Clinical trial NCT02992288
Conditions: Heart Failure
Keywords: Chronic Heart Failure Heart Failure with Reduced Ejection Fraction
Sponsor: Bayer
Start date: 2017-02-22; Completion date: 2018-05-16
Enrollment: 427 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of the study is to find the optimal dose of once daily oral neladenoson bialanate (BAY 1067197) when given in addition to standard therapy for heart failure with reduced ejection fraction (HFrEF).

Detailed description:

Arms: arm 1: Chronic heart failure with reduced ejection fraction arm 2: Chronic heart failure with reduced ejection fraction arm 3: Chronic heart failure with reduced ejection fraction arm 4: Chronic heart failure with reduced ejection fraction arm 5: Chronic heart failure with reduced ejection fraction arm 6: Chronic heart failure with reduced ejection fraction
Interventions: intervention 1: Neladenoson bialanate (BAY1067197) intervention 2: Neladenoson bialanate (BAY1067197) intervention 3: Neladenoson bialanate (BAY1067197) intervention 4: Neladenoson bialanate (BAY1067197) intervention 5: Neladenoson bialanate (BAY1067197) intervention 6: Placebo
Intervention descriptions: intervention 1: 5 mg orally once daily for 20 weeks intervention 2: 10 mg orally once daily for 20 weeks intervention 3: 20 mg orally once daily for 20 weeks intervention 4: 30 mg orally once daily for 20 weeks intervention 5: 40 mg orally once daily for 20 weeks intervention 6: Orally once daily for 20 weeks

Protocol documents:
Prot_001.pdf: 
 
Document Type: Study Protocol 
Official Title: 
A multicenter, randomized, placebo-controlled, parallel group, 
double blind, dose-finding Phase II trial to study the efficacy, 
safety, pharmacokinetic and pharmacodynamic effects of the oral 
partial adenosine A1 receptor agonist neladenoson bialanate over 
20 weeks in patients with chronic heart failure with reduced 
ejection fraction 
NCT Number: 
NCT02992288 
Document Date: 
17 FEB 2017 
 


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Cover page of the integrated protocol
A multicenter, randomized, placebo-controlled, parallel group, double blind, dose-
finding Phase II trial to study the efficacy, safety, pharmacokinetic and 
pharmacodynamic effects of the oral partial adenosine A1 receptor agonist 
neladenoson bialanate over 20 weeks in patients with chronic heart failure with 
reduced ejection fraction
This protocol version is an integration of the following documents / sections:
Original protocol, Version 1.0, dated 31 OCT 2016
Amendment no. 2 (described in Section 15.1)
forming integrated protocol Version 2.0, dated 17 FEB 2017
Amendments not included in the consecutive numbering of amendments are 
local amendments not forming part of this integrated global protocol.


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1.
Title page
A multicenter, randomized, placebo-controlled, parallel group, double blind, dose-finding 
Phase II trial to study the efficacy, safety, pharmacokinetic and pharmacodynamic effects of 
the oral partial adenosine A1 receptor agonist neladenoson bialanate over 20 weeks in 
patients with chronic heart failure with reduced ejection fraction
Short title:
PANTHEON
Test drug:
neladenoson bialanate / BAY 1067197
Study purpose:
dose finding
Clinical study phase:
IIb
Date:
17 FEB 2016
Registration:
EudraCT no.: 2016-003839-38
Version no.:
2.0
Sponsor’s study no.:
BAY 1067197 / 15128
Sponsor:
Non-US: Bayer AG, D-51368 Leverkusen, Germany
US territory: Bayer HealthCare Pharmaceuticals Inc., 100 Bayer 
Boulevard, P.O. Box 915, Whippany NJ 07981-0915, USA
Sponsor’s medical 
expert:
Bayer Vital GmbH
Kaiser-Wilhelm-Allee 70 / K56
51368, Leverkusen, Germany
Phone: 
Email: 
The study will be conducted in compliance with the protocol, ICH-GCP and any applicable 
regulatory requirements.
Confidential
The information provided in this document is strictly confidential and is intended solely for 
the guidance of the clinical investigation. Reproduction or disclosure of this 
document - whether in part or in full - to parties not associated with the clinical
investigation, or its use for any other purpose, without the prior written consent of the 
sponsor is not permitted.
Throughout this document, symbols indicating proprietary names (, TM) may not be displayed. Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.
PPD
PPD
PPD
PPD


17 FEB 2017 
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No. BAY 1067197 I 15128 
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Signature of the sponsor's medically responsible person 
Page: 3 of87 
The signatory agrees to the content of the final integrated clinical study protocol as presented. 
Name: 
 
Role: 
Global Clinical Leader 
Signature: 
PPD
PPD


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Signature of principal investigator
The signatory agrees to the content of the final clinical study protocol as presented.
Name:
Affiliation:
Date:
Signature:
Signed copies of this signature page are stored in the sponsor’s study file and in the respective 
center’s investigator site file.


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2.
Synopsis
Title
A multicenter, randomized, placebo-controlled, parallel group, double blind, 
dose-finding Phase II trial to study the efficacy, safety, pharmacokinetic and 
pharmacodynamic effects of the oral partial adenosine A1 receptor agonist 
neladenoson bialanate over 20 weeks in patients with chronic heart failure with 
reduced ejection fraction
Short title
PANTHEON
Clinical study phase
IIb
Study objective(s)
The objective of the study is to find the optimal dose of neladenoson bialanate 
for the Phase III trial by detecting and characterizing a significant dose-
response relationship in the two primary efficacy endpoints, absolute change 
from baseline in left ventricular ejection fraction (LVEF) and log-transformed 
NT-proBNP at 20 weeks, in patients with chronic heart failure with reduced 
ejection fraction (HFrEF), and by characterizing the safety, tolerability and 
pharmacodynamic effects of the compound when given in addition to standard 
therapy for HFrEF.
An exploratory objective is to further assess pharmacokinetic parameters and 
blood and urine biomarkers.
Test drug(s)
Name of active ingredient neladenoson bialanate
Dose(s)
5 mg, 10 mg, 20 mg, 30 mg, and 40 mg once daily
Route of administration
Oral
Duration of treatment
20 weeks
Reference drug(s)
Name of active ingredient Placebo
Dose(s)
Not applicable
Route of administration
Oral
Duration of treatment
20 weeks
Background treatment
Standard therapy for heart failure given concomitantly with the test 
drug / placebo
Indication
Chronic heart failure (NYHA class II-IV) with reduced ejection fraction
Diagnosis and main criteria 
for inclusion 
1.
Men or women aged 18 years and older
2.
Diagnosis of chronic heart failure, NYHA class II-IV, LVEF ≤ 35% 
assessed by any imaging modality (e.g. echocardiography, cardiac 
magnetic resonance, cine levocardiography) within 6 months prior to run-
in: if several values are available the last assessment of LVEF should be ≤ 
35%.
3.
One of the following (or both), 
a) Worsening chronic heart failure requiring hospitalization or an 
unscheduled outpatient visit in the last 3 months, both requiring 
initiation or intensification of heart failure therapy and with either:
o
BNP ≥ 100 pg/mL or NT-proBNP ≥400 pg/mL (sinus rhythm) or
o
BNP ≥ 300 pg/mL or NT-proBNP ≥1200 pg/mL (atrial fibrillation) 


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AND/OR 
b) at any time in the past 4 weeks one of:
o
BNP ≥ 300 pg/mL or NT-proBNP ≥ 1200 pg/mL (sinus rhythm)
o
BNP ≥ 600 pg/mL or NT-proBNP ≥2400 pg/mL (atrial fibrillation)
For patients on treatment with angiotensin receptor-neprilysin inhibitors 
(ARNIs), e.g. Entresto only NT-proBNP values can be used to assess 
eligibility.
4.
Written informed consent before any study-specific procedure
Diagnosis and main criteria 
for exclusion
1.
Acute de-novo heart failure 
2.
Requirement of any of the following 48 hours prior to randomization:
o
Intravenous (IV) vasodilating drugs (e.g. nitrates, nitroprusside)
o
IV natriuretic peptides (e.g. nesiritide, carperitide)
o
IV positive inotropic agents
o
IV diuretics 
o
IV antibiotics 
o
Mechanical support (e.g. intra-aortic balloon pump, endotracheal 
intubation, mechanical ventilation, or any ventricular assist device)
3.
Any cause of chronic heart failure other than ischemic cardiomyopathy and 
idiopathic dilated cardiomyopathy
4.
Known clinically significant persistent coronary ischemia based on 
medical history, preexisting or current exercise testing
5.
Occurrence of any of the following within 3 months prior to 
randomization:
o
Myocardial infarction
o
Hospitalization for unstable angina
o
Stroke or transient ischemic attack
o
Coronary artery bypass graft (CABG) 
o
Percutaneous coronary intervention (PCI)
o
Implantation of a cardiac resynchronization therapy device (CRTD)
o
Carotid angioplasty 
6.
PCI, CABG or implantation of a CRTD planned between randomization 
and end of study
7.
Sustained * systolic blood pressure ≤ 90 mmHg and / or signs and 
symptoms of hypotension prior to randomization
8.
Sustained * systolic blood pressure ≥ 160 mmHg
9.
Sustained * bradycardia with heart rate < 50 beats/minute or tachycardia 
with heart rate > 100 beats/minute prior to randomization 
10. Known clinically relevant ventricular arrhythmias (sustained ventricular 
tachycardia, ventricular flutter or fibrillation) within 3 months prior to 
consent based on either medical history or implantable cardioverter 
defibrillator (ICD)-testing results (if applicable)
11. Clinically relevant permanent or intermittent atrioventricular (AV)-block >
grade II in patients without a permanent pacemaker or ICD / CRTD
12. Severe valvular disease with indicated or planned valve 
repair / replacement 
13. Listing for heart transplantation and / or anticipated implantation of a 
ventricular assist device


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14. Severe pulmonary disease with any of the following:
o
Requirement of continuous (home) oxygen or 
o
History of chronic obstructive pulmonary disease ≥ GOLD III or 
o
Use of systemic corticosteroids
15. Asthma bronchiale with any of the following:
o
Symptoms not well-controlled within the past 6 months or
o
Ever intubated or in an intensive care unit for asthma
16. Anemia with hemoglobin < 10 g/dL within 3 months prior to 
randomization. If several values are available the latest result should be 
used. 
17. Body mass index (BMI) > 40 kg/m2 at randomization or a history of poor 
quality LVEF measurement by echocardiography 
18. Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2
calculated by Modification of Diet in Renal Disease (MDRD) formula 
within 3 months prior to randomization. If several values are available the 
latest result should be used.
19. Hepatic insufficiency classified as Child-Pugh B or C, or any of the 
following: 
o
Primary biliary cirrhosis (PBC)
o
Primary sclerosing cholangitis
o
PBC-autoimmune hepatitis overlap syndrome
20. Concomitant use of any of the following therapy that cannot be 
discontinued:
o
Moderate or strong CYP3A4 inhibitors (Of note: grapefruit is a 
strong CYP3A4 inhibitor.)
o
CYP3A4 inducers
o
Strong CYP2C8 inhibitors (Of note: clopidogrel is a strong CYP2C8 
inhibitor)
o
Theophylline
o
Drugs having significant pre-systemic clearance via UGT1A1 in the 
intestine
Respective substances must be stopped at least 7 days before 
randomization.
21. Women of childbearing potential (women are considered of childbearing 
potential if they are not surgically sterile or postmenopausal, defined as 
amenorrhea for > 12 months) 
22. Any condition or therapy, which would make the patient unsuitable for the 
study, or life expectancy less than 12 months (e.g. active malignancy)
23. Known current heavy alcohol consumption or the use of illicit drugs that, 
in the opinion of the investigator, may interfere with the patient’s safety 
and / or compliance
24. Previous (within 30 days or 5 half-lives of the investigational drug, 
whichever is longer) or concomitant participation in another clinical study 
with investigational medicinal product(s) or device(s)
25. Previous assignment to treatment during this study
26. Close affiliation with the investigational site; e.g. a close relative of the 
investigator, dependent person (e.g. employee or student of the 
investigational site)


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27. Known allergies, intolerance or hypersensitivities to the study treatment 
(active substance or excipients), adhesives or hydrogel 
* At two consecutive visits
Study design
Randomized, double-blind, placebo-controlled, parallel-group, multicenter
Methodology
The study will comprise a 1-week run-in period, 20-week treatment period, and 
a 6-week follow-up period (27 weeks total).
Patients will have site visits at weeks -1, 0 (baseline), 4, 8, 12, 20 (end-of-
treatment visit) and 24 (safety follow-up visit). In addition, 2 phone calls at 
weeks 2 and 26 will be made to assess patients’ safety, and one additional 
phone call - to remind the patients of AVIVO self-application at Week 19. 
LVEF will be measured by echocardiography at baseline and end of treatment, 
NT-proBNP will be measured at baseline, Week 4 and end of treatment. Safety 
will be monitored throughout the study. PK samples will be taken from all 
patients at dedicated time points. Additional biomarkers reflecting the 
pharmacodynamic activity of the drug will be examined, as well as candidate 
biomarkers that may predict drug response. 
Type of control
Placebo control
Data Monitoring Committee
Yes
Number of patients
Approximately 384 patients are planned to be randomized. 
Primary variables
Absolute change from baseline in left ventricular ejection fraction (LVEF; 
%) after 20 weeks of treatment measured by echocardiography
Absolute change from baseline in log-transformed NT-proBNP (pg/mL) 
after 20 weeks, i.e., log-transformed NT-proBNP at Week 20 minus log-
transformed NT-proBNP at baseline.
Time point / frame of 
measurement for 
primary variables
After 20 weeks of treatment
Plan for statistical analysis
The primary efficacy analysis will be performed on the primary efficacy 
variables in patients belonging to the per-protocol set using a type I error of 
5%. 
For the assessment of a dose-response relationship in the change in LVEF and 
NT-proBNP, the MCP-Mod method, combining multiple comparison 
procedures (MCP) principles with modeling techniques under model 
uncertainty, will be used. 
The overall outcome of the primary efficacy analysis will be considered 
positive if at least one of the two null hypotheses related to the primary efficacy 
variables can be rejected. The Hochberg (step-up) procedure will be applied to 
control the family-wise error rate. 
A set with 5 candidate dose-response models has been specified. For the 
detection of a dose-response signal, each of the dose-response models in the 
candidate set will be tested at the corresponding type I error level, using a one-
sided multiple contrast test based on pre-specified contrast coefficients. If a 
dose-response signal is established, a dose-response model will be fitted to the 
data and target dose(s) of interest will be estimated based on the estimated 
dose-response model. 
Other efficacy variables will be analyzed analogously to the primary variables
or descriptively.


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Table of contents
Cover page of the integrated protocol.................................................................................... 1
1.
Title page............................................................................................................................ 2
2.
Synopsis.............................................................................................................................. 5
Table of contents....................................................................................................................... 9
Table of tables......................................................................................................................... 11
Table of figures....................................................................................................................... 11
List of abbreviations............................................................................................................... 12
3.
Introduction..................................................................................................................... 16
3.1
Background.................................................................................................................... 16
3.2
Partial adenosine A1 receptor agonism in heart failure................................................. 17
3.3
Neladenoson bialanate ................................................................................................... 18
3.4
Rationale of the study .................................................................................................... 19
4.
Study objectives............................................................................................................... 19
5.
Study design..................................................................................................................... 20
5.1
Design overview ............................................................................................................ 20
5.2
Primary variables ........................................................................................................... 21
5.3
Justification of the design .............................................................................................. 21
5.4
End of study................................................................................................................... 21
6.
Study population ............................................................................................................. 21
6.1
Inclusion criteria ............................................................................................................ 21
6.2
Exclusion criteria ........................................................................................................... 22
6.3
Justification of selection criteria.................................................................................... 24
6.4
Withdrawal of patients from study ................................................................................ 24
Withdrawal ................................................................................................................. 24
6.4.1
Replacement ............................................................................................................... 26
6.4.2
6.5
Patient identification...................................................................................................... 26
7.
Treatments....................................................................................................................... 26
7.1
Treatments to be administered....................................................................................... 26
7.2
Identity of study treatment............................................................................................. 26
7.3
Treatment assignment.................................................................................................... 28
7.4
Dosage and administration............................................................................................. 28
7.5
Blinding ......................................................................................................................... 28
7.6
Drug logistics and accountability................................................................................... 29
7.7
Treatment compliance.................................................................................................... 29
8.
Non-study therapy........................................................................................................... 30
8.1
Prior and concomitant therapy....................................................................................... 30
Prohibited concomitant medication............................................................................ 30
8.1.1
Permitted therapy........................................................................................................ 30
8.1.2
8.2
Post-study therapy.......................................................................................................... 31


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9.
Procedures and variables ............................................................................................... 31
9.1
Tabular schedule of evaluations .................................................................................... 31
9.2
Visit description............................................................................................................. 34
Visit 1 (Week -1, run-in) ............................................................................................ 34
9.2.1
Visit 2 (Week 0, baseline) .......................................................................................... 34
9.2.2
Visit 3 (Week 2, phone call)....................................................................................... 35
9.2.3
Visit 4 (Week 4) ......................................................................................................... 35
9.2.4
Visit 5 (Week 8) ......................................................................................................... 36
9.2.5
Visit 6 (Week 12) ....................................................................................................... 36
9.2.6
Reminder phone call at Week 19................................................................................ 37
9.2.7
Visit 7 (Week 20, EOT or premature discontinuation) .............................................. 37
9.2.8
Visit 8 (Week 24, safety follow-up)........................................................................... 38
9.2.9
Visit 9 (Week 26, phone call)..................................................................................... 38
9.2.10
Unscheduled Visit ...................................................................................................... 38
9.2.11
9.3
Population characteristics .............................................................................................. 39
Demographic and vital signs ...................................................................................... 39
9.3.1
Medical history........................................................................................................... 39
9.3.2
Other baseline characteristics..................................................................................... 39
9.3.3
9.4
Efficacy.......................................................................................................................... 40
Echocardiography....................................................................................................... 40
9.4.1
Biomarker investigations............................................................................................ 41
9.4.2
Clinical efficacy variables .......................................................................................... 42
9.4.3
Patient-reported outcomes.......................................................................................... 43
9.4.4
9.5
Pharmacokinetics / pharmacodynamics ......................................................................... 44
9.6
Safety ............................................................................................................................. 45
Adverse events............................................................................................................ 45
9.6.1
Pregnancies................................................................................................................. 50
9.6.2
Further safety.............................................................................................................. 50
9.6.3
9.7
Other procedures and variables...................................................................................... 52
9.8
Appropriateness of procedures / measurements............................................................. 53
10. Statistical methods and determination of sample size ................................................. 53
10.1
General considerations................................................................................................... 53
10.2
Analysis sets .................................................................................................................. 53
10.3
Variables and planned statistical analyses..................................................................... 54
Variables..................................................................................................................... 54
10.3.1
Statistical and analytical plans.................................................................................... 55
10.3.2
Missing data, censoring due to death, and drop outs.................................................. 62
10.3.3
10.4
Determination of sample size......................................................................................... 64
10.5
Planned interim analyses ............................................................................................... 65
11. Data handling and quality assurance............................................................................ 65
11.1
Data recording................................................................................................................ 65
11.2
Monitoring ..................................................................................................................... 67
11.3
Data processing.............................................................................................................. 67
11.4
Missing data................................................................................................................... 67
11.5
Audit and inspection ...................................................................................................... 68


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11.6
Archiving ....................................................................................................................... 68
12. Premature termination of the study .............................................................................. 69
13. Ethical and legal aspects................................................................................................. 69
13.1
Investigator(s) and other study personnel...................................................................... 69
13.2
Funding and financial disclosure ................................................................................... 71
13.3
Ethical and legal conduct of the study........................................................................... 71
13.4
Patient information and consent .................................................................................... 72
13.5
Publication policy and use of data ................................................................................. 73
13.6
Compensation for health damage of patients / insurance............................................... 73
13.7
Confidentiality ............................................................................................................... 73
14. Reference list.................................................................................................................... 74
15. Protocol amendments...................................................................................................... 78
15.1
Amendment 2................................................................................................................. 78
Overview of changes .................................................................................................. 78
15.1.1
Changes to the protocol text....................................................................................... 80
15.1.2
16. Appendices....................................................................................................................... 87
16.1
Calculating glomerular filtration rate ............................................................................ 87
16.2
Calculating the Child-Pugh score .................................................................................. 87
Table of tables
Table 7–1: Identity of neladenoson bialanate (BAY 1067197) ............................................... 27
Table 7–2: Identity of placebo ................................................................................................. 27
Table 7–3: Assignment of tablets to dose groups .................................................................... 28
Table 9–1: Schedule of evaluations ......................................................................................... 32
Table 9–2: Sample types used for biomarker investigations.................................................... 42
Table 9–3: Liver function monitoring...................................................................................... 52
Table 10–1: Dose-response shapes used in the candidate set .................................................. 58
Table 10–2: Power for multiple contrast test for set of different alternatives.......................... 64
Table 16–1: Grading of severity of liver disease ..................................................................... 87
Table 16–2: Classification using the added score from Table 16–1 ........................................ 87
Table of figures
Figure 5–1: Study design overview.......................................................................................... 20
Figure 9–1: KCCQ Scores........................................................................................................ 44
Figure 10–1: Dose-response shapes used in the candidate set for change in LVEF................ 59


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List of abbreviations
A1R
A1 receptor
ACE
angiotensin-converting enzyme
ACEi
ACE inhibitor
ADHF
acute decompensated heart failure
ADP
adenosine diphosphate
AE(s)
adverse event(s)
AF
atrial fibrillation
ALT
alanine aminotransferase
AP
alkaline phosphatase
ARB(s)
angiotensin receptor blocker(s)
ARNI(s)
angiotensin receptor-neprilysin inhibitor(s)
AST
aspartate aminotransferase
ATP
adenosine triphosphate
AUC
area under the time-concentration curve
AV
atrioventricular
BCRP
breast cancer resistance protein
BMI
body mass index
BNP
b-type natriuretic peptide
BSA
body surface area
CABG
coronary artery bypass graft
CAD
coronary artery disease
CE mark
European Conformity mark (Conformité Européenne)
CEC
Clinical Events Committee
CHF
chronic heart failure
CI
cardiac index
CK
creatine kinase
CKD
chronic kidney disease
Cmax
maximum drug concentration in plasma
CO
cardiac output
CRF
case report form
CRO
contract research organization
CRTD
cardiac resynchronization therapy device
CV 
cardiovascular
CYP
cytochrome P450
DBP
diastolic blood pressure
DMC
Data Monitoring Committee
e.g.
for example (exempli gratia)
EC(s)
Ethics Committee(s)


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ECG
electrocardiogram
eCRF
electronic CRF
EDC
electronic data capture
EF
ejection fraction
eGFR
estimated glomerular filtration rate
EOT
end of treatment
EQ-5D-5L
EuroQol Group 5-dimensional, 5-level questionnaire
ESC
European Society of Cardiology
EU
European Union
EWDT
E-wave deceleration time
FAS
full analysis set
FDA
(US) Food and Drug Administration 
FFA
free fatty acids
FU
follow up
g
gram 
Gal-3
galectin-3
GCP
Good Clinical Practice
GDF-15
growth differentiation factor 15
GFR
glomerular filtration rate
GGT
gamma glutamyl transpeptidase
GMP
Good Manufacturing Practice
GOLD
Global Initiative for Chronic Obstructive Lung Disease
HbA1c
hemoglobin A1c
HCl
hydrochloride
HDL
high-density lipoprotein
HF
heart failure
HFpEF
heart failure with preserved ejection fraction
HFrEF
heart failure with reduced ejection fraction
HR
heart rate
hs-TNT
high sensitivity troponin T
i.e.
that is (id est)
IB
investigator's brochure
ICD
implantable cardioverter defibrillator
ICF
informed consent form
ICH
International Conference on Harmonization
IDMS
Isotope dilution mass spectroscopy
IEC
Independent Ethics Committee
INR
international normalized ratio
IRB
Institutional Review Board
ITT
intent-to-treat


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IV
intravenous(ly) 
IVSD
interventricular septum diameter
IxRS
interactive web / voice response system
KCCQ
Kansas City cardiomyopathy questionnaire
LA
left atrial
LAV
LA volume
LAVI
LA volume index
LDH
lactate dehydrogenase 
LDL
low-density lipoprotein
LV
left ventricular
LVEDV
LV end-diastolic volume
LVEDVI
LVEDV index 
LVEF
left ventricular ejection fraction
LVESV
left ventricular end-systolic volume
LVESVI
LVESV index
MAP
mean arterial pressure
MCH
mean corpuscular hemoglobin
MCHC
MCH concentration
MCP
multiple comparison procedures
MCV
mean corpuscular volume
MDRD
modification of diet in renal disease
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram 
min
minute 
mL
milliliter
mmHg
millimeter of mercury 
MR-proANP
mid-regional pro-atrial natriuretic peptide
MRA
mineralocorticoid receptor antagonist
NGAL
neutrophil gelatinase-associated lipocalin
NONMEM
non-linear mixed effect modeling
NT-proBNP
N-terminal pro-hormone b-type natriuretic peptide
NYHA
New York Heart Association
OPN
osteopontin 
PASP
pulmonary artery systolic pressure
PBC
primary biliary cirrhosis
PCI
percutaneous coronary intervention
PD
pharmacodynamic
PDV
premature discontinuation visit
Pes
end-systolic pressure
pg
picogram


