponsor.  
 
12.4 
Annual progress report 
The sponsor/investigator will submit a summary of the progress of the trial to the 
accredited METC once a year. Information will be provided on the date of inclusion of the 
first subject, numbers of subjects included and numbers of subjects that have completed 
the trial, serious adverse events/ serious adverse reactions, other problems, and 
amendments.  
 
12.5 
Temporary halt and (prematurely) end of study report 
The sponsor will notify the accredited METC and the competent authority of the end of 
the study within a period of 90 days. The end of the study is defined as the last patient’s 
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The sponsor will notify the METC immediately of a temporary halt of the study, including 
the reason of such an action. 
In case the study is ended prematurely, the sponsor will notify the accredited METC and 
the competent authority within 15 days, including the reasons for the premature 
termination. 
 Within one year after the end of the study, the investigator/sponsor will submit a final 
study report with the results of the study, including any publications/abstracts of the study, 
to the accredited METC and the Competent Authority.  
 
12.6 
Public disclosure and publication policy 
The trial will be registered in a public trial registry. The results will be disclosed 
unreservedly.  
 
 
13. STRUCTURED RISK ANALYSIS  
 
a. Level of knowledge about mechanism of action 
Empagliflozin is a reversible, highly potent (IC50 of 1.3 nmol) and selective competitive 
inhibitor of sodium-glucose co-transporter 2 (SGLT2). Empagliflozin does not inhibit other 
glucose transporters important for glucose transport into peripheral tissues and is 5000 
times more selective for SGLT2 versus SGLT1, the major transporter responsible for 
glucose absorption in the gut. SGLT2 is highly expressed in the kidney, whereas 
expression in other tissues is absent or very low. It is responsible, as the predominant 
transporter, for the reabsorption of glucose from the glomerular filtrate back into the 
circulation. In patients with type 2 diabetes and hyperglycaemia a higher amount of 
glucose is filtered and reabsorbed. 
Empagliflozin improves glycaemic control in patients with type 2 diabetes by reducing 
renal glucose reabsorption. The amount of glucose removed by the kidney through this 
glucuretic mechanism is dependent on blood glucose concentration and GFR. Inhibition of 
SGLT2 in patients with type 2 diabetes and hyperglycaemia leads to excess glucose 
excretion in the urine. 
In patients with type 2 diabetes, urinary glucose excretion increased immediately following 
the first dose of empagliflozin and is continuous over the 24 hour dosing interval. 
Increased urinary glucose excretion was maintained at the end of the 4-week treatment 
period, averaging approximately 78 g/day. Increased urinary glucose excretion resulted in 
an immediate reduction in plasma glucose levels in patients with type 2 diabetes. 
Empagliflozin improves both fasting and post-prandial plasma glucose levels. The 
mechanism of action of empagliflozin is independent of beta cell function and insulin 


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pathway and this contributes to a low risk of hypoglycaemia. Improvement of surrogate 
markers of beta cell function including Homeostasis Model Assessment-β (HOMA-β) was 
noted. In addition, urinary glucose excretion triggers calorie loss, associated with body fat 
loss and body weight reduction. The glucosuria observed with empagliflozin is 
accompanied by mild diuresis which may contribute to sustained and moderate reduction 
of blood pressure. 
 
b. Previous exposure of human beings with the test product(s) and/or products with a 
similar biological mechanism 
All of the drugs used in the study have been used extensively in clinical trials of patients 
with type 1 and type 2 diabetes and have been granted marketing approval for the 
treatment of cardiovascular complications in type 2 diabetes. Empagliflozin is currently 
being tested in patients with congestive heart failure. The present study is the first study in 
patients with acute heart failure with or without diabetes.  
 
 
c. Can the primary or secondary mechanism be induced in animals and/or in ex-vivo 
human cell material? 
Empagliflozin has been studied extensively in animals and human cell material before 
performing clinical trials in humans and generally the primary and secondary mechanisms 
can be induced in animals. 
 
d. Selectivity of the mechanism to target tissue in animals and/or human beings 
Empagliflozin selectively binds to the SGLT2 receptor, and is > 5000 times more selective 
for SGLT2 versus SGLT1, which is the major transporter in the gut responsible for glucose 
absorption. 
 
e. Analysis of potential effect 
The empagliflozin dose used in this trial has been safely used in trials of patients with type 
2 diabetes, renal impairment, and heart failure.  
 
f. Pharmacokinetic considerations 
In vitro data suggest that the primary route of metabolism of empagliflozin in humans is 
glucuronidation by uridine 5'-diphosphoglucuronosyltransferases UGT1A3, UGT1A8, 
UGT1A9, and UGT2B7. Empagliflozin is a substrate of the human uptake transporters 
OAT3, OATP1B1, and OATP1B3, but not OAT1 and OCT2. Empagliflozin is a substrate of 
P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). 
Co-administration of empagliflozin with probenecid, an inhibitor of UGT enzymes and 
OAT3, resulted in a 26% increase in peak empagliflozin plasma concentrations (Cmax) 
and a 53% increase in area under the concentration-time curve (AUC). These changes 


