Clinical trial NCT03332212
Conditions: Heart Failure
Sponsor: Boehringer Ingelheim
Start date: 2018-03-01; Completion date: 2020-05-28
Enrollment: 72 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of this trial is to assess the effect of empagliflozin on cardiac physiology and metabolism aiming to provide a scientific explanation of the underlying mechanism by which empagliflozin improves HF related outcomes in patients with chronic heart failure

Detailed description:

Arms: arm 1: Heart Failure with Reduced Ejection Fraction arm 2: Heart Failure with Preserved Ejection Fraction
Interventions: intervention 1: Empagliflozin intervention 2: Placebo
Intervention descriptions: intervention 1: 12 weeks intervention 2: 12 Weeks

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-03 (14.0) / Saved on: 17 Oct 2016
CLINICAL TRIAL PROTOCOL
TITLE PAGE
Document Number:
c14878151-05
EudraCT No.:
EU Trial No:
2017-000376-28
BI Trial No.:
1245.148
BI Investigational 
Product:
Empagliflozin
Title:
EMPA-VISION: A randomised, double-blind, placebo-controlled,
mechanistic cardiac magnetic resonance study to investigate the 
effects of empagliflozin treatment on cardiac physiology and 
metabolism in patients with heart failure
Lay Title:
A study that looks at the function of the heart in patients with heart 
failure who take empagliflozin
Clinical Phase:
III
Trial Clinical 
Monitor:
Tel: 
Investigators:
Chief Investigator
Tel:
Fax:
Principal Investigator
Tel:
Fax:
Status:
Final Protocol (Revised Protocol (based on Global Amendment 2))
Version and Date:
Version: 3
Date: 14 Aug 2018
Page 1 of 78
Proprietary confidential information.
2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Finished product name
Jardiance
Active ingredient name: Empagliflozin
Protocol date
29 March 2017
Revision date
14 Aug 2018
Trial number
1245.148
Title of trial:
EMPA-VISION: A randomised, double-blind, placebo-controlled, 
mechanistic cardiac magnetic resonance study to investigate the 
effects of empagliflozin treatment on cardiac physiology and 
metabolism in patients with heart failure
Investigators:
Chief Investigator
Tel:
Fax
Principal Investigator
Tel:
Fax:
Trial site:
Clinical phase:
III
Objective:
The objective of this trial is to assess the effect of empagliflozin on 
cardiac physiology and metabolism aiming to provide a scientific 
explanation of the underlying mechanism by which empagliflozin 
improves Heart Failure (HF) related outcomes in patients with 
chronic heart failure.
Methodology:
Randomised, double-blind, placebo-controlled trial
Number of patients
entered: 
Approximately 86 randomised, to achieve 60 evaluable patients (30
in each cohort)
Number of patients on 
each treatment:
Approximately 43 in each cohort, randomised 1:1 to treatment 
groups
Diagnosis :
Cohort A: Heart Failure (HF) with reduced ejection fraction 


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(HFrEF)
Cohort B: Heart Failure (HF) with preserved ejection fraction 
(HFpEF)
Main inclusion criteria

Chronic heart failure diagnosed at least 3 months before 
informed consent

NYHA class II-IV at screening
Cohort A (HFrEF)

LVEF ≤40% as measured by echocardiogram (ECHO) at 
screening

The following signs of heart failure;
o
Elevated NT-proBNP (>125 pg/mL) at screening in 
patient without atrial fibrillation (AF)
o
Elevated NT-proBNP (>600 pg/mL) at screening in 
patient with AF
Cohort B (HFpEF)

LVEF ≥50% as measured by ECHO at screening and no 
previous measurement of LVEF ≤ 40%.

The following combined signs of heart failure;
o
Structural heart disease (Left Atrial (LA) enlargement 
[Left Atrial Volume Index (LAVI) >34 mL/m2] and/or 
Left Ventricular Hypertrophy (LVH) [Left Ventricular 
Mass Index (LVMI) ≥ 115 g/m2 for males and ≥ 95 g/m2
for females]) by ECHO at screening or within 3 months 
prior to informed consent
AND 
o
NT-proBNP > 125pg/mL at screening in patient without 
AF or NT-proBNP > 600 pg/mL in patient with AF
Test product:
Empagliflozin
dose:
10 mg once daily
mode of 
administration:
Oral
Comparator products:
Placebo matching Empagliflozin
dose:
Not applicable
mode of 
administration:
Oral


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Duration of treatment:
12 weeks
Endpoints

Primary endpoint: Change from baseline to week 12 in 
Phosphocreatine/Adenosine Triphosphate (PCr/ATP) ratio in 
resting state measured by 31P Magnetic Resonance 
Spectroscopy (MRS)

There are no secondary endpoints defined for this trial

All other endpoints are exploratory
Safety criteria:

Adverse events (AE)

AE of special interest (AESI)

Incidence and intensity of AE including serious AE (SAE)

Withdrawal from trial medication due to AE

Clinically relevant new finding or worsening of existing 
condition on physical examination 

Clinically relevant changes in laboratory measurements from 
baseline
Statistical methods:
The analysis will be performed on the per protocol set (PPS) of 
patients having a valid PCr/ATP ratio measurements available at 
baseline and at week 12, and not having an important protocol 
violation relevant to the primary endpoint. 
Change from baseline of cardiac energetics (PCr/ATP ratio) at 
rest after 12 weeks of treatment will therefore be analysed by an 
analysis of variance (ANOVA) model. The model will include 
treatment, presence of atrial fibrillation at baseline (Yes/No) and 
history of diabetes (Yes/No) as fixed effects. 
All planned analyses will be conducted separately on the two 
cohorts.


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FLOWCHART
Trial Period
Screening
Treatment
Follow-up*
Visit
1
2**
3
4**
5
Timing
1-21 days 
prior to 
randomisation
Day 1
Day 15
±1 day
Day 84/
EOT
±4 days
7-14 days 
after last 
dose
Informed consent
X
Demographics, alcohol and smoking history
X
NYHA classification
X
X
Cardiac computed tomography (CT) scan
X1
Echocardiogram (ECHO)
X1
X2
X
X
Safety laboratory tests (blood)
X
X2
X
Safety laboratory tests (urine)
X3
Blood sampling for NT-proBNP asessment
X
 
12 lead-electrocardiogram (ECG)
X1
X2
X
Vital signs
X
X2
X
X
Height
X
Weight
X
X2
X
X
Pregnancy test4
X
X
X
X
Review of in-/exclusion criteria
X
X
Medical history
X
Physical examination
X
X
Randomisation
X
Dispense trial medication
X
Administer trial medication
Continuous daily dosing5
Medication compliance check
X
X
Cardiac Magnetic Resonance (CMR)
X
X
Adverse events
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
Telephone call to patient
X
Completion of patient participation
X
*
The follow-up visit must be completed for all randomised patients, including those who withdraw prematurely (see 
Section 3.3.4.1), unless the patient has withdrawn consent to follow-up. The follow-up visit is expected to be 
performed via a telephone call, but a clinic visit may be performed at the discretion of the investigator.
**
Patients must be fasting at Visits 2 and 4. See Section 6 for restrictions on the order of assessments during Visit 2 
and Visit 4.
1
If ischaemic clinical testing has been performed within 6 months and written results are available and adequate to 
assess eligibility, a cardiac CT is not required at screening. If echocardiogram and/or electrocardiogram is/are
performed as part of standard care within 3 months prior to informed consent, and written results are available, the 
assessment does not need to be repeated during the screening visit and the existing scan(s) can be used to assess 
eligibility.
2
The following assessments do not need to be repeated at visit 2 if performed within the previous 7 days; Safety 
laboratory tests (blood), Electrocardiogram, Vital signs, Weight. The echocardiogram does not need to be repeated 
at visit 2 if performed within the previous 21 days.
3
At Visit 3 only a urine test for ketone bodies is required.
4
For women of childbearing potential either a urine or serum pregnancy test is required. 
5
Daily dosing should continue until the last dose is taken on the day of Visit 4.


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TABLE OF CONTENTS
CLINICAL TRIAL PROTOCOL..........................................................................................1
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOWCHART.........................................................................................................................5
TABLE OF CONTENTS ........................................................................................................7
ABBREVIATIONS................................................................................................................10
1.
INTRODUCTION...............................................................................................13
1.1
MEDICAL BACKGROUND.............................................................................13
1.2
DRUG PROFILE................................................................................................14
1.2.1
Non-clinical assessment of safety.......................................................................14
1.2.2
Clinical pharmacokinetics..................................................................................14
1.2.3
Clinical efficacy and safety.................................................................................14
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................15
1.4
BENEFIT - RISK ASSESSMENT.....................................................................16
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................18
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........18
2.1.1
Main objectives....................................................................................................18
2.1.2
Primary endpoint................................................................................................18
2.1.3
Secondary endpoints...........................................................................................18
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................20
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................20
3.1.1
Administrative structure of the trial .................................................................20
3.1.1.1
Clinical Event Committee for Diabetic ketoacidosis (DKA)................................20
3.1.1.2
Hepatic external adjudication................................................................................20
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP...........................................................................................21
3.3
SELECTION OF TRIAL POPULATION .......................................................21
3.3.1
Main diagnosis for trial entry ............................................................................22
3.3.2
Inclusion criteria .................................................................................................22
3.3.3
Exclusion criteria ................................................................................................23
3.3.4
Withdrawal of patients from therapy or assessments .....................................25
3.3.4.1
Withdrawal from trial treatment ...........................................................................25
3.3.4.2
Withdrawal of consent for trial participation........................................................26
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................26
4.
TREATMENTS...................................................................................................27
4.1
INVESTIGATIONAL TREATMENTS ...........................................................27
4.1.1
Identity of the Investigational Medicinal Products..........................................27
4.1.2
Selection of doses in the trial..............................................................................27


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4.1.3
Method of assigning patients to treatment groups...........................................28
4.1.4
Drug assignment and administration of doses for each patient......................28
4.1.5
Blinding and procedures for unblinding...........................................................29
4.1.5.1
Blinding.................................................................................................................29
4.1.5.2
Unblinding and breaking the code ........................................................................29
4.1.6
Packaging, labelling, and re-supply...................................................................29
4.1.7
Storage conditions...............................................................................................30
4.1.8
Drug accountability.............................................................................................30
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................30
4.2.1
Other treatments and emergency procedures..................................................30
4.2.2
Restrictions ..........................................................................................................32
4.3
TREATMENT COMPLIANCE........................................................................32
5.
ASSESSMENTS..................................................................................................33
5.1
ASSESSMENT OF EFFICACY........................................................................33
5.1.1
New York Heart Association (NYHA) classification .......................................33
5.1.2
Body weight and height ......................................................................................33
5.2
ASSESSMENT OF CARDIAC EFFECTS OF EMPAGLIFLOZIN.............33
5.2.1
Echocardiogram (ECHO)...................................................................................33
5.2.4
Cardiac Magnetic Resonance (CMR) ...............................................................34
5.2.5
Cardiac Computerised Tomography (CT) Scan..............................................37
5.3
ASSESSMENT OF SAFETY.............................................................................37
5.3.1
Physical examination ..........................................................................................37
5.3.2
Vital signs.............................................................................................................37
5.3.3
Safety laboratory parameters ............................................................................37
5.3.3.1
Creatinine..............................................................................................................38
5.3.3.2
Renal function.......................................................................................................38
5.3.3.3
Pregnancy testing..................................................................................................39
5.3.3.4
Urine test for ketone..............................................................................................39
5.3.3.5
Criteria for hypoglycaemic events........................................................................39
5.3.3.6
Urinary tract infections and genital infections......................................................40
5.3.4
Electrocardiogram (ECG)..................................................................................40
5.3.5
Assessment of adverse events.............................................................................40
5.3.5.1
Definitions of AEs ................................................................................................40
5.3.5.2
Adverse event collection and reporting ................................................................43
5.4
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................45
5.5
ASSESSMENT OF BIOMARKERS.................................................................45
5.5.1
Biomarkers at screening.....................................................................................45
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................47
6.
INVESTIGATIONAL PLAN.............................................................................48


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6.1
VISIT SCHEDULE.............................................................................................48
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................48
6.2.1
Screening period..................................................................................................48
6.2.2
Treatment period ................................................................................................48
6.2.3
Follow up period and trial completion..............................................................49
6.2.4
Early discontinuation of trial medication .........................................................49
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................50
7.1
STATISTICAL DESIGN MODEL ...................................................................50
7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................50
7.3
PLANNED ANALYSES.....................................................................................50
7.3.1
Primary endpoint analyses.................................................................................51
7.3.2
Secondary endpoint analyses .............................................................................51
7.3.4
Safety analyses.....................................................................................................52
7.4
INTERIM ANALYSES ......................................................................................52
7.5
HANDLING OF MISSING DATA ...................................................................52
7.6
RANDOMISATION ...........................................................................................53
7.7
DETERMINATION OF SAMPLE SIZE .........................................................53
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........54
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................54
8.2
DATA QUALITY ASSURANCE ......................................................................55
8.3
RECORDS...........................................................................................................55
8.3.1
Source documents ...............................................................................................55
8.3.2
Direct access to source data and documents.....................................................56
8.3.3
Storage period of records ...................................................................................56
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................56
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........57
8.6
TRIAL MILESTONES.......................................................................................57
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................57
9.
REFERENCES....................................................................................................59
9.1
PUBLISHED REFERENCES............................................................................59
9.2
UNPUBLISHED REFERENCES......................................................................63
10.
APPENDICES.....................................................................................................64
10.1
NYHA FUNCTIONAL CLASSIFICATION....................................................64
10.3
COCKCROFT-GAULT FORMULA ...............................................................72
11.
DESCRIPTION OF GLOBAL AMENDMENTS............................................73


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ABBREVIATIONS
ACE
Angiotensin-converting enzyme
ACR
Albumin Creatinine Ratio
AE
Adverse Event
AESI
Adverse Event of Special Interest
AF
Atrial Fibrillation
ALT
Alanine-Aminotransferase
AMP
Auxiliary Medicinal Product
ARB
Angiotensin Receptor Blocker
ARNI
Angiotensin Receptor blocker-Neprilysin Inhibitor
ARO
Academic Research Organisation
AST
Aspertate-Aminotransaminase
ATP
Adenosine Triphosphate
BI
Boehringer Ingelheim
BMI
Body Mass Index
BP
Blood Pressure
BRPM
Blinded Report Planning Meeting
CA
Competent Authority
CAD
Coronary Artery Disease
CCTA
Coronary Computer Tomographic Angiography
CEC
Clinical Event Committee
CI
Confidence Interval
CK
Creatine Kinase
CKD
Chronic Kidney Disease
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration Equation
CMR
Cardiac Magnetic Resonance
CPET
Cardiopulmonary Exercise Test
CRA
Clinical Research Associate
CRO
Clinical Research Organisation
CRT
Cardiac Resynchronisation Therapy
CT
Computed Tomography
CTP
Clinical Trial Protocol
CV
Cardiovascular
DILI
Drug Induced Liver Injury
DKA
Diabetic Ketoacidosis
DM
Diabetes Mellitus
eCCR
Estimated creatinine clearance
ECG
Electrocardiogram
ECHO
Echocardiogram
eCRF
Electronic Case Report Form
EF
Ejection Fraction
eGFR
Estimated Glomerular Filtration Rate
EOT
End of treatment
EudraCT
European Clinical Trials Database


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GCP
Good Clinical Practice
GI
Gastrointestinal
GMP
Good Manufacturing Practice
HDL
High Density Lipoprotein
HF
Chronic Heart Failure
HHF
Hospitalisation for Heart Failure
HFpEF
Heart Failure with Preserved Ejection Fraction
HFrEF
Heart Failure with Reduced Ejection Fraction
HR
Hazard Ratio
IB
Investigator’s Brochure
ICD
Implantable Cardioverter Defibrillator
ICH
International Conference on Harmonisation 
IEC
Independent Ethics Committee
IPV
Important Protocol Violation
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
ITT
Intent to Treat
i.v.
Intravenous
LA
Left Atrial
LAVI
Left Atrial Volume Index
LDL
Low Density Lipoprotein
LGE
Late Gadolinium Enhancement
LPDD
Last Patient Drug Discontinuation
LV
Left Ventricular
LVAD
Left Ventricular Assist Device
LVEF
Left Ventricular Ejection Fraction
LVH
Left Ventricular Hypertrophy
LVMI
Left Ventricular Mass Index
MACE
Major Adverse Cardiovascular Event
MedDRA
Medical Dictionary for Drug Regulatory Activities
MI
Myocardial Infarction
MRA
Mineralocorticoid Receptor Antagonist
MRI
Magnetic Resonance Imaging
MRS
Magnetic Resonance Spectroscopy
NT-proBNP
N-terminal of the prohormone brain natriuretic peptide
NYHA
New York Heart Association Classification
PCr
Phosphocreatine
PK
Pharmacokinetics
PPS
Per Protocol Set
PSA
Prostate-Specific Antigen
RBC
Red Blood Cells
REP
Residual Effect Period, after the last dose of medication with measureable 


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drug levels or pharmacodynamic effects still likely to be present
RER
Respiratory Exchange Ratio
RPE
Rating of Perceived Exertion
RS
Randomised Set
SAE
Serious Adverse Event
SBP
Systolic blood Pressure
SGLT-1
Sodium-glucose co-transporter 1
SGLT-2
Sodium-glucose co-transporter 2
SMQ
Standardised MedDRA Query
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
T1DM
Type 1 diabetes mellitus
T2DM
Type 2 diabetes mellitus
TIA
Transient Ischaemic Attack
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
ULN
Upper limit of normal
UTI
Urinary Tract Infection
WBC
White Blood Cells
WOCBP
Women of childbearing potential


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Chronic heart failure (HF) is a progressive syndrome characterised by the inability of the 
heart to provide adequate blood supply to meet the metabolic demand of different tissues or 
do it at the expense of elevated left ventricle filling pressure. HF is a prevalent disease 
affecting an estimated 26 million people worldwide. In the United States alone the prevalence 
is 5.7 million, and there are 670,000 new cases per year [R16-1527]. In the UK, management 
of heart failure accounts for 1-2% of healthcare spending [P02-06417]. HF is associated with 
premature mortality and frequent hospitalisation. Approximately 50% of patients who 
develop HF die within 5 years after diagnosis [P16-03952]. Annually, more than 1 million 
patients are hospitalised with a primary diagnosis of HF. HF is the most common cause of 
hospitalisation among individuals above 65 years of age in the western countries [P16-
03760]. Two types of HF have been defined mainly based on the LV ejection fraction (EF) 
and also other structural changes in heart muscle. They consist of heart failure with reduced 
EF (HFrEF) ≤40% and heart failure with preserved EF (HFpEF) ≥40%. Relative prevalence 
of HFpEF among HF patients is approximately 50% [R16-1528]. Amongst patients with HF 
who require hospitalisation, the proportion of HFpEF is rising. Analysis of a large HF 
registry showed that the proportion of patients hospitalised with HF (HHF) who had HFpEF 
increased from 33% in 2005 to 39% in 2010 [R16-1529]. The rate of rehospitalisation among 
patients with HFrEF is close to 29% within 60-90 days of hospitalisation discharge which is 
equal to HFpEF [R16-1527].
Despite advances in therapy and management, HF remains a deadly clinical syndrome. After 
HHF, the one year mortality rate is high and not different between patients with preserved or 
reduced left ventricular ejection fraction (LVEF) [R16-2217], underscoring a high unmet 
medical need in this population.
About 25 to 45% of patients with HF have concomitant type 2 diabetes mellitus (T2DM), and 
nearly 15-25% have impaired glucose regulation (pre-diabetes), indicating a potential link 
between the HF syndromes and glucometabolic disturbances [R16-2382, R16-2384].
Despite the current standard of care for treatment of HFrEF such as medical therapy 
[angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), beta 
blockers, mineralocorticoid receptor antagonists (MRA), ivabradine and angiotensin receptor 
blocker-neprilysin inhibitor (ARNI)] or device therapy, the mortality and morbidity remains 
high. For HFpEF, however, control of congestive symptoms during acute episodes is the 
mainstay of management of these patients and no class of drugs have shown to increase 
survival or reduce hospitalisations for HFpEF [P16-03760, P16-05920].
Empagliflozin is an orally available inhibitor of the renal dependent glucose co-transporter 2 
(SGLT-2) indicated for reduction of blood glucose in patients with T2DM by promoting 
urinary glucose excretion. It also reduces blood pressure, arterial stiffness and measures of 
the myocardial workload, likely through various mechanisms, as well as improving other
cardiovascular (CV) risk factors (uric acid, visceral fat mass, albuminuria) [P15-00589, P15-
09541].