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PK
pharmacokinetic
PKS
PK analysis set
PP
pulse pressure
PPS
per-protocol set
PTT
partial thromboplastin time
PWT
posterior wall thickness
QC
quality control
QTcB
QT interval frequency-corrected according to Bazett’s formula
RV
right ventricular
SAC
systemic arterial compliance
SAE(s)
serious adverse event(s)
SAF
safety analysis set
SAP
statistical analysis plan
SBP
systolic blood pressure
SERCA
sarcoplasmic reticulum calcium adenoside triphosphatase
sST2
soluble suppression of tumorigenicity-2 
SUSAR(s)
suspected unexpected serious adverse reaction(s)
SV
stroke volume
SVI
SV index
SVT(s)
supraventricular tachycardia(s)
TAPSE
tricuspid annular plane systolic excursion
TD
tissue Doppler
TIMP-4
tissue inhibitor of metalloproteinase-4
TPR
total peripheral resistance
UACR
urine albumin-to-creatinine ratio
UGT1A1
uridine diphosphate glucuronosyltransferase 1A1
ULN
upper limit of normal
US, USA
United States (of America)
VAS
visual analogue scale
WCHF
worsening chronic heart failure


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3.
Introduction
3.1
Background
Chronic heart failure (CHF) is a major public health problem characterized by significant 
mortality, frequent hospitalizations, and poor quality of life, with an overall prevalence that is 
increasing throughout the world. The European Society of Cardiology (ESC) represents 
countries with a population of > 900 million, and there are at least 15 million patients with 
heart failure (HF) in those 51 countries (1). An estimated 5.7 million patients have HF in the 
United States (US) with increasing prevalence, and the incidence approaches 10 per 1000 
population after 65 years of age; the lifetime risk for developing HF is one in five for men and 
women (2). In developed countries 1–2% of the adult population has HF, with the prevalence 
rising to ≥ 10% among persons 80 years of age or older (3). HF carries a prognosis 
comparable to many forms of cancer with a 5-year survival rate of approximately 50% (4), 
which exceeds that of many cancers (5).
Frequent hospitalizations, along with other direct and indirect costs, also place an enormous 
financial burden on healthcare systems; more is spent annually in the US for the treatment of 
HF by Medicare than on any other Medicare-covered condition (6).
The pathophysiology and clinical constellation of patients hospitalized for HF differ 
substantially from ambulatory patients with HF. Each episode of acute hospitalization for HF 
occurring annually in up to 30% of HF patients with NYHA class III and IV indicates an 
unfavorable underlying pathophysiology and prognosis within the course of HF (7). These 
patients represent an important subpopulation of patients with HF, which is denominated as 
worsening CHF (WCHF).
The current treatment paradigm for patients with HF with reduced ejection fraction (HFrEF) 
centers on systemic blockade of the maladaptive neurohumoral response, notably the 
enhanced and sustained activities of the sympathetic and renin-angiotensin-aldosterone 
systems, with hemodynamically active medications that decrease cardiac workload by 
reducing heart rate, preload and afterload (8-10). For patients with stable chronic HFrEF 
neurohumoral antagonists such as ACE inhibitors, angiotensin receptor, aldosterone and beta-
blockers improve prognosis and are standard of care therapies. However, upon hospitalization 
for HFrEF mortality and re-hospitalization for HF remain high despite treatment with these 
neurohumoral blockers, indicating that this does not fully explore the complexity of HF 
pathophysiology.
Additionally, the repeated stepwise addition of hemodynamically active medications raises 
tolerability and safety concerns (e.g. hypotension and bradycardia) (11). Likewise, the high 
failure rate of Phase III HFrEF trials in recent years suggests that incremental benefit using 
the current approach may be difficult or unattainable (12), and hemodynamic compromise 
represents a frequent reason for failed HF drug development (13).
Therefore, addressing the failing heart directly and getting viable but not functional 
myocardium back to work might be a new option for the development of the next generation 
of hemodynamically silent HF drugs. In this context, neladenoson bialanate holds promise as 
a potentially hemodynamically neutral therapy for HF that could simultaneously improve 
cardiomyocyte energetics, calcium homeostasis, cardiac structure and function, and long-term 
clinical outcomes when added to background therapies.


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3.2
Partial adenosine A1 receptor agonism in heart failure
The failing heart is characterized by abnormal mitochondrial structure and function including 
hyperplasia and reduced organelle size, poor organelle respiration, reduced mitochondrial 
membrane potential, opening of membrane permeability pores, and reduced rates of adenosine 
triphosphate (ATP) synthesis and thereby reduced energy supply in cardiomyocytes in HFrEF 
and HF with preserved ejection fraction (HFpEF) (14-20). Additionally Ca2+ handling is 
disturbed and SERCA2a protein levels are decreased in HF (21). This changes the 
contraction / relaxation coupling in cardiomyocytes and leads to an intracellular calcium 
overload in the heart. Furthermore, systemic metabolic impairments in the skeletal muscle are 
increasingly recognized as contributing both to symptoms (muscle weakness, exercise 
limitation) and disease progression in HF (22). Preclinical studies have demonstrated that 
myocardial energy metabolism and utilization as well as calcium homeostasis are improved 
by the partial adenosine A1 receptor agonist capadenoson (15, 23). In the heart failure 
standard dog model, treatment with this drug showed fast improvement of cardiac energetics 
(ATP synthesis) via mitochondrial effects. Capadenoson further improved SERCA2a activity, 
leading to decreased intracellular calcium overload (15).
The prevalence of coronary artery disease (CAD) is high in patients with HFrEF and HFpEF 
and associated with greater deterioration in ventricular function and increased mortality (24, 
25) based mainly on ischemia driven injury of cardiac tissue. The primary physiological 
undertaking of adenosine is to preclude tissue injury and promote repair in response to stress 
mainly through adenosine A1 receptor (A1R) activation. Preclinical data showed 
cardioprotection from ischemia-induced injury by preconditioning and improvement of 
endothelial function in animal models with partial A1R agonists including capadenoson (15,
26, 27). Potential benefit of this targeted approach to the treatment of HF lies in the ability of 
partial A1R agonism to afford protection to the failing myocardium by limiting triggers of cell 
injury and death. Furthermore, the prevention of deterioration of myocardial ATP levels 
matching the ATP production to oxygen supply seems to be an important factor for 
cardioprotection. Especially patients with high risk for cardiac events (e.g. HF patients with 
diabetes, chronic kidney disease [CKD], advanced CAD) might benefit from A1R activation.
Furthermore, excessive activation of the adrenergic nerve system is detrimental in HF 
patients, inducing systemic vasoconstriction, increased sodium / water retention, and 
ventricular remodeling, all of which contribute to disease progression. Adenosine carries anti-
adrenergic properties that can protect the heart from adverse mechanical and metabolic 
stimulation from excessive catecholamine stimulation, thereby limiting ischemia. Activation
of the A1R may also inhibit norepinephrine release from cardiac presynaptic nerves (28, 29). 
Conceivably, these effects may be important for preventing disease progression and further 
adverse remodeling, particularly in those with ischemic cardiomyopathy. Partial adenosine 
A1R agonism might offer a unique opportunity to selectively modulate the sympathetic 
control of cardiac function via presynaptic A1R activation and cAMP inhibition (28). 
Heart failure is often associated with comorbidities like CKD and diabetes in HFrEF and 
HFpEF patients (30). Renal effects of adenosine A1R activation lead to vasoconstriction of 
the afferent arterioles in the kidneys (31) and thereby sodium retention and anti-diuretic 
effects. The effects were regarded as potential for renal benefit with adenosine antagonism in 
HF and led to large scale drug development programs with adenosine A1R antagonists, such 


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as rolofylline in patients with acute decompensated heart failure (ADHF). But the Phase III 
trial failed to show any renal protection. Instead, higher rates of persistent renal impairment, 
seizure and stroke were noted in the rolofylline group (32, 33). In contrast, an A1R agonist 
shows reno-protective effects in preclinical models of ischemia-induced renal injury (34).
Increased plasma levels of free fatty acids (FFAs) are often found in patients with HF (35, 36)
and result in an increase of insulin resistance and might be involved in the deterioration of 
heart function. A1R agonists can reduce plasma levels of FFAs in humans as shown in 
clinical trials (37). Furthermore, FFAs act as substrate for the energetic metabolism in the 
heart. HF is characterized by an added reliance on fatty acid oxidation, with downregulation 
of myocardial glucose transporters (38, 39). These changes characterize the transition of the 
failing heart to a fetal metabolic phenotype and gene profile, an adaptation that can further 
promote HF progression (38-40). Animal studies suggest that partial A1R agonist 
capadenoson can augment expression of the GLUT-1 and GLUT-4 glucose transporters to 
near normal levels (15). Moreover, therapy with capadenoson has also been associated with 
normalization of protein levels that mediate fatty acid oxidation (15). Thus, A1R agonism 
appears capable of partially correcting derangements in cardiac substrate utilization and 
restoring a physiologic metabolic profile in HF.
Previous attempts to address the A1 receptor, while offering potential therapeutic benefits, 
were limited by undesirable side effects that include bradycardia, atrioventricular blocks, 
sedation and antidiuretic effects. Furthermore, adenosine-like A1R agonists often have the 
drawback of a short half-life and low bioavailability making them not suitable for chronic oral 
therapy.
In contrast, partial adenosine A1 agonists may be used to modulate and trigger primarily 
favorable pharmacological responses for HF therapy, such as cardio- and renoprotection. A 
partial agonist is a low efficacy ligand, which elicits only a submaximal response from the 
receptor in contrast to a full agonist, even when all receptors are occupied. A partial agonist is 
expected to result in a robust signal response only in tissues with relative high receptor 
reserve, whereas a full agonist will elicit a robust signal also in tissue with a low receptor 
reserve. Thus, partial agonists are useful for achieving high selectivity for the target 
organ / tissue and minimizing toxicity and effects in non-target tissues (e.g. neurological 
effects, undesired kidney effects, AV conduction abnormalities). Hemodynamic effects 
evoked by A1R activation seem to have a lower receptor reserve in e.g. the AV node 
compared to cardioprotective effects. Furthermore, partial adenosine A1R agonists might 
induce less receptor desensitization than full agonists and be ideal for chronic treatment (41).
3.3
Neladenoson bialanate
Neladenoson bialanate (BAY 1067197, which is the free base of the hydrochloride BAY 86-
8901) is the pro-drug of the pharmacologically active compound BAY 84-3174, a highly 
potent and selective non-adenosine like partial adenosine A1 receptor agonist suitable for 
once daily oral use.
Pharmacological actions seem to be at least partly based on an acute restoration and improved 
utilization of myocyte energetics (ATP production within the mitochondria), and chronic 
improvement of calcium handling by restoration of SERCA2a protein levels, which result in 
protection of cardiac function and improvement of contraction / relaxation coupling. These 
effects were seen after a short treatment period of one week in nonclinical models. In 


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addition, neladenoson bialanate was characterized regarding mitochondrial function in 
isolated cardiomyocytes from normal and HF dogs (EF ~30%) produced by intracoronary 
microembolization as described in Sabbah et al (42). Neladenoson bialanate improved 
mitochondrial function (respiration, ATP synthesis, ATP / adenosine diphosphate [ADP] ratio, 
cytochrome c-dependent cyclooxygenase activity, membrane potential, and mitochondrial 
permeability transition pore opening) significantly and dose dependently in HF 
cardiomyocytes but had no effect on normal cardiomyocytes.
Nonclinical data showed that neladenoson bialanate is cardio- and renoprotective at doses 
lower than needed to elicit the clinically relevant undesirable effects on heart rate, AV-
conduction, blood pressure, renal function and the central nervous system.
In animal models and clinical studies in healthy volunteers, neladenoson bialanate
significantly reduces plasma levels of free fatty acids vs. placebo. Abnormal energetic activity 
in heart failure correlates inversely with plasma free-fatty-acid concentrations. The excess of 
fatty acids may adversely affect the myocardium and in HF may be associated with uncoupled 
respiration (43).
Further details can be found in the investigator’s brochure (IB), which contains 
comprehensive information on the study drug. The IB in its most current version is available 
in the study file.
3.4
Rationale of the study
The main limitations of using full A1R agonists in cardiovascular indications such as HF are 
undesired cardiac effects, such as bradycardia and higher degree AV block as well as negative 
cardiac inotropy and dromotropy. In contrast, preclinical data show that the partial adenosine 
A1R agonist neladenoson bialanate can be used to modulate and trigger primarily favorable 
pharmacological responses for HF therapy and avoid undesired effects such as AV conduction 
abnormalities and higher degree AV Block. Nevertheless, based on the mode of action, there 
are theoretical concerns particularly with regard to undesired effects, such as bradycardia and 
higher degree AV block for an A1R agonist, which might be aggravated by concomitant use 
of standard heart failure therapy.
The purpose of this clinical trial is to assess the safety, tolerability and the pharmacokinetic
and pharmacodynamic response of 20 weeks’ treatment with neladenoson bialanate compared 
to placebo in patients with chronic HFrEF on standard therapy for HF and to find the optimal 
dose for a further Phase III trial.
4.
Study objectives 
The objective of the study is to find the optimal dose of neladenoson bialanate for the Phase 
III trial by detecting and characterizing a significant dose-response relationship in the two 
primary efficacy endpoints, absolute change from baseline in LVEF and log-transformed NT-
proBNP at 20 weeks, in patients with chronic heart failure with reduced ejection fraction 
(HFrEF), and by characterizing the safety, tolerability and pharmacodynamic effects of the 
compound when given in addition to standard therapy for HFrEF.
An exploratory objective is to further assess pharmacokinetic parameters and blood and urine 
biomarkers.
For variables please see Section 10.3.1.


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5.
Study design
5.1
Design overview
Study 15128 is a randomized, double-blind, placebo-controlled, parallel group, multicenter, 
Phase II study. Figure 5–1 displays the overall study design. 
Figure 5–1: Study design overview
Abbreviations: CV = cardiovascular; ICF = informed consent form; W = week
Approximately 384 patients from approximately 90 study centers worldwide will be 
randomized to one of the active treatment dose arms or placebo, in addition to standard of 
care heart failure therapy (for details see Section 7).
The study will comprise a 1-week run-in period, 20-week treatment period, and a 6-week 
follow-up period (27 weeks total).
Patients will have site visits at weeks -1, 0 (baseline), 4, 8, 12, 20 (end-of-treatment visit) and 
24 (safety follow-up visit). In addition, 2 phone calls at weeks 2 and 26 will be made to assess 
patients’ safety, and one additional phone call - to remind the patients of AVIVO self-
application at Week 19.
LVEF will be measured by echocardiography at baseline and end of treatment, NT-proBNP 
will be measured at baseline, Week 4 and end of treatment. Safety will be monitored 
throughout the study. PK samples will be taken from all patients at dedicated time points. 
Additional biomarkers reflecting the pharmacodynamic activity of the drug will be examined, 
as well as candidate biomarkers that may predict drug response.
For detailed visit descriptions and rules for patients who discontinue study treatment earlier, 
please see Sections 9.1 and 9.2.
The anticipated duration of the study as a whole is approximately 19 months: this includes an 
anticipated recruitment period of 13 months followed by a run-in period of 1 week, a 
treatment period of 20 weeks and a follow-up period of 6 weeks after enrollment of the last 
patient into the trial.
W -1
Visit 1
W 4
Visit 4
W 8
Visit 5
W 12
Visit 6
W 2
Visit 3, 
phone call
W 20
Visit 7
W 24 
Visit 8
W 26
Visit 9
phone call
placebo
5 mg
10 mg
20 mg
30 mg
40 mg
Treatment
Follow up
W 0
Visit 2
W 19
Phone call
Run-in


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5.2
Primary variables

Absolute change from baseline in left ventricular ejection fraction (LVEF; %) after 20 
weeks measured by echocardiography.

Absolute change from baseline in log-transformed NT-proBNP (pg/mL) after 20 
weeks, i.e., log-transformed NT-proBNP at Week 20 minus log-transformed NT-
proBNP at baseline.
For secondary and other variables please see Section 10.3.1.
5.3
Justification of the design
This section was changed in Amendment 2, see Section 15.1 for details.
A parallel group design was chosen to compare five different once-daily dose regimens and 
one placebo arm to find the best dose for Phase III. Placebo control is used to control for 
observer and subject bias, and randomization - to control for assignment bias. Based on 
Phase I data in healthy volunteers and Phase II data in heart failure patients, a sequential dose 
escalation design was not deemed necessary for neladenoson bialanate since the safety profile 
of the compound could be verified in dose ranges up to 40 mg. Evidence of A1R target 
engagement could already be achieved in different tissues across different clinical trials with 
20 mg neladenoson bialanate. The dose range around 20 mg (5, 10, 30 and 40 mg) is to ensure 
different data points to feed the MCP-Mod predefined models and potential unforeseen 
variances. The doses studied will ensure a strong dose recommendation moving forward into 
phase III. Safety of the subjects in this parallel study design will be closely monitored by a 
Data Monitoring Committee (DMC).
5.4
End of study
The end of the study as a whole will be reached as soon as the last visit of the last patient has 
occurred in all centers in all participating countries (EU and non-EU).
6.
Study population
6.1
Inclusion criteria
Patients must meet all of the following inclusion criteria to be included in the study:
1.
Men or women aged 18 years and older
2.
Diagnosis of chronic heart failure (CHF), NYHA class II-IV, LVEF ≤ 35% assessed by 
any imaging modality (e.g. echocardiography, cardiac magnetic resonance, cine 
levocardiography) within 6 months prior to run-in: if several values are available the 
last assessment of LVEF should be ≤35%.
3.
One of the following (or both),
a) Worsening CHF requiring hospitalization or an unscheduled outpatient visit in 
the last 3 months, both requiring initiation or intensification of heart failure 
therapy and with either:
o
BNP ≥100 pg/mL or NT-proBNP ≥400 pg/mL (sinus rhythm) or


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o
BNP ≥300 pg/mL or NT-proBNP ≥1200 pg/mL (atrial fibrillation) 
AND/OR 
b) at any time in the past 4 weeks one of:
o
BNP ≥300 pg/mL or NT-proBNP ≥1200 pg/mL (sinus rhythm)
o
BNP ≥600 pg/mL or NT-proBNP ≥2400 pg/mL (atrial fibrillation)
For patients on treatment with angiotensin receptor-neprilysin inhibitors (ARNIs), e.g. 
Entresto only NT-proBNP values can be used to assess eligibility.
4.
Written informed consent signed before any study-specific procedure
6.2
Exclusion criteria
This section was changed in Amendment 2, see Section 15.1 for details.
Patients who meet any of the following exclusion criteria will be excluded from the study:
1.
Acute de-novo heart failure 
2.
Requirement of any of the following 48 hours prior to randomization:
o
IV vasodilating drugs (e.g. nitrates, nitroprusside)
o
IV natriuretic peptides (e.g. nesiritide, carperitide)
o
IV positive inotropic agents
o
IV diuretics 
o
IV antibiotics
o
Mechanical support (e.g. intra-aortic balloon pump, endotracheal intubation, 
mechanical ventilation, or any ventricular assist device)
3.
Any cause of chronic heart failure other than ischemic cardiomyopathy and idiopathic 
dilated cardiomyopathy
4.
Known clinically significant persistent coronary ischemia based on medical history, 
preexisting or current exercise testing
5.
Occurrence of any of the following within 3 months prior to randomization:
o
Myocardial infarction
o
Hospitalization for unstable angina
o
Stroke or transient ischemic attack
o
Coronary artery bypass graft (CABG) 
o
Percutaneous coronary intervention (PCI)
o
Implantation of a cardiac resynchronization therapy device (CRTD)
o
Carotid angioplasty 


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6.
PCI, CABG or implantation of a CRTD planned between randomization and end of study
7.
Sustained 1 systolic blood pressure ≤ 90 mmHg and / or signs and symptoms of 
hypotension prior to randomization
8.
Sustained 1 systolic blood pressure ≥ 160 mmHg
9.
Sustained 1 bradycardia with heart rate < 50 beats/minute or tachycardia with heart rate 
> 100 beats/minute prior to randomization 
10. Known clinically relevant ventricular arrhythmias (sustained ventricular tachycardia, 
ventricular flutter or fibrillation) within 3 months prior to consent based on either medical 
history or ICD-testing results (if applicable)
11. Clinically relevant permanent or intermittent AV-block > grade II in patients without a 
permanent pacemaker or ICD / CRTD
12. Severe valvular disease with indicated or planned valve repair / replacement
13. Listing for heart transplantation and / or anticipated implantation of a ventricular assist 
device
14. Severe pulmonary disease with any of the following:
o
Requirement of continuous (home) oxygen or 
o
History of chronic obstructive pulmonary disease ≥ GOLD III or 
o
Use of systemic corticosteroids
15. Asthma bronchiale with any of the following:
o
Symptoms not well-controlled within the past 6 months or
o
Ever intubated or in an intensive care unit for asthma
16. Anemia with hemoglobin < 10 g/dL within 3 months prior to randomization. If several 
values are available the latest result should be used. 
17. Body mass index (BMI) > 40 kg/m2 at randomization or a history of poor quality LVEF 
measurement by echocardiography
18. Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 calculated by 
Modification of Diet in Renal Disease (MDRD) formula within 3 months prior to 
randomization (see Appendix 16.1). If several values are available the latest result should 
be used.
19. Hepatic insufficiency classified as Child-Pugh B or C (see Appendix 16.2), or any of the 
following: 
o
Primary biliary cirrhosis (PBC)
o
Primary sclerosing cholangitis
o
PBC-autoimmune hepatitis overlap syndrome
                                                
1 At two consecutive visits


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20. Concomitant use of any of the following therapy that cannot be discontinued:
o
Moderate or strong CYP3A4 inhibitors (Of note: grapefruit is a strong CYP3A4 
inhibitor.)
o
CYP3A4 inducers
o
Strong CYP2C8 inhibitors (Of note: clopidogrel is a CYP2C8 inhibitor)
o
Theophylline
o
Drugs having significant pre-systemic clearance via UGT1A1 in the intestine
Respective substances must be stopped at least 7 days before randomization.
21. Women of childbearing potential (women are considered of childbearing potential if they 
are not surgically sterile or postmenopausal, defined as amenorrhea for > 12 months)
22. Known current heavy alcohol consumption or the use of illicit drugs that, in the opinion 
of the investigator, may interfere with the patient’s safety and / or compliance
23. Previous (within 30 days or 5 half-lives of the investigational drug, whichever is longer) 
or concomitant participation in another clinical study with investigational medicinal 
product(s) or device(s)
24. Previous assignment to treatment during this study
25. Any condition or therapy, which would make the patient unsuitable for the study, or life 
expectancy less than 12 months (e.g. active malignancy)
26. Close affiliation with the investigational site; e.g. a close relative of the investigator, 
dependent person (e.g. employee or student of the investigational site)
27. Known allergies, intolerance or hypersensitivities to the study treatment (active substance 
or excipients), adhesives or hydrogel
6.3
Justification of selection criteria
The selection criteria were chosen to exclude patients from the study who may potentially be 
exposed to specific risks after administration of the study drug, as well as patients with 
conditions that may have an impact on the aim of the study.
6.4
Withdrawal of patients from study
Withdrawal
6.4.1
This section was changed in Amendment 2, see Section 15.1 for details.
An excessive rate of withdrawals (either patients discontinuing study medication or study 
withdrawal) can render the study non-interpretable. Therefore, un-necessary withdrawal of 
patients should be avoided and all efforts should be taken to motivate patients to comply with 
all the study specific procedures and to be followed until the end of the trial to detect the 
occurrence of cardiovascular events / assess vital status.
Before permanently discontinuing study medication (either initiated by the patient or the 
investigator) an interruption should be considered. Patients, who have temporarily 
discontinued study medication for any reason, should restart as soon as medically justified in 
the opinion of the investigator; the patient can re-start at any time before the end of treatment 


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(EOT) visit. In addition, patients should not be withdrawn from the study drug or from the 
study solely due to reaching a potential cardiovascular event. 
All patients who permanently discontinue study medication should come in for the 
EOT / premature discontinuation visit as soon as possible after discontinuation of the study 
medication and the safety follow-up visit 4 weeks after the last dose. In addition, they will be 
contacted by the investigator via the scheduled Week 26 phone call to assess occurrence of 
cardiovascular events.
The investigator should show due diligence and explore all possible options to reach a patient 
who fails to return to a visit. The site must document all attempts to try to contact the patient 
in the medical records / source documents.
In order to avoid loss-to-follow-up, the investigator should ask the patient at the study start for 
the contact details of a relative or friend who can be contacted in case the patient cannot be 
reached.
Patients should not be withdrawn from follow-up unless the patient explicitly withdraws 
consent to be contacted. All efforts should therefore be made to minimize the number of 
patients who withdraw such consent as, in general, no further information on cardiovascular
events and survival status may be collected after that point.
Withdrawal criteria
Patients must be withdrawn from the study if any of the following occurs:
At their own request or at the request of their legally acceptable representative. At any 
time during the study and without giving reasons, a patient may decline to participate 
further. The patient will not suffer any disadvantage as a result.
Patients may be withdrawn from the study if any of the following occurs:
If, in the investigator's opinion, continuation of the study would be harmful to the 
patient's well-being.
At the specific request of the sponsor and in liaison with the investigator (e.g. obvious 
non-compliance, safety concerns).
If any investigational drug other than the study drug is used during the study period.
Depending on the time point of withdrawal, a withdrawn patient is referred to as either 
“screening failure” or “dropout” as specified below.
Screening failure
A patient who, for any reason (e.g. failure to satisfy the selection criteria), terminates the 
study before randomization is regarded a “screening failure”. 
Re-screening is allowed once and only in the following cases:
The patient had successfully passed the screening procedures, but could not start 
subsequent treatment on schedule.
Initial screening occurred too early to complete the required washout period for
prohibited substances.