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were not considered to be clinically meaningful. The effect of UGT induction on 
empagliflozin has not been studied. Co-medication with known inducers of UGT enzymes 
should be avoided due to a potential risk of decreased efficacy. An interaction study with 
gemfibrozil, an in vitro inhibitor of OAT3 and OATP1B1/1B3 transporters, showed that 
empagliflozin Cmax increased by 15% and AUC increased by 59% following co-
administration. These changes were not considered to be clinically meaningful. Inhibition 
of OATP1B1/1B3 transporters by co-administration with rifampicin resulted in a 75% 
increase in Cmax and a 35% increase in AUC of empagliflozin. These changes were not 
considered to be clinically meaningful. Empagliflozin exposure was similar with and 
without co-administration with verapamil, a P-gp inhibitor, indicating that inhibition of P-gp 
does not have any clinically relevant effect on empagliflozin. Interaction studies conducted 
in healthy volunteers suggest that the pharmacokinetics of empagliflozin were not 
influenced by co-administration with metformin, glimepiride, pioglitazone, sitagliptin, 
linagliptin, warfarin, verapamil, ramipril, simvastatin, torasemide and hydrochlorothiazide. 
 
Based on in vitro studies, empagliflozin does not inhibit, inactivate, or induce CYP450 
isoforms. Empagliflozin does not inhibit UGT1A1, UGT1A3, UGT1A8, UGT1A9, or 
UGT2B7. Drug-drug interactions involving the major CYP450 and UGT isoforms with 
empagliflozin and concomitantly administered substrates of these enzymes are therefore 
considered unlikely. Empagliflozin does not inhibit P-gp at therapeutic doses. Based on in 
vitro studies, empagliflozin is considered unlikely to cause interactions with drugs that are 
P-gp substrates. Empagliflozin does not inhibit human uptake transporters such as OAT3, 
OATP1B1, and OATP1B3 in vitro at clinically relevant plasma concentrations and, as 
such, drug-drug interactions with substrates of these uptake transporters are considered 
unlikely. Interaction studies conducted in healthy volunteers suggest that empagliflozin 
had no clinically relevant effect on the pharmacokinetics of metformin, glimepiride, 
pioglitazone, sitagliptin, linagliptin, simvastatin, warfarin, ramipril, digoxin, diuretics and 
oral contraceptives. 
 
g. Study population 
Patients with acute heart failure are included in this study. The patients are admitted to 
emergency department and/or at the cardiac care unit and are under close monitoring of 
treating physicians.  
 
h. Interaction with other products 
See “f” for PK interaction with other products.  
 
i. Predictability of effect 


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Previous studies with empagliflozin have suggested that the drug decreases extracellular 
volume and exerts a natriuretic diuretic effects. On the basis of these findings we 
anticpate that empagliflozin may be beneficial for patients with acute heart failure.  
 
j. Can effects be managed? 
Patients are regularly monitored and asked about adverse effects. 
 
13.1 
Synthesis 
 
In this study adverse events of special interest are collected. These include hepatic injury, 
decreased renal function and metabolic acidosis. These side effects are rare but will be 
monitored closely by regular monitoring of liver enzymes, serum creatinine, and metabolic 
acidosis. The potential benefits of empagliflozin to decrease complications of acute heart 
failure clearly outweigh the risk of developing these adverse events.  
 
 
14. REFERENCES 
 
1. Metra M, Teerlink JR. Heart Failure. Lancet. 2017 Apr 28. pii: S0140-6736(17)31071-1. 
doi: 10.1016/S0140-6736(17)31071-1. [Epub ahead of print] 
2. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and 
treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment 
of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed 
with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart 
Fail. 2016 Aug;18(8):891-975 
3. Zinman B, Wanner C, Lachin JM, et al. EMPA-REG OUTCOME Investigators. 
Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 
2015 Nov 26;373(22):2117-28 
4. Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, Johansen 
OE, Woerle HJ, Broedl UC, Zinman B; EMPA-REG OUTCOME Investigators. Empagliflozin 
and Progression of Kidney Disease in Type 2 Diabetes.N Engl J Med. 2016 Jul 
28;375(4):323-34 
 
 

SAP_001.pdf: 
1 
 
 
PROTOCOL TITLE : Randomized, double blind, placebo controlled, multicenter 
pilot study on the effects of empagliflozin on clinical outcomes in patients 
with acute decompensated heart failure (EMPA-RESPONSE-AHF) 
 