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In 2010 Boehringer Ingelheim (BI) initiated the EMPA-REG OUTCOME trial to explore CV 
benefit of the drug as well as to establish the safety profile of empagliflozin [P15-09840]. 
This trial completed in 2015 and showed empagliflozin, when given in addition to standard 
care treatment in high CV risk patients with T2DM, reduced the risk of 3-point Major 
Adverse Cardiovascular Event (MACE) by 14% mostly driven by a 38% reduction in CV 
death. Furthermore this trial demonstrated a reduction of 35% in HHF and a reduction of 34%
in the prespecified and adjudicated composite outcome of “HHF or CV death”.
Consistent with the main results of the EMPA-REG OUTCOME trial, in approximately 10%
of the trial population who had investigator-reported heart failure at baseline, empagliflozin
showed significant reduction in CV death, HHF, and composite of “HHF or CV death”
[P16-01253].
1.2
DRUG PROFILE
Empagliflozin is an orally available, potent, and selective inhibitor of the renal SGLT-2. Its 
selective inhibition reduces renal reabsorption of sodium and glucose. This leads to both 
increased urinary sodium and glucose excretion. While the urinary sodium excretion returns 
to normal within a few days of empagliflozin administration, the effect on urinary glucose 
continues.
Empagliflozin has been developed for the treatment of T2DM, and has received marketing 
approval in various regions including the European Union, Latin America, USA and Japan 
where it is marketed under the brand name Jardiance®.
For a more detailed description of the drug profile please refer to the current Investigator’s 
Brochure (IB) [c01678844] and local prescribing information for empagliflozin.
1.2.1
Non-clinical assessment of safety
For further information regarding pre-clinical evaluation, please refer to the current version 
of the Investigator Brochure (IB) for empagliflozin [c01678844].
1.2.2
Clinical pharmacokinetics
In humans, empagliflozin predominantly showed linear pharmacokinetics (PK). 
Empagliflozin reaches peak levels at approximately 1.5 hours and shows a biphasic decline 
with a terminal elimination half-life of 12.4 hours ranging from 10 to 19 hours.
Empagliflozin exposure increases with renal or hepatic impairment; however, no dose 
adjustment is recommended as the observed changes in exposure were not clinically 
meaningful. No clinically relevant PK interactions were observed with other oral 
antidiabetics, warfarin, verapamil, ramipril, simvastatin, digoxin, hydrochlorothiazide, 
torasemide, emfibrozil, rifampicin, probenecid and oral contraceptives (Microgynon®). For 
further details refer to the current version of the IB for empagliflozin.
1.2.3
Clinical efficacy and safety
Approximately 550 healthy volunteers were exposed to empagliflozin (up to 800 mg single 
dose and up to 50 mg multiple dosing). Approximately 10,000 patients with T2DM have been 


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treated with empagliflozin in research studies. Empagliflozin was tested in over 4600 patients 
with T2DM and high CV risk for median treatment duration of 2.6 years in the EMPA-REG 
OUTCOME trial.
The EMPA-REG OUTCOME trial was a randomised, placebo-controlled trial of 
empagliflozin 10 or 25 mg in 7020 patients with T2DM and high CV risk. It ended in 2015 
after accruing the minimum prespecified 691 major adverse CV events. Empagliflozin was 
associated with significant risk reduction of all-cause mortality by 32% (Hazard Ratio (HR)
0.68; 95% CI 0.57, 0.82 p<0.0001) and CV death by 38% (HR 0.62; 95% CI 0.49, 0.77, p 
<0.0001). In addition, the EMPA-REG OUTCOME trial showed a reduction in the 
prespecified and adjudicated composite outcome of “CV death or HHF” by 34% (HR 0.66; 
95% CI 0.55, 0.79, p value <0.0001). This result was consistent across various predefined 
sensitivity analysis and internal consistency was confirmed by showing overall homogeneity 
over a wide range of subgroups, including patients with and without history of HF at 
baseline. There was no significant difference in improving CV outcomes between the 10 and 
25 mg doses of empagliflozin.
The Phase III studies in patients with T2DM showed that treatment with empagliflozin 10 mg 
or 25 mg once daily for up to 24 weeks results in a reduction of glycated haemoglobin 
(HbA1c) up to 1%, body weight reduction between 2-3 kg, and a decrease in systolic blood
pressure (SBP) between 3-5 mmHg compared with placebo. This was consistently observed 
with empagliflozin as monotherapy, and as add on therapy to metformin, metformin and 
sulphonylurea, pioglitazone with or without metformin, and to basal insulin with metformin 
and/or sulphonylurea. The data from Phase III studies up to 104 weeks in patients with 
T2DM support the sustained effect of empagliflozin.
In clinical studies, empagliflozin was well tolerated in both healthy volunteers and patients 
with T2DM including patients with high CV risk up to a median duration of 2.6 years. The 
frequency of overall AEs, AEs leading to discontinuation and SAEs were comparable to 
placebo. There was no significant increase in frequency of hypoglycaemia with empagliflozin 
compared to placebo except when used in combination with a sulphonylurea or basal insulin. 
In general there was a small increase in frequency of urinary tract infections (UTIs) compared 
with placebo. There was an increase in frequency of genital infections with the use of 
empagliflozin. There was a small increase in total cholesterol, low-density lipoprotein (LDL) 
cholesterol and high-density lipoprotein (HDL) cholesterol and no statistically or clinically
significant changes in triglycerides. No clinically significant changes in electrolytes were 
observed with empagliflozin.
Diabetic ketoacidosis was reported infrequently and at similar rates in the empagliflozin and 
placebo treatment groups in the T2DM clinical program. In a number of reported cases the 
presentation of the condition was atypical with only moderately increased blood glucose 
values, below 14 mmol/L (250 mg/dL).
1.3
RATIONALE FOR PERFORMING THE TRIAL
Heart failure is an important public health problem, and one of the leading causes of 
hospitalisation in the Western countries. With the increasingly ageing population and 
increasing incidence of obesity, the scope and cost to society associated with this condition 
will progressively rise. There is an unmet medical need in treatment of patients with HF. 


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Despite advances in the management of HF, no new therapies have been found to improve 
outcomes by reducing mortality or morbidity (i.e. CV death or HHF) in HFpEF patients [P16-
03760]. HF also significantly decreases health-related quality of life (HRQOL) and 
pharmacological therapies have not shown consistent improvement in HRQOL.
In the EMPA REG OUTCOME® trial, empagliflozin showed clinically significant 
reductions of HHF events which was a prespecified exploratory endpoint (HR=0.65) in 
patients with T2DM and established CV disease. This led to the hypothesis that empagliflozin 
may provide significant benefits in HF outcome in patients with chronic heart failure. Thus 
two clinical trials have been designed to further investigate the efficacy and safety of 
empagliflozin in heart failure patients (c03946327 and c09098452). Whilst these trials will 
provide more information on efficacy and safety, they are not designed to provide detailed 
information on the mechanism of action of empagliflozin on cardiac function. 
Chronic heart failure is multifactorial. There are many reasons why a human heart can fail, 
but the available evidence suggests that altered energetics play an important role in the 
mechanisms of heart failure. In cardiomyocytes, ATP is synthesised and converted to PCr by 
Creatine Kinase (CK). The PCr/ATP ratio reflects the energetic state of the heart and can be 
assessed by 31P-MRS. When ATP demand outweighs synthesis (e.g. in ischemia or during 
exercise), PCr levels fall, resulting in a low PCr/ATP ratio. The current study will test the 
hypothesis that empagliflozin treatment leads to an increase in PCr and hence an increase in 
PCr/ATP ratio. This in turn leads to improved cardiac energetics (both resting and stress) and 
cardiac function, including exercise capability. 
1.4
BENEFIT - RISK ASSESSMENT
The overall benefits and safety profile of empagliflozin have been outlined in previous 
sections. A pharmacologic rationale for the use of empagliflozin in HF can be found in 
Section 1.1. The overall tolerability and safety profile outlined in Section 1.2, and the current 
IB, supports chronic administration of empagliflozin 10 mg in human studies. 
Investigators will be encouraged to treat participants to best standard of care in compliance 
with the local guidelines and recommendations for HF, and Diabetes Mellitus (DM) if present.
Based on the putative mechanism of actions (reviewed in Section 1.3) and the result of the 
EMPA-REG OUTCOME trial, it is assumed that patients with HF should benefit from 
empagliflozin treatment on top of guideline-directed therapies. The safety profile of 
empagliflozin in these patients is expected to be comparable to that previously observed in 
over 10,000 patients with T2DM treated with empagliflozin, including patients with high CV 
risk.  Safety will be ensured by close monitoring of the subjects for AEs both clinically and 
by laboratory testing. Special attention will be paid to prevent metabolic acidosis, 
ketoacidosis and diabetic ketoacidosis (DKA). For further details refer to Section 4.2.1. 
As with all drugs, the potential for hypersensitivity and allergic reactions has to be taken into 
consideration when empagliflozin is administered. Other risks to the patients are the risks 
inherent to any investigational medicinal product used in a clinical trial setting, such as 
unexpected adverse clinical or laboratory events.


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Some of the assessment techniques used in this trial are not standard in heart failure patients. 
Patients will be provided with full information about the anticipated risks of these procedures 
to enable them to make an informed decision about participation.
Empagliflozin causes intravascular volume contraction. In patients with volume depletion, 
correcting this condition prior to initiation of empagliflozin is recommended. 
Although rare, a potential for drug induced liver injury (DILI) is under constant surveillance 
by the Sponsor and regulators. Therefore this trial requires timely detection, evaluation and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure patients´ 
safety, see also Section 5.3.5.1.
Based on the findings in the nonclinical trials conducted to date and in accordance with 
international regulatory guidelines, the inclusion of women of childbearing potential 
(WOCBP) in this trial is justified. To minimise the risk of unintentional exposure of an 
embryo or foetus to the investigational drug, WOCBP must agree to the requirements for 
pregnancy testing and contraceptive methods described in this protocol.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The objective of this trial is to assess the effect of empagliflozin on cardiac physiology and 
metabolism aiming to provide a scientific explanation of the underlying mechanism by which 
empagliflozin improves HF related outcomes in patients with chronic heart failure.
2.1.2
Primary endpoint
The primary endpoint is the change from baseline to week 12 in PCr/ATP ratio in the resting 
state measured by 31P MRS.
2.1.3
Secondary endpoints
There are no secondary endpoints defined for this trial.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This randomised, double-blind, placebo-controlled trial investigates the effects of 
empagliflozin on cardiac metabolism and function in heart failure patients. Empaglifozin will 
be compared to placebo as add-on to standard of care treatment in heart failure patients. The 
effects of empagliflozin will be assessed independently in two separate cohorts of patients; 
those with reduced ejection fraction (rEF) and those with preserved ejection fraction (pEF), 
but the randomised treatment and trial assessments for both cohorts are identical.
Figure 3.1: 1 Trial design
3.1.1
Administrative structure of the trial
3.1.1.1
Clinical Event Committee for Diabetic ketoacidosis (DKA)
An independent external committee (CEC) will be established to adjudicate centrally and in a 
blinded fashion events suspected of DKA (for further details see Section 5.3.5.1). 
For any events that qualify for adjudication, study sites will be asked to provide clinical
documentation such as laboratory values, discharge summaries etc. to support the external 
event adjudication.
The tasks and responsibilities of the CEC will be specified in a charter. The CEC will 
maintain the adjudication results in writing. The assessments will be analysed and reported 
based on empagliflozin data combined from multiple trials (i.e. on project level).
3.1.1.2
Hepatic external adjudication
Certain hepatic events will be adjudicated by external independent experts for severity and 
causal relationship with the trial medication in a blinded fashion. The events which will be
reviewed are defined in a charter for hepatic events. Events may either be defined by 
abnormal laboratory values and/or relevant adverse events or both. For example, assessments 
will be made for hepatic injury events, including liver enzyme elevations.


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For qualifying events, relevant source documents generated from any medical evaluations of 
these events will be requested including laboratory values, histological analysis, results of
ultrasound, CT, MRI, scintigraphy, hospital discharge letters, and medical reports from other 
physicians. All evaluations will be performed in a blinded fashion. The assessments will be 
analysed based on empagliflozin data combined from multiple trials (i.e. on project level).
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
The trial follows a standard randomised double-blind design so that the effects of 
empagliflozin in heart failure patients can be assessed without bias. The chosen comparator is 
placebo so that any differences observed between the groups can be attributed to 
empagliflozin. The two cohorts are independent and therefore unblinding may be performed 
at different timepoints if required. Unblinding of a cohort will only be performed following 
the completion of that cohort.
The duration of treatment is 12 weeks and this has been chosen because the expected effects 
of empagliflozin on cardiac energetics and function are expected to be observed at this 
timepoint based on observations from other similar compounds [R17-1107] and from the 
EMPA-REG trial [P15-09840].
3.3
SELECTION OF TRIAL POPULATION
The trial will be conducted in a single centre specialising in cardiac imaging. Approximately 
180 patients will be screened in total in order to identify 43 eligible patients for each cohort. 
Screening will continue until 43 eligible patients have been randomised into each cohort.
Once one cohort is full, recruitment into that cohort will be closed and patients will only be 
screened for the cohort which remains open. Any patients already in screening at the time a 
cohort is closed will be allowed to continue to randomisation if eligible.
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the investigator site file (ISF) at the investigational site irrespective of whether 
they have been treated with investigational drug or not.
Re-screening of patients who do not meet the inclusion/exclusion criteria will not be 
permitted, however assessments may be repeated within the screening period and the latest 
assessment prior to randomisation must always be used to assess eligibility.
Cohort A will contain 43 patients with heart failure with reduced ejection fraction (HFrEF) 
and Cohort B will contain 43 patients with heart failure with preserved ejection fraction 
(HFpEF). Within each cohort patients will be randomised 1:1 to receive either empagliflozin 
or matching placebo. A drop-out rate of 30% is expected and the total sample size for a 
cohort may be increased if the drop-out rate is higher than expected (Section 7.7).
Patients with T2DM will be eligible to enter the trial and are expected to account for 30-40% 
of randomised patients. There are no targets or restrictions on the recruitment of patients with 
T2DM but randomisation will be stratified according to history of diabetes (Yes/No) to 
ensure a balance between the arms (see also Section 7.1).


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3.3.1
Main diagnosis for trial entry
The trial will be performed in patients with chronic heart failure. Patients with reduced 
ejection fraction (≤40%) or preserved ejection fraction (≥50%) will be included.
Patients who do not meet all of the inclusion criteria or who meet any of the exclusion criteria
are not eligible for study participation and are not eligible to receive study medication. Please 
refer to Section 8.3.1 (Source Documents) for the documentation requirements pertaining to 
the in- and exclusion criteria.
3.3.2
Inclusion criteria
1. Chronic heart failure diagnosed at least 3 months before informed consent
2. NYHA class II-IV at screening
3. Inclusion criterion no longer applicable
4. Age ≥ 18 years at screening
5. Male or female patients. Women of childbearing potential (WOCBP)1 must be ready and 
able to use highly effective methods of birth control per ICH M3 (R2) [R09-1400] that 
result in a low failure rate of less than 1% per year when used consistently and correctly. 
A list of contraception methods meeting these criteria is provided in Section 4.2.2 and 
also in the patient information.
6. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial
Cohort A (HFrEF)
7. Left ventricular ejection fraction (LVEF) ≤40% as measured by ECHO at screening
8. The following signs of heart failure;
o
Elevated NT-proBNP (>125 pg/mL) at screening in patient without atrial 
fibrillation (AF)
o
Elevated NT-proBNP (>600 pg/mL) at screening in patient with AF
9. Appropriate dose of medical therapy for HF (such as ACEi, ARB, β-blocker, oral
diuretics, MRA, ARNI, ivabradine) consistent with prevailing local and international HF
guidelines, stable for at least one week prior to Visit 1 and during screening period until 
Visit 2 (Randomisation) with the exception of diuretics which must be stable for at least
one week prior to Visit 2 to control symptoms. If required, the investigator must 
document in the source documents the reason why the patient is not on the target dose per 
local guidelines.
                                                
1 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming 
postmenopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy 
and bilateral oophorectomy. Tubal ligation is not a method of permanent sterilisation. A postmenopausal state is defined as 
no menses for 12 months without an alternative medical cause.