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In any case, the investigator has to ensure that the repeated screening procedures do not 
expose the patient to an unjustifiable health risk. For re-screening, the patient must sign a new 
informed consent form, even if its version was not changed after the patient’s previous 
screening. In the event of re-screening the patient will be assigned a new patient identification 
number.
Dropout
A patient who discontinues study participation prematurely for any reason is defined as a 
“dropout” if the patient has already been randomized whether or not any study medication 
was taken.
General procedures
In all cases, the reason for withdrawal must be recorded in the CRF and in the patient's 
medical records. 
The patient may object to the generation and processing of post-withdrawal data as specified 
in Section 13.4.
Details for the premature termination of the study as a whole (or components thereof) are 
provided in Section 12.
Replacement
6.4.2
Randomized patients who drop out or withdraw prematurely will not be replaced.
6.5
Patient identification
The patient number is a 9-digit number consisting of:
Digits 1 to 5 
=  Unique center number
Digits 6 to 9
=  Current patient number within the center
7.
Treatments
7.1
Treatments to be administered
Patients will receive either active treatment with neladenoson bialanate or placebo; treatment
assignment is described in Section 7.3. Patients will be instructed to take two study tablets 
once daily, preferably in the morning, over a period of 20 weeks. On visit days, the study drug 
should be taken as specified in Table 9–1. The study drug should be taken with a glass of 
water, and can be taken with or without food. There will be no dose modifications; patients 
will stay on the dose which they were randomized to. For guidance regarding drug 
discontinuation please see Section 6.4.1.
This treatment will be in addition to patients’ regular heart failure treatments (see Section 
8.1.2).
7.2
Identity of study treatment
Three different “BAY-numbers” are used within this document, corresponding to three 
different chemical appearances of neladenoson bialanate:


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BAY 1067197 is a pro-drug. BAY 1067197 represents the “pharmaceutical principle” of 
neladenoson bialanate, and thus this BAY number is used when generally speaking about 
neladenoson bialanate. Present dosages refer to BAY 1067197.
BAY 86-8901 is the hydrochloride salt of BAY 1067197. BAY 86-8901 is used to formulate 
the immediate release tablets to be administered to study patients. This BAY number is used 
when speaking about the oral preparation of neladenoson bialanate.
BAY 1067197 cannot be found in measurable concentrations, or only at very low 
concentrations in the blood plasma. Orally administered drug is converted by ester cleavage 
into the active metabolite BAY 84-3174, which is responsible for the pharmacodynamic 
effects. BAY 84-3174 is used in the context of plasma pharmacokinetic data measurements.
Details of BAY 1067197 are given in Table 7–1; details of placebo are given in Table 7–2. 
For more information please refer to the latest available version of the investigator’s brochure. 
Table 7–1: Identity of neladenoson bialanate (BAY 1067197)
Sponsor’s internal 
reference number
BAY 1067197
Formulation
Pink coated tablets 
Galenical form
Round biconvex, diameter 8 mm 
Markings: One side PT; Other side blank
Composition
Active ingredient: neladenoson bialanate, 2-{4-[2-({[2-(4-chlorophenyl)-1,3-thiazol-4-
yl]methyl}sulfanyl)-3,5-dicyano-6-(pyrrolidin-1-yl)pyridin-4-yl]phenoxy}ethyl L-alanyl-
L-alaninate 
Empirical formula: C35 H34 Cl N7 O4 S2 * HCl
Molecular mass: 716.29 + 36.46 [g/mole]
Excipients: Lactose anhydrous, Crospovidone and magnesium stearate
Coating: Lacquer pink (Opadry Pink 02A34744)
Strength
5 mg,10 mg and 20 mg
Packaging
Blister
Table 7–2: Identity of placebo
Formulation
Pink coated tablets 
Galenical form
Round, biconvex, diameter 8 mm 
Markings: One side PT; Other side blank
Composition
lactose monohydrate, cellulose microcrystalline and magnesium stearate
Coating: Lacquer pink (Opadry Pink 02A34744)
Packaging
Blister
Storage requirements
Study drug will be stored at the investigational sites according to the label requirements in a 
place inaccessible to unauthorized personnel, i.e. in a locked cabinet. 
All study drugs will be labeled according to the requirements of local law and legislation.
Label text will be approved according to the sponsor’s agreed procedures, and a copy of the 
labels will be made available to the study site upon request.


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For all study drugs, a system of numbering in accordance with all requirements of GMP will 
be used, ensuring that each dose of study drug can be traced back to the respective bulk batch 
of the ingredients. Lists linking all numbering levels will be maintained by the sponsor’s 
clinical supplies quality assurance group. 
A complete record of batch numbers and expiry dates of all study treatment as well as the 
labels will be maintained in the sponsor’s study file.
7.3
Treatment assignment
The intention is to randomize approximately 384 subjects to the doses 5 mg, 10 mg, 20 mg, 
30 mg, 40 mg of neladenoson bialanate, and placebo according to an allocation ratio of
1:2:2:2:2:3, respectively.
At the baseline visit, the investigator will first perform all required pre-treatment 
examinations and will then randomize the qualified patients to one of the six treatment arms.
The randomization will be stratified by atrial fibrillation (AF): yes vs. no.
Enrollment into the AF stratum may be stopped (after the discussion between the sponsor and 
the Steering Committee) when the AF stratum constitutes 30% of the total expected 
enrollment.
The randomization lists will be provided by Bayer’s Global Randomization Management 
Group. Randomization will be done using an interactive voice / web response system (IxRS).
A handbook describing how to use the IxRS will be provided to each study site.
7.4
Dosage and administration
For dosage and administration please refer to Section 7.1.
7.5
Blinding
This section was changed in Amendment 2, see Section 15.1 for details.
All patients will receive the same number of tablets (only active, combination of active and 
placebo or only placebo, depending on the treatment arm) to maintain the blind (Table 7–3). 
Table 7–3: Assignment of tablets to dose groups
Treatment arm/ 
Formulation
5 mg
10 mg
20 mg
30 mg
40 mg
Placebo
5 mg
1
0
0
0
0
0
10 mg
0
1
0
1
0
0
20 mg
0
0
1
1
2
0
Placebo
1
1
1
0
0
2
Total tablets/day
2
2
2
2
2
2
The following parties will be unblinded: sponsor’s IxRS and Medication Manager, Clinical 
Supply Manager and Clinical Pharmacometrics analyst (who will be provided with a 
randomization list for selected bioanalyses of the active metabolite BAY 84-3174 in plasma), 
the drug supply’s Project Manager, and the DMC.


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For all other sponsor’s study personnel, the Steering Committee and the Clinical Events 
Committee (CEC) the blinding will be strictly kept.
In compliance with applicable regulations, in the event of a SUSAR (see Section 9.6.1.5) 
related to the blinded treatment, the patient’s treatment code will usually be unblinded before 
reporting to the health authorities, ethic committees and investigators (see Section 9.6.1.4).
For exceptions please see Section 9.6.1.4.
Emergency unblinding by the investigator
In the event of emergency, and where knowledge of assigned treatment allocation is required 
for the acute treatment strategy, the investigator may unblind the case. Unblinding will be 
handled in IxRS.
The occurrence of SAEs should not routinely precipitate the immediate unblinding. The 
investigator is required to promptly document and explain to the sponsor any premature 
unblinding (e.g. unblinding due to an SAE) of the study drug. The investigator should report 
unblinding of treatment to the EC / IRB according to the EC / IRB’s requirements.
7.6
Drug logistics and accountability
All study drugs will be stored at the investigational site in accordance with GCP and GMP 
requirements and the instructions given by the clinical supplies department of the sponsor (or 
its affiliate), and will be inaccessible to unauthorized personnel. Special storage conditions 
and a complete record of batch numbers and expiry dates can be found in the sponsor’s study 
file; the site-relevant elements of this information will be available in the investigator site file. 
On the day of receipt, the responsible site personnel will confirm receipt of study drug via 
IxRS. The personnel will use the study drug only within the framework of this clinical study 
and in accordance with this protocol. Receipt, distribution, return and destruction (if any) of 
the study drug must be properly documented according to the sponsor’s agreed and specified 
procedures.
Written instructions on medication destruction will be made available to affected parties as 
applicable.
7.7
Treatment compliance
To monitor compliance, the investigator will be required to document drug dispensing for 
each patient. Overall compliance with study drug intake should be between 80% and 120% of 
the scheduled dose at the end of study drug treatment. The date of dispensing the study drug 
to the patient will be documented.
Study drug will be dispensed according to the schedule provided in Section 9.1.
Patients will return at scheduled visits or at the premature discontinuation / EOT visit, if 
applicable, with all remaining unused study drug, when accountability will be determined for 
all tablets. To facilitate this, patients must be instructed to return all of the study drug 
packaging including unused study drug and empty packaging.
Any discrepancies between actual and expected amount of returned study medication must be 
discussed with the patient at the time of the visit, and any explanation must be documented in 
the source records.


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8.
Non-study therapy 
8.1
Prior and concomitant therapy
Prohibited concomitant medication
8.1.1
This section was changed in Amendment 2, see Section 15.1 for details.
Concomitant therapy with any of the following drug classes is prohibited:

Moderate or strong CYP3A4 inhibitors (Of note: grapefruit is a also strong CYP3A4 
inhibitor)

CYP3A4 inducers

Strong CYP2C8 inhibitors (Of note: clopidogrel is a strong CYP2C8 inhibitor)

Theophylline

Drugs having significant pre-systemic clearance via UGT1A1 in the intestine
Respective substances must be stopped at least 7 days before randomization and can only be 
started 6 weeks after the last intake of study drug. A list of prohibited medications will be 
provided to the investigators.
If a prohibited concomitant medication (e.g. moderate / strong CYP3A4 inhibitor) is used 
during the study conduct, the study drug should be interrupted immediately and restarted as 
soon as possible, when the prohibited medication has been stopped. Prior to re-starting the 
study drug, a washout period of at least two days after discontinuation of the prohibited 
medication should be adhered to.
Permitted therapy
8.1.2
This section was changed in Amendment 2, see Section 15.1 for details.

In accordance with standard local or international heart failure guidelines, all patients 
should be on standard HF therapy (an ACEi or ARB, beta-blockers, MRA, ARNI, as 
applicable), unless contraindicated or (to the investigator’s knowledge) not tolerated

Concomitant therapy of comorbidities is allowed unless listed in the prohibited 
medication section.
During the treatment period the background medications should be kept stable and changes in 
treatment should be based on clinical need. 
Neladenoson bialanate is a weak Breast Cancer Resistance Protein (BCRP) inhibitor. The risk 
of clinically relevant drug–drug interactions at doses up to 40 mg BAY 1067197 due to 
inhibition of BCRP is regarded as low, but cannot be excluded (BCRP substrates are 
atorvastatin, simvastatin, rosuvastatin, fluvastatin, methotrexate, etc.; a list of BCRP 
substrates will be made available to the investigators).
If neladenoson bialanate is given concomitantly with other drugs that may increase the 
exposure of BCRP substrates, the respective drug labels should be consulted.
All concomitant medication will be documented in the eCRF.


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8.2
Post-study therapy
The investigator must provide follow-up medical care for all patients who complete the study 
or who are prematurely withdrawn from the study, or must refer them for appropriate ongoing 
care, as required.
Study medication will not be available to patients after completion of the study.
9.
Procedures and variables
9.1
Tabular schedule of evaluations
This section was changed in Amendment 2, see Section 15.1 for details.


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Table 9–1: Schedule of evaluations
Study period
Run
-in
Treatment a
EOT /
PDV
Safety 
FU

Unscheduled e
Visit number
1
2
3
4
5
6
7
8
9
Visit type
site
site

site
site
site
b
site
site

Week
Day and allowed deviations
-1
-7
W0
0+2
W2
14±2
W4
28±2
W8
56±2
W12
84±2
W19
133-2
W20 a
140±2
W24 c
168 ±2
W26 a
182+7
Pre-rand.
Signed informed consent 
f
●
Inclusion / exclusion 
●
●
KCCQ
●
●
●
●
EQ-5D-5L
●
●
Demographic data
●
Medical and surgical 
history
●
Smoking & alcohol history
●
Caffeine & chocolate 
consumption
●
●
Physical exam
●
●
●
●
●
●d
●
Height
●
Weight
●
●
●
●
●
●
●
12-lead ECG 
●
●
●
NYHA class
●
●
●
●
●
●
●
Blood pressure and heart 
rate
●
●
●
●
●
●
●
●
Adverse events
●
●
●e
●
●
●
●
●
●e
●
Concomitant medication
●
●
●
●
●
●
●
●
●
●
AVIVO application, worn 
for 7 days
●
●
●
f
●
Collection of AVIVO
device
●
●
●
●
Echocardiography (central)
●
●
Randomization via IxRS 
●
post-rand.
Laboratory (central lab)
Blood sample for safety
pre-
dose
●
●
●
●
●
●
PK sample (exact time to 
be documented) g
2h post-
dose
pre-
dose
pre-
dose
~2h & 4h 
post-dose
1 day
post-dose
●
Blood sample for 
biomarkers
pre-
dose
●
●
●h
Urine sample for 
biomarkers
pre-
dose
●
●
Study drug i
Study drug intake at the 
site
●
●
●
Study drug intake before 
the visit
~2h 
before
1 day 
before
Patients to remember time 
of the study drug intake 
day 
before
day 
before
●
day of last 
dose
Dispense contact card
●
Dispense study drug 
●
●
●
●
Collect unused study drug 
●
●
●
●


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Table 9-1: Schedule of evaluations (continued)
Abbreviations: ECG = electrocardiogram; EOT = end of treatment; EQ-5D-5L = EuroQol Group 5-
dimensional, 5-level questionnaire; FU = follow-up; h = hour(s); IxRS = interactive web/voice response 
system; KCCQ = Kansas City Cardiomyopathy Questionnaire; NYHA = New York Heart Association; 
PDV = premature discontinuation visit; post-rand. = post-randomization; PK = pharmacokinetics; pre-
rand. = pre-randomization; W = week
a For patients who discontinue study medication prematurely:

EOT / premature discontinuation visit must be performed as soon as possible after 
discontinuation of the study drug.

Safety FU visit must be scheduled 4 weeks after the last dose (± 2 days).

Week 26 follow-up call will be made 26 weeks after the start of treatment (+7 days).
b Phone call to remind patients to self-apply AVIVO device. The phone can be made up to 2 days 
before Week 19, but not later than Week 19, to have 7 days of data for evaluation at the Week 20 
visit.
c Safety FU visit is relative to the last dose of study medication and is 4 weeks after the last dose.
d Targeted physical examination based on symptoms
e If there is an AE reported during a phone call, the investigator, at his / her discretion, may ask the 
patient to come for an unscheduled visit at the patient’s earliest convenience (Section 9.2.11).
f At Visit 6 (Week 12) the site will hand over AVIVO device to patients for self-application at Week 19 
and instruct them how to apply the device.
g At Visit 2: One PK sample will be drawn not earlier than 2 hours and not later than 6 hours after the 
first dose of study medication. Exact time of the first dose must be recorded by the investigator.
At Visits 4 and 5: One PK sample at each of the visits will be drawn pre-dose. Patients must not 
take study medication before the visit but should remember exact time of the previous dose.
At Visit 6: Two PK samples will be drawn post-dose
1. 2 hours after the study drug intake (range 1:30 hour to 3:29 hours)
2. 4 hours after the study drug intake (range 3:30 hours to 5:30 hours)
The minimum time between the two samples should be at least 1 hour.
Patients will be instructed to take the study drug about 2 hours before the visit and to remember the 
exact time. If a patient does not take the study drug before the visit, he / she can take it at the start 
of the visit, in which case PK sampling will occur as described above.
At Visit 7: One PK sample will be drawn 1 day after the last dose. Patients should remember the 
exact time of their last dose.
h Only NT-proBNP
i It is important that the patients remember the time of the tablet intake as precisely as possible (i.e. 
exact hour and minute) on the following days:
1.
On the day before Visits 4 and 5
2.
On the day of Visit 6
3.
On the day of their last dose. 
This information will be recorded in the patient’s file. A phone call to remind the patients is 
recommended. Investigator must record the time of the dose when the study drug is taken at the site.


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9.2
Visit description
This section was changed in Amendment 2, see Section 15.1 for details.
Visit 1 (Week -1, run-in)
9.2.1

Confirm signed informed consent is available (Section 13.4)

Allocate unique patient identification number (Section 6.5)

Eligibility assessment (Sections 6.1 and 6.2)

Demographic data collection and recording (Section 9.3.1)

Blood pressure and heart rate measurement (Section 9.6.3.4) 

Adverse events assessment (Section 9.6.1.3)

Concomitant medication collection and recording (Section 8.1)

AVIVO device application, worn for 7 days (Section 9.6.3.5)

Contact card dispensing
Visit 2 (Week 0, baseline)
9.2.2
At Visit 2 eligibility must be re-assessed before the patient is randomized to a treatment arm. 
Please note: laboratory eligibility criteria are based upon local and historical records, not 
central laboratory findings. Even retrospectively, central laboratory results from the baseline 
visit will not render a patient ineligible for the study. If a patient is not eligible for 
randomization, or withdraws for other reasons before randomization, he / she will be 
considered a screening failure even though the visit is not named a screening visit (for details 
see Section 6.4.1).
The following procedures will be performed before randomization:

Review in/exclusion criteria and confirm patient eligibility

Quality of life questionnaires (KCCQ and EQ-5D-5L), to be completed by the patient
(Section 9.4.4)

Medical and surgical history collection and recording (Section 9.3.2)

Tobacco smoking and alcohol history collection and recording

Assessment of caffeine-containing beverage and chocolate consumption during the 
previous 4 weeks

Physical examination (Section 9.6.3.2)

Weight and height measurement (BMI will be calculated automatically)

12-lead ECG (Section 9.6.3.3)

NYHA class assessment (Section 9.4.3.2)

Blood pressure and heart rate measurement (Section 9.6.3.4)

Adverse events assessment (Section 9.6.1.3)

Concomitant medication collection and recording (Section 8.1)

Collection of AVIVO device applied at Visit 1 (Week -1)

Echocardiography (Section 9.4.1)


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
AVIVO device application, worn for 7 days (Section 9.6.3.5)
After all above procedures are done, the patient can be randomized via IxRS (Section 7.3).
The following procedures should be performed after randomization and before study 
medication intake:

Blood sampling for safety (Section 9.6.3.1)

Blood and urine sampling for biomarkers (Section 9.4.2)

Study drug dispensing (Section 7.7)
The following procedures should be performed during and after study medication intake:

Start of study medication (Section 7.1). The first dose of study medication will be 
taken after all previous procedures are completed; the time of intake should be 
recorded. The patients will be instructed to remember the time of medication intake as 
precisely as possible on selected days.

PK sampling not earlier than 2 hours and not later than 6 hours after the first dose of 
study medication; exact time of PK sampling and drug intake is to be documented in 
the patient’s file (Section 9.5)
Visit 3 (Week 2, phone call)
9.2.3
After 2 weeks of treatment (± 2 days) the site personnel will call the patients to inquire about 
adverse events and to collect information on concomitant medications. If there is an AE 
reported during the phone call, the investigator may ask the patient to come for an 
unscheduled visit (Section 9.2.11). Information collected during the phone call must be 
recorded in the patient’s medical records / source documents.
Visit 4 (Week 4)
9.2.4

Quality of life questionnaire (KCCQ), to be completed by the patient (Section 9.4.4.1)

Physical examination (Section 9.6.3.2) 

Weight measurement

NYHA class assessment (Section 9.4.3.2)

Blood pressure and heart rate measurement (Section 9.6.3.4)

Adverse events assessment (Section 9.6.1.3)

Concomitant medication collection and recording (Section 8.1)

Collection of AVIVO device applied at Visit 2 (Week 0)

Blood sampling for safety (Section 9.6.3.1)

PK sampling (pre-dose). Please note: on this day the patients should not take the study 
medication before the visit but only after the PK sampling. Ideally, the study personnel 
should contact the subject prior to Visit 4 to remind them not to take the study drug as 
usual in the morning at home. The patient should remember the time of the previous 
study drug intake as precisely as possible. Exact time of PK sampling and drug intake 
is to be documented in the patient’s file.


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
Blood and urine sampling for biomarkers (Section 9.4.2)

Study drug dispensing and unused study drug collection (Section 7.7)
Visit 5 (Week 8)
9.2.5

Physical examination (Section 9.6.3.2)

Weight measurement

NYHA class assessment (Section 9.4.3.2)

Blood pressure and heart rate measurement (Section 9.6.3.4)

Adverse events assessment (Section 9.6.1.3)

Concomitant medication collection and recording (Section 8.1)

AVIVO device application, worn for 7 days (Section 9.6.3.5)

Blood sampling for safety (Section 9.6.3.1). 

PK sampling (pre-dose). Please note: on this day the patients should not take the study 
medication before the visit but only after the PK sampling. Ideally, the study personnel 
should contact the subject prior to Visit 5 to remind them not to take the study drug as 
usual in the morning at home. The patient should remember the time of the previous 
study drug intake as precisely as possible. Exact time of PK sampling and drug intake 
is to be documented in the patient’s file.

Study drug dispensing and unused study drug collection (Section 7.7)
Visit 6 (Week 12)
9.2.6

Quality of life questionnaire (KCCQ), to be completed by the patient (Section 9.4.4.1)

PK sampling (Section 9.5):
o Study drug is to be taken at home approximately 2 hours before the visit; it is 
important that the patients remember the time of study drug intake as precisely as 
possible; a phone call on the previous day to remind the patients is recommended.
This information will be documented in the patient’s file.
o The first PK sample is to be taken approximately 2 hours after study drug intake
(range 1:30 hour to 3:29 hours). Time of sampling should be precisely 
documented in the patient’s file.
o The second PK sample is to be taken approximately 4 hours after study drug
intake (range 3:30 hours to 5:30 hours). Time of sampling should be precisely 
documented in the patient’s file.
o The minimum time between the two samples should be at least 1 hour.
If a patient does not take the study drug before the visit, he / she can take it at the start 
of the visit, in which case PK sampling will occur as described above.

Physical examination (Section 9.6.3.2)

Weight measurement

12-lead ECG (Section 9.6.3.3)


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
NYHA class assessment (Section 9.4.3.2)

Blood pressure and heart rate measurement (Section 9.6.3.4)

Adverse events assessment (Section 9.6.1.3)

Concomitant medication collection and recording (Section 8.1)

Collection of AVIVO device applied at Visit 5 (Week 8)

Handing-over AVIVO device to patients for self-application at Week 19 (Section 
9.2.7) and instruction of patients how to apply the device

Blood sampling for safety (Section 9.6.3.1)

Study drug dispensing and unused study drug collection (Section 7.7)
Reminder phone call at Week 19
9.2.7
After 19 weeks of treatment (- 2 days) the site personnel will call the patients to remind them 
to self-apply the AVIVO device provided at Visit 6 (Week 12); if the device has not been 
provided at site, it should have been shipped to the patients. If there is an AE reported during 
the phone call, the investigator will have to make sure this is further assessed at the Week 20 
visit or at an unscheduled visit prior to this. 
Every effort should be made that the Week 20 visit at the site is conducted 7 days after the 
patient has applied the AVIVO device to have 7 days of data for evaluation. Accordingly, 
scheduling of Week 19 reminder-call and Week 20 visit should be aligned to achieve this. If 
the site prefers to have an on-site visit at Week 19 for the purposes mentioned above, an 
unscheduled visit (Section 9.2.11) can be conducted instead of the phone call (the patient’s 
preference should also be considered). Information collected during the phone call must be 
recorded in the patient’s medical records / source documents.
Visit 7 (Week 20, EOT or premature discontinuation)
9.2.8
The last dose of study drug should be taken the day before the visit. The patients should 
remember the time of the last dose as precisely as possible; this information will be recorded 
in the patient’s file. It is recommended to make a reminder phone call to the patients on the 
previous day.
If a patient discontinues study treatment prematurely, this visit should be completed as soon 
as possible after the last dose.