September 2019 
 
NCT03200860 
 
 


2 
 
EMPA-RESPONSE-AHF 
Statistical Analysis Plan 
 
 
 
 
 
 
 
 
 
 
 
 
Version 1.0 
September 2019 
 
 
 
________________ 
 
 
 
 
__________________________ 
Prof. dr. A.A. Voors 
 
 
 
 
Prof. dr. H.J. Lambers Heerspink 
 
 


3 
 
1. Population for analysis 
The following analysis population will be defined for statistical analysis: 
a) The Full Analysis Set (FAS) population consists of all randomized patients. Following the 
Intention To Treat (ITT) principle, all randomized patients will be analyzed, according to the 
treatment they were assigned to at randomization 
b) Per Protocol (PP) population consists of a subset of FAS, will consist of all randomized 
patients without major protocol deviations. 
c) Safety Population will consist of the FAS population and includes patients that received at 
least one dose of the study drug and had one safety assessment thereafter 
The co-primary efficacy variables will be analyzed using the FAS population. All primary analysis will 
be repeated for the per protocol population. All secondary analyses will be analyzed using the FAS 
population 
2. Demographics 
Demographics of the population will be summarized in a baseline characteristics table stratified for 
treatment group. Continuous variables will be summarized using mean, median, standard deviation, 
25th and 75th, depending on distribution. Categorical variables will be summarized using frequency 
and percentage. Characteristics include (but not limited to): Age, sex, race, height, weight, body mass 
index (BMI), left ventricular ejection fraction (LVEF), systolic and diastolic blood pressure, heart rate, 
NYHA class, history of: heart failure, myocardial infarction, diabetes mellitus, atrial fibrillation, 
hypertension, cerebrovascular disease, medical therapy including medication and devices, and 
laboratory measurements at baseline, including hemoglobin, hematocrit, sodium, potassium, serum 
creatinine/eGFR, NTproBNP.  
Treatment groups will be compared using Chi-square or fisher exacts test for categorical variables 
and t-test or Wilcoxon rank-sum test for continuous normal and non-normally distributed variables. 
P-values will be provided for descriptive purposes. For exploratory analyses, if an imbalance in any of 
the variables between groups exist, adjustment for these variables in the model may be considered.  
 
3. Analysis of the Primary Endpoints 
The primary endpoints of this study are: 
- 
Change in Dyspnea VAS from Baseline to Day 4 
- 
Diuretic response (defined as Δ weight kg/[(total i.v. dose)/40mg]+[(total oral dose)/80mg)] 
furosemide (or equivalent loop diuretic dose) 
- 
Length of initial hospital stay 
- 
Change in NTproBNP from baseline to Day 4 
As this is an exploratory study with limited power, all 4 individual endpoints will be tested separately, 
with no formal correction for multiplicity. As sensitivity analysis, if at least 2 out of 4 primary 
endpoints show significant difference in the same direction (favoring either investigational drug or 
placebo) a Bonferroni correction will be applied. The significance level for the primary outcomes will 


4 
 
be a conservative two-tailed P < 0.2. With Bonferroni correction sensitivity analysis, the significance 
level will be P < 0.05.   
The difference between treatments in the change in Dyspnea VAS score from Baseline to Day 4 will 
be assessed by comparing the area under the curve (AUC) of VAS score over time by student’s t test. 
To do so, individual changes in VAS score will be visualized (virtually) as a curve where the X-axis 
shows study day baseline to day 4, and y-axis shows VAS score. Using this approach, area under the 
curves for each study day (trapezoids) can be calculated, and added together, resulting in an overall 
VAS AUC score (mmxh) that can be compared across treatment groups. This method follows 
methods described by the DOSE and RELAX-AHF trials. 
The difference in Diuretic response through day 4 will be assessed using either students t test if 
normally distributed or Wilcoxon rank-sum test if non-normally distributed. Diuretic response will be 
calculated as the change in weight from baseline to day 4 divided by the total dose of administered 
furosemide (total intravenous dose /40 mg + total oral dose/80 mg). Bumetanide will be recalculated 
to furosemide equivalents by the following equation: 1 mg of Bumetanide = 40 mg Furosemide. 
Difference in Length of stay will be assessed using either students t test if normally distributed or 
Wilcoxon rank-sum test if non-normally distributed. 
The difference in percentage change in NTproBNP from baseline to day 4 will be assessed using 
students t test if normally distributed or Wilcoxon rank-sum test if non-normally distributed. 
Secondly, using all NTproBNP levels at all timepoints through day 4, using a mixed effect repeated 
measures model (covariates including randomized treatment, study day, interaction between 
randomized treatment and study day) the interaction between change in NTproBNP over time and 
randomized treatment will be evaluated. NTproBNP will be log transformed if non normally 
distributed for this analysis.  
As an exploratory analysis, and for graphical presentation, individual responses to the above 
mentioned endpoints will be standardized. This will be done by dividing the difference of the overall 
mean (or log transformed mean if non normally distributed) of each endpoint by the overall standard 
deviation (SD) of that variable. The treatment effect can then be measured by the mean difference of 
standardized scores, which can be visually presented on a forest plot by mean +/- 80% CI (given the P 
<0.2).  
Then, all four standardized scores for each individual endpoints will be averaged, and mean 
treatment difference and associated 95% CI for this overall treatment effect visually presented. 
Statistical analysis for the treatment difference will then be carried out by students t-test. 
The primary analysis will be repeated for the per-protocol population as supportive. 
4. Analysis of the Secondary Endpoints 
The secondary endpoints of the study are: 
- 
Death through day 30 
- 
Heart Failure Re-admission through day 30 
- 
Death or Heart Failure re-admission through day 30 
- 
Change in cardiorenal biomarkers from baseline to day 4 or day 30 