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Cohort B (HFpEF)
10. Left ventricular ejection fraction (LVEF) ≥50% as measured by ECHO at screening and 
no previous measurement of LVEF ≤ 40%.
11. The following combined signs of heart failure;
o
Structural heart disease (LA enlargement [LAVI >34 mL/m2] and/or LVH [LVMI 
≥115 g/m2 for males and ≥95 g/m2 for females]) by ECHO at screening or within 
3 months prior to informed consent
AND
o
NT-proBNP > 125pg/mL at screening in patient without AF or NT-pro-BNP > 
600 pg/mL in patient with AF
12. Oral diuretics, if prescribed, should be stable for at least one week prior to Visit 1 and
during screening period until Visit 2 (Randomisation).
3.3.3
Exclusion criteria
1. Stroke or transient ischaemic attack (TIA) within 6 months prior to informed consent.
2. Any patients with myocardial scars and/or non-viable myocardium in the interventricular 
septum, unstable angina due to significant coronary artery disease (CAD), or major (in 
the opinion of the investigator) cardiovascular surgery.
3. Any contraindication for MRI, CPET and/or dobutamine stress test in accordance with 
the institution guidance, including implanted left ventricular assist device (LVAD), 
implantable cardioverter defibrillator (ICD), cardiac resynchronisation therapy (CRT) or 
any cardiac device.
4. Heart transplant recipient or listed for heart transplant
5. Cardiomyopathy based on infiltrative diseases (e.g. amyloidosis), accumulation diseases 
(e.g. haemochromatosis, Fabry disease), muscular dystrophies, cardiomyopathy with 
reversible causes (e.g. stress cardiomyopathy), hypertrophic obstructive cardiomyopathy 
or known pericardial constriction
6. Moderate to severe uncorrected valvular heart disease, obstructive or regurgitant, or any 
valvular heart disease expected to lead to surgery in the Investigator’s opinion
7. Acute decompensated HF (exacerbation of chronic HF) requiring intravenous (i.v.)
diuretics, i.v. inotropes or i.v. vasodilators, or LVAD or hospitalisation within 1 week
prior to Visit 1 (Screening), or during screening period until Visit 2 (Randomisation)
8. Systolic blood pressure (SBP) ≥ 180 mmHg at screening. If SBP >150 mmHg and 
<180mmHg at screening, the patient is ineligible if receiving 3 or more antihypertensive 
drugs
9. Symptomatic hypotension and/or a SBP < 100 mmHg at Screening
10. Atrial fibrillation which is uncontrolled in the opinion of the investigator
11. Untreated ventricular arrhythmia with syncope documented within the 3 months prior to 
informed consent in patients without ICD 
12. Diagnosis of cardiomyopathy induced by chemotherapy or peripartum within the 12 
months prior to informed consent


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13. Symptomatic bradycardia or second or third degree heart block in need of a pacemaker 
after adjusting beta-blocker therapy or any other negative inotropic agents, if appropriate
14. Chronic pulmonary disease requiring home oxygen, oral steroid therapy or hospitalisation 
for exacerbation within 12 months prior to informed consent, or significant chronic 
pulmonary disease in the Investigator’s opinion, or primary pulmonary arterial 
hypertension
15. Indication of liver disease, defined by serum levels of either ALT (SGPT), AST (SGOT), 
or alkaline phosphatase above 3 x upper limit of normal (ULN) as determined at 
screening
16. Impaired renal function, defined as estimated Creatinine Clearance < 30 mL/min (using 
Cockcroft-Gault formula) or requiring dialysis, as determined at screening
17. Haemoglobin < 10 g/dL at screening
18. Type 1 Diabetes Mellitus (T1DM)
19. History of ketoacidosis
20. Major surgery (major according to the investigator’s assessment) performed within 3 
months prior to informed consent, or scheduled major elective surgery (e.g. hip 
replacement) within 3 months after Visit 1
21. Gastrointestinal (GI) surgery or GI disorder that could interfere with absorption of trial 
medication in the investigator’s opinion
22. Any documented active or suspected malignancy or history of malignancy within 6 
months prior to informed consent, except appropriately treated basal cell carcinoma of the 
skin, in situ carcinoma of uterine cervix or low risk prostate cancer (patients with 
pretreatment PSA <10 ng/mL, and biopsy Gleason score of ≤ 6 and clinical stage T1c or
T2a)
23. Presence of any other disease than heart failure with a life expectancy of <1 year in the 
investigator’s opinion
24. Patients who must or wish to continue the intake of restricted medications (see Section 
4.2.2) or any drug considered likely to interfere with the safe conduct of the trial
25. Patients with requirement for treatment with empaglifozin according to local standard of 
care
26. Treatment with any SGLT-2 inhibitor or combined SGLT-1 and 2 inhibitor within 1 week 
prior to informed consent or during screening period until Visit 2 (Randomisation)
27. Currently enrolled in another investigational device or drug study, or less than 30 days
between randomisation and ending another investigational device or drug study, or 
receiving other investigational treatment(s). Patients participating in a purely 
observational trial will not be excluded.
28. Known allergy or hypersensitivity to empagliflozin or other SGLT-2 inhibitors
29. Chronic alcohol or drug abuse or any condition that, in the investigator’s opinion, makes 
them an unreliable trial subject or unlikely to complete the trial
30. Women who are pregnant, breastfeeding, or who plan to become pregnant while in the 
trial


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31. Any clinical condition that would jeopardise patients safety while participating in this 
trial, or may prevent the subject from adhering to the trial protocol
3.3.4
Withdrawal of patients from therapy or assessments
Every effort should be made to keep randomised patients in the trial until the completion of 
visit 4. Measures to control the withdrawal rate include careful patient selection, appropriate 
explanation of the trial requirements and procedures prior to randomisation, as well as an
explanation of the consequences of withdrawal.
Patients may potentially be withdrawn from trial treatment or from the trial as a whole 
(“withdrawal of consent”) as described in Sections 3.3.4.1 and 3.3.4.2 below.
The decision to withdraw from trial treatment or from the whole trial as well as the reason, if 
given, must be documented in the patient files and eCRF.
3.3.4.1
Withdrawal from trial treatment
An individual patient is to be withdrawn from trial treatment if:

The patient wants to withdraw from trial treatment, without the need to justify the 
decision.

The patient does not want to undergo the trial assessments at visit 4 required to assess the 
primary endpoint.

The patient needs to take concomitant drugs that interfere with the investigational product 
or other trial medication (see Section 4.2.2).

The patient becomes pregnant. Note that the patient must be followed until the end of the 
pregnancy (see Section 5.3.5.2).

The patient can no longer be treated with trial medication for other medical reasons (such 
as surgery, AEs or other diseases).

The patient has repeatedly shown to be non-compliant with important trial procedures 
and/or, in the opinion of both the investigator and sponsor representative, is not willing or 
able to stick to the trial requirements in the future.
In the event that a patient is withdrawn from trial treatment prior to Visit 4, the patient should 
be asked to return all remaining trial medication. If the patient’s agrees, the following EOT 
safety assessments will be conducted;

Pregnancy test

Safety laboratory tests

Vital signs
In addition, if the patient agrees, the patient will have a follow-up visit 7-14 days after the last 
dose of trial medication.
For all patients the reason for withdrawal from trial treatment (e.g. AEs) must be recorded in 
the eCRF. These data will be included in the trial database and reported.


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3.3.4.2
Withdrawal of consent for trial participation
If a patient wants to withdraw consent to trial participation, the investigator should explain 
the difference between treatment withdrawal and withdrawal of consent for trial participation 
and explain the safety follow up after withdrawal from trial treatment as described in Section 
3.3.4.1 above.
Patients may withdraw their consent for trial participation at any time without the need to 
justify the decision. If this occurs, no further information may be collected for the purpose of 
the trial and patient follow up for safety cannot occur.
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial
3. Violation of GCP, the trial protocol, or the contract impairing the appropriate conduct of 
the trial
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
Eligible patients will receive treatment with empagliflozin or matching placebo for 12 weeks.
4.1.1
Identity of the Investigational Medicinal Products
Table 4.1.1: 1
Empagliflozin
Substance:
Empagliflozin
Pharmaceutical formulation:
Film-coated tablet
Source:
Boehringer Ingelheim
Unit strength:
10mg
Posology
1 tablet, once daily
Route of administration:
Oral
Table 4.1.1: 2
Placebo matching Empagliflozin
Substance:
Placebo matching Empagliflozin
Pharmaceutical formulation:
Film-coated tablet
Source:
Boehringer Ingelheim
Unit strength:
Not applicable
Posology
1 tablet, once daily
Route of administration:
Oral
4.1.2
Selection of doses in the trial
Empagliflozin 10 mg and 25 mg tablets are approved for the treatment of T2DM. 
Empagliflozin exerts its effect by promoting glucosuria and consequent hemodynamic 
changes associated with diuresis, improvement in arterial stiffness, blood pressure lowering
effect with no increase in heart rate and reduction in heart rate x Pressure product, an index of 
myocardial oxygen consumption. These modes of actions support the scientific rationale of 
using empagliflozin in patients with HF.


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In the EMPA-REG-OUTCOME trial (P16-06807) both approved doses were administered to 
patients with T2DM and were found to be equally effective in reducing CV death, HHF, and 
composite of HHF or CV death in patients with a history of cardiac failure (MedDRA narrow 
SMQ 20000004) at baseline.
In subgroup analysis, empagliflozin improved the main outcome of CV death and HHF with 
a similar magnitude in patients with low or high levels of HbA1c at baseline. This indicates 
the risk reduction for HF outcome is independent of the degree of glycaemic control at 
baseline, suggesting that similar benefits to those seen with the 25mg dose  may also be 
achieved with the 10 mg dose in the non-diabetic population. The mechanism of action is 
supported by studies in healthy volunteers where both doses were associated with about 
50g/day excretion of glucose in the urine.
Given the lower exposure attained with 10 mg empagliflozin dosing and the similar general 
safety profile and CV efficacy observed with both empagliflozin doses, empagliflozin 10 mg 
once daily has been selected for this trial.
For further details see current version of the IB (c01678844).
4.1.3
Method of assigning patients to treatment groups
During Visit 2 eligible patients will be randomised to receive empagliflozin 10mg, or 
matching placebo in a 1:1 ratio according to the randomisation plan. The assignment will 
occur in a blinded fashion via Interactive Response Technology (IRT).
For information on stratification, please refer to Sections 3.3 and 7.1.
4.1.4
Drug assignment and administration of doses for each patient
Trial medication will be assigned via IRT at randomisation and dispensed in a double-blind 
manner. At Visit 2 the patient will be dispensed sufficient medication for the whole treatment 
period. Further dispensing will only occur in the event that the patient requires replacement 
medication. For further details regarding packaging please refer to Section 4.1.6.
From the start of the treatment period patients will be instructed to take the trial medication 
once daily with a glass of water. Empagliflozin can be taken with or without food.
To ensure a dose interval of about 24 hours, the medication should be taken at approximately 
the same time every day, preferably in the morning. If a dose is missed by more than 12 
hours, that dose should be skipped and the next dose should be taken as scheduled. No double 
doses should be taken. On the day of Visit 4 the dose should be taken at the usual scheduled 
time, regardless of the timing of assessments.
For logistical reasons, Visit 4 can be scheduled on Day 84 ± 4 days. Daily dosing should 
continue until the day of Visit 4, when the last dose is taken. Sufficient extra medication is 
provided in case Visit 4 takes place later than Day 84.


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4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
Patients, investigators and everyone involved in trial conduct or analysis or with any other
interest in this double-blind trial will remain blinded with regard to the randomised treatment 
assignments within a cohort until after all patients in the cohort have completed the study and 
database lock has taken place. Database lock and subsequent unblinding may be performed 
independently for each cohort if required (e.g. if one cohort completes substantially earlier 
than the other).
The randomisation code of a cohort will be kept secret by Clinical Trial Support up to 
database lock for the cohort.
There are several examples of medications showing effects for patients with HFrEF but not 
for patients with HFpEF. The populations of the two cohorts are therefore considered to be 
independent: results in one cohort do not inform about possible results in the other cohort. 
Therefore independent unblinding is not expected to introduce bias on the ongoing cohort.
4.1.5.2
Unblinding and breaking the code
Emergency unblinding will be available to the investigator via IRT. It must only be used in
an emergency situation when the identity of the trial drug must be known to the investigator
in order to provide appropriate medical treatment or otherwise assure safety of trial
participants. Whenever possible and if time allows, the need for unblinding will be discussed 
with the medical representative of the sponsor before the unblinding of trial medication takes 
place. The reason for unblinding must be documented in the source documents and/or on the
appropriate eCRF page along with the date and the initials of the person who broke the code.
If unblinded, the patient may continue in the trial as planned, unless in the opinion of the 
investigator there is a reason why the patient must discontinue (see Section 3.3.4).
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions 
(SUSARs), it may be necessary for a representative from BI’ s Pharmacovigilance group to 
access the randomisation code for individual patients during trial conduct. The access to the 
code will only be given to authorised Pharmacovigilance representatives and will not be 
shared further. 
4.1.6
Packaging, labelling, and re-supply
The empagliflozin and matching placebo tablets will be packaged into wallets, each 
containing 91 tablets blister packaging. This is sufficient for 12 weeks of treatment (84 
tablets) and one week of reserve (7 tablets). For further details of packaging and the 
description of the label, refer to the ISF.
The investigational products will be provided by BI or a designated Clinical Research 
Organisation (CRO). They will be packaged and labelled in accordance with the principles of 
Good Manufacturing Practice (GMP). Re-supply to the sites will be managed via an IRT 
system, which will also monitor expiry dates of supplies available at the sites.


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4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A
temperature log must be maintained for documentation. If the storage conditions are found to 
be outside the specified range, the process outlined in the ISF should be followed.
4.1.8
Drug accountability
The investigator and/or pharmacist and/or investigational drug storage manager will receive 
the investigational drugs delivered by the sponsor or delegate when the following 
requirements are fulfilled:

Approval of the clinical trial protocol by the IRB / ethics committee;

Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site,

Approval/notification of the regulatory authority, e.g. competent authority,

Availability of the curriculum vitae of the Principal Investigator,

Availability of a signed and dated clinical trial protocol,

Availability of the proof of a medical license for the Principal Investigator
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. Patients should be instructed to return 
unused investigational drug.
The investigator and/or pharmacist and/or investigational drug storage manager must 
maintain records of the product’s delivery to the trial site, the inventory at the site, the use by 
each patient, and the return to the sponsor or warehouse/drug distribution centre or alternative 
disposal of unused products. If applicable, the sponsor or warehouse/drug distribution centre
will maintain records of the disposal. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use-by’) dates, 
and the unique code numbers assigned to the investigational product and trial patients. The 
investigator / pharmacist / investigational drug storage manager will maintain records that 
document adequately that the patients were provided the doses specified by the clinical Trial 
protocol (CTP) and reconcile all investigational products received from the sponsor. 
At the time of returning investigational product to the sponsor/CRO at the end of the trial, the 
investigator / pharmacist / investigational drug storage manager must verify that all unused or 
partially used drug supplies have been returned by the clinical trial patients and that no 
supplies will remain in the investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
The use of medication for the treatment of HF will be at the discretion of the Investigator and 
should be in accordance with local/international guidelines. 


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All concomitant (additional) medications and other therapies should be recorded on the 
appropriate pages of the eCRF. 
The dobutamine administered during the MRS will be commercial stock supplied by the 
investigator’s institution. It will be considered an auxiliary medicinal product (AMP) and 
administered as described in Section 5.2.4. AEs/SAEs related to dobutamine will be 
documented as described in Section 5.3.5.
For diabetic patients, concomitant antidiabetic medications should be adjusted individually as 
clinically indicated by the patient’s usual diabetes care provider. Restrictions of antidiabetic 
background therapy are described in Section 4.2.2.
Patients without a diagnosis of DM experiencing repeated or severe symptoms such as 
nervousness, sweating, intense hunger, trembling, weakness and palpitations should contact 
the Investigator or other healthcare professional, as these symptoms might be suggestive of 
hypoglycaemia. In the case of hypoglycaemia, in patients with or without DM, that may put 
the patient at risk (e.g. repeated symptomatic hypoglycaemia or severe hypoglycaemia), 
appropriate care should be provided at the discretion of the Investigator.
Special attention must be paid to the prevention of ketoacidosis. All patients must be made 
aware of this risk and need to be instructed to contact the Investigator or other healthcare 
professional in case of symptoms of metabolic acidosis, ketoacidosis and DKA. 
Cases of DKA have been reported in patients treated with empagliflozin, including fatal cases
[c01678844]. In a number of reported cases, the presentation of the condition was atypical 
with only moderately increased blood glucose values; below 14 mmol/L (250 mg/dL).
The risk of DKA must be considered in the event of non-specific symptoms such as nausea, 
vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing, confusion, unusual 
fatigue or sleepiness.
Patients should be assessed and treated for ketoacidosis immediately according to local 
guidelines if these symptoms occur, regardless of blood glucose level. If ketoacidosis is 
suspected, the trial medication should be discontinued, the patient should be evaluated, and 
prompt treatment should be initiated.
Patients who may be at higher risk of ketoacidosis while taking empagliflozin in this trial
include patients on a very low carbohydrate diet (as the combination may further increase 
ketone body production), patients with an acute illness, patients with a history of pancreatitis 
or pancreatic surgery, patients with a history of alcohol abuse and patients with severe 
dehydration. Empagliflozin should be used with caution in these patients. In patients 
requiring insulin, caution should be taken when the dose of insulin is reduced.
In clinical situations known to predispose to ketoacidosis (e.g. prolonged fasting due to acute 
illness or surgery), the Investigator should consider monitoring for ketoacidosis and 
temporarily discontinue the trial medication.
There are no trial specific emergency procedures to be followed.