Quality of life questionnaires (KCCQ and EQ-5D-5L), to be completed by the patient 
(Section 9.4.4)

Physical examination (Section 9.6.3.2)

Weight measurement 

Assessment of caffeine-containing beverage and chocolate consumption during the 
previous 4 weeks

12-lead ECG (Section 9.6.3.3)

NYHA class assessment (Section 9.4.3.2)


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
Blood pressure and heart rate measurement (Section 9.6.3.4)

Adverse events assessment (Section 9.6.1.3)

Concomitant medication collection and recording (Section 8.1)

Collection of AVIVO device applied at Week 19 

Echocardiography (Section 9.4.1)

Blood sampling for safety (Section 9.6.3.1)

PK sampling one day after the last dose (Section 9.5)

Blood and urine sampling for biomarkers (Section 9.4.2)

Unused study drug collection (Section 7.7)
Visit 8 (Week 24, safety follow-up)
9.2.9
If a patient discontinues study treatment prematurely this visit should be completed 4 weeks 
±2 days after the last dose.

Physical examination (targeted examination based on symptoms) (Section 9.6.3.2)

Weight measurement 

NYHA class assessment (Section 9.4.3.2)

Blood pressure and heart rate measurement (Section 9.6.3.4)

Adverse events assessment (Section 9.6.1.3)

Concomitant medication collection and recording (Section 8.1)

Blood sampling for safety (Section 9.6.3.1)

PK sampling (Section 9.5)

Blood sampling for NT-proBNP (Section 9.4.2)
Visit 9 (Week 26, phone call)
9.2.10
Twenty-six weeks after the start of study treatment the site personnel will call the patients to 
inquire about adverse events, including cardiovascular events, and to collect information on 
concomitant medications. For patients who discontinue study drug treatment early, the phone 
call will still be made 26 weeks after the start of study treatment. Information collected during 
the phone call must be recorded in the patient’s medical records / source documents.
Unscheduled Visit 
9.2.11
If a patient experiences an adverse event for which the investigator determines a follow-up 
site visit is necessary (either before the next scheduled study visit or during the Week 26
phone call), then the following assessments will be performed:

Physical examination (Section 9.6.3.2)

Weight measurement 

NYHA class assessment (Section 9.4.3.2)


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
Blood pressure and heart rate measurement (Section 9.6.3.4)

Adverse events assessment (Section 9.6.1.3)

Concomitant medication collection and recording (Section 8.1)

Blood sampling for safety (Section 9.6.3.1)
9.3
Population characteristics
Demographic and vital signs
9.3.1
The following demographic and vital signs data will be collected and recorded in the eCRF:

Year of birth

Age (to be calculated by the investigator)

Gender

Race / ethnicity (collection may be restricted per local regulations)

Weight

Height
BMI will be calculated automatically.
Medical history
9.3.2
Medical history findings (i.e. previous diagnoses, diseases or surgeries) meeting all criteria 
listed below will be collected as available to the investigator:

Start before signing of the informed consent 

Pertaining to the study indication

Considered relevant to the study (e.g. cardiovascular and metabolic diseases)

Considered relevant for the patient’s study eligibility

Related to concomitant medication
Detailed instructions on the differentiation between (i) medical history and (ii) adverse events 
can be found in Section 9.6.1.1.
Other baseline characteristics
9.3.3
In addition, the following baseline characteristics will be collected and recorded:

Pre-defined medical history

NYHA class

Tobacco smoking history

Alcohol consumption history

Recent caffeine-containing beverage and chocolate consumption history


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9.4
Efficacy
Echocardiography
9.4.1
Transthoracic echocardiography and tissue Doppler will be performed at the time points 
specified in Section 9.1. The readings will be assessed centrally. SBP, DBP, and HR will be 
measured during echocardiography in addition to acquisition of echo data. The following 
parameters (but not limited to) will be analyzed by the central reader:

LV ejection fraction (LVEF, %)

LV end-diastolic volume (LVEDV), LVEDV index (LVEDVI, calculated as 
LVEDV/BSA) 

LV end-systolic volume (LVESV), LVESV index (LVESVI, calculated as 
LVESV/BSA)

LA size (LA diameter, area, volume index [LAVI, calculated as LAV/BSA])

Lateral e' (early diastolic mitral annular relaxation velocity at the lateral mitral annulus 
by Tissue Doppler, TD)

Septal e' (early diastolic mitral annular relaxation velocity at septal mitral annulus by 
TD), including calculation of average e'

Global longitudinal strain (%)

Pulmonary artery systolic pressure (PASP), estimated by tricuspid regurgitation 
velocity and inferior vena cava diameter, including its change with respiration, and 
hepatic vein flow in patients with tricuspid regurgitation

Tricuspid annular plane systolic excursion (TAPSE), right ventricular (RV) s' 
(velocity of the tricuspid annular systolic excursion at the RV free wall by TD)

Mitral regurgitation

LV mass, LV mass index (calculated as LV mass/BSA)

Wall thicknesses, incl. interventricular septum diameter (IVSD), posterior wall 
thickness (PWT), anteroseptal wall thickness (ASWT)

E, A (if in sinus rhythm), calculation of E/A and E/e' (using lateral, septal, average e') 
ratios

E-wave deceleration time (EWDT)

Stroke volume (SV, calculated by LVEDV - LVESV) and derived parameters, 
including SV index (SVI, calculated as SV/BSA), cardiac output (CO, calculated as 
SV*HR), cardiac index (CI, calculated as CO/BSA), systemic arterial compliance 
(SAC, calculated as SV/PP), total peripheral resistance (TPR, calculated as 
MAP/CO*80)

Effective arterial elastance (Ea), estimated as end-systolic pressure (Pes) [Pes 
calculated as SBP times 0.9 (44)] divided by SV (SBP*0.9/SV)
Final details of all echocardiography parameters to be measured and analyzed will be 
included in a separate echocardiography manual.


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Biomarker investigations
9.4.2
This section was changed in Amendment 2, see Section 15.1 for details.
Biomarker investigations in the present study will include the biomarkers listed below. 
Mandatory (sampled at all time points): 
-
NT-proBNP (baseline disease status & efficacy)
-
High sensitivity troponin T (hs-TNT) (baseline disease status)
-
Cystatin C (baseline disease status & efficacy)
-
Free fatty acid (FFA) (target engagement / mechanistic marker)
-
Urine albumin-to-creatinine ratio (UACR)
-
Hemoglobin A1c (HbA1c) (target engagement / mechanistic marker)
-
Neutrophil gelatinase-associated lipocalin (NGAL) (baseline disease status & 
efficacy)
Additional exploratory biomarker sampling:
-
Soluble suppression of tumorigenicity-2 (sST2) (baseline disease status & efficacy)
-
Galectin-3 (Gal-3) (baseline disease status & efficacy)
-
Growth differentiation factor 15 (GDF-15) (baseline disease status & efficacy)
-
Mid-regional pro-atrial natriuretic peptide (MR-proANP) (baseline disease status & 
efficacy)
-
Copeptin (baseline disease status & efficacy)
-
Osteopontin (OPN) (baseline disease status & efficacy)
-
Tissue inhibitor of metalloproteinase-4 (TIMP-4) (baseline disease status & efficacy)
-
Additional newly emerging HF or safety biomarkers
Blood sampling for biomarkers is scheduled for the time points as given in Section 9.1. All 
biomarkers will be measured using validated assay systems. Quality control (QC) and 
calibration samples will be analyzed concurrently with study samples. The results of the QC 
samples will be reported in a separate analytical report. Details on the collection, processing, 
storage and shipment of biomarker samples will be provided in separate documents (e.g. 
sample handling sheets or lab manual). Additional exploratory biomarkers sampling is to be 
used for research purposes to identify and / or verify biomarkers that are predictive or 
correlate with the efficacy / safety and the response in terms of tolerability of neladenoson 
bialanate. The analysis of exploratory biomarker may include the listed above exploratory 
biomarkers, safety biomarkers or new emerging HF biomarkers. Exploratory biomarker 
statistics may be reported separately. Exploratory biomarker analysis completed in the first 
year after the end of the study will be reported back to the investigator, if this provides 
additional meaningful information. Pure exploratory measures without an established 
interpretation might be withheld of reporting, considering that this will be of no value to the 
investigator or patient. The steering committee will provide guidance to the sponsor on 
reporting of exploratory biomarkers to investigators and patients.


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In addition to the biomarkers listed above, other biomarkers deemed relevant to gain further 
knowledge about the pathomechanism of the disease or about the drug (i.e. mode of action 
related effect or safety of the drug) may be measured, based on newly emerging data from 
other ongoing studies and / or literature data.
Table 9–2: Sample types used for biomarker investigations
Sample type, short form
Description
Biomarker serum
Blood sample for serum preparation for biomarker analysis
Biomarker plasma 
Blood sample for plasma preparation for biomarker analysis
Biomarker urine
Urine sample for biomarker analysis
Clinical efficacy variables
9.4.3
9.4.3.1
Clinical outcome events
The following clinical outcome events will be collected:

All deaths (CV and non-CV)

HF hospitalizations and urgent visits for HF

Myocardial infarction

Stroke
The CEC will adjudicate all deaths as either CV or non-CV, and other events listed above in 
accordance with the pre-specified endpoint criteria in the adjudication charter. Investigators 
are mandated to report all suspected potential endpoints for adjudication by the CEC.
Events for adjudication should be reported as soon as critical data (as defined in the eCRF 
page) to the event adjudication is available. A query will be posted for events that require 
additional supporting documentation from the sites in order to render an adjudicated result 
and will be followed up by the sponsor. Every effort will be made to provide the CEC with 
clean eCRF data and required clinical data prior to event adjudication.
9.4.3.2
NYHA class assessment
NYHA 
class
Symptoms
I
Patients with cardiac disease but without resulting limitation of physical activity. Ordinary physical 
activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain.
II
Patients with cardiac disease resulting in slight limitation of physical activity. They are comfortable at 
rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain.
III
Patients with cardiac disease resulting in marked limitation of physical activity. They are comfortable 
at rest. Less than ordinary activity causes fatigue, palpitation, dyspnea, or anginal pain.
IV
Patients with cardiac disease resulting in inability to carry on any physical activity without discomfort. 
Symptoms of heart failure or the anginal syndrome may be present even at rest. If any physical 
activity is undertaken, discomfort is increased.
Source: (45)


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Patient-reported outcomes
9.4.4
At study visits where the questionnaire is required (see Table 9–1), patients should complete it
before any other study procedures or assessments.
At collection, the questionnaire will be reviewed for completeness, and the patient will be 
encouraged to answer any blank data fields. Subsequently, a member of the investigator’s 
team will enter the responses into the eCRF. Details about scoring and calculating algorithms 
will be provided in the SAP.
9.4.4.1
KCCQ
The KCCQ is the leading health-related quality-of-life measure for patients with CHF. It was 
developed in the late 1990s to early 2000s by Dr. John Spertus at the Mid-America Heart 
Institute, Kansas City, MO, USA. It is a 23-item questionnaire that independently measures 
the impact of patients’ HF, or its treatment, on 7 distinct domains: 
1) Symptom Frequency – the KCCQ Symptom scale quantifies the frequency of clinical 
symptoms in HF, including fatigue, shortness of breath, paroxysmal nocturnal dyspnea, 
and edema / swelling.
2) Symptom Burden – the KCCQ Symptom burden scale quantifies the severity of clinical 
symptoms in HF, including fatigue, shortness of breath and edema / swelling.
3) Physical Limitation – the KCCQ Physical limitation scale measures the limitations 
patients experience, due to their HF, in performing routine activities.
4) Quality of Life – the KCCQ Quality of life scale is designed to reflect patients’ 
assessment of their quality of life, given the current status of their HF. 
5) Social Limitations – the KCCQ Social limitation scale quantifies the extent to which HF 
symptoms impair patients’ abilities to interact in social roles.
6) Self-efficacy – numerous studies have underscored the importance of patients being 
engaged in the management of their disease. The KCCQ Self-efficacy scale quantifies 
patients’ perception of how to prevent HF exacerbations and manage complications when 
they arise.
7) Symptoms Stability– unlike the other 5 domains that provide cross-sectional 
quantification of patients’ current status, the KCCQ Symptom stability domain measures 
recent changes in patients’ symptoms. As a measure of change, it is most interpretable as 
a baseline assessment of the stability of patients’ symptoms at the start of the study and 
thereafter.
In addition, there are 3 summary scores, a Total Symptom Score that combines the Symptom 
Frequency and the Symptom Burden scores, a Clinical Summary Score that combines the 
Total Symptom and Physical Limitation scores to replicate the NYHA classification; and an 
Overall Summary Score that includes the Total Symptom, Physical Limitation, Social 
Limitations, and Quality of Life scores (Figure 9–1).


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Figure 9–1: KCCQ Scores
9.4.4.2
EQ-5D-5L
The EQ-5D-5L consists of 2 pages: the EQ-5D-5L descriptive system and the EQ visual 
analogue scale (EQ VAS). The EQ-5D-5L descriptive system comprises 5 dimensions: 
mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Each 
dimension has 5 levels: no problems, slight problems, moderate problems, severe problems 
and extreme problems. The respondent is asked to indicate his / her health state by ticking (or 
placing a cross) in the box against the most appropriate statement in each of the 5 dimensions.
The EQ VAS records the respondent’s self-rated health on a vertical, visual analogue scale 
where the endpoints are labeled ‘the best health you can imagine’ and ‘the worst health you 
can imagine’. This information can be used as a quantitative measure of health outcome as 
judged by the individual respondents.
9.5
Pharmacokinetics / pharmacodynamics
It is planned to collect PK samples from all patients randomized. The data collected are 
intended to be used for PK analysis of the study population as a whole and should also give 
information about individual exposure to BAY 84-3174. Only the active metabolite BAY 84-
3174 will be measured from the plasma samples collected (see Section 7.2 for details 
regarding different BAY numbers). 
A sparse sampling schema has been developed, which will allow for a limited number of PK 
samples to be obtained from each patient. The sampling time points have been included in the 
flow chart (see Table 9–1). The PK sampling schedule is detailed in the visit description 
(Section 9.2). It is important to exactly record in the patient’s file the time point when the PK 
sample is taken, as well as the times of the most recent medication intake prior to the blood 
sampling. The sampling variability will be used for modelling the PK and PD characteristics 
of the study medication.
Details about the collection, processing, storage and shipment of samples will be provided 
separately (e.g. sample handling sheets or laboratory manual).


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9.6
Safety
Adverse events
9.6.1
9.6.1.1
Definitions
Definition of adverse event (AE)
In a clinical study, an AE is any untoward medical occurrence (i.e. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
A surgical procedure that was planned prior to the start of the study by any physician treating 
the patient should not be recorded as an AE (however, the condition for which the surgery is 
required may be an AE).
In the following differentiation between medical history and AEs, the term “condition” may 
include abnormal physical examination findings, symptoms, diseases, laboratory, or ECG 
findings.
Conditions that started before signing of informed consent and for which no symptoms 
or treatment are present until signing of informed consent are recorded as medical 
history (e.g. seasonal allergy without acute complaints).
Conditions that started before signing of informed consent and for which symptoms or 
treatment are present after signing of informed consent, at unchanged intensity, are 
recorded as medical history (e.g. allergic pollinosis).
Conditions that started or deteriorated after signing of informed consent will be 
documented as adverse events.
Definition of serious adverse event (SAE)
An SAE is classified as any untoward medical occurrence that, at any dose, meets any of the 
following criteria (a – f):
a.
Results in death
b. Is life-threatening
The term ‘life-threatening’ in the definition 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 which 
hypothetically might have caused death if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
A hospitalization or prolongation of hospitalization will not be regarded as an SAE if 
at least one of the following exceptions is met:
The admission results in a hospital stay of less than 12 hours
The admission is pre-planned 


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(e.g. elective or scheduled surgery arranged prior to the start of the study; 
admission is part of the study procedures as described in Section 9.2)
The admission is not associated with an AE 
(e.g. social hospitalization for purposes of respite care).
However, it should be noted that invasive treatment during any hospitalization may 
fulfill the criterion of ‘medically important’ and as such may be reportable as an SAE 
dependent on clinical judgment. In addition, where local regulatory authorities 
specifically require a more stringent definition, the local regulation takes precedence.
d. Results in persistent or significant disability / incapacity
Disability means a substantial disruption of a person’s ability to conduct normal life’s 
functions.
e.
Is a congenital anomaly / birth defect
f.
Is another serious or important medical event as judged by the investigator
Definition of treatment-emergent adverse event
An AE is classified as treatment-emergent if it occurs or worsens after the first dose of study 
drug up to 6 weeks after the last dose of study drug.
9.6.1.2
Classifications for adverse event assessment
All AEs will be assessed and documented by the investigator according to the categories 
detailed below.
9.6.1.2.1
Seriousness
For each AE, the seriousness must be determined according to the criteria given in 
Section 9.6.1.1.
9.6.1.2.2
Intensity
The intensity of an AE is classified according to the following categories:

Mild - usually transient in nature and generally not interfering with normal activities

Moderate - sufficiently discomforting to interfere with normal activities

Severe - prevents normal activities
9.6.1.2.3
Causal relationship 
The assessment of the causal relationship between an AE and the administration of treatment 
is a decision to be made by the investigator, who is a qualified physician, based on all 
information available at the time of the completion of the CRF.
The assessment is based on the question whether there was a “reasonable causal relationship” 
to the study treatment in question.
Possible answers are “yes” or “no”.
An assessment of “no” would include:


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1.
The existence of a highly likely alternative explanation, e.g. mechanical bleeding at 
surgical site.
or
2.
Non-plausibility, e.g. the patient is struck by an automobile when there is no indication 
that the drug caused disorientation that may have caused the event; cancer developing a 
few days after the first drug administration.
An assessment of “yes” indicates that that the AE is reasonably associated with the use of the 
study treatment.
Factors to be considered in assessing the relationship of the AE to study treatment include:
The temporal sequence from drug administration: The event should occur after the drug is 
given. The length of time from drug exposure to event should be evaluated in the clinical 
context of the event.
Recovery on drug discontinuation (de-challenge), recurrence on drug re-introduction 
(re-challenge): Patient’s response after de-challenge or re-challenge should be considered 
in view of the usual clinical course of the event in question.
Underlying, concomitant, intercurrent diseases: 
Each event should be evaluated in the context of the natural history and course of the 
disease being treated and any other disease the patient may have.
Concomitant medication or treatment: 
The other drugs the patient is taking or the treatment the patient receives should be 
examined to determine whether any of them might have caused the event in question.
Known response pattern for this class of drug.
Exposure to physical and / or mental stresses: The exposure to stress might induce adverse 
changes in the recipient and provide a logical and better explanation for the event
The pharmacology and pharmacokinetics of the study treatment: 
The pharmacokinetic properties (absorption, distribution, metabolism and excretion) of 
the study treatment, coupled with the individual patient’s pharmacodynamics should be 
considered.
The assessment is not possible.
Causal relationship to protocol-required procedure(s)
The assessment of a possible causal relationship between the AE and protocol-required 
procedure(s) is based on the question whether there was a “reasonable causal relationship” to 
protocol-required procedure(s).
Possible answers are “yes” or “no”.


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9.6.1.2.4
Action taken with study treatment 
Any action on study treatment to resolve the AE is to be documented using the categories 
listed below.
Drug withdrawn
Drug interrupted
Dose not changed
Not applicable
Unknown
9.6.1.2.5
Other specific treatment(s) of adverse events
None
Remedial drug therapy
Other
9.6.1.2.6
Outcome
The outcome of the AE is to be documented as follows: 
Recovered / resolved
Recovering / resolving
Recovered / resolved with sequelae
Not recovered / not resolved
Fatal
Unknown
9.6.1.3
Assessments and documentation of adverse events
The investigator has to record on the respective CRF pages all adverse events occurring in the 
period between the signing of the informed consent and the end of the follow-up phase; after 
the end of the follow-up phase there is no requirement to actively collect AEs including 
deaths. The type of information that should be assessed and recorded by the investigator for 
each AE is listed in Section 9.6.1.2. 
“Death” should not be recorded as an AE on the AE page. Instead, “death” is the outcome of 
an underlying AE(s).
For all serious adverse events (SAEs) the sponsor has to carry out a separate assessment for 
expectedness, seriousness and causal relationship to study drug.
9.6.1.4
Reporting of serious adverse events
The definition of serious adverse events (SAEs) is given in Section 9.6.1.1. Each SAE must 
be followed up until resolution or stabilization by submission of updated reports to the 
designated recipient.


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If an SAE is unexpected, i.e. the event is not previously documented in the investigator’s 
brochure (IB) (new occurrence) and is suspected to be related to the study drug, this event is 
considered a Suspected Unexpected Serious Adverse Reaction (SUSAR). In general, SUSARs 
will be unblinded by the sponsor for regulatory reporting (see below for exceptions). 
Investigator’s notification of the sponsor
All investigators will be thoroughly instructed and trained on all relevant aspects of the 
investigator’s reporting obligations for SAEs. This information, including all relevant contact 
details, is summarized in the investigator site file. This information will be updated as needed.
The investigator must report immediately (within 24 hours of the investigator’s awareness) all 
SAEs occurring during the observation period defined in Section 9.6.1.3 to the recipient 
detailed in the instructions for SAE reporting included in the Investigator File. For this, an AE 
page and the complementary SAE pages in the CRF must be completed for each SAE.
SAEs occurring after the protocol-defined observation period will be processed by the 
sponsor according to all applicable regulations.
Notification of the IECs / IRBs
Notification of the IECs / IRBs about all relevant events (e.g. SAEs, SUSARs) will be 
performed by the sponsor and / or by the investigator according to all applicable regulations.
Notification of the authorities
The processing and reporting of all relevant events (e.g. SAEs, SUSARs) to the authorities 
will be done by the sponsor according to all applicable regulations.
Sponsor’s notification of the investigational site
The sponsor will inform all investigational sites about reported relevant events (e.g. SUSARs) 
according to all applicable regulations.
Protocol-specific exceptions to SAE unblinding / reporting
If reported as SUSARs, the following clinical events will be exempted from unblinding and 
expedited reporting by the sponsor to investigators, IECs / IRBs, and regulatory agencies, 
since they are considered, consistent with the underlying condition, as disease related in the 
defined study population:

CV death 

Worsening of heart failure

Non-fatal myocardial infarction

Non-fatal stroke

Transient ischemic attack

Cardiac arrhythmias

Coronary revascularization procedures.


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Note that all of these events will be reviewed and monitored by an external DMC unblinded 
to treatment as part of the overall assessment of safety and efficacy for neladenoson bialanate. 
Based upon their regular review of unblinded safety results, the DMC is empowered to make 
recommendations with regard to trial conduct to assure the continuing appropriate safety of 
the subjects participating in the study.
9.6.1.5
Expected adverse events
For this study, the applicable reference document is the most current version of the 
investigator’s brochure (IB) for neladenoson bialanate.
Overview listings of frequent events that have occurred so far in the clinical development are 
shown in the current IB. If relevant new safety information is identified, the information will 
be integrated into an update of the IB and distributed to all participating sites.
The expectedness of AEs will be determined by the sponsor according to the applicable 
reference document and according to all local regulations.
9.6.1.6
Adverse events of special interest
Adverse events of special interest have to be reported to the sponsor along the timelines set 
for serious adverse events (even though they may not be classified as serious), i.e. within 24 
hours of the investigator’s awareness, as described in Section 9.6.1.4.
Adverse events of special interest are:

Symptomatic bradycardia (HR < 50 bpm)

Findings in ECG and / or AVIVO device as follows:
o
Mobitz type I AV-block leading to withdrawal or interruption of study drug
o
Mobitz type II AV block leading to withdrawal or interruption of study drug or 
leading to any change in therapy 
o
Third degree AV blocks
Pregnancies
9.6.2
Females of childbearing potential are excluded from the study. However, the investigator 
must report to the sponsor any pregnancy occurring in a female study patient during her 
participation in this study. The outcome of the pregnancy should be followed up carefully, 
and any outcome of the mother and the child at delivery should be reported.
The child’s health should be evaluated at birth.
For a pregnancy in the partner of a male study patient, all efforts will be made to obtain 
similar information on course and outcome, subject to the partner’s consent.
For all reports, the forms provided are to be used. The investigator should submit them within
the same timelines as an SAE. 
Further safety
9.6.3
9.6.3.1
Laboratory evaluations
All laboratory evaluations will be done by central laboratory. Additional re-tests for liver 
monitoring (Section 9.6.3.6) will be done locally.