5 
 
The difference in the incidence of the mortality/rehospitalization endpoints between both 
randomized treatment groups will be assessed using logistic regression. Crude event rates, 
percentages per treatment group and odds ratio’s with 95% confidence intervals will be presented. 
Changes in cardiorenal biomarkers and the difference in change between treatment groups, 
including plasma or urinary biomarkers will be assessed using t-test for normal distributed variables 
and Wilcoxon rank sum test if non-normally distributed for change between two timepoints. For 
change over time at multiple timepoints a mixed effect repeated measures model (covariates 
including randomized treatment, study day, interaction between randomized treatment and study 
day)will be carried out. Alternatively, an ANCOVA model using similar approach may be used. 
5. Analysis of the Safety Endpoints 
Analysis of safety endpoints will be conducted in the Safety Population. Adverse events include: 
- 
Adverse events  (general) 
- 
Adverse events that lead to treatment discontinuation 
- 
Serious Adverse Events (which could include a secondary endpoint) 
- 
Adverse Events of Special Interest (AESI), including: 
o Hepatic Injury 
o Worsening Renal Function 
o Metabolic Acidosis, Ketoacidosis and Diabetic Ketoacidosis 
Overall adverse event rates in the treatment groups will be presented as counts (percentages) and 
will be compared using Fisher’s exact test. 
 
6. Subgroup analysis 
As this is a small randomized controlled trial, subgroup analysis are supportive and exploratory in 
nature. Subgroup analyses will be performed in the FAS population. The primary outcome variables, 
it’s individual components and the mean treatment score, will be evaluated using the primary 
analysis and adding the specific subgroup as a factor and treatment x subgroup as interaction term.  
The following subgroups will be analyzed, no adjustment for multiple comparisons will be carried 
out: 
- 
Age groups 
- 
Gender 
- 
De novo versus acute decompensated (known) heart failure 
- 
Heart failure with preserved versus reduced ejection fraction 
- 
eGFR groups (above/below median baseline values) 
- 
History of Diabetes Mellitus (yes/no) 
- 
Blood pressure groups 
- 
NTproBNP at admission (above/below median levels) 
 
 


6 
 
7. Sample Size and Power calculation 
 
Our sample size calculation is based on capturing the primary outcome measures in the placebo 
group with a degree of certainty. With 40 patients in the control group, a given mean continuous 
response can be estimated within ± 0.2 Standard deviations (SD) with 80% confidence. We estimate 
the following mean responses for the primary outcome measures (in the placebo group):  
1. 
Change in dyspnea VAS score: 1756±2353 mmxh,  
2. 
Diuretic response (of 0.56 ± 0.78 kg/40 mg Furosemide (or equivalent))  
3. 
Length of stay 9.6 to 10.5 days (± 9.1) 
4. 
Percentage change in NT-proBNP 24 (-1.0 – 88.7)% (SD 67% assuming normal distribution)   
(all at 96 hours (day 4)) 
 
For the Secondary outcomes, including  death and/or HF re-admission at 60 days, an event rate of 
10% can be estimated within ± 6.1% and a rate of 15% within ± 7.2% with 80% confidence.  
Treatment effect: 
As this is an exploratory analysis the overall power to establish small treatment effects is limited. 
Forty patients per group provides approximately 80% power to detect standardized mean treatment 
differences of approximately 0.48 SDs at the two-sided 20% significance level, which gives around the 
following differences: 
1. Dyspnea VAS score of 1129 mmxh 
2. Diuretic response of 0.37 kg/40 mg Furosemide 
3. Length of initial hospital stay of 4 days 
4. Percentage change in NT-proBNP of 32% 
with the above SDs the control group (and corresponding mean response).