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4.2.2
Restrictions
The use of any SGLT-2 inhibitors or combined SGLT-1 and 2 inhibitors except the blinded
trial medication is prohibited during the course of the trial. This also includes the 7 day 
period between the EOT and the Follow Up Visit.
If any restricted treatment is given during the conduct of the trial, the trial medication must be 
permanently discontinued.
If the patient is in need of any additional treatment during this period, this may be given at 
the discretion of the Investigator. The patient can still remain on trial medication.
Women of childbearing potential must use two medically approved methods of birth control 
throughout the study, and for a period of at least 7 days after last study drug intake. They 
must use one barrier method, i.e. condom or occlusive cap with spermicide, or vasectomised 
partner, and one highly effective non-barrier method including oral, injected or implanted 
hormonal contraceptives, intrauterine device or system.
4.3
TREATMENT COMPLIANCE
Patients are requested to bring all remaining trial medication including empty package 
material with them when attending visits. Based on tablet counts, treatment compliance will 
be calculated as shown in the formula below.
Treatment compliance (%) =
Number of tablets actually taken 100
     Number of tablets which should have been taken
Compliance should be between 80% and 120%. If the number of doses taken is not between 
80-120%, site staff will explain to the patient the importance of treatment compliance.
If the assessment of compliance at Visit 4 indicates a compliance of less than 80%, the 
investigator may decide to perform limited Visit 4 assessments (as defined in Section 3.3.4.1) 
as the patient will not be used for the primary analysis.


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
5.1.1
New York Heart Association (NYHA) classification
The NYHA functional classification will be used to classify the severity of symptoms in the 
patients with heart failure (Appendix 10.1). The investigator should place the patients in one 
of the four categories based on how limited their physical activities are.
Candidates for screening are required to have a NYHA functional class II, III or IV.
5.1.2
Body weight and height
Measurement of height and body weight will be performed at the time points specified in the 
Flowchart.
Body Mass Index (BMI) (kg/m2) will be calculated at Visit 1 to determine eligibility.
5.2
ASSESSMENT OF CARDIAC EFFECTS OF EMPAGLIFLOZIN
An assessment of the effect of empagliflozin on cardiac metabolism function will be 
performed using the techniques described in the following section.
5.2.1
Echocardiogram (ECHO)
Transthoracic echocardiography will be used to evaluate cardiac structure and function 
according to British Society of Echocardiography [R17-0836]. The standard methodology of 
the institution will be used and the following clinical information will be recorded;

Left Ventricular Ejection Fraction (LVEF), LV end-diastolic and end-systolic 
volumes, LV mass index

Diastolic function (eg E/A, e’, LA index)

Chamber size including thickness and wall motion

Haemodynamic status (cardiac output)   

Valves status
Further exploratory parameters may be recorded if required.
 
 
 
 
 


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5.2.4
Cardiac Magnetic Resonance (CMR)
CMR will be performed on a 3.0 Tesla MR scanner. The same scanner will be used for the 
Visit 2 and Visit 4 scan for each patient. Prior to undergoing CMR scanning, the patient will 
be cannulated to allow the administration of contrast agent and dobutamine while in the 
scanner. The cannula will also be used to collect venous blood samples. All imaging will be 
done under fasting conditions for all participants. All participants will undergo a CMR and 
MRS protocol which is standard within the institution. 
Cardiac MRI
Patients will lie in a supine position and a dedicated cardiac coil will be placed around their 
chest. Images will be obtained using breath hold and ECG gating. Cine images will be 
acquired for cardiac volumes, mass and function using steady state free precession cine 
imaging as recommended [R17-0837]. Tagged MR images will be acquired for measurement 
of LV strain using an ECG-triggered segmented k-space fast gradient echo sequence with 
spatial modulation of magnetization in orthogonal planes creating a square grid of parallel tag 
lines [R17-0838]. Late gadolinium enhancement (LGE) will be performed with an inversion-
recovery-prepared, segmented gradient echo sequence after a 8-10 minute time delay 


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following administration of a gadolinium-based contrast agent for resting perfusion [R17-
0695].
T1 mapping and extracellular volume quantification (ECV) will be performed using a 
shortened modified look-locker inversion recovery sequence [R17-0839]
Cardiac MR spectroscopy (31P MRS and proton MRS)
31P MRS (rest and dobutamine stress)
Rest31P MRS will be performed to obtain the PCr/ATP ratio from a voxel placed in the 
midventricular septum, with the subjects lying prone with their heart over the centre of the 
phosphorus coil in the iso-centre of the magnet as previously described [R17-0693]. After 
resting spectroscopy, dobutamine will be infused intravenously at incremental rates between 
5 and 40 mcg/kg with a target of 65% of age maximal heart rate. During this time, blood 
pressure will be measured every minute. Heart rate, pulse oximetry, and ECG will also be 
monitored continuously during both dobutamine infusion. Heart rate will be maintained at 
target for the duration of the scans (8-10 minutes for 31P-MRS) [R17-0697]. Where possible, 
additional cine imaging will be acquired at rest and during dobutamine stress for assessment 
of cardiac function.
1H MRS
Myocardial 1H-MR spectra will be obtained from the mid-interventricular septum. 
Spectroscopic acquisitions will be performed using ECG trigger at end-expiration to 
minimize motion artefacts. Since water is the most abundant molecule in the human body 
water signal will be suppressed to amplify weaker lipid signal. Both spectra with and without 
water suppression (used as an internal standard) will be acquired [R17-0694].
Figure 5.2.4:1 gives an overview of the scanning process; all times are approximate and may 
be adjusted if required.


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Figure 5.2.4: 1 CMR protocol summary
The following parameters are collected during the CMR assessment;

Cardiac energetics (rest and dobutamine stress PCr/ATP ratio, 31P MR 
Spectroscopy) 


Strain (circumferential, longitudinal, radial, torsion, diastolic parameters) 

LV volumes, mass and function

Myocardial fibrosis, infarction (Late gadolinium enhancement)


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Images obtained during CMR will be stored by the institution for at least 25 years.
5.2.5
Cardiac Computerised Tomography (CT) Scan
If ischaemic clinical testing has been performed within 6 months and written results are 
available and adequate (in the opinion of the investigator) to assess eligibility, a cardiac CT is 
not required at screening. Otherwise, a cardiac CT will be performed at screening to 
document the extent of any coronary artery disease. This may be performed at the 
investigator’s institution or at an accredited facility chosen by the investigator.
Coronary computed tomographic angiography (CCTA) will be performed to assess eligibility
and for quantification of epicardial fat volumes according to a standard methodology [R17-
0690]. CCTA scans will be performed on 320-slice computed tomography scanner in 
accordance with performance guidelines from the Society of Cardiovascular Computed 
Tomography [R17-0840]. Participants will receive beta-blockade (intravenous metoprolol) 
and sublingual glyceryl trinitrate prior to the scan to achieve a heart rate of <60 beats/min. 
During the CCTA acquisition, intravenous iodinated contrast will be injected through a 
peripheral vein, followed by a saline flush. The scan will cover a region from 1 to 2 cm above 
the left main coronary artery to 1 to 2 cm below the myocardial apex in a single breath hold. 
CT images will also be reconstructed for epicardial fat volume quantification.
5.3
ASSESSMENT OF SAFETY
This trial does not have any safety endpoints. The examinations detailed in this section will 
be performed to monitor the safety of the patients whilst participating in the trial.
5.3.1
Physical examination
A complete physical examination will be performed at the time points specified in the 
Flowchart. Documentation of, and findings from the physical examination, must be part of 
the source documents available at the site.
5.3.2
Vital signs
Vital signs will be evaluated at the time points specified in the Flowchart, prior to blood 
sampling. Systolic and diastolic blood pressure and pulse rate (electronically or by palpation 
count for 1 minute) will be measured in a supine position after 5 minutes of rest. Three 
measurements taken over approximately 10 minutes will be recorded. All recordings should 
be made using a similar type of and validated certified blood pressure recording instrument 
on the same arm.
5.3.3
Safety laboratory parameters
Safety laboratory samples will be collected at the timepoints indicated in the Flowchart. 
Safety laboratory parameters to be assessed are listed in Table 5.3.3:1. All analyses will be 
performed by a central laboratory. The respective reference ranges and details about sample 
handling and shipment will be provided in the ISF.


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Table 5.3.3:1 
Safety laboratory parameters – whole blood, serum or plasma tests
Haematology

Hematocrit

Haemoglobin

Reticulocyte Count

Red Blood Cells (RBC) / 
Erythrocytes

White Blood Cells (WBC) / 
Leukocytes

Platelet Count / Thrombocytes

Differential Automatic (relative and 
absolute count): Neutrophils, 
Eosinophils, Basophils, Monocytes, 
Lymphocytes
Clinical chemistry

Albumin

Alkaline phosphatase

γ-GT (gamma-glutamyl transferase) 

ALT (alanine transaminase, SGPT)

AST (aspartate transaminase, SGOT)

Bicarbonate

Bilirubin total, fractionated if 
increased

Calcium

Chloride

Creatinine

Creatine kinase (CK)

Hs Troponin I (reflex tests if CK is 
elevated)

Glucose

Magnesium

Phosphate

Potassium

Protein total

Sodium

Urea (BUN)

Uric acid
Lipids

Cholesterol (total)

HDL cholesterol

Calculated LDL cholesterol

Triglycerides (reflex test for direct measurement of LDL cholesterol triggered if 
triglycerides are > 400 mg/dL or 4.52 mmol/L)
5.3.3.1
Creatinine
In addition to the central safety laboratory analyses above, at Visit 1, Visit 2 and Visit 4 there 
will be an additional creatinine test using one drop of blood from the collected blood samples. 
The purpose is to check patient safety and this will be analysed locally.
5.3.3.2
Renal function
Eligibility for the trial will be assessed using estimated Creatinine Clearance (eCCR), 
calculated using the Cockcroft-Gault formula [R96-0690] (Appendix 10.3).
In addition, the estimated glomerular filtration rate (eGFR) will be derived from serum 
creatinine values, age, sex and race based on the CKD-EPI equation [R12-1392]:


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GFR = 141 × min (Scr /κ, 1)α × max(Scr /κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 1.159 
[if black]
where:
Scr is serum creatinine in mg/dL,
κ is 0.7 for females and 0.9 for males,
α is -0.329 for females and -0.411 for males,
min indicates the minimum of Scr /κ or 1, and
max indicates the maximum of Scr /κ or 1
The race of the patient will be entered because of potential differences due to race.  The 
CKD-EPI equation considers the race as an adjustment factor, therefore the race must be 
known for accurate estimation.
Kidney function will be classified as described in the table below (Table 5.3.3.2:1).
Table 5.3.3.2: 1 Classification of kidney function
CKD stage
eGFR
(mL/min/1.73m²)
1
≥90
2
60-89
3a
3b
45-59
30-44
4
15-29
5
< 15
5.3.3.3
Pregnancy testing
Pregnancy testing (in urine or serum) will be performed in female patients of child bearing 
potential according to the time points indicated in the Flowchart. Urine pregnancy test kits 
will be provided by the investigator site. For reporting of a pregnancy event refer to Section 
5.3.5.2.
5.3.3.4
Urine test for ketone
At visit 3 (day 15) a urine sample will be taken and analysed locally for ketone.
5.3.3.5
Criteria for hypoglycaemic events
In Diabetes Mellitus (DM) patients, all symptomatic hypoglycaemia events, or severe 
hypoglycaemias (e.g. if the patient required assistance of another person), or any 
hypoglycaemia episode with glucose values < 54 mg/dL (< 3.0 mmol/L), or if the 
investigator considered the event to be an AE should be documented as an AE 
"hypoglycaemic event". 


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In non-diabetic or pre-diabetic patients, the investigator should consider and rule out other 
alternative causes for such symptoms and may measure blood glucose levels to confirm the 
diagnosis of hypoglycaemia.
5.3.3.6
Urinary tract infections and genital infections
Patients having a history of chronic/recurrent urinary tract infections (UTI) or genital 
infections, or an acute episode of UTI or genital infection at screening will be identified and 
the condition documented as medical history or baseline condition, as appropriate, in the 
eCRF.
For documentation of a symptomatic acute UTI during trial conduct, a urine culture sample 
has to be taken and sent to a local laboratory for confirmation of the diagnosis.
5.3.4
Electrocardiogram (ECG)
ECGs will be performed at the timepoints indicated in the Flowchart. Printed paper traces 
from 12-lead ECGs (I, II, III, aVR, aVL, aVF, V1-V6) will be collected. They should be 
evaluated, signed, dated and commented upon by the treating physician/Investigator and 
stored locally. The diagnosis and results from the ECG reports should be collected in the 
eCRF.
In the event of any cardiac symptoms (i.e. suspicion of heart rhythm disorders or cardiac 
ischaemia) during the course of the trial, if an additional ECG is recorded at time of event, or 
later at the next regular visit, they will be evaluated, signed, dated and commented upon by 
the treating physician/Investigator and stored locally. Any clinically relevant new changes in 
the ECG (regardless of patients’ symptoms) should be reported as AEs and followed up 
and/or treated locally until normal or stable condition. 
Each ECG tracing stored locally should be labelled with the trial and patient number, patient 
initials and date.
5.3.5
Assessment of adverse events
5.3.5.1
Definitions of AEs 
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:
-
results in death,


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-
is life-threatening, which refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe.
-
requires inpatient hospitalisation or 
-
requires prolongation of existing hospitalisation,
-
results in persistent or significant disability or incapacity, or
-
is a congenital anomaly / birth defect,
or
-
is deemed serious for any other reason if it is an important medical event when based 
on 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.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or 
development of dependency or abuse. 
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as 
defined above.
A copy of the latest list of “Always Serious AEs” will be provided in the ISF. These events 
should always be reported as SAEs as described above.
Note: Cancers of new histology and exacerbations of existing cancer must be classified as a 
serious adverse event regardless of the duration between discontinuation of the drug and the 
occurrence of the cancer and must be reported as described in Section 5.3.5.2.
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. 
AESIs need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAEs, please see below.
The following are considered as AESIs:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters, 
when observed at any timepoint 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 draw sample, and/or

aminotransferase (ALT, and/or AST) elevations ≥ 5 fold ULN
These laboratory findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” provided in the ISF.


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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. Should the results meet 
the criteria of hepatic injury alert, the procedures described in the DILI checklist should be 
followed.
Decreased renal function
Decreased renal function is defined by a creatinine value showing a ≥2 fold increase from 
baseline and is above the ULN.
For the AESI “decreased renal function” the patient needs to be followed-up appropriately 
based on local clinical guidance. 
Ketoacidosis
If metabolic acidosis, ketoacidosis or DKA is suspected, further investigations should be 
done according to the medical judgment and the clinical course until a diagnosis is made 
and/or the patient is recovered.
Due to its mechanism of action, empagliflozin may potentially modify the clinical 
presentation of ketoacidosis which may occur at lower plasma glucose levels in patients with 
DM and potentially also in non-diabetic patient population. The diagnosis of ketoacidosis in 
these patients can be based on arterial pH ≤7.30, serum bicarbonate levels <15 and 
measurement of serum beta-hydroxybutrate levels. Other diagnostic criteria which can 
support the diagnosis of ketoacidosis are urine ketones and anion gap >10. 
Investigators should note that not all criteria mentioned above need to apply for the diagnosis 
of ketoacidosis, and clinical judgment should also be taken into consideration.
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Sufficient discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
Medical judgement 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. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug.

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced


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
No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.
5.3.5.2
Adverse event collection and reporting
AE Collection
The investigator shall maintain and keep detailed records of all AEs in the patient files.
The following must be collected and documented on the appropriate eCRF(s) by the 
investigator:

From signing the informed consent onwards until the individual patient’s end of trial:
o
all AEs (serious and non-serious) and all AESIs.

After the individual patient’s end of trial: 
o
the investigator does not need to actively monitor the patient for AEs but 
should only report related SAEs and related AESIs of which the investigator
may become aware of by any means of communication, e.g. phone call. Those 
AEs should however, not be reported in the eCRF.


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Figure 5.3.5.2: 1
Requirements for Adverse Event collection
AE reporting to sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours ) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
Information required
For each AE, the investigator should provide the information requested on the appropriate 
eCRF pages and the BI SAE form. The investigator should determine the causal relationship 
to the IMP and any possible involvement of the AMP.
The following should also be recorded as an (S)AE in the eCRF and BI SAE form (if 
applicable):
Worsening of the underlying disease or of other pre-existing conditions
Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the investigator. If such abnormalities already pre-
exist prior to trial inclusion they will be considered as baseline conditions and 
collected in the eCRF only.
All (S)AEs, including those persisting after individual patient’s end of trial must be followed 
up until they have resolved, have been assessed as “chronic” or “stable” , or no further 
information can be obtained.
For some types of AEs additional information will be collected in the eCRF due to the nature 
of the event and mechanisms of action of the trial medication. These listed AEs are distinct 
from AESI and are captured and reported in the standard way for AEs and SAEs:

Hypoglycaemic event


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
Genital infection

Acute pyelonephritis

Sepsis

Urinary tract infection

Bone fracture
This list may be changed by the sponsor during the trial in response to new knowledge about 
the safety profile of empagliflozin.
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in the 
clinical trial and has taken trial medication, the investigator must report any drug exposure 
during pregnancy in a trial participant immediately (within 24 hours) by means of Part A of 
the Pregnancy Monitoring Form to the sponsor’s unique entry point.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.
5.4
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Not applicable.
5.5
ASSESSMENT OF BIOMARKERS
5.5.1
Biomarkers at screening
N-terminal-pro Brain Natriuretic Peptide (NT-proBNP) will be measured at Visit 1
(screening) by the central laboratory and used to assess patient eligibility.
 