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Hematology: erythrocytes, hemoglobin, hematocrit, MCV, MCH, MCHC, reticulocytes, 
leukocytes, differential blood count, platelets
Clinical chemistry: aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
alkaline phosphatase (AP), gamma glutamyl transpeptidase (GGT), lactate dehydrogenase 
(LDH), creatine kinase (CK), amylase, lipase, glucose, cholesterol (HDL, LDL, total), 
triglycerides, creatinine, urea, uric acid, bilirubin, total protein, albumin, sodium, potassium, 
calcium, chloride, magnesium, anorganic phosphate
Coagulation: partial thromboplastin time (PTT), international normalized ratio (INR)
9.6.3.2
Physical examination
The physical examination (by means of inspection, palpation, auscultation) will be performed 
by a physician at the investigational site covering at least the organs of the cardiovascular, 
respiratory, abdominal and neurological system. 
Abnormal physical examination findings are recorded either as medical history or as adverse 
events (see Section 9.6.1.1).
9.6.3.3
12-lead ECG
The standard 12-lead ECG will be evaluated by the investigator and the following parameters 
will be recorded in the eCRF: HR, PR interval, QRSD interval, QT interval (uncorrected). 
QTcB (QT interval frequency-corrected according to Bazett’s formula) will also be calculated 
but will not be valid for evaluation. The frequency-corrected QT interval will be calculated by 
data management according to the formulas of both Bazett and Fridericia. 
All ECGs recorded during the study will be evaluated by a physician. He / she will document 
the diagnosis(es) including an overall assessment of the findings and their clinical relevance. 
Any clinically relevant abnormality will be documented as an AE or SAE.
9.6.3.4
Blood pressure and heart rate
Heart rate and blood pressure (systolic and diastolic) will be measured by a member of the 
investigator’s study team with the patient at rest. 
9.6.3.5
AVIVO monitoring
This section was changed in Amendment 2, see Section 15.1 for details.
AVIVO Mobile Patient Management System will be used to monitor patients’ cardiovascular 
status as part of the safety assessment. The cardiac monitoring device will be worn as 
specified in Section 9.1. 
The system is intended to continuously measure, record and periodically transmit ECG data. 
The system can detect (but is not limited to) higher degree AV-blocks > I°, SVTs (e.g. atrial 
fibrillation [AF], atrial flutter, paroxysmal SVTs), ventricular ectopy, bradyarrhythmias, 
conduction disorders and heart rate variability. Included in the service is the monitoring center 
- an independent certified diagnostic testing center staffed with ECG-trained technicians who 
read through the transmitted events 24h/7d. An electrophysiologist is also on staff for 
interpretation of difficult rhythms. The system has achieved CE mark and has US FDA 
clearance. 


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Apart from safety assessments, also the patient’s everyday physical activity (e.g. duration, 
intensity) will be tracked. 
Details of the cardiac monitoring and the device to be worn by the patient will be outlined in a 
manual that will be provided to all participating centers. 
9.6.3.6
Liver function monitoring
Any patient with an ALT or AST > 3 x ULN or alkaline phosphatase (AP) >2 x ULN must be 
re-tested as soon as possible but at the latest within 48-72 hours of the investigator becoming 
aware of the result. This re-testing and any subsequent testing based on elevated levels should 
include measurement of ALT, AST, total and direct bilirubin, and AP, and will be assessed by 
local laboratory. Every effort should be made to clarify the etiology of elevated levels. Patient 
management is at the discretion of the investigator but the treating physician may continue the 
study drug during retesting. Liver function test monitoring should be performed as above for 
all patients even if the study drug is interrupted until tested values have normalized or 
returned to patient’s baseline. If close liver monitoring is not possible then the patient should 
discontinue study medication.
For ALT or AST > 3 x ULN concurrent with a total bilirubin > 2 x ULN, every effort should 
be made to clarify any possible underlying disease(s).
The frequency of liver function tests based on re-test values is shown in Table 9–3. 
Table 9–3: Liver function monitoring 
ALT, AST or AP level
at re-test
Frequency
Further notice
ALT or AST > 3 x ULN
2-3 times a week
Obtain details on liver related symptoms and 
exclude other causes of liver enzyme elevations
ALT or AST ≤ 3 x ULN
Once a week
Until return to normal or patient baseline levels
AP >2 x ULN
2-3 times a week
Obtain details on liver related symptoms and 
exclude other causes of liver enzyme elevations
Abbreviations: ALT = alanine aminotransferase; AP = alkaline phosphatase; AST = aspartate aminotransferase; 
ULN = upper limit of normal
Discontinuation of treatment should be considered if: 

ALT or AST > 8 x ULN 

ALT or AST > 5 x ULN for more than 2 weeks 

ALT or AST > 3 x ULN and (total bilirubin >2 x ULN or INR > 1.5) 

ALT or AST > 3 x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and / or eosinophilia (> 5%) 

AP > 2 x ULN or ALT/AP < 2 for more than 2 weeks if other causes of cholestasis are 
excluded
9.7
Other procedures and variables
Not applicable.


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9.8
Appropriateness of procedures / measurements
All parameters, as well as the methods to measure them, are standard variables / methods in 
clinical studies and / or clinical practice. They are widely used and generally recognized as 
reliable, accurate, and relevant.
10.
Statistical methods and determination of sample size
10.1
General considerations
Statistical analyses will be performed by or under the supervision of the sponsor’s study 
statistician and the assigned study statistical analyst using statistical analysis system (SAS); 
the version used will be specified in the statistical analysis plan (SAP). 
A general description of the statistical methods to be used to analyze efficacy and safety in 
this is study is outlined below. A detailed SAP will be provided as a separate document that 
will be finalized and approved before database lock. The SAP will accommodate protocol 
amendments or unexpected issues in study execution or data that affect planned analyses and 
will provide more details on the analytical approaches, output tables and figures.
A meta-analysis of this study (15128) and of the study 17582 in patients with HFpEF, which 
is conducted at the same time, will be specified in a separate SAP. 
10.2
Analysis sets
Documentation of protocol deviations and assignment of patients to analysis sets will be 
performed according to the sponsor’s applicable Standard Operating Procedures and / or 
Operation Instructions.
The primary efficacy variables will be analyzed using the per-protocol set (PPS) and the full 
analysis set (FAS) for sensitivity analyses.
Data for all patients who signed informed consent but were not randomized will not be 
included in any statistical analyses except standard disposition tables and listings provided in 
the clinical study report (Screening failures and discontinued patients). 
The statistical analysis sets are defined as follows:
Full analysis set (FAS)
The FAS population consists of all randomized unique patients. According to the ICH E9 
guideline, this analysis set is as complete as possible and as close as possible to the intent-to-
treat (ITT) ideal. Patients will be analyzed as randomized. The FAS will be used to display 
baseline characteristics and to display efficacy analyses.
Safety analysis set (SAF)
The SAF population consists of all randomized patients who received at least one dose of 
study medication after randomization. The SAF will be used to display safety analyses. For 
safety analyses, patients will be analyzed as treated.


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Per-protocol set (PPS)
The PPS population consists of all FAS population patients without validity findings. Validity 
findings may include adherence and compliance issues and the violation of 
inclusion / exclusion criteria affecting efficacy evaluation. A list of potential validity findings
will be provided in a separate protocol deviation document which will be finalized before 
database lock. The detailed definitions and the assignment of patients to this analysis set will 
be based on the validity review meeting. Patients will be analyzed as treated.
Pharmacokinetic analysis set (PKS)
The PKS population consists of all patients treated with neladenoson bialanate with at least 
1 valid BAY 84-3174 plasma concentration and without protocol deviation that would 
interfere with the evaluation of the PK data.
10.3
Variables and planned statistical analyses
Variables
10.3.1
10.3.1.1
Primary efficacy variables

Absolute change from baseline in left ventricular ejection fraction (LVEF; %) after 20 
weeks measured by echocardiography.

Absolute change from baseline in log-transformed NT-proBNP (pg/mL) after 20 
weeks, i.e., log-transformed NT-proBNP at Week 20 minus log-transformed NT-
proBNP at baseline 
10.3.1.2
Secondary efficacy variables
Secondary efficacy variables across different domains are: 

Key echocardiographic parameters, measured values and absolute change from 
baseline at 20 weeks:
o
Left ventricular end-systolic volume (LVESV; mL) 
o
Left ventricular end-diastolic volume (LVEDV; mL)

High sensitivity troponin T (hs-TNT; ng/L), measured values (log transformed) and 
absolute / relative change from baseline at 20 weeks as a biomarker of myocardial 
injury

CV mortality, HF hospitalization and urgent visits for HF as clinical outcomes
10.3.1.3
Other exploratory variables
This section was changed in Amendment 2, see Section 15.1 for details.

Activity (duration, intensity) reported values and absolute change from baseline at 20 
weeks

Echocardiographic parameters, as described in Section 9.4.1, measured values and 
absolute / relative change from baseline at 20 weeks

Left ventricular ejection fraction (LVEF; %), measured values, number of patients in 
whom absolute change from baseline after 20 weeks is > 5%


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
Mandatory biomarkers, as described in Section 9.4.2, measured values and 
absolute / relative change from baseline at 20 weeks, including 
o
NT-proBNP (pg/mL), measured values and relative change from baseline at 20 
weeks to assess elevated filling pressures
o
UACR, cystatin-C, NGAL for the evaluation of kidney function 

KCCQ and EQ-5D-5L, as described in Section 9.4.4, measured values and 
absolute / relative change from baseline

All-cause mortality, non-fatal myocardial infarction, non-fatal stroke

Change in NYHA class
10.3.1.4
Safety variables
Safety and tolerability variables are:

Adverse events (Section 9.6.1), including
o
SAEs, AEs, treatment-emergent AEs and AEs of special interest, including AV 
blocks > I°
o
SAEs and AEs leading to discontinuation of interruption of study drug, 
including AV blocks in particular

Laboratory abnormalities (Section 9.6.3.1), measured values and change from 
baseline, in particular
o
Change in renal function measured by eGFR change from baseline
o
Change in liver function measured by bilirubin (total and fractions), AST and 
ALT from baseline

12-ECG abnormalities (Section 9.6.3.3) and PR interval duration

Blood pressure and heart rate (Section 9.6.3.4); measured values and change from 
baseline

Number of clinically significant findings in ECG and / or AVIVO device report
Statistical and analytical plans 
10.3.2
All data will be listed and all variables will be summarized by means of descriptive statistics 
according to their type.
Summaries by treatment group using appropriate descriptive statistics will be provided for all 
study variables including demographic and baseline characteristics. Summary statistics will be 
presented for the original data as well as for the difference to baseline. Descriptive statistics 
such as arithmetic mean (or geometric mean, if applicable), median, standard deviation, 
quantiles, minimum, and maximum will be used to summarize continuous variables. Counts 
and percentages will be used to summarize categorical variables. Life tables and 
Kaplan-Meier estimates will be used to summarize time-to-event variables. Graphical data 
displays may also be used to summarize the data. Confidence intervals will be provided at a 2-
sided level of 90% unless otherwise stated.
For this combined proof-of-concept and dose-finding study, an overall one-sided type I error 
level of 5% is planned to be used. The type I error will be controlled for the primary analysis 
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There will be no formal control of the type I error for secondary or explorative analyses of the 
primary variables and any analysis of other efficacy variables.
10.3.2.1
Subgroups
In order to assess the homogeneity of the dose response across the most important prognostic 
and predictive factors, subgroup analyses will be performed. 
‘Key’ subgroups comprise: 

LVEF(%) at baseline: ≤25 vs. >25

NT-proBNP (pg/ml) at baseline: ≤median vs. > median

NYHA class at baseline: II vs. III / IV

Prior ß-blocker: yes vs. no
Truly exploratory analyses, i.e., mainly summary statistics, will be provided for a spectrum of 
demographic, disease and clinical characteristics, including

Age (years): <65, 65-75, >75 

Gender: male vs. female

Race: White vs. non-white

Region: North America / South America / West Europe / East Europe / Asia

Region: Japan vs. rest-of-the-world (analysis to be included in reports specific for 
Japan only)

BMI at baseline (kg/m²): ≤30 vs. >30

Time of CHF diagnosis to randomization (months): ≤3 vs. >3

Prior hospitalization for heart failure: yes vs. no

Etiology of CHF: ischemic vs. non-ischemic

Diabetes: yes vs. no

Atrial fibrillation: yes vs. no

Hypertension: yes vs. no

Prior CHF medication:
o
Prior ß-blocker in max tolerated dose: yes vs. no
o
Prior use of ivabradine: yes vs. no
o
Prior use of aldosterone antagonist: yes vs. no
o
Prior use of ACE inhibitor: yes vs. no
o
Prior use of ARB: yes vs. no
o
Prior use of angiotensin receptor-neprilysin inhibitor (ARNI): yes vs. no

Estimated GFR (ml/min/1.73 m2): ≤60 vs. >60
Further details will be described in detail in the SAP. 


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10.3.2.2
Analysis of the primary efficacy variables
This section was changed in Amendment 2, see Section 15.1 for details.
For both primary efficacy variables, it is planned to perform a test for a dose-response signal,
respectively, under the assumption of a nearly monotone dose-response relationship in the 
dose range considered. The MCP-Mod method (46) combining multiple comparison 
procedures (MCP) principles with modeling techniques will be used for the primary statistical 
analysis of the primary efficacy variables. This method allows the flexibility of modeling for 
dose estimation, while preserving the robustness to model misspecification associated with 
MCP procedures.
Two primary variables have been defined to better evaluate multiple dimensions of the 
treatment effect, thereby adding a source of multiplicity. The overall outcome of the primary 
efficacy analysis will be considered positive if at least one of the two null hypotheses related 
to the primary efficacy variables can be rejected. The Hochberg (step-up) procedure will be 
applied to control the family-wise error rate (FWER):
Consider the null hypotheses for LVEF, H0,LVEF, and for NT-proBNP, H0,NT-proBNP, and their 
associated raw p-values pLVEF and pNT-proBNP. The Hochberg test is performed using the 
following steps:
1. If max(pLVEF, pNT-proBNP) ≤α = 0.05, both null hypotheses H0,LVEF and H0,NT-proBNP will 
be rejected and the procedure stops. 
2. If max(pLVEF, pNT-proBNP) > α = 0.05 and min(pLVEF, pNT-proBNP) ≤α/2 = 0.025,
the null hypothesis related to the larger p-value max(pLVEF, pNT-proBNP) will be accepted 
and the null hypothesis related to the smaller p-value min(pLVEF, pNT-proBNP) will be 
rejected. 
3. Otherwise, both null hypotheses H0,LVEF and H0,NT-proBNP will be accepted.
Assumptions
Five active doses of neladenoson bialanate will be used in this study: 5 mg, 10 mg, 20 mg, 30
mg, and 40 mg, as well as a placebo arm corresponding to a 0 mg dose. 
The measurements of the primary efficacy variables are assumed to be normally distributed 
with the same standard deviation σ and independent between patients, respectively.
LVEF: The following assumptions were made for the absolute change from baseline in LVEF 
over 20 weeks:

the expected mean effect under the placebo dose is conservatively assumed as an 
absolute increase from baseline of up to = 2% with a standard deviation of = 7%

while the maximum observable mean effect under neladenoson bialanate within the 
dose range considered is assumed as an absolute increase of = 5% with a standard 
deviation of = 7%.
This results in an expected maximum effect size of (5-2)/7 = 3/7 = 0.43 under conservative 
assumptions. Note that the threshold of clinical relevance is an absolute difference of 3% in 
the change from baseline over the placebo control group.


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NT-proBNP: The following assumptions were made for the absolute change from baseline in 
the log-transformed NT-proBNP over 20 weeks:

the expected mean effect under the placebo dose is assumed as an absolute decrease 
from baseline of -0.105 log(pg/mL) with a standard deviation of = 0.85 log(pg/mL), 
which is equivalent to a 10% relative reduction from a mean of 2,500 pg/mL at 
baseline.

while the maximum observable mean effect under neladenoson bialanate within the 
dose range considered is assumed as an absolute decrease from baseline of 
-0.357 log(pg/mL) with a standard deviation of = 0.85 log(pg/mL), which is 
equivalent to a 30% relative reduction from a mean of 2,500 pg/mL at baseline.
It is assumed that the respective primary response efficacy variable, denoted as , is observed 
for the 6 parallel groups corresponding to doses levels: (placebo =) 1 < 2 < … < k, where 
k = 6.
For patient j within treatment group i the response can then be described by the following 
model:
 = 	(, ) + ,       ~(0, ),       = 1, … , ,    = 1,  … ,  ,  
where 	(. ) is parameterized by a vector of parameters  and  is the error term.
A candidate set with M=5 different dose response shapes (. ) based on four models was 
chosen for the MCP-Mod method. Table 10–1 displays the response expressions for the 
shapes in the candidate sets for both, change in LVEF and change in log-transformed NT-
proBNP. Figure 10–1 shows the corresponding dose-response shapes for change in LVEF.
The model parameters were obtained through discussions with experts in the clinical team, 
taking prior beliefs and uncertainty into account. The dose-response shapes for NT-proBNP 
are equivalent to those for LVEF but with decreasing trends. 
Table 10–1: Dose-response shapes used in the candidate set
Model
Response as function of dose d
LVEF
NT-proBNP
Linear
2 + 0.075d
–0.105 – 0.0063d
Sigmoidal Emax 1
2 + 3.007689d4 / (94 + d4)
–0.105 – 0.2526d4 / (94 + d4)
Sigmoidal Emax 2
2 + 3.375d3 / (203 + d3)
–0.105 – 0.2835d3 / (203 + d3)
Emax
2 + 3.09375d / (1.25 + d)
–0.105 – 0.2599d / (1.25 + d)
Quadratic
2 + 0.2d – 0.00333d²
–0.105 – 0.0168d + 0.00028d²


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Figure 10–1: Dose-response shapes used in the candidate set for change in LVEF
Abbreviations: LVEF = left ventricular ejection fraction
Based on the standardized versions of the models in the candidate set and the sample size 
allocation planned for this study, the optimum contrast coefficients for the 5 contrast tests on 
the dose-response shapes can be derived for both primary variables.
Analysis
Step 1: Detection of dose-response signal
For detecting an overall trend, or a dose-response signal, each of the M=5 dose-response 
shapes in the candidate set will be tested, using a single contrast test based on the updated 
version of contrast coefficients taking the actual sample sizes per treatment group into 
account.
For each model m, m = 1, …, 5, in the candidate set 
the null hypothesis
: !"
 = 0
will be tested against 
the respective 1-sided alternative hypothesis
#: !"
 > 0,
where "
 = ("#
 , … , "%
 )& = (	
(#, 
 ), … , 	
(%, 
 ))′ and
	 is the standardized version of the dose-response model 	(, ) = ( + (#	(, ). In 
this parameterization, ( is a location parameter and (# is a scale parameter such that only 
 determines the shape of the model function. 


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A “proof-of-concept” dose-response relationship is detected if at least one single contrast test, 
is statistically significant, while controlling the family-wise error rate at level . The smallest 
of the corresponding adjusted p-values will be used for the Hochberg test.
This analysis will be performed for the FAS and PPS populations, where the PPS analysis is 
the primary analysis.
If no candidate model is statistically significant, the procedure stops, indicating that a dose-
response relationship cannot be established from the observed data.
Out of the statistically significant models in the candidate set a best model can be selected for 
the next step: modeling and estimation.
Step 2: Modeling and estimation of target doses
If a dose-response signal is established, the selected dose-response model(s) will be fitted to 
the observed data to estimate the model parameters. 
The estimated dose-response model will be plotted against the doses including 90% 
confidence bands. Once the dose-response model has been successfully fitted to the data, 
target dose(s) of interest are estimated. Given a clinically relevant effect ∆ , a minimum 
effective dose (*+,∆) associated with model 	(, ) is defined as
*+,∆= argmin3∈(35,36]{	(, ) ≥	(#, ) + ∆}.
Estimates of *+,∆will be calculated for a clinically relevant change in LVEF assumed as 
∆ = 3% and potentially a plausible range of ∆values which will be defined in the SAP. 
Estimation for change in log-transformed NT-proBNP will be performed analogously, 
ensuring an adequate back-transformation to allow for better interpretability of the results. In 
addition, estimates considering confidence bounds for the predicted value at a certain dose 
may be used. The final choice of the target dose depends on the evaluation of the primary 
efficacy variables and other efficacy variables, as well as safety considerations.
Modeling and estimation will be performed for the FAS and PPS populations as well as for 
relevant subgroups.
Further details will be described in the SAP.
As a secondary analysis pairwise comparisons of the active neladenoson bialanate dose 
groups with the placebo group will be performed without controlling the family-wise error 
rate.
10.3.2.3
Analysis of the secondary efficacy variables
The primary analysis of secondary efficacy variables will be performed in PPS, sensitivity 
analyses might be performed in the FAS. The secondary efficacy variables, except for the 
clinical outcomes, will be analyzed using similar statistical methods as for the primary 
efficacy variables, i.e. the MCP-Mod method with the same standardized candidate dose-
response shapes (with the proper direction: increasing or decreasing trend) and corresponding
coefficients as for the primary variables. In addition to analyses comparing population means 
in the different dose groups, the number of patients in whom the individual change from
baseline value crossed clinically meaningful thresholds will be analyzed. The totality of 


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evidence for the primary and secondary efficacy variables will be combined and used to 
assess the drug effect over dose levels.
Time to clinical outcome events since randomization (using both separate and composite 
outcomes) will be described by means of life table statistics and Kaplan-Meier estimates.
All other efficacy variables will be analyzed descriptively. 
Further details will be described in the SAP.
10.3.2.4
Analysis of the safety variables 
If not indicated otherwise, evaluation of safety variables will be done using the SAF.
Adverse events
The adverse events (AE) analysis will be performed as treated in the SAF. All tabulations will 
be descriptive only.
Individual listings of AEs will be provided. The incidence of treatment-emergent AEs and 
drug-related (treatment-emergent) AEs will be tabulated by treatment group using MedDRA 
terms. Separate tables and listing for serious AEs and death will be provided. 
Further safety parameters
The safety evaluation of laboratory data will include:

Descriptive analysis of continuous laboratory parameters, and their changes from 
baseline by visit and treatment group.

Incidence rates of treatment-emergent laboratory values outside of normal range by 
treatment group.

Listings of laboratory data out of normal range.
Vital signs and their changes from baseline will be analyzed descriptively by visit and by 
treatment group.
ECG-findings (like AV-conduction abnormalities) will be summarized in frequency tables. A 
table displaying the number of patients with AV-block > I° will be provided.
Data from the AVIVO monitoring will be summarized; details will be described in the SAP.
Summary statistics and figures of heart rate and blood pressure (systolic, diastolic, and mean 
arterial pressure) will be created.
10.3.2.5
Pharmacokinetic analyses
Pharmacokinetic analyses will be performed on the population valid for pharmacokinetics.
For the investigation of systemic exposure to BAY 84-3174 and its relationship with 
treatment effects, the plasma concentrations of BAY 84-3174 will be determined at different 
time points using a sparse sampling approach in all participating patients (see Section 9.5).
The plasma concentration vs. time data will be evaluated descriptively separated by dose and 
visit. Plots will be prepared pooling all individual plasma concentrations (naive pooling) vs. 
actual relative study times (time of sample collection after time of study drug administration).


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Furthermore, the pharmacokinetic data and the relationship of markers of BAY 84-3174 
exposure (e.g. Cmax, AUC) with treatment effects will be evaluated using non-linear mixed 
effect modeling (NONMEM). The latter evaluation will be described in a separate analysis 
plan and will be reported under separate cover.
The PK bioanalysis will be performed under the responsibility of the Sponsor’s Bioanalytics 
Laboratory.
10.3.2.6
Biomarker analyses
Biomarker data will be described by the following summary statistics: arithmetic mean, 
standard deviation, median, quantiles, minimum, and maximum.
Graphical displays of individual data as well as mean values with standard deviation will be 
included.
Missing data, censoring due to death, and drop outs 
10.3.3
Generally, missing data will be handled as such, i.e., no imputation of missing data will be 
performed. An exception is the analysis of the primary and secondary efficacy variables 
(except for the clinical outcomes), as described below, and the timing of events relative to 
other events. For this purpose, data rules for the handling of missing or incomplete dates will 
be described in the SAP.
All missing or partial data will be presented in the patient data listing as they are recorded in 
the eCRF. 
A number of descriptive analyses will be performed to better understand missing data 
patterns. The frequency, proportion and the reasons for premature discontinuation of both the 
study and study treatment will be reported. Kaplan-Meier plots for “time to end of study 
treatment (calculated as days from first dose to the earliest date of last dose, including 
premature stop of study medication and death)” and “time to end of study” will be provided, 
by treatment group and overall. 
The number of patients who prematurely discontinue study participation or intake of study 
medication will be carefully evaluated with respect to the key baseline characteristics, which 
will be further specified in the SAP, and the reasons for premature discontinuation of study 
and / or study treatment. If the proportion of patients who withdraw across the dose groups is 
not fairly balanced, the impact on the primary variables will be further explored. To further 
explore the missingness pattern with regards to the “missing at random” assumption, the mean 
of the baseline values of the efficacy variable will be summarized for patients with and 
without post-baseline observations, by treatment group and overall. 
For the analysis of the primary and secondary variables, it cannot necessarily be assumed that 
data are missing at random. As the choice of primary analysis will be based on assumptions 
that cannot be verified, the robustness of the results of the primary analysis will be 
investigated through appropriate sensitivity analyses making different assumptions, in 
accordance with the European Medicines Agency (EMA) “Guideline on missing data in 
confirmatory clinical trials”.