 


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5.7
APPROPRIATENESS OF MEASUREMENTS
The majority of methods used in this trial, including ECHO, CPET and CMR, are considered 
standard in heart failure patients. 
The following methods are not standard in heart failure patients:
Cardiac CT
CT is the standard non-invasive procedure for the diagnosis of coronary artery disease. It is 
required in this trial in order to document any coronary artery disease.
Cardiac 31P Magnetic Resonance Spectroscopy (MRS)
Myocardial phosphocreatine to adenosine triphosphate concentration ratio (PCr/ATP) is a 
sensitive indicator of the myocardial energy status, and phosphorus magnetic resonance 
spectroscopy (31P-MRS) allows noninvasive assessment of the PCr/ATP [R17-0687, R17-
0691, R17-0693, R17-0695, R17-0696, R17-0697].
Cardiac 1H MRS
Proton (1H) magnetic resonance spectroscopy (MRS) allows non-invasive measurement of 
myocardial lipid (triglyceride) content, and by using this technique, elevated myocardial lipid 
(steatosis) has been shown in aortic stenosis, metabolic syndrome, obesity and type 2 diabetes 
mellitus, R17-0688, R17-0689, R17-0690, R17-0692, R17-0694.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
All patients are to adhere to the visit schedule as specified in the Flowchart. If any visit has to 
be rescheduled, subsequent visits should follow the original visit date schedule calculated 
from the date of randomisation. The trial medication packs contain sufficient medication to 
allow for these time windows.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
Please refer to the Flowchart and Section 5 for details of the procedures performed at each 
visit.
6.2.1
Screening period
Following informed consent, the patient will undergo visit 1/screening assessments as 
indicated in the Flowchart.The assessments must all fall within the acceptable screening visit 
window but do not need to be performed on the same day. The patient should be registered in 
IRT as a screened patient.
There is no mandatory order of assessments but it is recommended that ECHO is performed 
prior to cardiac CT so that patients who are ineligible based on the ECHO are not required to 
undergo further assessment.
If the patient does not meet the eligibility criteria, the patient should be registered as a screen 
failure in IRT. 
Re-screening is not allowed in this trial. Screening assessments may be repeated as long as 
they fall within the screening visit window. If more than one screening assessment is 
available, the latest assessment prior to randomisation must be used to assess eligibility.
If the patient meets the eligibility criteria during screening (Visit 1), Visit 2 should be 
scheduled. Any baseline conditions which are present at Visit 1 should be reported in the 
eCRF.
6.2.2
Treatment period
Visit 2 (Randomisation)
The investigator must perform a final assessment of eligibility when the results of all 
screening assessments are available. If the patient does not meet the eligibility criteria, the 
patient should be registered as a screen failure in IRT. Re-screening is not allowed in this trial.
If the patient is eligible for trial participation, the patient is randomised using IRT and 
treatment is allocated. The visit 2 assessments as listed in the Flowchart are then performed. 
Some assessments do not need to be repeated if performed during the last 7 days as part of
the screening visit; see Flowchart for details.


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The patient should be fasting in preparation for the blood sampling at this visit (no food or 
liquid except water for at least 6 hours prior to sampling). The following rules apply for the 
order of assessments at this visit;


Blood tests and iv cannulation must be performed before the CMR scan.

Echo must be performed before Dobutamine stress

CPET must be performed before Dobutamine stress

All Visit 2 assessments must be performed before the first dose is taken
Visit 3 (Day 15)
The patient will return to the clinic for visit 3 on day 15 ± 1 day of treatment. The purpose of 
this visit is to check patient safety, to check medication compliance and to perform limited 
assessments. Assessments to be performed are indicated in the Flowchart.
 
Visit 4 (Day 84)
Visit 4 will take place on Day 84 of treatment, which is also the last day of treatment. If the
visit cannot be scheduled for Day 84, it should be scheduled as close as possible, but within 4
days and the patient should continue to take the medication daily until the day of the visit. All 
Visit 4 assessments must be performed within 48 hours of the last dose, regardless of which 
day this is. The patient should be asked to return all remaining medication during this visit.
The assessments to be performed at Visit 4 are indicated in the Flowchart. The patient should 
be fasting in preparation for the blood sampling at this visit (no food or liquid except water 
for at least 6 hours prior to sampling). The following rules apply for the order of assessments 
at this visit;

.

Blood tests and iv cannulation must be performed before the CMR scan.

Echo must be performed before Dobutamine stress

CPET must be performed before Dobutamine stress
6.2.3
Follow up period and trial completion
A follow up visit (Visit 5) will be performed 7-14 days after the last dose of trial medication. 
The expectation is that this visit will be performed via a telephone call, but where 
appropriate, a clinic visit may be scheduled. The assessments to be performed at Visit 5 are 
indicated in the Flowchart.
Visit 5 marks the completion of the study for the individual patient. After the completion of 
the study the patient will receive standard medical care.
6.2.4
Early discontinuation of trial medication
See Section 3.3.4.1 for procedures to be followed in case a randomised patient does not reach 
Visit 4 for any reason.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN MODEL
This is a randomised, double-blind, single-centre placebo-controlled trial. The eligible 
patients for this trial will be randomised to empagliflozin 10 mg or placebo in a 1:1 ratio. 
Randomisation will be stratified by cohort (HFpEF / HFrEF) and history of diabetes (Yes / 
No). 
The primary endpoint of change from baseline in cardiac energetics (PCr/ATP ratio) at rest is 
regarded as normally distributed based on literature data.
Change from baseline of cardiac energetics (PCr/ATP ratio) at rest after 12 weeks of 
treatment will therefore be analyzed by an analysis of variance (ANOVA) model. The model 
will include treatment, presence of atrial fibrillation at baseline (Yes / No) and history of 
diabetes (Yes / No) as fixed effects. 
The analysis will be performed on the per protocol set (PPS) of patients having a valid 
PCr/ATP ratio measurements available at baseline and at week 12, and not having an 
important protocol violation relevant to the primary endpoint. 
All planned analyses will be conducted separately on the two cohorts.
7.2
NULL AND ALTERNATIVE HYPOTHESES
The null hypothesis is that for patients in HFrEF and  HFpEF cohorts, the change from 
baseline to week 12 in the resting state PCr/ATP ratio measured by 31P MRS is not different 
from placebo. The alternative hypothesis is that the change is different.
If the null hypothesis is rejected, and the result is more favourable for empagliflozin, 
superiority is concluded in the tested cohort.
The primary objective will be addressed by a two-sided test at level alpha=0.05 conducted 
separately for each cohort. 
7.3
PLANNED ANALYSES
Adherence to the protocol (such as inclusion/exclusion criteria, times of measurement, 
compliance with intake of trial medication, treatment dispensing errors, prohibited 
concomitant medication, completeness and consistency of data) will be checked. Important 
protocol violations (IPVs) will be identified no later than in the Blinded Report Planning 
Meeting and provided in the TSAP.
The following analysis sets will be defined for this trial:

Randomised set (RS):
This subject set includes all randomised patients, whether treated or not.

Treated set (TS):


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This patient set includes all subjects from the RS who were documented to have 
received one dose of study drug. This is the Intent to treat (ITT) population. 

Per-protocol set (PPS):
This patient set includes all patients from the TS who provide evaluable data at 
baseline and on-treatment for the primary endpoint and are not affected by protocol 
violations relevant to the statistical evaluation of the primary endpoint. 
Whether a primary endpoint data is evaluable or a protocol violation is relevant will be 
decided no later than at the final Blinded Report Planning Meeting (BRPM).
Relevant protocol violations may include:

Use of prohibited medication

Patient was non-compliant to study drug intake (e.g.: study drug compliance <80%)
For both efficacy and safety analyses, treatment will be evaluated as treated.
Baseline will be defined as the last available measurement before start of randomised trial 
medication. 
7.3.1
Primary endpoint analyses
The patient set for the evaluation of cardiac energetics endpoints will be the PPS.
Change from baseline of cardiac energetics (PCr/ATP ratio) at rest after 12 weeks of 
treatment will be analyzed by an analysis of variance (ANOVA) model. The model will 
include treatment, history of atrial fibrillation and history of diabetes as fixed effects.
A sensitivity analysis will be conducted on the randomized set (ITT population). Subgroup 
analyses will be performed for the primary endpoint including subgroup analyses by history 
of diabetes and by eGFR (CKD-EPI)Cr at baseline (<60 vs ≥60 mL/min/1.73m²).
For the subgroup analysis an ANOVA model as the primary will be conducted, additionally 
including the terms of the subgroup and subgroup by treatment interaction.
7.3.2
Secondary endpoint analyses
There are no secondary endpoints.


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7.3.4
Safety analyses
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities 
(MedDRA). Standard ARO summary tables and listings will be produced. All adverse events 
with an onset between start of treatment and end of the residual effect period (REP), a period 
of 7 days after the last dose of trial medication, will be assigned to the on-treatment period for 
evaluation.
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events, i.e. all adverse events occurring between start of treatment and end of the 
residual effect period. Adverse events that start before first drug intake and deteriorate under 
treatment will also be considered as ‘treatment-emergent’.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the Medical 
Dictionary for Drug Regulatory Activities (MedDRA) at the database lock.
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be summarised. Treatment 
groups will be compared descriptively with regard to distribution parameters as well as with 
regard to frequency and percentage of patients with abnormal values or clinically relevant 
abnormal values.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.
The details of the analysis will be specified in the TSAP.
7.4
INTERIM ANALYSES
If recruitment is different between the cohorts such that one cohort’s last patient out visit is 
considerably earlier than the last patient out of the other cohort, an interim analysis may be 
planned in order to report the data the completed cohort. For this interim analysis only the 
completed cohort will be unblinded.
Blinded sample size re-calculations may be performed according to Section 7.7 based on the 
observed drop-out rate.
7.5
HANDLING OF MISSING DATA
No missing data are expected for the primary analysis since it is defined on a set of patients 
with available values. Therefore no imputation of missing values is planned. 


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Futher details on handling of other missing data will be specified in the TSAP. 
7.6
RANDOMISATION
The trial will be performed as a double-blind design with respect to placebo and
empagliflozin. Subjects will be randomised to the trial treatments in a 1:1 ratio. The
randomisation will be stratified by the following factors:

Cohort (HFpEF/ HFrEF)

History of diabetes (Yes/ No)
Patients will be randomised in blocks to double-blind treatment via an IRT system. BI will 
arrange for the randomisation and the packaging and labelling of trial medication. The 
randomisation list will be generated using a validated system, which involves a pseudo-
random number generator so that the resulting treatment will be both reproducible and non-
predictable. The block size will be documented in the Clinical Trial Report. Access to the 
codes will be controlled and documented.
7.7
DETERMINATION OF SAMPLE SIZE
Based upon literature [R17-0695] and advice from experts the study is designed to detect a 
treatment effect of the primary endpoint of 0.3 with an SD of 0.28 with a power of 80%.
The significance level for the sample size calculation is 0.05 two-sided for each cohort. 
In order to have an power of at least 80% in each cohort, there should be at least 30 evaluable 
patients for the primary analysis for each cohort.
Expecting a drop-out rate of about 30%, it is planned to randomise 43 patients to each cohort.
The drop-out rate will be monitored during the trial. If the drop-out rate in a cohort is higher 
or lower than expected, the sample size in this cohort may be increased or decreased 
accordingly but not above a maximum of 60 patients in order to achieve 30 evaluable patients 
for the primary analysis.
Calculations were performed using nQuery Advisor® 7.0 statistical package by Statistical 
Solutions Ltd.


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline 
for Good Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU 
regulation 536/2014 and other relevant regulations.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial patients against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor
with regard to publication of the results of this trial are described in the investigator contract. 
The certificate of insurance cover is made available to the investigator and, on request, to the 
patients, and is stored in the ISF.
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH / GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.”
The patient must be given sufficient time to consider participation in the trial. The 
investigator obtains written consent of the patient’s own free will with the informed consent 
form after confirming that the patient understands the contents. The investigator must sign (or 
place a seal on) and date the informed consent form. If a trial collaborator has given a 
supplementary explanation, the trial collaborator also signs (or places a seal on) and dates the 
informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.


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The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual patients will be provided by the sponsor or sponsor’s delegate. See 
Section 4.1.5.2 for rules about emergency code breaks. For drug accountability, refer to 
Section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial patient. Source data as well as reported 
data should follow good documentation practices and be attributable, legible, 
contemporaneous, original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the eCRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case the investigator must make three documented attempts to retrieve 
previous medical records. If this fails a verbal history from the patient, documented in their 
medical records, would be acceptable.
The investigator must ensure that all patient identifiers (e.g. patient’s name, initials, address, 
phone number, NHS number, hospital number) have properly been removed or redacted from 
any copy of the patients’ source documents before sending them to the sponsor or sponsor’s 
delegate.
If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
For the eCRF, data must be derived from source documents, for example:

Patient identification: gender, year of birth (in accordance with local laws and 
regulations)

Patient participation in the trial (substance, trial number, patient number, date patient was 
informed)

Dates of patient’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

Adverse events (onset date (mandatory), and end date (if available))


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
Serious adverse events (onset date (mandatory), and end date (if available))

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available)

Completion of patient’s participation in the trial” (end date; in case of premature 
discontinuation document the reason for it).

Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the patient or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not make 
the patient eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The sponsor or sponsor’s delegate will monitor the conduct of the trial by regular on-site 
monitoring visits and in-house data quality review. The frequency of site monitoring will be 
determined by assessing all characteristics of the trial, including its nature, objective, 
methodology and the degree of any deviations of the intervention from normal clinical 
practice.
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the eCRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). They may review all eCRFs and informed consents. The accuracy of the data will 
be verified by direct comparison with the source documents described in Section 8.3.1. The 
sponsor or sponsor’s delegate will also monitor compliance with the protocol and GCP.
8.3.3
Storage period of records
Trial site:
The trial site must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Academic Research Organisation (ARO):
During the conduct of the trial the ARO must retain the essential documents according to the 
ARO SOPs. At the conclusion of the trial these documents will be transferred to the sponsor.
Sponsor:
After the conclusion of the trial the sponsor must retain the essential documents according to 
the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements. The reporting may be delegated to an ARO where appropriate and 
this delegation will be documented.


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8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted below. Patient privacy will 
be ensured by using patient identification code numbers.
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook. Treatment data may be given to the patient’s personal physician or to other 
appropriate medical personnel responsible for the patient’s welfare. Data generated as a result 
of the trial need to be available for inspection on request by the participating physicians, the 
sponsor’s representatives, by the IRB / IEC and the regulatory authorities.
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first patient in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial
(“Last Patient Out”).The Last Patient Drug Discontinuation (LPDD) date is defined as the 
date on which the last patient at an individual trial site ends trial medication (as scheduled per 
protocol or prematurely). Individual investigators will be notified of SUSARs occurring with 
the trial medication until 30 days after LPDD at their site.
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the respective laws.
A final report of the clinical trial data will be written only after all patients have completed 
the trial to incorporate and consider all data in the report. An interim report for one cohort 
may be produced if one cohort ends significantly earlier than the other.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI). The majority of the organisation of the 
trial will be delegated to an Academic Research Organisation (ARO) with which the 
responsibilities and tasks will have been agreed and a written contract filed before initiation 
of the clinical trial. The SOPs to be followed will be documented.


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Statistical Evaluation of the primary endpoint and Data Management will be done by the 
ARO according to ARO SOPs.
A central laboratory service and an IRT vendor will be used in this trial. Details will be 
provided in the IRT Manual and Central Laboratory Manual, available in the ISF.


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9.
REFERENCES
9.1
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Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman 
M, Das SR, de Ferranti S, DesprésJ-P, Fullerton HJ, Howard VJ, 
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D, Yeh RW, Turner MB; on behalf of the American Heart Association 
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and stroke statistics - 2016 update: a report from the American Heart 
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Acute and Chronic Heart Failure of the European Society of Cardiology 
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Wanner C, Inzucchi SE, Lachin JM, Fitchett D, Eynatten M von, 
Mattheus M, et al, EMPA-REG OUTCOME Investigators Empagliflozin 
and progression of kidney disease in type 2 diabetes. N Engl J Med 375 
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creatinine. Nephron 1976. 16(1):31-41
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European Medicines Agency (EMEA). ICH topic M3 (R2) non-clinical 
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Levey AS, Stevens LA, Schmid CH, Zhang Y, Castro AF, Feldman HI, 
Kusek JW, Eggers P, Lente F van, Greene T, Coresh J, Chronic Kidney 
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D, Franklin B, Guazzi M, Gulati M, Keteyian SJ, Lavie CJ, Macko R, 
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Rehabilitation, and Prevention Committee of the Council on Clinical 
Cardiology, Council on Epidemiology and Prevention, Council on 
Peripheral Vascular Disease, Interdisciplinary Council on Quality of 
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Ambrosy AP, Fonarow GC, Butler J, Chioncel O, Greene SJ, 
Vaduganathan M, Nodari S, Lam CSP, Sato N, Shah AN, Gheorghiade 
M The global health and economic burden of hospitalizations for heart
failure: lessons learned from hospitalized heart failure registries.              


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Steinberg BA, Zhao X, Heidenreich PA, Peterson ED, Bhatt DL, Cannon 
CP, Hernandez AF, Fonarow GC, Get With the Guidelines Scientific 
Advisory Committee and Investigators Trends in patients hospitalized 
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Cheng RK, Cox M, Neely ML, Heidenreich PA, Bhatt DL, Eapen ZJ, 
Hernandez AF, Butler J, Yancy CW, Fonarow GC Outcomes in patients 
with heart failure with preserved, borderline, and reduced ejection 
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Clark AL, Cleland JG Elevated glycated haemoglobin is a strong 
predictor of mortality in patients with left ventricular systolic dysfunction 
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Rouleau JL, Sigouin C, Solymoss CB, Tsuyuki R, White M, Yusuf S. 
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Abbara S, Arbab-Zadeh A, Callister TQ, Desai MY, Mamuya W, 
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9.2
UNPUBLISHED REFERENCES
c01678844
Empagliflozin Investigator’s Brochure, Current Version
c03946327
A phase III randomised, double-blind trial to evaluate efficacy and safety 
of once daily empagliflozin 10 mg compared to placebo, in patients with 
chronic Heart Failure with preserved Ejection Fraction (HFpEF).
c09098452
A phase III randomised, double-blind trial to evaluate efficacy and safety 
of once daily empagliflozin 10 mg compared to placebo, in patients with 
chronic Heart Failure with reduced Ejection Fraction (HFrEF)


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10.
APPENDICES
10.1
NYHA FUNCTIONAL CLASSIFICATION
Class
Patient symptoms
I
No limitation of physical activity. Ordinary physical activity does not cause 
undue fatigue, palpitation, dyspnea (shortness of breath)
II
Slight limitation of physical activity. Comfortable at rest. Ordinary physical 
activity results in fatigue, palpitation, dyspnea (shortness of breath)
III
Marked limitation of physical activity. Comfortable at rest. Less than ordinary 
activity causes fatigue, palpitation, or dyspnea
IV
Unable to carry on any physical activity without discomfort. Symptoms of heart 
failure at rest. If any physical activity is undertaken, discomfort increases


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10.3
COCKCROFT-GAULT FORMULA
The following formula may be used for estimated creatinine clearance rate (eCCR) using 
Cockcroft-Gault formula.  The use of on-line calculators or formulas which are institution 
standards for eCCR and differ slightly may also be used.  The calculations and results must be 
filed in the patient’s chart.
When serum creatinine is measured in mg/dL;







mg/dL
in 
Creatinine
Serum
72
85
.0
kilograms
in 
Mass
Age
140
eCCR





Female
if
When serum creatinine is measured in µmol/L;






µmol/L
in 
Creatinine
Serum
Constant
kilograms
in 
Mass
Age
140
eCCR




Where Constant is 1.23 for men and 1.04 for women.


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11.
DESCRIPTION OF GLOBAL AMENDMENTS
Number of global amendment
1
Date of CTP revision
26 Mar 2018
EudraCT number
2017-000376-28
BI Trial number
1245.148
BI Investigational Product(s)
Empagliflozin
Title of protocol
EMPA-VISION: A randomised, double-blind, 
placebo-controlled, mechanistic cardiac magnetic 
resonance study to investigate the effects of 
empagliflozin treatment on cardiac physiology and 
metabolism in patients with heart failure
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
X
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Title Page and Synopsis
Description of change
Addition of EMPA-VISION to trial title
Rationale for change
Administrative
Section to be changed
Synopsis, abbreviations and section 1.3
Description of change
Correction of spelling errors in Phosphocreatine 
/Adenosine Triphosphate and Creatine Kinase
Rationale for change
Correction
Section to be changed
Flowchart
Description of change
Safety laboratory tests (urine and blood) split into 
two rows
Rationale for change
Clarification of requirements
Section to be changed
Flowchart


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Description of change
Addition of blood sample for metabolomic analysis
Rationale for change
Scientific interest in performing metabolomic 
analysis
Section to be changed
Abbreviations
Description of change
Addition of Coronary Artery Disease (CAD)
Rationale for change
Administrative change
Section to be changed
3.1.1.1 Clinical Event Committee for Diabetic 
ketoacidosis (DKA)
Description of change
Removal of reference to adjudication endpoints and 
addition of explanation that analysis will be 
performed on project level.
Rationale for change
Clarification. There are no adjudication endpoints 
for this trial.
Section to be changed
3.3.3 Exclusion criteria
Description of change
Exclusion criteria 2 changed from 
Previous myocardial infarction (increase in cardiac 
enzymes in combination with symptoms of 
ischaemia or newly developed ischaemic ECG 
changes), unstable angina pectoris, percutaneous 
coronary intervention (PCI), coronary artery bypass 
graft surgery or other major cardiovascular surgery
to
Any significant coronary artery disease (CAD) 
with >50% luminal obstruction, unstable angina 
due to significant CAD, percutaneous coronary 
intervention (PCI), coronary artery bypass graft 
surgery or other major (in the opinion of the 
investigator) cardiovascular surgery.
Rationale for change
Patients who had previous NSTEMI or less 
extensive MI will still have viable myocardium to 
produce ATP so those patients are technically 
eligible for MRS and there is no reason to exclude 
them.
Section to be changed
4.1.4 Drug assignment and administration of doses 
for each patient
Description of change
Requirement to take the medication in the morning 
changed to a recommendation. Requirement to take 


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the dose at the usual scheduled time on the day of 
visit 2 removed.
Rationale for change
The dose at visit 2 is the first one and therefore the 
‘usual scheduled time’ does not apply. Due to 
scheduling of assessments it may not be possible to 
take the medication in the morning at visit 2 so 
more flexibility has been introduced.
Section to be changed
Description of change
 
Rationale for change
Administrative change
Section to be changed
5.2.4 Cardiac Magnetic Resonance (CMR)
Description of change
Dobutamine dose changed from g/kg to mcg/kg
Rationale for change
Correction
Section to be changed
5.2.5 Cardiac Computerised Tomography (CT) 
Scan
Description of change
CT scanner changed from 64-slice to 320-slice and 
heart rate changed from <65 beats/min to <60 
beats/min.
Rationale for change
Correction
Section to be changed
5.3.3.1 Creatinine
Description of change
Addition of local creatinine test at Visit 1
Rationale for change
Required to check patient safety before 
administration of contrast agent
Section to be changed
Table 5.3.3:1 Safety laboratory parameters
Description of change
Reticulocyte count and γ-GT will be measured as 
standard rather than as reflex tests
Rationale for change
Reflex testing of these parameters is not feasible 
due to limited sample stability
Section to be changed
Description of change
 
Rationale for change
Section to be changed
Description of change
 
Rationale for change
Clarification


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Section to be changed
Description of change
Rationale for change
Administrative
Section to be changed
 
Description of change
 
 
Rationale for change
Administrative change
Section to be changed
Description of change
 
Rationale for change
 
 
 
 
 
 
 
 
 
Number of global amendment
2
Date of CTP revision
14 Aug 2018
EudraCT number
2017-000376-28
BI Trial number
1245.148
BI Investigational Product(s)
Empagliflozin
Title of protocol
EMPA-VISION: A randomised, double-blind, 
placebo-controlled, mechanistic cardiac magnetic 
resonance study to investigate the effects of 
empagliflozin treatment on cardiac physiology and 
metabolism in patients with heart failure
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
X
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 


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Clinical Trial Protocol
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Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Flowchart
Description of change
Modification of requirements so that the
echocardiogram does not need to be repeated at 
visit 2 if performed within the previous 21 days.
Rationale for change
The time window has been modified to avoid 
unnecessary assessments. The echocardioagram 
data is not expected to change significantly within 
21 days so one assessment within 21 days of start 
of treatment is sufficient.
Section to be changed
Flowchart and section 5.2.5
Description of change
Modification of requirements so that a CT scan is 
not required at screening if ischaemic clinical 
testing has been performed within 6 months and 
written results are available and adequate (in the 
opinion of the investigator) to assess eligibility
Rationale for change
There is no medical reason to repeat the CT scan if 
results from within the previous 6 months are 
available.
Section to be changed
3.3.2 Inclusion criteria
Description of change
Inclusion criterion number 3 ‘Body mass index 
(BMI) <40 kg/m2 at screening’ deleted
Rationale for change
There is no medical reason to exclude patients with 
a high BMI who are otherwise eligible and able to 
undergo MRI scanning. Patients with a high BMI 
who are unable to undergo MRI scanning will be 
excluded from the study by exclusion criterion 
number 3 which covers contraindications for MRI 
scanning. 
Section to be changed
3.3.3 Exclusion criteria
Description of change
Exclusion criteria 22 changed from 
‘Any documented active or suspected malignancy 
or history of malignancy within 2 years prior to 


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informed consent……’
To
‘Any documented active or suspected malignancy 
or history of malignancy within 6 months prior to 
informed consent…….’
Rationale for change
Patients who received chemotherapy or 
radiotherapy should be considered individually by 
investigators as the status of malignancy after 
treatment varies according to individual, type of 
malignancy, and the effect of treatment. Taking 
these into account it is considered acceptable to 
include patients in the trial as soon as 6 months if 
the investigator believes it is appropriate to do so.
Section to be changed
3.3.3 Exclusion criteria
Description of change
Exclusion criterion 2 changed from;
‘Any significant coronary artery disease (CAD) 
with >50% luminal obstruction, unstable angina 
due to significant CAD, percutaneous coronary 
intervention (PCI), coronary artery bypass graft 
surgery or other major (in the opinion of the 
investigator) cardiovascular surgery.’
to
‘Any patients with myocardial scars and/or non-
viable myocardium in the interventricular septum, 
unstable angina due to significant coronary artery 
disease (CAD), or major (in the opinion of the 
investigator) cardiovascular surgery.’
Rationale for change
The measurement of PCr/ATP is performed in the 
interventricular septum and therefore patients with 
non-viable septal tissue (myocardial scars and/or 
non-viable myocardium in the interventricular 
septum) will be excluded.
The current exclusion criterion also excludes 
patients with flow limitation of the non-septal 
region. Coronary flow limitation resulting in scars 
or non-viable myocardium elsewhere (non-septal 
regions) will not affect measurement of PCr/ATP 
so the exclusion criteria has been modified to allow 
inclusion of these patients. 


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c14878151
5.0
clinical-trial-protocol-version-03
EMPA-VISION: A randomised, double-blind, placebo-controlled, mechanistic
cardiac magnetic resonance study to investigate the effects of empagliflozin
treatment on cardiac physiology and metabolism in patients with heart failure
Approval-Team Member Medicine
15 Aug 2018 14:48 CEST
Author-Trial Statistician
15 Aug 2018 14:59 CEST
Approval-Therapeutic Area 
15 Aug 2018 16:54 CEST
Author-Trial Clinical Monitor
21 Aug 2018 15:37 CEST
Verification-Paper Signature
Completion
23 Aug 2018 22:27 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c14878151
5.0

SAP_001.pdf: 
20200312_1245.148_EMPA-VISION TSAP_v2.0 
Confidential 
Page 1 of 36 
Statistical Analysis Plan for EMPA-VISION 
Version: 2.0 
Date: 12th-March-2020 
 Trial No.:TRG17-01 
BI Trial No.: 1245.148 
EudraCT No.: 2017-000376-28 
EMPA-VISION: A RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
MECHANISTIC CARDIAC MAGNETIC RESONANCE STUDY TO INVESTIGATE 
THE EFFECTS OF EMPAGLIFLOZIN TREATMENT ON CARDIAC PHYSIOLOGY 
AND METABOLISM IN PATIENTS WITH HEART FAILURE 
 [PROTOCOL VERSION 3.0/DATE: 14TH AUGUST 2018] 
Prepared By: 
 
Prepared For: Boehringer Ingelheim 
 
[Sponsor] 


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Revision History 
Version Date 
Author(s) and Role 
Summary of Changes/Comments 
2.0 
12 March 2020 
 
Lead Statistician 
The main changes in this version 
are as follows: 
Section 1.4, details added for 
changes to the planned protocol 
analyses.  
 
 
Analysis sets/populations in 
Section 3 have been renamed to 
match the clinical trial protocol. 
SAS code provided in Section 5.3 
for the primary endpoint analyses 
Section 5.3.2, sensitivity analysis 
of primary endpoint including 
adopted using ANCOVA. 
Section 5.5, analysis model 
changed to ANCOVA. 
 
 
 


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SAP Approval 
Signature of Approval for Statistical Analysis Plan for EMPA-VISION [BI Trial No: 1245.148]: 
Lead Statistician 
 
Signature 
Date 
Trial Statistician 
(BI) 
Signature 
Date 
Project 
Statistician (BI) 
Signature 
Date 
Co-Investigator 
 
Signature 
Date 
Principal 
Investigator 
 
Signature 
Date 
Chief 
Investigator 
 
Signature 
Date 


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TABLE OF CONTENT 
1 
Introduction ........................................................................................................................... 9 
1.1 
Study Objectives .............................................................................................................. 9 
1.1.1 
Primary Objectives .............................................................................................................................. 9 
1.1.2 
Secondary Objectives .......................................................................................................................... 9 
 
 
1.2 
Study Design .................................................................................................................. 10 
1.2.1 
OVERALL TRIAL DESIGN AND PLAN ................................................................................................... 10 
1.2.2 
Administrative structure of the trial ................................................................................................. 10 
Clinical Event Committee for Diabetic ketoacidosis (DKA) ...................................................... 10 
Hepatic external adjudication .................................................................................................. 11 
1.2.3 
SELECTION OF TRIAL POPULATION ................................................................................................... 11 
Main diagnosis for trial entry .................................................................................................. 11 
Inclusion criteria ...................................................................................................................... 11 
Exclusion criteria ...................................................................................................................... 12 
1.3 
Schedule of Study Assessments ...................................................................................... 14 
1.3.1 
VISIT SCHEDULE ................................................................................................................................. 14 
1.3.2 
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ....................................................................... 14 
Screening period ...................................................................................................................... 16 
Treatment period .................................................................................................................... 16 
Follow up period and trial completion .................................................................................... 17 
Early discontinuation of trial medication ................................................................................ 17 
1.4 
Changes to the Planned Analysis .................................................................................... 17 
2 
Endpoints ............................................................................................................................. 18 
2.1 
Primary Endpoints ......................................................................................................... 18 
2.1.1 
Definition and Derivation of Primary Endpoint ................................................................................. 18 
2.1.2 
Primary Hypothesis under Investigation ........................................................................................... 18 
2.1.3 
Handling of Outliers and Missing Data .............................................................................................. 18 
2.2 
Secondary Endpoints ...................................................................................................... 18 
2.2.1 
Definitions and Derivations of Secondary Endpoints ........................................................................ 18 
2.2.2 
Secondary Hypotheses under Investigation ...................................................................................... 18 
 
 
 
 
 
 
3 
Analysis Sets/Populations ................................................................................................... 21 
3.1 
Per-protocol Set (PPS) .................................................................................................... 21 
3.2 
Randomised Set (RS) ...................................................................................................... 21 
3.3 
Treated set (TS) .............................................................................................................. 21 
4 
General Issues for Statistical Analysis ............................................................................... 22 
4.1 
Analysis Software .......................................................................................................... 22 
4.2 
Multiplicity, Multiple Comparisons and Interim Analyses ................................................ 22 
 
 
5 
Statistical Methodology ....................................................................................................... 23 
5.1 
Disposition of Patients ................................................................................................... 23 
5.2 
Demographic and Baseline Characteristics ...................................................................... 23 
5.3 
Primary Endpoint Analysis .............................................................................................. 23 
5.3.1 
Primary Efficacy Analysis ................................................................................................................... 23 


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5.4 
Secondary Endpoint Analyses ......................................................................................... 24 
 
 
6 
Safety and Tolerability Analysis ......................................................................................... 26 
6.1 
Drug Exposure ............................................................................................................... 26 
6.2 
Adverse Events and Tolerability...................................................................................... 26 
6.3 
Laboratory Data ............................................................................................................. 27 
6.4 
Vital Signs, Electrocardiogram, and Other Safety Assessments ........................................ 27 
7 
Data Handling Conventions ............................................................................................... 28 
7.1 
Data Quality Assurance and Monitoring ......................................................................... 28 
7.2 
Data Transformations .................................................................................................... 28 
8 
References ........................................................................................................................... 33 
9 
Appendices ........................................................................................................................... 34 
9.1 
Appendix 1: Reporting Conventions ................................................................................ 34 
9.2 
Appendix 2: Important Protocol Deviations (iPDs) .......................................................... 34 
Figure 1-1. Trial Design ............................................................................................................... 10 
Figure 1-2. Schedule of Assessment ............................................................................................ 15 
Figure 1-3. Requirements for Adverse Event Collection ............................................................. 15 


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LIST OF ABBREVIATIONS 
 
 
ACE 
Angiotensin-converting enzyme 
ACR 
Albumin Creatinine Ratio 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
AF 
Atrial Fibrillation 
ALT 
Alanine-Aminotransferase 
AMP 
Auxiliary Medicinal Product 
ANOVA 
Analysis of Variance 
ARB 
Angiotensin Receptor Blocker 
ARNI 
Angiotensin Receptor blocker-Neprilysin Inhibitor 
ARO 
Academic Research Organisation 
AST 
Aspartate-Aminotransaminase 
ATP 
Adenosine Triphosphate 
BI 
Boehringer Ingelheim 
BMI 
Body Mass Index 
 
BP 
Blood Pressure 
BRPM 
Blinded Report Planning Meeting 
CA 
Competent Authority 
CAD 
Coronary Artery Disease 
CCTA 
Coronary Computed Tomographic Angiography 
CEC 
Clinical Event Committee 
CI 
Confidence Interval 
CK 
Creatine Kinase 
CKD 
Chronic Kidney Disease 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration Equation 
CMR 
Cardiac Magnetic Resonance 
CPET 
Cardiopulmonary Exercise Test 
CRA 
Clinical Research Associate 
CRO 
Clinical Research Organisation 
CRT 
Cardiac Resynchronisation Therapy 
CT 
Computed Tomography 
CTP 
Clinical Trial Protocol 
CV 
Cardiovascular 
DBL 
Data Base Lock 
DBP 
Diastolic Blood Pressure 
DILI 
Drug Induced Liver Injury 
DKA 
Diabetic Ketoacidosis 
DM 
Diabetes Mellitus 
 
 
eCCR 
Estimated creatinine clearance 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
eCRF 
Electronic Case Report Form 
 
 
EF 
Ejection Fraction 
eGFR 
Estimated Glomerular Filtration Rate 
EOT 
End of treatment 
 
 
EudraCT 
European Clinical Trials Database 
 
 
 
 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 


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GMP 
Good Manufacturing Practice 
GLM 
General Linear Model 
HAF 
History of Atrial Fibrillation 
 
 
HDL 
High Density Lipoprotein 
HF 
Chronic Heart Failure 
HHF 
Hospitalisation for Heart Failure 
HFpEF 
Heart Failure with Preserved Ejection Fraction 
HFrEF 
Heart Failure with Reduced Ejection Fraction 
HR 
Hazard Ratio 
 
 
IB 
Investigator’s Brochure 
ICD 
Implantable Cardioverter Defibrillator 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IPV 
Important Protocol Violation 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ISF 
Investigator Site File 
ITT 
Intent to Treat 
i.v.
Intravenous 
 
 
LA 
Left Atrial 
LAEF 
Left Atrial Emptying Function 
LAVI 
Left Atrial Volume Index 
LDL 
Low Density Lipoprotein 
LGE 
Late Gadolinium Enhancement 
LPDD 
Last Patient Drug Discontinuation 
LV 
Left Ventricular 
LVAD 
Left Ventricular Assist Device 
LVEF 
Left Ventricular Ejection Fraction 
LVH 
Left Ventricular Hypertrophy 
LVMI 
Left Ventricular Mass Index 
MACE 
Major Adverse Cardiovascular Event 
MedDRA 
Medical Dictionary for Drug Regulatory Activities 
MI 
Myocardial Infarction 
MRA 
Mineralocorticoid Receptor Antagonist 
MRI 
Magnetic Resonance Imaging 
MRS 
Magnetic Resonance Spectroscopy 
NT-proBNP 
N-terminal of the prohormone brain natriuretic peptide
NYHA 
New York Heart Association Classification 
PCr 
Phosphocreatine 
PP 
Per Protocol 
PPS 
Per Protocol Set 
PMRS 
Proton Magnetic Resonance Spectroscopy 
PSA 
Prostate Specific Antigen 
 
 
SAEs 
Serious Adverse Events 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SGLT-1 
Sodium-glucose co-transporter 1 
SGLT-2 
Sodium-glucose co-transporter 2 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
T1DM 
Type 1 Diabetes Mellitus 


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T2DM 
Type 2 Diabetes Mellitus 
TIA 
Transient Ischaemic Attack 
ULN 
Upper Limit of Normal 
WOCBP 
Women of childbearing potential 


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1 Introduction 
This Statistical Analysis Plan (SAP) describes the planned analyses and reporting of the 
Boehringer Ingelheim [BI Trial No: 1245.148 & EU Trial No: 2017-000376-28] Protocol No: 
1245-148 "A randomised, double-blind, placebo-controlled, mechanistic cardiac magnetic 
resonance study to investigate the effects of empagliflozin treatment on cardiac physiology and 
metabolism in patients with heart failure": The EMPA-VISION Study Protocol version 3.0 
dated 14th August 2018). 
The purpose of this SAP is to outline the planned analyses that are to be performed on the data 
to support the completion of the Clinical Study Report (CSR) for protocol 1245-148. The SAP 
will be amended if substantial changes to the planned analyses, and in any case, will be 
finalized before the database lock for this study. 
Exploratory post-hoc or unplanned analyses not necessarily identified in this SAP may be 
performed on these data as required. These analyses will be clearly identified in the CSR or the 
statistical report for the study. In addition, all the planned analyses identified or unplanned 
analyses not specified in this SAP may be included in the future manuscripts. 
The reader of this SAP is encouraged also to read the clinical protocol for details on the conduct 
of this study, and the operational aspects of clinical assessments and the timing of the process of 
completing a patient in this study. 
1.1 Study Objectives 
The objective of this trial is to assess the effect of empagliflozin on cardiac physiology and 
metabolism aiming to provide a scientific explanation of the underlying mechanism by which 
empagliflozin improves HF related outcomes in patients with chronic heart failure. 
1.1.1 Primary Objectives 
The primary endpoint is the change from baseline (Randomisation) to week 12 (Day 84) in the 
PCr / ATP ratio in the resting state measured by 31P MRS. 
1.1.2 Secondary Objectives 
There are no secondary endpoints defined in this trial. 