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Efficacy analysis using the PPS
The primary efficacy analysis aims at evaluating the dose-response relationship of the primary 
and secondary efficacy variables (except for clinical outcomes) for all randomized patients
who have remained in the study and adhered to study treatment according to the study 
protocol until Week 20 (“completers and treatment adherers” analysis). Therefore, the 
primary analysis will be performed in the per-protocol set, a subset of the FAS comprising 
“compliant and adherent” patients (as much as possible, defined via validity criteria). To 
avoid bias, the PPS will also include those “compliant and adherent” patients who are 
“censored” due to CV death or a hospitalization for HF preventing the assessment of the 
relevant efficacy endpoints 20 weeks after randomization to take place as planned. It is 
expected that these are the only patients for whom missing observations need to be considered 
in the primary analysis. A “worst case” approach will be used, where the missing change from 
baseline value will be imputed with a multiple of the worst change from baseline value, which 
is possible given the individual baseline value observed in the respective treatment group, or 0 
if the worst change in that treatment group is positive for LVEF / negative for NT-proBNP.
As a sensitivity analysis, a “completers and treatment adherers” only analysis excluding the 
censored patients in the per-protocol analysis set will be performed. This strategy leads to 
unbiased estimates only if missing values are “missing completely at random” (MCAR), i.e. 
the missingness – including missing data due to death – is independent of both observed and 
unobserved outcomes. This condition is unlikely to hold exactly but rather approximately.
Further sensitivity analyses on the PPS may be performed if the missing data patterns suggest 
further exploration.
Efficacy analysis using the FAS
The efficacy analysis in the FAS aims at evaluating the dose-response relationship of the 
primary and secondary efficacy variables for all randomized patients. Efficacy analyses in the 
FAS will include the following:

Generally, it will be assumed that missing observations for the respective efficacy
variables are missing at random. This implies that the behavior of the post dropout 
observations can be predicted from the observed variables using appropriate 
imputation models. Likely exceptions to the missing at random assumption are 
observations which are missing due to a patient’s CV death or HF hospitalization prior 
to the visit in Week 20. These observations can be assumed to be missing not at 
random (MNAR), i.e., that missingness depends both on observed and unobserved 
outcomes and that an explicit model for the patient’s statistical behavior after drop-out 
(or death) is required. Therefore, an analysis based on a pattern mixture framework 
(47) with different imputation rules depending on the reason for missingness will be 
used using a multiple imputation model, followed by a modification of the imputed 
data applying penalties: 
1. First, multiple imputation will be applied to draw sets of completed data, using an 
appropriate imputation model. Baseline characteristics which should be considered 
in the imputation model include but are not restricted to the baseline values of the 
respective efficacy variable, the treatment group, and sex. 


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2. The imputed data will be modified by applying penalties. The choice of the penalty 
may be guided by the worst observed change from baseline for the respective 
outcome in the corresponding treatment group, e.g. by choosing the penalty as a 
multiple of the worst observed change from baseline value.
3. After modifying the completed data sets, the primary analysis using the MCP-step 
of the MCP-Mod methodology will be applied to the multiply imputed datasets 
and the results will be combined. 

An analysis where for each patient without an observation at the visit in Week 20 the
missing value will be imputed according to a last observation carried forward 
approach, including the baseline value. Such an analysis is usually biased but will 
make use of the observations obtained at early EOT visits.
For reproducibility, the SAS seed number for creating the random numbers for the multiple 
imputation will be set to the study number. More details will be described in the SAP.
10.4
Determination of sample size
In the first step, this combined proof-of-concept and Phase IIb dose-finding study has been
powered for the detection of a dose response signal in the primary efficacy variable change in 
LVEF.
The sample size for the primary efficacy variable change in LVEF was evaluated under the 
assumptions described in Section 10.3.2.2 and a type I error level = 5% with the aim to 
achieve at least 80% power for the one-sided primary multiple contrast test. The overall 
randomization ratio was assumed to be 3:1:2:2:2:2 for doses 0, 5, 10, 20, 30, and 40 mg.
Table 10–2 displays the power for the multiple contrast test in the MCP-Mod approach, used 
as primary analysis, for the set of specified alternatives.
Table 10–2: Power for multiple contrast test for set of different alternatives
Sample size
Power for alternative based on respective dose-response model (in %)
Overall
Per 
group a
Linear
Sigmoidal
Emax 1
Sigmoidal
Emax 2
Emax
Quadratic
Minimum
240
40
73.36
86.24
81.20
82.26
79.97
73.36
252
42
75.26
87.73
82.94
83.94
81.70
75.26
264
44
77.10
89.13
84.58
85.58
83.31
77.10
276
46
78.71
90.30
85.97
86.94
84.70
78.71
288
48
80.31
91.39
87.30
88.25
86.09
80.31
300
50
81.62
92.27
88.42
89.32
87.24
81.62
312
52
82.99
93.15
89.53
90.38
88.39
82.99
324
54
84.25
93.92
90.54
91.37
89.50
84.25
336
56
85.43
94.60
91.45
92.22
90.39
85.43
348
58
86.56
95.22
92.31
93.02
91.28
86.56
a
Number of patients randomized to dose levels 10 mg, 20 mg, 30 mg, and 40 mg of neladenoson bialanate, 
for placebo sample size per group to be multiplied by 3/2, for dose level 5 mg sample size per group to be 
divided by 2.
To achieve at least 80% power for the multiple contrast test in the MCP-Mod approach under 
all different alternatives, a minimum of 48 patients per treatment group (72 patients for the 
placebo and 24 patients for the 5 mg group) is needed, resulting in an overall sample size of N 
= 288 patients.


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In the second step, the power for the multiple contrast test in the MCP-Mod approach for the 
absolute change in log-transformed NT-proBNP was estimated, based on the assumptions 
outlined in Section 10.3.2.2 and a given sample size of N = 288. Statistical simulations were 
used to assess the power of the Hochberg test to reject at least one of the two null hypotheses. 
It was concluded that an overall sample size of N = 288 patients is sufficient to reject at least 
one of the two primary efficacy hypotheses with a power of about 83%. 
This power would drop to less than 80%, if the relative reduction of NT-proBNP from 
baseline within the investigated dose range for neladenoson bialanate is < 27.5% compared to 
an expected reduction from baseline of 10% under placebo.
Based on these considerations, a total of 384 patients are planned to be randomized to the 
6 treatment groups:

96 patients are planned to be randomized to placebo (0 mg), 

64 patients each are planned to be randomized to the dose levels 10 mg, 20 mg, 30 mg, 
and 40 mg of neladenoson bialanate, and 

32 patients are planned to be randomized to the dose level 5 mg of neladenoson
bialanate.
These numbers already include adequate assumptions on expected drop-out after 
randomization and invalid or missing data. In the selected population it is expected that only 
about 75% of all randomized patients, i.e. about 288 patients, will contribute complete data to 
the primary analysis in the PPS. 
All power estimations and simulations were performed with the DoseFinding package in R, 
version 3.0.2 (2013-09-25).
10.5
Planned interim analyses
A formal interim analysis is not planned. Periodic data review by a DMC will be performed to 
monitor safety.
11.
Data handling and quality assurance
11.1
Data recording 
This section was changed in Amendment 2, see Section 15.1 for details.
The data collection tool for this study will be a validated electronic data capture system called 
RAVE. Patient data necessary for analysis and reporting will be entered / transmitted into a 
validated database or data system (e.g. TOSCA; SAS). 
Data required according to this protocol will be recorded by investigational site personnel via 
data entry into the internet based EDC software system RAVE, which Bayer has licensed 
from Medidata Solutions Worldwide. RAVE has been validated by Medidata Solutions 
Worldwide and Bayer for use in its clinical studies. RAVE allows for the application of 
software logic to set-up data entry screens and data checks to ensure the completeness and 
accuracy of the data entered by the site personnel. Bayer extensively applies the logic to 
ensure data are complete and reflect the clinical data requirements of the study. Data queries 


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resulting from the application of the software logic are resolved by the site personnel. The 
data are stored at a secure host facility maintained by Medidata Solutions Worldwide and 
transferred on a periodic basis to Bayer's internal computer system via a secure Virtual Private 
Network.
All access to the RAVE system is through a password-protected security system that is part of 
the RAVE software. All internal Bayer and external investigator site personnel seeking access 
must go through a thorough RAVE training process before they are granted access to RAVE 
for use in Bayer's clinical studies. Training records are maintained.
All personnel with access to the RAVE system are supported by a Service Desk staffed with 
trained personnel to answer questions and ensure access is maintained such that data entry can 
proceed in a timely manner.
The RAVE System contains a system-generated audit trail that captures any changes made to 
a data field, including who made the change, why the change was made and the date and time 
it was made. This information is available both at the investigator’s site and at Bayer. Data 
entries made in the RAVE EDC screens are supported by source documents maintained for all 
patients enrolled in this study.
Source documentation
The site must implement processes to ensure availability of all required source 
documentation. A source document checklist (not part of this protocol) will be used at the site 
to identify the source data for key data points collected and the monitor will work with the site 
to complete this.
It is the expectation of the sponsor that all data entered into the CRF has source 
documentation available at the site.
Data recorded from screening failures
At minimum, the following data should be recorded in the CRF:
Demographic information (patient number; year of birth / age; sex; if permitted locally,
race / ethnicity)
Date of informed consent
Inclusion / exclusion criteria
Reason for premature discontinuation
o
AE information, if applicable
Date of last visit.
These data will be transferred to the respective database.
For screening failures with an SAE, the following data should be collected in the CRF in 
addition to the data specified above:


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All information related to the SAE such as: 
-
The SAE itself
-
Concomitant medication
-
Medical history
-
Other information needed for SAE complementary page
11.2
Monitoring
In accordance with applicable regulations, GCP, and sponsor’s / CRO’s procedures, monitors 
will contact the site prior to the start of the study to review with the site staff the protocol, 
study requirements, and their responsibilities to satisfy regulatory, ethical, and sponsor’s 
requirements. When reviewing data collection procedures, the discussion will also include 
identification and documentation of source data items.
The sponsor / designee will monitor the site activity to verify that the:
Data are authentic, accurate and complete. 
Supporting data may be requested (example: blood glucose readings to support a 
diagnosis of diabetes). 
Safety and rights of patients are being protected
Study is conducted in accordance with the currently approved protocol 
(including study treatment being used in accordance with the protocol)
Any other study agreements, GCP, and all applicable regulatory requirements are met.
The investigator and the head of the medical institution (where applicable) agrees to allow the 
monitor direct access to all relevant documents.
11.3
Data processing
Data will be collected as described in Section 11.1. Clinical data management will be 
performed in accordance with sponsor’s applicable standards and data cleaning procedures.
This is applicable for data recorded in the eCRF as well as for data from other sources (e.g. 
IxRS, laboratory, ECG, AVIVO).
For data coding (e.g. AEs, medication), internationally recognized and accepted dictionaries 
will be used.
After its initial release for biometrical analysis, the clinical database is planned to be re-
opened for the inclusion of the following additional data: pharmacokinetic data and biomarker 
data. 
11.4
Missing data 
The following measures will be implemented to minimize the amount of missing data.

Encourage further participation in the study, i.e. phone call 26 weeks after the start of 
treatment, even if the study medication is discontinued early.


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
If the patient does not attend the visits in person, the investigator should make every effort 
to collect information on mortality and / or hospitalization from other sources, e.g.
family / friend / general physician / etc.

Ask sites to call patients the day before certain study visits to remind them to remember 
the time they take their study medication and to remind them in case study medication 
should not be taken at home the next day.

Educate patients on the AVIVO device and train sites to prepare the patient’s skin for 
adherence of the sensor. Ask sites to call patients at the end of the wearing period to 
provide instructions for removal, storage and return at the next visit.

Try to avoid unnecessary patient withdrawals (see Section 6.4).
11.5
Audit and inspection
To ensure compliance with GCP and regulatory requirements, a member of the sponsor’s (or a 
designated CRO’s) quality assurance unit may arrange to conduct an audit to assess the 
performance of the study at the study site and of the study documents originating there. The 
investigator / institution will be informed of the audit outcome.
In addition, inspections by regulatory health authority representatives and IEC(s) / IRB(s) are 
possible. The investigator should notify the sponsor immediately of any such inspection.
The investigator / institution agrees to allow the auditor or inspector direct access to all 
relevant documents and allocate his / her time and the time of his / her staff to the 
auditor / inspector to discuss findings and any issues. Audits and inspections may occur at any 
time during or after completion of the study.
11.6
Archiving
Essential documents shall be archived safely and securely in such a way that ensures that they 
are readily available upon authorities’ request.
Patient (hospital) files will be archived according to local regulations and in accordance with 
the maximum period of time permitted by the hospital, institution or private practice. Where 
the archiving procedures do not meet the minimum timelines required by the sponsor
(minimum is 25 years; longer if required by local regulation), alternative arrangements must 
be made to ensure the availability of the source documents for the required period.
The investigator / institution notifies the sponsor if the archival arrangements change (e.g. 
relocation or transfer of ownership).
The investigator site file is not to be destroyed without the sponsor’s approval.
The contract with the investigator / institution will contain reference to all regulations relevant 
for the study center.


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12.
Premature termination of the study
The sponsor has the right to close this study (or, if applicable, individual segments thereof 
[e.g. treatment arms; dose steps; centers]) at any time, which may be due but not limited to the 
following reasons: 
If risk-benefit ratio becomes unacceptable owing to, for example,
Safety findings from this study (e.g. SAEs)
Results of parallel clinical studies
Results of parallel animal studies 
(on e.g. toxicity, teratogenicity, carcinogenicity or reproduction toxicity).
If the study conduct (e.g. recruitment rate; drop-out rate; data quality; protocol 
compliance) does not suggest a proper completion of the trial within a reasonable time 
frame.
The investigator has the right to close his / her center at any time.
For any of the above closures, the following applies:
Closures should occur only after consultation between involved parties. Final decision 
on the closure must be in writing.
All affected institutions (e.g. IEC(s)  / IRB(s); competent authority(ies); study center; 
head of study center) must be informed as applicable according to local law.
All study materials (except documentation that has to remain stored at site) must be 
returned to the sponsor. The investigator will retain all other documents until 
notification is given by the sponsor for destruction.
In the event of a partial study closure, ongoing patients, including those in post study 
follow-up, must be taken care of in an ethical manner.
Details for individual patient's withdrawal can be found in Section 6.4.1.
13.
Ethical and legal aspects
13.1
Investigator(s) and other study personnel
This section was changed in Amendment 2, see Section 15.1 for details.
Sponsor’s study medical expert is identified on the Title page.
Coordinating investigators in this study will be:
The Netherlands
Tel. 
Fax 
E-mail: 
PPD
PPD
PPD
PPD


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 USA
Tel. 
Fax: 
E-mail: 
All other study personnel not included in this section are identified in a separate personnel list 
(not part of this clinical study protocol) as appropriate. This list will be updated as needed; an 
abbreviated version with personnel relevant for the centers will be available in each center’s 
investigator site file.
Whenever the term ‘investigator’ is noted in the protocol text, it may refer to either the 
principal investigator at the site, or an appropriately qualified, trained and delegated 
individual of the investigational site.
The principal investigator of each center must sign the protocol signature page and must 
receive all required external approvals (e.g. health authority, ethics committee, sponsor) 
before patient recruitment may start at the respective center. Likewise, all amendments to the 
protocol must be signed by the principal investigator and must receive all required external 
approvals before coming into effect at the respective center.
A complete list of all participating centers and their investigators, as well as all required 
signature documents, will be maintained in the sponsor’s study file.
The global sponsor of this study is identified on the title page of this protocol. If required by 
local law, local co-sponsors will be nominated; they will be identified on the respective 
country-specific signature pages.
External data evaluation bodies
Steering Committee
The main task of the Steering Committee, which is composed of a panel of experts in the 
field, is to support the conduct of the study and to advise the sponsor on clinical, medical, and 
scientific questions. Details of the committee will be specified in the Steering Committee 
charter.
Data Monitoring Committee 
Ongoing safety monitoring during the conduct of the study will be performed by an external 
and unblinded DMC. Analysis periods and procedures will be defined in an operational 
charter (DMC Charter) filed in the study file. Following data review, the DMC will provide 
written recommendations that will be transferred to Bayer. All other definitions will be 
provided in the DMC charter. 
PPD
PPD
PPD
PPD


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Clinical Events Committee
Blinded adjudication of all hospitalizations, urgent visits for HF and deaths will be performed 
by a central CEC as described in the CEC charter. Data entry procedures and documentation 
necessary for case adjudication will also be described in the CEC charter. Adjudication results 
will be the basis for the final analysis.
13.2
Funding and financial disclosure
Funding
This study will be funded by its sponsor.
Financial disclosure 
Each investigator (including principal and / or any sub investigators) who is directly involved 
in the treatment or evaluation of research patients has to provide a financial disclosure 
according to all applicable legal requirements. All relevant documentation will be filed in the 
trial master file.
13.3
Ethical and legal conduct of the study
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the sponsor and investigator abide by 
Good Clinical Practice (GCP) guidelines and the guiding principles detailed in the 
Declaration of Helsinki. The study will also be carried out in keeping with applicable local 
law(s) and regulation(s).
Documented approval from appropriate IEC(s) / IRBs will be obtained for all participating 
centers / countries before start of the study, according to GCP, local laws, regulations and 
organizations. When necessary, an extension, amendment or renewal of the IEC / IRB 
approval must be obtained and also forwarded to the sponsor. The responsible unit (e.g. 
IEC / IRB, head of the study center / medical institution) must supply to the sponsor, upon 
request, a list of the EC / IRB members involved in the vote and a statement to confirm that 
the IEC / IRB is organized and operates according to GCP and applicable laws and 
regulations.
Strict adherence to all specifications laid down in this protocol is required for all aspects of 
study conduct; the investigator may not modify or alter the procedures described in this 
protocol. 
Modifications to the study protocol will not be implemented by either the sponsor or the 
investigator without agreement by both parties. However, the investigator or the sponsor may 
implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) 
to the trial subjects without prior IEC / IRB / sponsor approval / favorable opinion. As soon as 
possible, the implemented deviation or change, the reasons for it and if appropriate the 
proposed protocol amendment should be submitted to the IEC / IRB / head of medical 
institution / sponsor. Any deviations from the protocol must be explained and documented by 
the investigator.
Details on discontinuation of the entire study or parts thereof can be found in Section 12.


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13.4
Patient information and consent
All relevant information on the study will be summarized in an integrated patient information 
sheet and informed consent form provided by the sponsor or the study center. A sample 
patient information and informed consent form is provided as a document separate to this 
protocol.
Based on this patient information sheet, the investigator or designee will explain all relevant 
aspects of the study to each patient prior to his / her entry into the study (i.e. before any 
examinations and procedures associated with the selection for the study are performed or any 
study-specific data is recorded on study-specific forms).
The investigator will also mention that written approval of the IRB / IEC has been obtained.
Each patient will be informed about the following aspects of premature withdrawal:
Each patient has the right to withdraw from the study at any time without any 
disadvantage and without having to provide reasons for this decision.
The patient’s consent covers end-of-study examinations as specified in the visit 
description described in Section 9.2 to be conducted after withdrawal of consent to 
treatment.
The patient’s data that have been collected until the time of withdrawal will be retained 
and statistically analyzed in accordance with the statistical analysis plan. 
Patient-specific data on the basis of material obtained before withdrawal may be 
generated after withdrawal (e.g. image reading, analysis of biological specimen such as 
blood, urine or tissues); these data would also be retained and statistically analyzed in 
accordance with the statistical analysis plan. The patient has the right to object to the 
generation and processing of this post-withdrawal data. The patient’s oral objection may 
be documented in the patient’s source data.
Each patient will have ample time and opportunity to ask questions.
Only if the patient voluntarily agrees to sign the informed consent form and has done so, may 
he / she enter the study. Additionally, the investigator will personally sign and date the form.
The patient will receive a copy of the signed and dated form.
The signed informed consent statement is to remain in the investigator site file or, if locally 
required, in the patient’s note / file of the medical institution.
In the event that informed consent is obtained on the date that baseline study procedures are 
performed, the study record or patient´s clinical record must clearly show that informed 
consent was obtained prior to these procedures.
The informed consent form and any other written information provided to patients will be 
revised whenever important new information becomes available that may be relevant to the 
patient’s consent, or there is an amendment to the protocol that necessitates a change to the 
content of the patient information and / or the written informed consent form. The investigator 
will inform the patient of changes in a timely manner and will ask the patient to confirm 
his/her participation in the study by signing the revised informed consent form. Any revised 
written informed consent form and written information must receive the IEC / IRB’s 
approval / favorable opinion in advance of use.


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13.5
Publication policy and use of data
The sponsor has made the information regarding the study protocol publicly available on the 
internet at www.clinicaltrials.gov. 
All data and results and all intellectual property rights in the data and results derived from the 
study will be the property of the sponsor who may utilize them in various ways, such as for 
submission to government regulatory authorities or disclosure to other investigators.
Regarding public disclosure of study results, the sponsor will fulfill its obligations according 
to all applicable laws and regulations. The sponsor is interested in the publication of the 
results of every study it performs. 
The sponsor recognizes the right of the investigator to publish the results upon completion of 
the study. However, the investigator, whilst free to utilize study data derived from his / her 
center for scientific purposes, must obtain written consent of the sponsor on the intended 
publication manuscript before its submission. To this end, the investigator must send a draft 
of the publication manuscript to the sponsor within a time period specified in the contract.
The sponsor will review the manuscript promptly and will discuss its content with the 
investigator to reach a mutually agreeable final manuscript. 
13.6
Compensation for health damage of patients / insurance
The sponsor maintains clinical trial insurance coverage for this study in accordance with the 
laws and regulations of the country in which the study is performed.
13.7
Confidentiality
All records identifying the patient will be kept confidential and, to the extent permitted by the 
applicable laws and / or regulations, will not be made publicly available.
Patient names will not be supplied to the sponsor. Only the patient number will be recorded in 
the CRF, and if the patient name appears on any other document (e.g. pathologist report), it 
must be obliterated before a copy of the document is supplied to the sponsor. Study findings 
stored on a computer will be stored in accordance with local data protection laws. As part of 
the informed consent process, the patients will be informed in writing that representatives of 
the sponsor, IEC / IRB, or regulatory authorities may inspect their medical records to verify 
the information collected, and that all personal information made available for inspection will 
be handled in strictest confidence and in accordance with local data protection laws.
If the results of the study are published, the patient’s identity will remain confidential.
The investigator will maintain a list to enable patients to be identified.


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19. Sharov VG, Todor A, Khanal S, Imai M, Sabbah HN. Cyclosporine A attenuates 
mitochondrial permeability transition and improves mitochondrial respiratory function in 
cardiomyocytes isolated from dogs with heart failure. J Mol Cell Cardiol. 
2007;42(1):150-8.
20. Neubauer S. The failing heart--an engine out of fuel. N Engl J Med. 2007;356(11):1140-
51.
21. Hasenfuss G, Pieske B. Calcium cycling in congestive heart failure. J Mol Cell Cardiol. 
2002;34(8):951-69.
22. Conraads VM, Van Craenenbroeck EM, De Maeyer C, Van Berendoncks AM, Beckers 
PJ, Vrints CJ. Unraveling new mechanisms of exercise intolerance in chronic heart 
failure: role of exercise training. Heart Fail Rev. 2013;18(1):65-77.
23. Nell PG, Albrecht-Kupper B. The adenosine A1 receptor and its ligands. Prog Med 
Chem. 2009;47:163-201.
24. Hwang SJ, Melenovsky V, Borlaug BA. Implications of coronary artery disease in heart 
failure with preserved ejection fraction. Journal of the American College of Cardiology. 
2014;63(25 Pt A):2817-27.
25. Rusinaru D, Houpe D, Szymanski C, Levy F, Marechaux S, Tribouilloy C. Coronary 
artery disease and 10-year outcome after hospital admission for heart failure with 
preserved and with reduced ejection fraction. European journal of heart failure. 
2014;16(9):967-76.
26. Baxter GF, Hale SL, Miki T, Kloner RA, Cohen MV, Downey JM, et al. Adenosine A1 
agonist at reperfusion trial (AART): results of a three-center, blinded, randomized, 
controlled experimental infarct study. Cardiovascular drugs and therapy / sponsored by 
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27. Veres G, Radovits T, Otila G, Hirschberg K, Haider H, Krieger N, et al. Efficacy of the 
non-adenosine analogue A1 adenosine receptor agonist (BR-4935) on cardiovascular 
function after cardiopulmonary bypass. The Thoracic and cardiovascular surgeon. 
2010;58(2):86-92.
28. Bott-Flugel L, Bernshausen A, Schneider H, Luppa P, Zimmermann K, Albrecht-Kupper 
B, et al. Selective attenuation of norepinephrine release and stress-induced heart rate 
increase by partial adenosine A1 agonism. PloS one. 2011;6(3):e18048.
29. Richardt G, Waas W, Kranzhofer R, Mayer E, Schomig A. Adenosine inhibits exocytotic 
release of endogenous noradrenaline in rat heart: a protective mechanism in early 
myocardial ischemia. Circ Res. 1987;61(1):117-23.
30. Cavender MA, Steg PG, Smith SC, Eagle K, Ohman EM, Goto S, et al. Impact of 
Diabetes on Hospitalization for Heart Failure, Cardiovascular Events, and Death: 
Outcomes at 4 Years from the REACH Registry. Circulation. 2015.
31. Fredholm BB, AP IJ, Jacobson KA, Klotz KN, Linden J. International Union of 
Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol 
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32. Massie BM, O'Connor CM, Metra M, Ponikowski P, Teerlink JR, Cotter G, et al. 
Rolofylline, an adenosine A1-receptor antagonist, in acute heart failure. N Engl J Med. 
2010;363(15):1419-28.
33. Teerlink JR, Iragui VJ, Mohr JP, Carson PE, Hauptman PJ, Lovett DH, et al. The safety 
of an adenosine A(1)-receptor antagonist, rolofylline, in patients with acute heart failure 
and renal impairment: findings from PROTECT. Drug Saf. 2012;35(3):233-44.
34. Joo JD, Kim M, Horst P, Kim J, D'Agati VD, Emala CW, Sr., et al. Acute and delayed 
renal protection against renal ischemia and reperfusion injury with A1 adenosine 
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35. Capurso C, Capurso A. From excess adiposity to insulin resistance: the role of free fatty 
acids. Vascular pharmacology. 2012;57(2-4):91-7.
36. Djousse L, Benkeser D, Arnold A, Kizer JR, Zieman SJ, Lemaitre RN, et al. Plasma free 
fatty acids and risk of heart failure: the Cardiovascular Health Study. Circulation Heart 
failure. 2013;6(5):964-9.
37. Staehr PM, Dhalla AK, Zack J, Wang X, Ho YL, Bingham J, et al. Reduction of free fatty 
acids, safety, and pharmacokinetics of oral GS-9667, an A(1) adenosine receptor partial 
agonist. J Clin Pharmacol. 2013;53(4):385-92.
38. Razeghi P, Young ME, Alcorn JL, Moravec CS, Frazier OH, Taegtmeyer H. Metabolic 
gene expression in fetal and failing human heart. Circulation. 2001;104(24):2923-31.
39. Sack MN, Kelly DP. The energy substrate switch during development of heart failure: 
gene regulatory mechanisms (Review). Int J Mol Med. 1998;1(1):17-24.
40. Thum T, Galuppo P, Wolf C, Fiedler J, Kneitz S, van Laake LW, et al. MicroRNAs in the 
human heart: a clue to fetal gene reprogramming in heart failure. Circulation. 
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41. Albrecht-Kupper BE, Leineweber K, Nell PG. Partial adenosine A1 receptor agonists for 
cardiovascular therapies. Purinergic signalling. 2012;8(Suppl 1):91-9.
42. Sabbah HN, Shimoyama H, Kono T, Gupta RC, Sharov VG, Scicli G, et al. Effects of 
long-term monotherapy with enalapril, metoprolol, and digoxin on the progression of left 
ventricular dysfunction and dilation in dogs with reduced ejection fraction. Circulation. 
1994;89(6):2852-9.
43. Murray AJ, Anderson RE, Watson GC, Radda GK, Clarke K. Uncoupling proteins in 
human heart. Lancet. 2004;364(9447):1786-8.
44. Kelly RP, Ting CT, Yang TM, Liu CP, Maughan WL, Chang MS, et al. Effective arterial 
elastance as index of arterial vascular load in humans. Circulation. 1992;86(2):513-21.
45. The Criteria Committee of the New York Heart Association. Nomenclature and Criteria 
for Diagnosis of Diseases of the Heart and Great Vessels. 9th ed. Boston, Mass: Little 
Brown & Co; 1994. p. 253-6.
46. Bretz F, Pinheiro JC, Branson M. Combining multiple comparisons and modeling 
techniques in dose-response studies. Biometrics. 2005;61(3):738-48.
47. Carpenter JR, Kenward MG. Missing data in randomized controlled trials - a practical 
guide. Chapter 6.2008.
48. Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, et al. Using 
standardized serum creatinine values in the modification of diet in renal disease study 
equation for estimating glomerular filtration rate. Annals of internal medicine. 
2006;145(4):247-54.
49. Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the 
oesophagus for bleeding oesophageal varices. The British journal of surgery. 
1973;60(8):646-9.


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15.
Protocol amendments
15.1
Amendment 2
The purpose of Amendment 2 is to implement clarifications after review by regulatory 
authorities and IRBs and to correct minor errors or omissions.
Overview of changes
15.1.1
15.1.1.1
Modification 1 – justification of the dose added
Additional wording on the justification of the study drug dose was included.
Affected section: Section 5.3 Justification of the design
15.1.1.2
Modification 2 – update in exclusion criteria

Exclusion criterion related to asthma: a separate criterion for asthma was created to 
more clearly describe the condition. 

Exclusion criterion related to prohibited therapy was corrected to align with the 
Investigator Brochure.

Exclusion criterion related to allergies or hypersensitivities was modified to also 
exclude patients that are intolerant or hypersensitive to the study treatment.
Affected sections:

Section 2 Synopsis

Section 6.2 Exclusion criteria

Section 8.1.1 Prohibited concomitant medication
15.1.1.3
Modification 3 – update to withdrawal section
The withdrawal criterion related to the use of investigational drug other than the study drug 
was moved from the “must” category to the “may” category (but recent or concomitant 
participation in another clinical trial at study entry must still be excluded). Concomitant use of 
other investigational drugs during the study does not lead to withdrawal from the study. If 
parallel participation in another study is judged harmful for the patient or there is a possibility 
of drug-drug interactions that would impact analyses (e.g. PK sampling or ECG), the patient 
will be withdrawn from the study treatment. However, the patient should preferably still stay 
in the study for follow-up safety assessments and Week 26 phone call. If the patient is 
completely withdrawn from the study, no follow-up information can be collected, which will 
increase the amount of missing data.
Affected section: Section 6.4.1 Withdrawal criteria
15.1.1.4
Modification 4 – change in tablet assignment 
Tablet combination for patients in 10 mg and 20 mg dose arms was changed as a result of the 
update on the study drug packaging.
Affected section: Section 7.5 Blinding


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15.1.1.5
Modification 5 –prohibited medications use – guidance added
Guidance was added for the cases when prohibited medications are taken. 
Affected section: Section 8.1.1 Prohibited concomitant medication
15.1.1.6
Modification 6 – guidance on concomitant use of BCRP substrates –
text added
Information concerning a weak drug-drug interaction with BCRP substrates has been included
based on recent availability of phase I data.
Affected section: Section 8.1.2 Permitted therapy
15.1.1.7
Modification 7 – updated wording for CEC description
Clinical events for adjudication in Section 13.1 were corrected to be consistent with events 
defined as secondary efficacy variables in Section 10.3.1.2. “Manual” was replaced by 
“charter”. 
Affected section: Section 13.1 Investigator(s) and other study personnel
15.1.1.8
Modification 8 – updated statistical calculations for dose-response 
expressions
Dose-response expressions for the shapes in the candidate sets for change in log-transformed 
NT-proBNP were updated to align with the SAP
Affected section: Section 10.3.2.2 Analysis of the primary efficacy variables. 
15.1.1.9
Modification 9 – minor corrections and clarifications
Minor changes were made for better clarity and consistency.
Affected sections:

Section 2 Synopsis

Section 3.2 Partial adenosine A1 receptor agonism in heart failure

Section 6.2 Exclusion criteria

Section 7.5 Blinding

Section 9.1 Tabular schedule of evaluations

Section 9.2 Visit description

Section 9.4.2 Biomarker investigations

Section 9.6.3.5 AVIVO monitoring

Section 10.3.1.3 Other exploratory variables

Section 11.1 Data recording


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Changes to the protocol text
15.1.2
All changes are presented in this section by underlining additions and crossing out deletions. 
Editorial changes and correction of typos are not highlighted in this section.
15.1.2.1
Section 2 Synopsis
This section was changed as a result of Modifications 2 and 9.
The same changes were made in the exclusion criteria of the synopsis as the ones detailed in 
Section 15.1.2.4.
15.1.2.2
Section 3.2 Partial adenosine A1 receptor agonism in heart failure
This section was changed as a result of Modification 9.
Old text:
Inhibition of the A1R may also inhibit norepinephrine release from cardiac presynaptic nerves 
(28, 29). 
New text:
Activation of the A1R may also inhibit norepinephrine release from cardiac presynaptic 
nerves (28, 29).
15.1.2.3
Section 5.3 Justification of the design
This section was changed as a result of Modification 1.
Added text:
Evidence of A1R target engagement could already be achieved in different tissues across 
different clinical trials with 20 mg neladenoson bialanate. The dose range around 20 mg (5, 
10, 30 and 40 mg) is to ensure different data points to feed the MCP-Mod predefined models 
and potential unforeseen variances. The doses studied will ensure a strong dose 
recommendation moving forward into phase III.
15.1.2.4
Section 6.2 Exclusion criteria
This section was changed as a result of Modifications 2 and 9.
Added text:
7. Sustained
1 systolic blood pressure ≤ 90 mmHg and / or signs and symptoms of hypotension 
prior to randomization
8. Sustained 1 systolic blood pressure ≥ 160 mmHg
9. Sustained 1 bradycardia with heart rate < 50 beats/minute or tachycardia with heart rate
At two consecutive visits.


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Old text:
14. Severe pulmonary disease with any of the following:
o
Requirement of continuous (home) oxygen or 
o
History of chronic obstructive pulmonary disease ≥ GOLD III or 
o
Asthma bronchiale
New text:
14. Severe pulmonary disease with any of the following:
o
Requirement of continuous (home) oxygen or 
o
History of chronic obstructive pulmonary disease ≥ GOLD III or 
o
Use of systemic corticosteroids
15. Asthma bronchiale with any of the following:
o
Symptoms not well-controlled within the past 6 months or
o
Ever intubated or in an intensive care unit for asthma
Old text:
19. Concomitant use of any of the following therapy that cannot be discontinued:
o
Potent CYP3A4 inhibitors or inducers or strong CYP2C8 inhibitors (Of note: 
grapefruit is a strong CYP3A4 inhibitor.)
o
Theophylline
o
Drugs that are mainly metabolized by UGT1A1 (irinotecan)
New text:
20. Concomitant use of any of the following therapy that cannot be discontinued:
o
Moderate or strong CYP3A4 inhibitors (Of note: grapefruit is also a strong 
CYP3A4 inhibitor.)
o
CYP3A4 inducers
o
Strong CYP2C8 inhibitors (Of note: clopidogrel is a strong CYP2C8 inhibitor)
o
Theophylline
o
Drugs having significant pre-systemic clearance via UGT1A1 in the intestine
Old text:
21. Heavy alcohol consumption or the use of illicit drugs that, in the opinion of the 
investigator, may interfere with the patient’s safety and / or compliance
New text:
22. Known current heavy alcohol consumption or the use of illicit drugs that, in the opinion of 
the investigator, may interfere with the patient’s safety and / or compliance


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Old text:
22. Use of other investigational drugs. Previous (within 30 days or 5 half-lives of the 
investigational drug, whichever is longer) or concomitant participation in another clinical 
study with investigational medicinal product(s) or device(s)
New text:
23. Previous (within 30 days or 5 half-lives of the investigational drug, whichever is longer) 
or concomitant participation in another clinical study with investigational medicinal 
product(s) or device(s)
Old text:
26. Known allergies or hypersensitivities to adhesives or hydrogel 
New text:
27. Known allergies, intolerance or hypersensitivities to the study treatment (active substance 
or excipients), adhesives or hydrogel 
15.1.2.5
Section 6.4.1 Withdrawal criteria
This section was changed as a result of Modification 3.
Old text:
Patients must be withdrawn from the study if any of the following occurs:
[…]
If any investigational drug other than the study drug is used during the study period.
New text:
Patients may be withdrawn from the study if any of the following occurs:

[…]

If any investigational drug other than the study drug is used during the study period.
15.1.2.6
Section 7.5 Blinding
This section was changed as a result of Modifications 4 and 9.
Old text:
Table 7–3: Assignment of tablets to dose groups
Treatment arm/ 
Formulation
5 mg
10 mg
20 mg
30 mg
40 mg
Placebo
5 mg
1
2
0
0
0
0
10 mg
0
0
2
1
0
0
20 mg
0
0
0
1
2
0
Placebo
1
0
0
0
0
2
Total tablets/day
2
2
2
2
2
2


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New text:
Table 7–3: Assignment of tablets to dose groups
Treatment arm/ 
Formulation
5 mg
10 mg
20 mg
30 mg
40 mg
Placebo
5 mg
1
0
0
0
0
0
10 mg
0
1
0
1
0
0
20 mg
0
0
1
1
2
0
Placebo
1
1
1
0
0
2
Total tablets/day
2
2
2
2
2
2
Added text:
The following parties will be unblinded: sponsor’s IxRS and Medication Manager, Clinical 
Supply Manager and Clinical Pharmacometrics analyst (who will be provided with a 
randomization list for selected bioanalyses of the active metabolite BAY 84-3174 in plasma), 
the drug supply’s Project Manager, and the DMC. 
For all other sponsor’s study personnel, the Steering Committee and the Clinical Events 
Committee (CEC) the blinding will be strictly kept.
15.1.2.7
Section 8.1.1 Prohibited concomitant medication
This section was changed as a result of Modifications 2 and 5.
The same changes were made to the list of excluded medications as described in Section 
15.1.2.4. In addition, the following text was added:
A list of prohibited medications will be provided to the investigators.
If a prohibited concomitant medication (e.g. moderate / strong CYP3A4 inhibitor) is used 
during the study conduct, the study drug should be interrupted immediately and restarted as 
soon as possible, when the prohibited medication has been stopped. Prior to re-starting the 
study drug, a washout period of at least two days after discontinuation of the prohibited 
medication should be adhered to.
15.1.2.8
Section 8.1.2 Permitted therapy
This section was changed as a result of Modification 6.
Added text:
Neladenoson bialanate is a weak Breast Cancer Resistance Protein (BCRP) inhibitor. The risk 
of clinically relevant drug–drug interactions at doses up to 40 mg BAY 1067197 due to 
inhibition of BCRP is regarded as low, but cannot be excluded (BCRP substrates are 
atorvastatin, simvastatin, rosuvastatin, fluvastatin, methotrexate, etc.; a list of BCRP 
substrates will be made available to the investigators).
If neladenoson bialanate is given concomitantly with other drugs that may increase the 
exposure of BCRP substrates, the respective drug labels should be consulted.


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15.1.2.9
Section 9.1 Tabular schedule of evaluations
This section was changed as a result of Modification 9.
Old text (“dots” were replaced by “pre-dose”):
Week
Day and allowed 
deviations
-1
-7
W0
0+2
Blood sample for safety 
●
Blood sample for 
biomarkers
●
Urine sample for 
biomarkers
●
New text:
Week
Day and allowed 
deviations
-1
-7
W0
0+2
Blood sample for safety
pre-
dose
Blood sample for 
biomarkers
pre-
dose
Urine sample for 
biomarkers
pre-
dose
Old text:
g […] If a patient does not take the study drug before the visit, he / she can take it at the start of the 
visit, in which case PK sampling will occur 2 and 4 hours after the study drug intake.
New text:
g […] If a patient does not take the study drug before the visit, he / she can take it at the start of the 
visit, in which case PK sampling will occur as described above.
15.1.2.10
Section 9.2 Visit description
This section was changed as a result of Modification 9.
The following sentence was added to Visit 4 (Week 4) and Visit 5 (Week 8):
Ideally, the study personnel should contact the subject prior to Visit 4/Visit 5 to remind them 
not to take the study drug as usual in the morning at home.
15.1.2.11 Section 9.4.2 Biomarker investigations
This section was changed as a result of Modification 9.
Deleted text:
Mandatory (sampled at all time points): 
-
High sensitivity troponin T (hs-TNT) (baseline disease status & safety)
-
Cystatin C (baseline disease status, safety & efficacy)


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15.1.2.12
Section 9.6.3.5 AVIVO monitoring
This section was changed as a result of Modification 9.
Old text:
Apart from safety assessments, also the patient’s everyday physical activity (frequency, 
duration, intensity) will be tracked. 
New text:
Apart from safety assessments, also the patient’s everyday physical activity (e.g. duration, 
intensity) will be tracked. 
15.1.2.13 Section 10.3.1.3 Other exploratory variables
This section was changed as a result of Modification 9.
Old text:

Activity (frequency, duration, intensity) reported values and absolute change from 
baseline at 20 weeks
New text:

Activity (duration, intensity) reported values and absolute change from baseline at 20 
weeks
15.1.2.14 Section 10.3.2.2 Analysis of the primary efficacy variables
This section was changed as a result of Modification 8.
Old text:
Table 10–1: Dose-response shapes used in the candidate set
Model
Response as function of dose d
LVEF
NT-proBNP
Linear
2 + 0.075d
–0.105 – 0.005425d
Sigmoidal Emax 1
2 + 3.007689d4 / (94 + d4)
–0.105 – 0.21756d4 / (94 + d4)
Sigmoidal Emax 2
2 + 3.375d3 / (203 + d3)
–0.105  – 0.24413d3 / (203 + d3)
Emax
2 + 3.09375d / (1.25 + d)
–0.105  – 0.22378d / (1.25 + d)
Quadratic
2 + 0.2d – 0.00333d²
–0.105  – 0.01447d + 0.00241d²
New text:
Table 10–1: Dose-response shapes used in the candidate set
Model
Response as function of dose d
LVEF
NT-proBNP
Linear
2 + 0.075d
–0.105 – 0.0063d
Sigmoidal Emax 1
2 + 3.007689d4 / (94 + d4)
–0.105 – 0.2526d4 / (94 + d4)
Sigmoidal Emax 2
2 + 3.375d3 / (203 + d3)
–0.105 – 0.2835d3 / (203 + d3)
Emax
2 + 3.09375d / (1.25 + d)
–0.105 – 0.2599d / (1.25 + d)
Quadratic
2 + 0.2d – 0.00333d²
–0.105 – 0.0168d + 0.00028d²


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15.1.2.15 Section 11.1 Data recording
This section was changed as a result of Modification 9.
Added text:
Patient data necessary for analysis and reporting will be entered / transmitted into a validated 
database or data system (e.g. TOSCA; SAS). 
15.1.2.16 Section 13.1 Investigator(s) and other study personnel
This section was changed as a result of Modification 7.
Old text:
Clinical Events Committee
Blinded adjudication of all hospitalizations and deaths will be performed by a central CEC as 
described in the CEC manual. Data entry procedures and documentation necessary for case 
adjudication will also be described in the CEC manual.
New text:
Clinical Events Committee
Blinded adjudication of all hospitalizations, urgent visits for HF and deaths will be performed 
by a central CEC as described in the CEC charter. Data entry procedures and documentation 
necessary for case adjudication will also be described in the CEC charter.


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16.
Appendices
16.1
Calculating glomerular filtration rate
In accordance with established nephrology practice and guidelines, renal function at baseline 
and throughout the study will be assessed by means of the estimated glomerular filtration rate 
(eGFR), calculated using the Modification of Diet in Renal Disease (MDRD) study 
abbreviated formula.
Isotope dilution mass spectroscopy (IDMS)-traceable MDRD Study Equation:
Conventional units (serum creatinine level is measured in mg/dL)
GFR (mL/min/1.73 m2) = 175 x (serum creatinine)-1.154 x (Age)-0.203 x (0.742 if female) x 
(1.212 if African American)
GFR can be estimated using the calculator provided in the following link:
http://www.kidney.org/professionals/kdoqi/gfr_calculator
For further information on assessing renal function using GFR estimates, see reference (48).
16.2
Calculating the Child-Pugh score
The severity of liver disease (Table 16–1) will determine the Child-Pugh score (Table 16–2).
Table 16–1: Grading of severity of liver disease
Factor
+1
+2
+3
Bilirubin (mg/dL)
< 2
2 – 3
> 3
Albumin (g/dL)
> 3.5
2.8 – 3.5
< 2.8
International Normalized Ratio
< 1.7
1.7 – 2.3
> 2.3
Ascites
None
Mild
Moderate / Severe
Encephalopathy
None
Grade I - II
Grade III – IV
Source: adapted from (49)
Table 16–2: Classification using the added score from Table 16–1
Child-Pugh Class
A
B
C
Points
5 6
7 – 9
10 15
Source: adapted from (49)

SAP_000.pdf: 
 
Document Type: Statistical Analysis Plan 
Official Title: 
A multicenter, randomized, placebo-controlled, parallel group, 
double blind, dose-finding Phase II trial to study the efficacy, 
safety, pharmacokinetic and pharmacodynamic effects of the oral 
partial adenosine A1 receptor agonist neladenoson bialanate over 
20 weeks in patients with chronic heart failure with reduced 
ejection fraction 
NCT Number: 
NCT02992288 
Document Date: 
29 MAY 2018 
 


Statistical Analysis Plan
Protocol No.: BAY 1067197/15128
Page: 1 of 39:
Title page
A multicenter, randomized, placebo-controlled, parallel group, double 
blind, dose-finding Phase II trial to study the efficacy, safety, 
pharmacokinetic and pharmacodynamic effects of the oral partial 
adenosine A1 receptor agonist neladenoson bialanate over 20 weeks in 
patients with chronic heart failure with reduced ejection fraction
short title: PANTHEON
Bayer study drug
Neladenoson bialanate / BAY 1067197
Study purpose:
dose finding
Clinical study 
phase:
IIb
Date:
29MAY2018
Study No.:
BAY 1067197 / 15128
Version:
3.0
Author:
Confidential
The information provided in this document is strictly confidential and is intended solely 
for the guidance of the clinical investigation.  Reproduction or disclosure of this 
document, whether in part or in full, to parties not associated with the clinical 
investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted.
Throughout this document, symbols indicating proprietary names (®, TM) are not displayed.  Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.
This Statistical Analysis Plan is produced on a word-processing system and bears no signatures.
The approval of the Statistical Analysis Plan is documented in a separate Signature Document.
PPD


Statistical Analysis Plan
Protocol No.: BAY 1067197/15128
Page: 2 of 39:
Table of Contents
Title page................................................................................................................................... 1
Abbreviations............................................................................................................................ 4
1.
Introduction ....................................................................................................................... 7
2.
Study Objectives................................................................................................................ 7
3.
Study Design ...................................................................................................................... 8
4.
General Statistical Considerations .................................................................................. 9
4.1
General Principles............................................................................................................ 9
4.2
Handling of Dropouts ...................................................................................................... 9
4.3
Handling of Missing Data.............................................................................................. 10
4.4
Interim Analyses and Data Monitoring.......................................................................... 11
4.5
Data Rules...................................................................................................................... 11
4.5.1
Baseline and Change from Baseline........................................................................... 11
4.5.2
Repeated Measurements............................................................................................. 12
4.5.3
Laboratory Data Handling .......................................................................................... 12
4.5.4
Subgroup analyses ...................................................................................................... 12
4.6
Blind Review ................................................................................................................. 13
5.
Analysis Sets..................................................................................................................... 13
5.1
Assignment of analysis sets ........................................................................................... 13
6.
Statistical Methodology................................................................................................... 15
6.1
Population characteristics .............................................................................................. 15
6.1.1
Disposition of Subjects............................................................................................... 15
6.1.2
Demographic and Baseline Characteristics ................................................................ 15
6.1.3
Medical history........................................................................................................... 16
6.1.4
Prior and Concomitant Medications........................................................................... 16
6.2
Efficacy.......................................................................................................................... 18
6.2.1
Primary efficacy variables and analyses..................................................................... 18
6.2.1.1
Primary efficacy variables....................................................................................... 18
6.2.1.2
Primary analysis of primary efficacy variables ....................................................... 18
6.2.1.3
Secondary analysis of primary efficacy variables ................................................... 23
6.2.1.4
Sensitivity analyses of primary efficacy variables .................................................. 23
6.2.1.5
Additional analysis of primary efficacy variables................................................... 24
6.2.2
Secondary efficacy variables and analyses................................................................. 24
6.2.2.1
Secondary efficacy variables................................................................................... 24
6.2.2.2
Primary analyses of secondary efficacy variables................................................... 24
6.2.2.3
Sensitivity analyses of secondary efficacy variables .............................................. 25
6.2.2.4
Additional analyses of secondary efficacy variables .............................................. 25
6.2.3
Exploratory efficacy variables and analyses............................................................... 25
6.3
Safety ............................................................................................................................. 26