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1.2 Study Design 
1.2.1 OVERALL TRIAL DESIGN AND PLAN 
This randomised, double-blind, placebo-controlled trial investigates the effects of empagliflozin 
on cardiac metabolism and function in heart failure patients. Empagliflozin will be compared to 
placebo as add-on to standard of care treatment in heart failure patients. The effects of 
empagliflozin will be assessed independently in two separate cohorts of patients; those with 
reduced ejection fraction (rEF) and those with preserved ejection fraction (pEF), but the 
randomised treatment and trial assessments for both cohorts are identical. 
Figure 1-1. Trial Design 
1.2.2 Administrative structure of the trial 
Clinical Event Committee for Diabetic ketoacidosis (DKA) 
An independent external committee (CEC) will be established to adjudicate centrally and in a 
blinded fashion events suspected of DKA (for further details see Protocol (1245.148, version 
3.0, dated 14th August 2018) Section 5.3.5.1). The CEC will evaluate whether pre-specified 
criteria for adjudication endpoints are met. 
For any events that qualify for adjudication, study sites will be asked to provide clinical 
documentation such as laboratory values, discharge summaries etc. to support the external 
event adjudication. The tasks and responsibilities of the CEC will be specified in a charter. The 
CEC will maintain the adjudication results in writing. 


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Hepatic external adjudication 
Certain hepatic events will be adjudicated by external independent experts for severity and a 
causal relationship with the trial medication in a blinded fashion. The events which will be 
reviewed are defined in a charter for hepatic events. Events may either be defined by abnormal 
laboratory values and/or relevant adverse events or both. For example, assessments will be 
made for hepatic injury events, including liver enzyme elevations. 
For qualifying events, relevant source documents generated from any medical evaluations of 
these events will be requested, including laboratory values, histological analysis, and results of 
ultrasound, CT, MRI, scintigraphy, hospital discharge letters, and medical reports from other 
physicians. All evaluations will be performed in a blinded fashion. The assessments will be 
analysed based on empagliflozin data combined from multiple trials (i.e. on project level). 
1.2.3 SELECTION OF TRIAL POPULATION 
The trial will be conducted in a single centre specialising in cardiac imaging. Approximately 
180 patients will be screened in total in order to identify 43 eligible patients for each cohort. 
Screening will continue until 43 eligible patients have been randomised into each cohort. Once 
one cohort is full, recruitment into that cohort will be closed and patients will only be screened 
for the cohort which remains open. Any patients already in screening at the time a cohort is 
closed will be allowed to continue to randomisation if eligible. 
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the investigator site file (ISF) at the investigational site irrespective of whether 
they have been treated with an investigational drug or not. 
Re-screening of patients who do not meet the inclusion/exclusion criteria will not be permitted, 
however, assessments may be repeated within the screening period and the latest assessment 
prior to randomisation must always be used to assess eligibility. 
Cohort A will contain 43 patients with heart failure with reduced ejection fraction (HFrEF) and 
Cohort B will contain 43 patients with heart failure with preserved ejection fraction (HFpEF). 
Within each cohort patients will be randomised 1:1 to receive either empagliflozin or matching 
placebo. A drop-out rate of 30% is expected and the total sample size for a cohort may be 
increased if the drop-out rate is higher than expected (Protocol (1245.148) Section 7.7). 
Patients with T2DM will be eligible to enter the trial and are expected to account for 30-40% of 
randomised patients. There are no targets or restrictions on the recruitment of patients with 
T2DM but randomisation will be stratified according to history of diabetes (Yes/No) to ensure a 
balance between the arms (see also Protocol (1245.148) Section 7.1). 
Main diagnosis for trial entry 
The trial will be performed in patients with chronic heart failure. Patients with reduced ejection 
fraction (≤40%) or preserved ejection fraction (≥50%) will be included. 
Patients who do not meet all of the inclusion criteria or who meet any of the exclusion criteria 
are not eligible for study participation and are not eligible to receive study medication. Please 
refer to Protocol (1245.148, version 3.0, dated 14th August 2018) Section 8.3.1 (Source 
Documents) for the documentation requirements pertaining to the in- and exclusion criteria. 
Inclusion criteria 
1. Chronic heart failure diagnosed at least 3 months before informed consent
2. NYHA class II-IV at screening
3. Inclusion criterion no longer applicable


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4. Age ≥ 18 years at screening
5. Male or female patients. Women of childbearing potential (WOCBP)1 must be ready and
able to use highly effective methods of birth control per ICH M3 (R2) [R09-1400] that result
in a low failure rate of less than 1% per year when used consistently and correctly. A list of
contraception methods meeting these criteria are provided in the Protocol (1245.148)
Section 4.2.2 and also in the patient information.
6. Signed and dated written informed consent in accordance with ICH-GCP and local
legislation prior to admission to the trial
Cohort A (HFrEF) 
7. Left ventricular ejection fraction (LVEF) ≤ 40% as measured by ECHO at screening
8. The following signs of heart failure;

Elevated NT-proBNP (>125 pg/mL) at screening in patient without atrial fibrillation
(AF)

Elevated NT-proBNP (>600 pg/mL) at screening in patient with AF
9. Appropriate dose of medical therapy for HF (such as ACEi, ARB, β-blocker, oral diuretics,
MRA, ARNI, ivabradine) consistent with prevailing local and international HF guidelines,
stable for at least one week prior to Visit 1 and during screening period until Visit 2
(Randomisation) with the exception of diuretics which must be stable for at least one week
prior to Visit 2 to control symptoms. If required, the investigator must document in the
source documents the reason why the patient is not on the target dose per local guidelines.
Cohort B (HFpEF) 
10. Left ventricular ejection fraction (LVEF) ≥ 50% as measured by ECHO at screening and no
previous measurement of LVEF ≤ 40%.
11. The following combined signs of heart failure;

Structural heart disease (LA enlargement [LAVI >34 mL/m2] and/or LVH [LVMI ≥
115 g/m2 for males and ≥ 95 g/m2 for females]) by ECHO at screening or within 3
months prior to informed consent
AND 

NT-proBNP > 125pg/mL at screening in patient without AF or NT-pro-BNP > 600
pg/mL in patient with AF
12. Oral diuretics, if prescribed, should be stable for at least one week prior to Visit 1 and
during screening period until Visit 2 (Randomisation).
Exclusion criteria 
1. Stroke or transient ischaemic attack (TIA) within 6 months prior to informed consent.
2. Any patients with myocardial scars and/or non-viable myocardium in the interventricular
septum, unstable angina due to significant coronary artery disease (CAD), or major (in the
opinion of the investigator) cardiovascular surgery.
3. Any contraindication for MRI, CPET and/or dobutamine stress test in accordance with the
institution guidance, including implanted left ventricular assist device (LVAD), implantable
cardioverter defibrillator (ICD), cardiac resynchronisation therapy (CRT) or any cardiac
device.
4. Heart transplant recipient or listed for heart transplant
1 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming 
postmenopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and 
bilateral oophorectomy. Tubal ligation is not a method of permanent sterilisation. A postmenopausal state is defined as no 
menses for 12 months without an alternative medical cause. 


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5. Cardiomyopathy based on infiltrative diseases (e.g. amyloidosis), accumulation diseases
(e.g. haemochromatosis, Fabry disease), muscular dystrophies, cardiomyopathy with
reversible causes (e.g. stress cardiomyopathy), hypertrophic obstructive cardiomyopathy or
known pericardial constriction
6. Moderate to severe uncorrected valvular heart disease, obstructive or regurgitant, or any
valvular heart disease expected to lead to surgery in the Investigator’s opinion
7. Acute decompensated HF (exacerbation of chronic HF) requiring intravenous (i.v.)
diuretics, i.v. inotropes or i.v. vasodilators, or LVAD or hospitalisation within 1 week prior
to Visit 1 (Screening), or during screening period until Visit 2 (Randomisation)
8. Systolic blood pressure (SBP) ≥ 180 mmHg at screening. If SBP >150 mmHg and
<180mmHg at screening, the patient is ineligible if receiving 3 or more antihypertensive
drugs
9. Symptomatic hypotension and/or a SBP < 100 mmHg at Screening
10. Atrial fibrillation which is uncontrolled in the opinion of the investigator
11. Untreated ventricular arrhythmia with syncope documented within the 3 months prior to
informed consent in patients without ICD
12. Diagnosis of cardiomyopathy induced by chemotherapy or peripartum within the 12 months
prior to informed consent
13. Symptomatic bradycardia or second or third degree heart block in need of a pacemaker
after adjusting beta-blocker therapy or any other negative inotropic agents, if appropriate
14. Chronic pulmonary disease requiring home oxygen, oral steroid therapy or hospitalisation
for exacerbation within 12 months prior to informed consent, or significant chronic
pulmonary disease in the Investigator’s opinion, or primary pulmonary arterial
hypertension
15. Indication of liver disease, defined by serum levels of either ALT (SGPT), AST (SGOT), or
alkaline phosphatase above 3 x upper limit of normal (ULN) as determined at screening
16. Impaired renal function, defined as estimated Creatinine Clearance < 30 mL/min (using
Cockcroft-Gault formula) or requiring dialysis, as determined at screening
17. Haemoglobin < 10 g/dL at screening
18. Type 1 Diabetes Mellitus (T1DM)
19. History of ketoacidosis
20. Major surgery (major according to the investigator’s assessment) performed within 3
months prior to informed consent, or scheduled major elective surgery (e.g. hip
replacement) within 3 months after Visit 1
21. Gastrointestinal (GI) surgery or GI disorder that could interfere with absorption of trial
medication in the investigator’s opinion
22. Any documented active or suspected malignancy or history of malignancy within 6 months
prior to informed consent, except appropriately treated basal cell carcinoma of the skin, in
situ carcinoma of uterine cervix or low risk prostate cancer (patients with pretreatment PSA
<10 ng/mL, and biopsy Gleason score of ≤ 6 and clinical stage T1c or T2a)
23. Presence of any other disease than heart failure with a life expectancy of <1 year in the
investigator’s opinion
24. Patients who must or wish to continue the intake of restricted medications (see Protocol
(1245.148, version 3.0, dated 14th August 2018, Section 4.2.2) or any drug considered likely
to interfere with the safe conduct of the trial
25. Patients with requirement for treatment with empaglifozin according to local standard of
care
26. Treatment with any SGLT-2 inhibitor or combined SGLT-1 and 2 inhibitor within 1 week
prior to informed consent or during screening period until Visit 2 (Randomisation)
27. Currently enrolled in another investigational device or drug study, or less than 30 days
between randomisation and ending another investigational device or drug study, or


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receiving other investigational treatment(s). Patients participating in a purely observational 
trial will not be excluded. 
28. Known allergy or hypersensitivity to empagliflozin or other SGLT-2 inhibitors
29. Chronic alcohol or drug abuse or any condition that, in the investigator’s opinion, makes
them an unreliable trial subject or unlikely to complete the trial
30. Women who are pregnant, breastfeeding, or who plan to become pregnant while in the trial
31. Any clinical condition that would jeopardise patients safety while participating in this trial,
or may prevent the subject from adhering to the trial protocol
1.3 Schedule of Study Assessments 
1.3.1 VISIT SCHEDULE 
All patients are to adhere to the visit schedule as specified in the Figure 1-2. Schedule of 
Assessment. If any visit has to be rescheduled, subsequent visits should follow the original visit 
date schedule calculated from the date of randomisation. The trial medication packs contain 
sufficient medication to allow for these time windows. 
1.3.2 DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS 
Please refer to the Figure 1-2. Schedule of Assessment and Protocol (1245.148) Protocol 
(1245.148) Section 5 for details of the procedures performed at each visit. 


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Figure 1-2. Schedule of Assessment 
Trial Period 
Screening 
Treatment 
Follow-up* 
Visit 
1 
2** 
3 
4** 
5 
Timing 
1-21 days prior to 
randomisation 
Day 1 
Day 15 ±1 day 
Day 84/ EOT ±4 days 
7-14 days after last dose
Informed consent 
X 
Demographics, alcohol and smoking 
history 
X 
NYHA classification 
X 
X 
Cardiac computed tomography (CT) scan 
X 
Echocardiogram (ECHO) 
X1 
X2 
X 
X 
Safety laboratory tests (urine and blood) 
X 
X2 
X3 
X 
 
 
 
 
 
 
12 lead-electrocardiogram (ECG) 
X1 
X2 
X 
Vital signs 
X 
X2 
X 
X 
Height 
X 
Weight 
X 
X2 
X 
X 
Pregnancy test4 
X 
X 
X 
X 
Review of in-/exclusion criteria 
X 
X 
Medical history 
X 
Physical examination 
X 
X 
Randomisation 
X 
Dispense trial medication 
X 
Administer trial medication 
Continuous daily dosing5 
Medication compliance check 
X 
X 
 
 
 
 
 
 
Cardiac Magnetic Resonance (CMR) 
X 
X 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
Concomitant therapy 
X 
X 
X 
X 
X 
Telephone call to patient 
X 
Completion of patient participation 
X 
* The follow-up visit must be completed for all randomised patients, including those who withdraw prematurely (see Protocol (1245.148) Section 3.3.4.1), unless the patient has 
withdrawn consent to follow-up. The follow-up visit is expected to be performed via a telephone call, but a clinic visit may be performed at the discretion of the investigator. 
** Patients must be fasting at Visits 2 and 4. See Protocol (1245.148) Section 6 for restrictions on the order of assessments during Visit 2 and Visit 4.
1 If echocardiogram and/or electrocardiogram is/are performed as part of standard care within 3 months prior to informed consent, and written results are available, the 
assessment does not need to be repeated during the screening visit and the existing scan(s) can be used to assess eligibility. 
2 The following assessments do not need to be repeated at visit 2 if performed within the previous 7 days; Safety laboratory tests (urine and blood), Echocardiogram, 
Electrocardiogram, Vital signs, Weight. 
3 At Visit 3 only a urine test for ketone bodies is required. 
4 For women of childbearing potential either a urine or serum pregnancy test is required.  
5 Daily dosing should continue until the last dose is taken on the day of Visit 4. 
 
 
Figure 1-3. Requirements for Adverse Event Collection 


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Screening period 
Following informed consent, the patient will undergo visit 1/screening assessments as indicated 
in the Figure 1-2. Schedule of Assessment. The assessments must all fall within the acceptable 
screening visit window but do not need to be performed on the same day. The patient should be 
registered in IRT as a screened patient. 
There is no mandatory order of assessments but it is recommended that ECHO is performed 
prior to cardiac CT so that patients who are ineligible based on the ECHO are not required to 
undergo further assessment. 
If the patient does not meet the eligibility criteria, the patient should be registered as a screen 
failure in IRT.  
Re-screening is not allowed in this trial. Screening assessments may be repeated as long as they 
fall within the screening visit window. If more than one screening assessment is available, the 
latest assessment prior to randomisation must be used to assess eligibility. 
If the patient meets the eligibility criteria during screening (Visit 1), Visit 2 should be 
scheduled. Any baseline conditions which are present at Visit 1 should be reported in the eCRF. 
 Treatment period 
Visit 2 (Randomisation) 
The investigator must perform a final assessment of eligibility when the results of all screening 
assessments are available. If the patient does not meet the eligibility criteria, the patient should 
be registered as a screen failure in IRT. Re-screening is not allowed in this trial. 
If the patient is eligible for trial participation, the patient is randomised using IRT and 
treatment is allocated. The visit 2 assessments as listed in the Figure 1-2. Schedule of 
Assessment are then performed. Some assessments do not need to be repeated if performed 
during the last 7 days as part of the screening visit; see Figure 1-2. Schedule of Assessment for 
details. 
The patient should be fasting in preparation for the blood sampling at this visit (no food or 
liquid except water for at least 6 hours prior to sampling). The following rules apply for the 
order of assessments at this visit; 
•
Blood tests and iv cannulation must be performed before the CMR scan.
•
Echo must be performed before Dobutamine stress
•
CPET must be performed before Dobutamine stress
•
All Visit 2 assessments must be performed before the first dose is taken
Visit 3 (Day 15) 
The patient will return to the clinic for visit 3 on day 15 ± 1 day of treatment. The purpose of 
this visit is to check patient safety, to check medication compliance and to perform limited 
assessments. Assessments to be performed are indicated in the Figure 1-2. Schedule of 
Assessment.
 
 


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Visit 4 (Day 84) 
Visit 4 will take place on Day 84 of treatment, which is also the last day of treatment. If the visit 
cannot be scheduled for Day 84, it should be scheduled as close as possible, but within 4 days 
and the patient should continue to take the medication daily until the day of the visit. All Visit 4 
assessments must be performed within 48 hours of the last dose, regardless of which day this is. 
The patient should be asked to return all remaining medication during this visit. 
The assessments to be performed at Visit 4 are indicated in the Figure 1-2. Schedule of 
Assessment. The patient should be fasting in preparation for the blood sampling at this visit (no 
food or liquid except water for at least 6 hours prior to sampling). The following rules apply for 
the order of assessments at this visit; 
•
•
Blood tests and iv cannulation must be performed before the CMR scan.
•
Echo must be performed before Dobutamine stress
•
CPET must be performed before Dobutamine stress
Follow up period and trial completion 
A follow up visit (Visit 5) will be performed 7-14 days after the last dose of trial medication.  
The expectation is that this visit will be performed via a telephone call, but where appropriate, 
a clinic visit may be scheduled. The assessments to be performed at Visit 5 are indicated in the 
Figure 1-2. Schedule of Assessment. 
Visit 5 marks the completion of the study for the individual patient. After the completion of the 
study the patient will receive standard medical care. 
Early discontinuation of trial medication 
See Protocol (1245.148) Section 3.3.4.1 for procedures to be followed in case a randomised 
patient does not reach Visit 4 for any reason. 
1.4 Changes to the Planned Analysis 
The main statistical model defined in the protocol does not include baseline response as a 
covariate, as baseline response is usually predictive of response the following changes to the 
protocol have been introduced: 

A sensitivity analysis of the primary efficacy endpoint has been included that includes
baseline in an analysis of covariance (ANCOVA) model. Note the main analysis of the
primary efficacy endpoint remains as defined in the protocol (i.e. without the addition of
baseline as a covariate).

The analysis of variance (ANOVA) model will be replaced by an ANCOVA model for
all applicable exploratory endpoints in order to fit baseline response as a covariate.


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2 Endpoints 
Absolute change (Δ): will be defined as the value obtained at Week 12 minus value obtained at 
Baseline [Δ = Week 12 (Value) -Baseline (Value)]. Positive value represents an increase from 
baseline. Negative value represents a decrease from Baseline. 
2.1 Primary Endpoints 
2.1.1 Definition and Derivation of Primary Endpoint 
The primary endpoint is the change from the baseline to week 12 in PCr/ATP ratio in resting state 
measured by 31PMRS after treatment with Empagliflozin or matching placebo. 
2.1.2 Primary Hypothesis under Investigation 
The null hypothesis is that for patients in each of the HFrEF and HFpEF cohorts, the change 
from the baseline to week 12 in PCr/ATP ratio in resting state measured by 31P Magnetic 
Resonance Spectroscopy (MRS) after treatment with Empagliflozin is not different from 
matching placebo.  The alternative hypothesis is that the change is different. 
2.1.3 Handling of Outliers and Missing Data 
For the primary outcome, patients who do not have a measurement taken at baseline and week 
12 will be excluded from the primary analysis. For primary analyses, missing efficacy data will 
not be imputed. 
Any outliers will be identified and documented prior to the database lock and unblinding. Cases 
that are visually “extreme” will be assessed for possible influence on the results and conclusions 
by comparing results from analyses with or without outliers.  Any discrepant results from the 
two analyses will be reported and discussed in the CTR and publication manuscripts. 
2.2 Secondary Endpoints 
2.2.1 Definitions and Derivations of Secondary Endpoints 
No secondary endpoints are defined for this trial. 
2.2.2 Secondary Hypotheses under Investigation 
No secondary hypotheses are defined for this trial. 


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3 Analysis Sets/Populations 
The following analysis sets are defined in this trial. 
3.1 Per-protocol Set (PPS) 
The primary endpoint analysis will be performed using the per protocol (PP) set of patients 
having a valid PCr/ATP ratio measurements available at baseline and week 12, and not having 
an important protocol violation relevant to the primary endpoint. Protocol violations will be 
reviewed by the study team before the database lock to determine which violations disqualify a 
patient from the Per-Protocol analysis. A preliminary list of criteria that may disqualify a patient 
from the Per-Protocol analysis are presented in Section 9.2 in the SAP. The list is suggestive 
and subject to change at the final Blinded Report Planning Meeting (BRPM) pre-lock review. 
3.2 Randomised Set (RS) 
This set will include all subjects who are randomised to study treatment. The RS set will be 
employed for a sensitivity analysis to check for an unbiased estimation of the primary endpoint 
result if a substantial number of protocol violations resulted in a reduced sample size used for 
the primary endpoint estimates. The analysis of exploratory endpoints will be performed on the 
RS of patients with available data. 
3.3 Treated set (TS) 
All randomised and treated patients will be included in the safety analysis and safety summaries 
will be presented by actual treatment received. 


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4 General Issues for Statistical Analysis 
Patients randomised into the incorrect stratum, cohort (HFrEF or HFpEF) and/or history of 
diabetes (Yes or No) will be analysed according to the stratum that they should have been 
randomised into. 
The summary statistics and statistical estimates (effect sizes) will be presented to one decimal 
place greater than the raw data collected.  All p-values will be rounded to 4 decimal places. All 
estimates of treatment effects will be presented with corresponding 95% confidence intervals. 
For parameters which are known to follow a log-normal distribution (e.g. NT-proBNP and 
BNP), the geometric mean and geometric coefficient of variation will be used instead of the 
mean and standard deviation for any by visit descriptive summaries. Changes from baseline will 
be presented as geometric mean ratios. 
4.1 Analysis Software 
All statistical analyses will be conducted using SAS 9.4, software. All the statistical analyses 
outputs/results will be reviewed and validated by an independent DTU statistician. 
4.2 Multiplicity, Multiple Comparisons and Interim Analyses 
If recruitment is different between the cohorts such that one cohort’s last patient out visit is 
considerably earlier than the last patient out of the other cohort, an interim analysis may be 
planned in order to report the data the completed cohort. For this interim analysis only the 
completed cohort will be unblinded. 
A single hypothesis is being tested for each cohort for a single primary efficacy endpoint.  The 
analysis of all other endpoints will be considered exploratory in nature with nominal p-values.  
All p-values will be two-sided at an alpha-level of 0.05. 


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5 Statistical Methodology 
A table of contents for all outputs that will be produced along with supporting templates will be 
provided in separate documentation. 
5.1 Disposition of Patients 
All patients in the screened set (signed informed consent) will be included in the summary of 
patient disposition. Frequencies and percentages of the total number of patients screened, 
randomised, treated, prematurely discontinued treatment (along with reason for discontinuation) 
and status at trial completion will be summarised in tabular forms for each cohort and for both 
cohorts overall. 
A summary of the frequency and percentage of patients by treatment group will be produced for 
the randomised, treated and per-protocol analysis sets. Summaries by cohort and overall will be 
produced. 
5.2 Demographic and Baseline Characteristics 
The screening demographic and the clinical characteristics will be tabulated and summarised by 
the treatment group. The demographic and baseline data will include gender, age, race, weight, 
height, SBP, DBP, T2DM, history of atrial fibrillation, alcohol use, smoking, heart rate, vital 
signs medical history, and other cardiac parameters (EF, BNP) measured at screening. 
5.3 Primary Endpoint Analysis 
5.3.1 Primary Efficacy Analysis 
The primary efficacy endpoint of change from baseline to week 12 in PCr/ATP will be analysed 
for each cohort (HFrEF and HFpEF) separately, to test the hypothesis detailed in Section 2.1.2.  
The analytical procedure will include a descriptive summary and a formal (inferential) statistical 
summary, ANOVA, for the primary endpoint hypothesis testing. Plots of individual patient 
changes from baseline to week 12 will be produced by treatment group and cohort, including 
the mean change also. 
Formal analysis 
The formal statistical analysis will employ an Analysis of Variance (ANOVA) model to test the 
primary hypothesis for each individual cohort using the following for the model inputs: 

Response (outcome) variable is defined as:
The change (PCr/ATP absolute change) from baseline to week 12 is calculated for each
patient by subtracting each patient's baseline PCr/ATP measurement from the 12 weeks
measurement.

Factors:
Treatment (Empagliflozin vs. Placebo), History of diabetes (Yes/No) and History of
atrial fibrillation (Yes/No)
The null hypothesis of no difference in change between the treatment and placebo groups will 
be tested by an ANOVA on the PCr/ATP ratio absolute change using treatment (empagliflozin 
vs. placebo), history of diabetes (yes vs, no) and history of atrial fibrillation (yes vs no) as fixed 
effects.  If the treatment main effect is significant then we reject the null hypothesis. 


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The formal model will be specified in SAS as follows (equivalent to ANOVA): 
PROC MIXED data=values cl method=reml covtest; 
CLASS af diab trt; 
MODEL endpt = af diab trt / ddfm=kr solution; 
LSMEANS trt / cl diff om alpha=0.05; 
RUN; 
Though the primary endpoint is regarded to generally be normally distributed some model 
checking will be performed. The model adequacy assessment will be based on the normality of 
residuals, homogeneity of variance between groups and homoscedasticity. Any violation of the 
model assumptions will be investigated and ratified accordingly and will be reported in the 
clinical trial report. 
5.4 Secondary Endpoint Analyses 
Not applicable as no secondary endpoints defined for the study. 


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6 Safety and Tolerability Analysis 
All safety and tolerability summaries will be produced on the treated set of patients. 
6.1 Drug Exposure 
Empagliflozin 10 mg for 12 weeks, see for the drug exposure and accountability plans 
throughout the trial (see also Protocol (1245.148) Section 4.0). Both empagliflozin and placebo 
exposure will be tabulated, duration of exposure will be calculated from the day of first 
exposure to the day of last exposure, ignoring any missed doses between. . Summaries of 
exposure by days and weeks will be produced. Cumulative dose (mg) will be summarized using 
descriptive statistics, where cumulative dose is the actual dose taken summed across all visits, 
missed days will be counted as 0 mg. The number of missed doses will also be tabulated.  
6.2 Adverse Events and Tolerability 
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events, i.e., all adverse events occurring between the start of treatment and end of the 
residual effect period, 7 days after the last dose of medication. Adverse events that start before 
first drug intake and deteriorate during the treatment period will also be considered as 
‘treatment-emergent’. All AEs will be listed, according to whether the AE start date occurred 
during the screening period, treatment period, or during the follow-up period. 
The safety analyses will be purely descriptive statistics (number and percentage, n (%)) and 
will be based on the current version of Dictionary of Drug Regulation (MedDRA) coding 
system and display in tables and data listings using SOC and preferred term. The analyses will 
be provided for each cohort and also pooled across all cohorts. No hypothesis testing is planned. 
An overall summary of AEs will be presented, in addition the following tables will be produced 
by MedDRA SOC and preferred term: 

All AEs

AEs by severity

Serious AEs

Drug-related AEs

AEs leading to treatment discontinuation
In addition a summary of all AEs by investigator-defined category and MedDRA preferred term 
will be produced, the following categories will be included: 

Hypoglycaemic event

Genital infection

Acute pyelonephritis

Sepsis

Urinary tract infection

Bone fracture

Hepatic injury

Ketoacidosis (metabolic acidosis, ketoacidosis, diabetic ketoacidosis)

Decreased renal function

Other


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Further details on the specific AEs of hypoglycaemia, genital infections, acute pyelonephritis, 
sepsis, bone fractures and ketoacidosis will be listed.  Additional summaries of these specific 
AEs and other specific AEs (e.g. volume depletion) may be produced dependent upon the 
frequency of occurrence. 
6.3 Laboratory Data 
Descriptive statistics (Mean (SD) and Median (IQR)) of the laboratory data will be presented. 
The presentation will cover data collected at screening or baseline to week 12 (screening to 
treatment period). Summaries of actual values at baseline and last value on-treatment along with 
the change from baseline will be tabulated for the individual parameter. Baseline data will be 
taken as the last available laboratory measurement on or prior to the day of starting study 
treatment. The individual patient values profile over time will plotted. The marginal means of 
individual parameter will also be included in these plots.  Laboratory values will be compared 
to their reference ranges at baseline and the last measurement on-treatment.  Frequency tables 
will summarise the number of patients with potentially clinically significant abnormalities (as 
defined by BI project standards).  Laboratory measurements taken up to 3 days after the last 
administration of randomised study treatment will be considered as on-treatment. 
6.4 Vital Signs, Electrocardiogram, and Other Safety Assessments 
Vital signs, ECG and other safety assessments will be summarised descriptively. 


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7 Data Handling Conventions 
7.1 Data Quality Assurance and Monitoring 
For the data monitoring and quality assurance procedures for the study, see the study in 
Protocol (1245.148) Section 8.2 – Section 8.7 
7.2 Data Transformations 


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8 References 
1.
Fragasso G, Perseghin G, De Cobelli F, Esposito A, Palloshi A, Lattuada G, et al. Effects
of 
metabolic 
modulation 
by 
trimetazidine 
on 
left 
ventricular 
function 
and
phosphocreatine/adenosine triphosphate ratio in patients with heart failure. Eur Heart J.
2006;27(8):942-8.
2.
Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin,
Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;373(22):2117-
28.
3.
Bonate PL. Analysis of pretest-posttest designs. Boca Raton: Chapman & Hall/CRC;
2000. 205 p. p.
4.
Dimitrov DM, Rumrill PD, Jr. Pretest-posttest designs and measurement of change. Work.
2003;20(2):159-65.
5.
Altman DG, Bland JM. Statistics Notes - Regression Towards the Mean - Reply. Brit Med
J. 1994;309(6953):539-.


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9 Appendices 
9.1 Appendix 1: Reporting Conventions 

This section clarifies the reporting conventions adopted or utilized in the SAP related
statistical operations that could be utilized in the reporting of the study.

All tables, listings and figures will be presented in landscape orientation unless there is
a specific reason to use portrait orientation.
9.2 Appendix 2: Important Protocol Deviations (iPDs) 
The IPDs listing below is taken from the Medical and Quality Review Plan document, Version 
2.0, dated 27th February 2018, for Study 1245-0148. The listing is tentative and subject to a 
review before the data lock. The updated version of the IPDs listing in the Medical and Quality 
Review Plan document will be used for the statistical analyses and the CTR.  
Category / 
Code 
Description 
Requirements 
Excluded 
from 
A 
Entrance criteria not met 
A1 
Target indication not met 
A1.06 
No chronic HF NYHA class 
II-IV
Inclusion criterion #2 violated 
<None or 
PPS> 
A1.07 
Conditions on ejection 
fraction (EF) violated 
Inclusion criterion #7 for Cohort 
A, #10 for Cohort B violated 
PPS 
A1.08 
Conditions on NT-proBNP 
violated 
Inclusion criterion #8 for Cohort 
A, #11 for Cohort B violated 
PPS 
A1.09 
Conditions on HF violated 
Inclusion criterion #1 and #9 for 
Cohort A, or #1 and #12 for 
Cohort B violated 
PPS 
A2 
Inclusion criteria not met 
A2.02 
Age out of range 
Inclusion criterion #4 violated 
None 
A2.08 
Specific inclusion criterion 
for women of child-bearing 
potential violated 
Inclusion criterion #5 violated 
None 
A3 
Exclusion criteria not met 
A3.44 
Patient with unstable 
conditions 
Exclusion criteria #1, #2, #4, #7, 
#11, #14, #15, #16 or #20 violated 
None 
tba 
All other in/exclusion 
criteria  
Individual 
discussion 
B 
Informed consent 
B1 
Informed consent not 
available/not done 
Informed consent date missing or 
inclusion criterion #6 violated 
PPS 
B2 
Informed consent too late 
Informed consent date was after 
Visit 1  
None 
C 
Trial medication and 
randomisation 
C1 
Încorrect trial medication 


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C1.02 
Incorrect trial medication 
taken
Medication from wrong treatment 
arm taken for more than 20% of 
the overall treatment duration  
Can only be finally judged after 
data base lock (DBL) since 
unblinding information is required. 
 None 
C2 
Randomisation not followed 
C2.01 
Treated without 
randomisation 
Patient treated according to eCRF, 
but not randomised according to 
IVRS.  
None 
C3 
Non-compliance 
C3.01 
Non-compliance with study 
drug intake 
Overall study treatment 
compliance outside 80% and 
120% (exclusive) or study 
treatment compliance below 80% 
Missing compliance will be 
considered iPD.         
None 
C4 
Medication code broken 
C4.01 
Medication code broken at 
site without just cause 
Medication code was broken for 
no valid reason. 
Final decision at the DBL meeting 
based on medical judgement.  
None 
D 
Concomitant medication 
D1.02 
Use of other investigational 
drug  
Review of eCRF for prohibited 
medication. 
Final decision at the DBL meeting 
based on medical judgement.  
None 
D2.01 
Use of protocol defined 
prohibited medication during 
treatment period 
Use of SGLT-2 or combined 
SGLT-1 and 2 – inhibitors after 
randomization until the follow-up 
visit.  
None 
E 
Missing data 
E1.05 
No baseline resting 31P MRS 
result 
No valid baseline PCr/ATP ratio at 
resting and dobutamine stress. 
PPS 
E1.06 
No baseline stress 31P MRS 
result 
No valid baseline PCr/ATP ratio at 
dobutamine stress. 
PPS 
F 
Other 
F1.02 
Other PD related to safety 
only 
Manually detected, safety related 
protocol deviations  
Final decision at the DBL meeting 
based on medical judgement. 
None 
F1.03 
Other PD related to primary 
endpoint 
Final decision at the DBL meeting 
based on medical judgement. 
PPS 


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F1.04 
Other PD related to patient 
rights 
Manually detected protocol 
deviations related to patient rights 
Final decision at the DBL meeting. 
None 


APPROVAL / SIGNATURE PAGE 
Document Number: 
 
Technical Version Number:
Document Name: 
Title: 
Signatures (obtained electronically) 
Meaning of Signature  
Signed by 
Date Signed 
 
c32019191
1.0
8-01-tsap-core-v2-2020-03-12
8-01-tsap-core-v2-2020-03-12
Approval-Biostatistics
21 Apr 2020 14:15 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
Technical Version Number:
 
(Continued) Signatures (obtained electronically) 
Meaning of Signature  
Signed by 
Date Signed 
c32019191
1.0