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6.3.1
Extent of exposure...................................................................................................... 26
6.3.2
Treatment Compliance................................................................................................ 27
6.3.3
Adverse events............................................................................................................ 27
6.3.4
Deaths ......................................................................................................................... 28
6.3.5
Clinical laboratory evaluations................................................................................... 28
6.3.6
AVIVO/HealthPatch monitoring................................................................................ 29
6.3.7
Other safety measures................................................................................................. 29
6.4
Subgroup Analysis ......................................................................................................... 29
6.4.1
Subgroups ................................................................................................................... 29
6.4.2
Subgroup analysis of efficacy variables ..................................................................... 29
6.4.3
Subgroup analysis of safety variables......................................................................... 29
6.5
Pharmacokinetics/pharmacodynamics........................................................................... 30
6.6
Biomarker analyses........................................................................................................ 30
7.
Document history and changes in the planned statistical analysis ............................. 30
8.
References ........................................................................................................................ 31
9.
Appendices ....................................................................................................................... 32
9.1
AVIVO device variable specification............................................................................ 32
9.2
Echocardiography parameters........................................................................................ 33
9.3
KCCQ Scoring............................................................................................................... 34
9.3.1
Physical Limitation..................................................................................................... 34
9.3.2
Symptom Stability ...................................................................................................... 34
9.3.3
Symptom Frequency................................................................................................... 35
9.3.4
Symptom Burden........................................................................................................ 35
9.3.5
Self-Efficacy............................................................................................................... 36
9.3.6
Quality of Life ............................................................................................................ 36
9.3.7
Social Limitation ........................................................................................................ 37
9.3.8
Total Symptom Score ................................................................................................. 37
9.3.9
Overall Summary Score.............................................................................................. 37
9.3.10
Clinical Summary Score............................................................................................. 37
9.4
Combining inferences from multiple imputed data sets ................................................ 37


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Abbreviations
A1R
A1 receptor
ACE
angiotensin-converting enzyme
ACEi
ACE inhibitor
AE(s)
adverse event(s)
AF
atrial fibrillation
ALT
alanine aminotransferase
ARB(s)
angiotensin receptor blocker(s)
ARNI(s)
angiotensin receptor-neprilysin inhibitor(s)
AST
aspartate aminotransferase
AUC
area under the time-concentration curve
AV
atrioventricular
BMI
body mass index
BNP
b-type natriuretic peptide
BSA
body surface area
CHF
chronic heart failure
Cmax
maximum drug concentration in plasma
CO
cardiac output
CRF
case report form
CV 
cardiovascular
DMC
Data Monitoring Committee
e.g.
for example (exempli gratia)
ECG
electrocardiogram
eCRF
electronic CRF
EF
ejection fraction
eGFR
estimated glomerular filtration rate
EQ-5D-5L
EuroQol Group 5-dimensional, 5-level questionnaire
EU
European Union
EWDT
E-wave deceleration time
FAS
full analysis set
GFR
glomerular filtration rate
GGT
gamma glutamyl transpeptidase
HDL
high-density lipoprotein
HF
heart failure
HFpEF
heart failure with preserved ejection fraction
HFrEF
heart failure with reduced ejection fraction
HR
heart rate
hs-TNT
high sensitivity troponin T
i.e.
that is (id est)
ICF
informed consent form


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ICH
International Conference on Harmonization
INR
international normalized ratio
ITT
intent-to-treat
IVSD
interventricular septum diameter 
KCCQ
Kansas City cardiomyopathy questionnaire
LA
left atrial
LAV
LA volume
LAVI
LA volume index
LDH
lactate dehydrogenase 
LDL
low-density lipoprotein
LV
left ventricular
LVEDV
LV end-diastolic volume
LVEDVI
LVEDV index 
LVEF
left ventricular ejection fraction
LVESV
left ventricular end-systolic volume
LVESVI
LVESV index
MAP
mean arterial pressure
MCH
mean corpuscular hemoglobin
MCHC
MCH concentration
MCP
multiple comparison procedures
MCV
mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
mL
milliliter
MRA
mineralocorticoid receptor antagonist
NGAL
neutrophil gelatinase-associated lipocalin
NONMEM
non-linear mixed effect modeling
NT-proBNP
N-terminal pro-hormone b-type natriuretic peptide
NYHA
New York Heart Association
PASP
pulmonary artery systolic pressure
PDV
premature discontinuation visit
Pes
end-systolic pressure
pg
picogram
PK
pharmacokinetic
PKS
PK analysis set
PP
pulse pressure
PPS
per-protocol set
PTT
partial thromboplastin time
PWT
posterior wall thickness
RV
right ventricular
SAC
systemic arterial compliance


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SAE(s)
serious adverse event(s)
SAF
safety analysis set
SAP
statistical analysis plan
SBP
systolic blood pressure
SV
stroke volume
SVI
SV index
TAPSE
tricuspid annular plane systolic excursion
TD
tissue Doppler
TPR
total peripheral resistance
UACR
urine albumin-to-creatinine ratio
US
United States (of America)


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1.
Introduction
Chronic heart failure (CHF) is a major public health problem characterized by significant 
mortality, frequent hospitalizations, and poor quality of life, with an overall prevalence that is 
increasing throughout the world. HF carries a prognosis comparable to many forms of cancer 
with a 5-year survival rate of approximately 50% (1), which exceeds that of many cancers (2). 
Frequent hospitalizations, along with other direct and indirect costs, also place an enormous 
financial burden on healthcare systems; more is spent annually in the US for the treatment of 
HF by Medicare than on any other Medicare-covered condition (3).Upon hospitalization for 
HFrEF mortality and re-hospitalization for HF remain high despite treatment with stable 
chronic HFrEF neurohumoral blockers, indicating that this does not fully explore the 
complexity of HF pathophysiology. Additionally, the repeated stepwise addition of 
hemodynamically active medications raises tolerability and safety concerns (e.g. hypotension 
and bradycardia) (4). 
Therefore, addressing the failing heart directly and getting viable but not functional 
myocardium back to work might be a new option for the development of the next generation 
of hemodynamically silent HF drugs. In this context, neladenoson bialanate holds promise as 
a potentially hemodynamically neutral therapy for HF that could simultaneously improve 
cardiomyocyte energetics, calcium homeostasis, cardiac structure and function, and long-term 
clinical outcomes when added to background therapies.
Neladenoson bialanate (BAY 1067197, which is the free base of the hydrochloride BAY 86-
8901) is the pro-drug of the pharmacologically active compound BAY 84-3174, a highly 
potent and selective non-adenosine like partial adenosine A1 receptor agonist suitable for 
once daily oral use.
The main limitations of using full A1R agonists in cardiovascular indications such as HF are 
undesired cardiac effects, such as bradycardia and higher degree AV block as well as negative 
cardiac inotropy and dromotropy. In contrast, preclinical data show that the partial adenosine 
A1R agonist neladenoson bialanate can be used to modulate and trigger primarily favorable 
pharmacological responses for HF therapy and avoid undesired effects such as AV conduction 
abnormalities and higher degree AV Block. Nevertheless, based on the mode of action, there 
are theoretical concerns particularly with regard to undesired effects, such as bradycardia and 
higher degree AV block for an A1R agonist, which might be aggravated by concomitant use 
of standard heart failure therapy.
The purpose of this clinical trial is to assess the safety, tolerability and the pharmacokinetic 
and pharmacodynamic response of 20 weeks’ treatment with neladenoson bialanate compared 
to placebo in patients with chronic HFrEF on standard therapy for HF and to find the optimal 
dose for a further Phase III trial.
This statistical analysis plan (SAP) is based on the Global Integrated Clinical Study Protocol BAY 
106-7197/15128 version 2.0, dated 17 FEB 2017. 
2.
Study Objectives
The objective of the study is to find the optimal dose of neladenoson bialanate for the Phase 
III trial by detecting and characterizing a significant dose-response relationship in the two 


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primary efficacy endpoints, absolute change from baseline in LVEF and log-transformed NT-
proBNP at 20 weeks, in patients with chronic heart failure with reduced ejection fraction 
(HFrEF), and by characterizing the safety, tolerability and pharmacodynamic effects of the 
compound when given in addition to standard therapy for HFrEF.
An exploratory objective is to further assess pharmacokinetic parameters and blood and urine
biomarkers.
3.
Study Design
Study 15128 is a randomized, double-blind, placebo-controlled, parallel group, multicenter, 
Phase II study. Figure 3–1 displays the overall study design. 
Figure 3–1: Study design overview
Abbreviations: CV = cardiovascular; ICF = informed consent form; W = week
Approximately 384 patients from approximately 90 study centers worldwide will be 
randomized to one of the active treatment dose arms or placebo, in addition to standard of care 
heart failure therapy (for details see Section 7).
The study will comprise a 1-week run-in period, 20-week treatment period, and a 6-week 
follow-up period (27 weeks total).
Patients will have site visits at weeks -1, 0 (baseline), 4, 8, 12, 20 (end-of-treatment visit) and 
24 (safety follow-up visit). In addition, 2 phone calls at weeks 2 and 26 will be made to assess 
patients’ safety, and one additional phone call - to remind the patients of AVIVO self-
application at Week 19. 
LVEF will be measured by echocardiography at baseline and end of treatment, NT-proBNP 
will be measured at baseline, Week 4 and end of treatment. Safety will be monitored 
throughout the study. PK samples will be taken from all patients at dedicated time points. 


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Additional biomarkers reflecting the pharmacodynamic activity of the drug will be examined, 
as well as candidate biomarkers that may predict drug response.  
For detailed visit descriptions and rules for patients who discontinue study treatment earlier, 
please see protocol Sections 9.1 and 9.2.
The anticipated duration of the study as a whole is approximately 19 months: this includes an 
anticipated recruitment period of 13 months followed by a run-in period of 1 week, a 
treatment period of 20 weeks and a follow-up period of 6 weeks after enrollment of the last 
patient into the trial.
A parallel group design was chosen to compare five different once-daily dose regimens and 
one placebo arm to find the best dose for Phase III. Placebo control is used to control for 
observer and subject bias, and randomization - to control for assignment bias. Based on Phase 
I data in healthy volunteers and Phase II data on heart failure patients, a sequential dose 
escalation design was not deemed necessary for neladenoson bialanate since the safety profile 
of the compound could be verified in dose ranges up to 40 mg. Safety of the subjects in this 
parallel study design will be closely monitored by an Data Monitoring Committee (DMC).
The end of the study as a whole will be reached as soon as the last visit of the last patient has 
occurred in all centers in all participating countries (EU and non-EU).
4.
General Statistical Considerations
4.1
General Principles
The statistical evaluation will be performed by using the software package SAS version 9.2 or 
higher (SAS Institute Inc., Cary, NC, USA). Unless otherwise noted, data will be analyzed by 
descriptive statistical methods: The number of data available and missing data, mean, standard 
deviation, minimum, quartiles, median, and maximum will be calculated for metric data. 
Frequency tables will be generated for categorical data.
Definition of efficacy and safety endpoints, analysis strategies, structure of analysis datasets 
and layout of analysis data displays are following Bayer AG standards: Neladenoson bialanate
Project Standards, the Therapeutic Area Cardiovascular Standards (TAS) and the Global 
Medical Standards (GMS), respectively. The given ordering reflects the priority of the 
different standards, i.e. specifications of the latter ones have to be followed only if not 
specified in standards mentioned before. Study-specific specifications may be included in 
addition to the Project Standards, if needed.
4.2
Handling of Dropouts
A “dropout” is defined as a subject who has been randomized and discontinues study 
participation prematurely for any reason. Subjects withdrawn from study treatment will not be 
replaced. Refer to Section 6.4 in the Clinical Study Protocol for withdrawal of subjects from 
study.
See following chapters for more details on deriving efficacy endpoints in case of missing data.


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4.3
Handling of Missing Data
All missing or partial data will be presented in the patient data listing as they are recorded in 
the eCRF. 
A number of descriptive analyses will be performed to better understand missing data 
patterns. The frequency, proportion and the reasons for premature discontinuation of both the 
study and study treatment will be reported. Kaplan-Meier plots for “time to end of study 
treatment (calculated as days from first dose to the earliest date of stop medication, including 
premature stop of study medication and death, for the calculation all the subjects will be 
considered to have an event-stop of study medication)” and “time to end of study”(calculated 
from randomization to the earliest date of visit 9, death,  and the last visit if subject drops off 
from study prematurely, for the calculation all the subjects will be considered to have an 
event-stop of study) will be provided, by treatment group and overall. 
The number of patients who prematurely discontinue study participation or intake of study 
medication will be summarized with respect to the key subgroups, see section 6.4.1. and the 
reasons for premature discontinuation of study and / or study treatment. If the proportion of 
patients who withdraw across the dose groups is not fairly balanced, the impact on the 
primary variables will be further explored. To further explore the missingness pattern with 
regards to the “missing at random” assumption, the mean of the baseline values of the efficacy 
variable will be summarized for patients with and without post-baseline observations, by 
treatment group and overall. 
For the analysis of the primary and secondary variables, it cannot necessarily be assumed that 
data are missing at random. As the choice of primary analysis will be based on assumptions 
that cannot be verified, the robustness of the results of the primary analysis will be 
investigated through appropriate sensitivity analyses making different assumptions, in 
accordance with the EMA “Guideline on missing data in confirmatory clinical trials”. Detail 
missing data handling are specified in Section 6.2.1.4.
When appropriate, the following rules will be implemented so as not to exclude subjects from 
statistical analyses due to missing or incomplete data:

Date of CHF diagnosis 
For cases where start month and year are reported but day is missing, impute it with 
the 1st day of month. If the month is not available, this date will not be imputed. 

Clinical outcomes
For cases where start month and year are reported but day is missing, impute the 
maximum of (date of randomization, first date of study medication, 15.month.year). 
For cases where only start year is reported or completely missing, impute the 
maximum of (date of randomization, first date of study medication, 15.01.year), but 
not later than death date if the subject died. 

Heart failure related concomitant medication start date
For case where start month and year are reported but day is missing, impute it with 
15th day of month. For cases where only start year is reported or completely missing, 
impute it as maximum of (15.01.year, randomization).

Heart failure related concomitant medication stop date


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For case where stop month and year are reported but day is missing, impute it as 
minimum of  [(15, month, year) and (last visit date) and (death date)].
If the stop day and month are missing, then the stop date will be imputed as minimum 
of [(15.12.year) and (last visit date) and (death date)].
If the date is completely missing then the stop date will be imputed as minimum of 
[the last visit date and death date]. If the concomitant medication is “Ongoing at 
subject's last visit”, for the respective stop date variable the ‘last visit date’ from the 
corresponding domain is merged in the concomitant medication database by data 
management programming.

Study medication start date for subjects took study medication
If the start date and time is missing it will be imputed with the randomization date and 
time. If start date and time is recorded as earlier than randomization and cannot be 
clarified, date and time of randomization will be used for the statistical analysis.

Study medication stop date for subjects took study medication
If the stop day is missing, but the stop month and stop year are available then the stop 
date will be imputed as minimum of [(15, month, year) and (last on treatment visit 
date before the observational visit) and (death date)].
If the stop day and month are missing or the date is completely missing then the stop 
date will be imputed as minimum of [the last on treatment visit date before the 
observational visit and death date].
4.4
Interim Analyses and Data Monitoring
A formal interim analysis is not planned. Periodic data review by a DMC will be performed to 
monitor safety and tolerability. An Independent Data Monitoring Committee (IDMC) will be 
applied to this study. An external statistical analysis center will provide results to the DMC
4.5
Data Rules
Generally, for each date stored in database a set of organizational variables will be derived in 
order to describe the temporal context of that date in the specific study: Phase of treatment 
(pre, during or post study treatment), day relative to the start of study treatment, day relative 
to the end of study treatment will be provided.
4.5.1
Baseline and Change from Baseline
For efficacy endpoints, the efficacy baseline is defined as the last available value prior to or 
on the date of randomization. Safety baseline is defined as the last available value before the 
first study medication administration. If values are missing at the baseline (visit 2, week 0), 
data recorded at run-in (Visit 1) will be considered as safety baseline value. If run-in record is 
also missing, the baseline value will be left as missing.
Change from baseline for vital signs or laboratory parameters will in general be displayed as 
the difference to baseline defined as:
Change = Post baseline value – baseline value.
In addition, for some parameters the relative change will be analyzed defined as


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Relative change = 100% * [(post baseline value – baseline value) / baseline value].
4.5.2
Repeated Measurements
At all visits post-randomization and if not stated otherwise, only the values at scheduled time 
points will be used for analysis, although unscheduled results will be included in tables 
reporting any abnormalities, e.g. incidences of high laboratory abnormalities.
For the derived visit “Any time post baseline” this will include any measurement after 
initiation of study drug, including unscheduled assessments.
4.5.3
Laboratory Data Handling
The data of hematology, clinical chemistry, and coagulation will be provided by central 
laboratories. Additional re-tests for liver monitoring will be done locally.
For values which are below the lower limit of quantification (LLOQ), half the value of the 
LLOQ will be used for analysis.  Differences between two values of below the LLOQ will be 
assigned values of 0. 
In case of measurements above the upper limit of quantification (ULOQ), the following rules 
will be applied:

The ULOQ will be used for calculations.

Corresponding tables and figures will get a footnote indicating that “Values above the 
upper limit of quantification of ULOQ were replaced by ULOQ.”

Tables displaying maximum values will show up “>ULOQ” as maximum.
If more than one assessment occurred at any post-baseline visit (repeated measures at same 
visit), the last valid (non-missing) value will be used in the summaries. Unscheduled 
laboratory data will be listed and included in the summary tables.
4.5.4
Subgroup analyses
In order to assess the homogeneity of the dose response across the most important prognostic 
and predictive factors, subgroup analyses will be performed. 
‘Key’ subgroups include: 

LVEF(%) at baseline: ≤25 vs. >25

LVEF(%) at baseline: ≤40 vs. >40 

LVEF(%) at baseline: ≤45 vs. >45

NT-proBNP (pg/ml) at baseline: ≤ median vs. > median

NYHA class at baseline: II vs. III / IV

Prior ß-blocker: yes vs. no
All other exploratory subgroups comprise demographic and baseline characteristics specified 
in section 6.1.2. 


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If the total number of subjects in a subgroup category is too small, the respective subgroup 
category will be either omitted from the analysis or combined with other categories, if a 
logical combination to another subgroup category is possible.
Prior hospitalization for heart failure is defined based on one of inclusion criterions.
CRF item (subject group) selected 
Prior hospitalization (outpatients 
visit)
CHF Hospitalization/ unscheduled outpatient 
clinic visit with BNP/NTproBNP measurement 
in the last 3 months 
Yes
Only BNP/NTproBNP measurement in the last 
4 weeks 
No
Combination of CHF Hospitalization/
unscheduled outpatient clinic visit with
BNP/NTproBNP measurement in the
last 3 months and additional measurement in 
the last 4 weeks
Yes
4.6
Blind Review
The results of the final data assessment will be documented in the final list of important 
deviations, validity findings and assignment to analysis set(s). Any changes to the statistical 
analysis prompted by the results of the review of study data will be documented in an 
amendment and, if applicable, in a supplement to this SAP.
5.
Analysis Sets
Documentation of protocol deviations and assignment of patients to analysis sets will be 
performed according to the sponsor’s applicable Standard Operating Procedures and ocor 
Operation Instructions.
5.1
Assignment of analysis sets
Final decisions regarding the assignment of subjects to analysis sets will be made during the 
review of study data and documented in the final list of important deviations, validity findings 
and assignment to analysis set(s) (see section 4.6).
Data for all patients who signed informed consent but were not randomized will not be 
included in any statistical analyses except standard disposition tables and listings provided in 
the clinical study report (Screening failures and discontinued patients). 
The statistical analysis sets are defined as follows:
Full analysis set (FAS)


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The FAS population consists of all randomized unique patients. According to the ICH E9 
guideline, this analysis set is as complete as possible and as close as possible to the intent-to-
treat (ITT) ideal. Patients will be analyzed as randomized. The FAS will be used to display 
baseline characteristics and to display efficacy analyses. Sensitivity analyses are based on the 
FAS population. For the analyses conducted in FAS, patients will be analyzed as randomized 
per IxRs. 
Safety analysis set (SAF)
The SAF population consists of all randomized patients who received at least one dose of 
study medication after randomization. The SAF will be used to display safety analyses. For 
analyses conducted in SAF, patients will be analyzed as treated.
Per-protocol set (PPS)
The protocol defines a PPS. Since there are two primary efficacy variables, we will define 
PPS LVEF and PPS BNP, specific to the presence of non-missing data for each variable 
separately.
Per-protocol set for LVEF (PPS LVEF):  The PPS LVEF population consists of all FAS 
population patients without validity findings. Validity findings may include adherence and 
compliance issues and the violation of inclusion / exclusion criteria affecting efficacy 
evaluation. If the left ventricular ejection fraction of this subject is measured after first dose of 
study medication but within a specified time frame this subject will not be excluded from PPS
LVEF. The patients with invalid/missing baseline value or missing post-baseline value not 
due to CV death or HF hospitalization will be excluded from the PPS LVEF. The primary 
analysis of LVEF will be conducted in PPS LVEF.
Per-Protocol set for NT-proBNP (PPS BNP): The PPS BNP population consists of all FAS 
population patients without validity findings. Validity findings may include adherence and 
compliance issues and the violation of inclusion / exclusion criteria affecting efficacy 
evaluation. If the NT-proBNP (pg/mL)  of this subject is measured after first dose of study 
medication but within a specified time frame this subject will not be excluded from PPS BNP. 
The patients with invalid/missing baseline value or missing post-baseline value not due to CV 
death or HF hospitalization will be excluded from the PPS BNP. The primary analysis of NT-
proBNP will be conducted in PPS BNP.
A list of potential validity findings will be provided in a separate important deviations and 
validity specifications document which will be finalized before database lock. The detailed 
definitions and the assignment of patients to this analysis set will be based on the validity 
review meeting. Patients will be analyzed as treated.
Pharmacokinetic analysis set (PKS)
The PKS population consists of all patients treated with neladenoson bialanate with at least 
1 valid BAY 84-3174 plasma concentration and without protocol deviation that would 
interfere with the evaluation of the PK data.


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6.
Statistical Methodology
The formal statistical analyses will be both descriptive and inferential. Summaries will be 
provided for each of the treatment group. All of analyses planned in this SAP will be repeated 
in Japanese subjects only.
6.1
Population characteristics
6.1.1
Disposition of Subjects
The following will be tabulated overall and/or by treatment group:

Study sample sizes (FAS, PPS LVEF, PPS BNP, SAF and PKS )

Study sample sizes by region, country, and site

Subject disposition

Number of subjects and primary reasons for screening failures (only overall)

Number of subjects and primary reasons for permanent discontinuation of study 
medication (by treatment group and overall for FAS and SAF)

Number of subjects and primary reasons for discontinuation from study (by treatment
group and overall for FAS and SAF)
6.1.2
Demographic and Baseline Characteristics
Descriptive summaries of demographics and baseline characteristics will be presented by 
treatment group and overall for the PPS LVEF, PPS BNP, FAS and SAF populations. 
Comparability of the treatment groups with respect to demographics and baseline 
characteristics will be assessed using the descriptive summaries. Same analyses will also be 
performed for subjects who prematurely discontinue study participation or intake of study 
medication.
The following demographic data will be summarized:

Age at baseline (years);

Age category: <65, 65-75, >75 years;

Gender (male vs. female)

Race and ethnicity;

Height (cm);

Weight (kg) at baseline;

BMI (kg/m²);

BMI category: ≤30 vs. >30 kg/m²;

Tobacco smoking history

Alcohol consumption history

Recent caffeine-containing beverage and chocolate consumption history
The following baseline characteristics will be summarized:


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
LVEF(%) at baseline: ≤25 vs. >25

LVEF(%) at baseline: ≤40 vs. >40 

LVEF(%) at baseline: ≤45 vs. >45

LVEF(%) at baseline: ≤mean vs. >mean

NT-proBNP (pg/ml) at baseline: ≤ median vs. > median

NYHA class at baseline: II vs. III / IV

Prior ß-blocker: yes vs. no

Region: North America /West Europe / East Europe / Asia

Region: Japan vs. rest-of-the-world (analysis to be included in reports specific for 
Japan only)

Time of CHF diagnosis to randomization (months): ≤3 vs. >3

Prior hospitalization for heart failure: yes vs. no

Etiology of CHF: ischemic vs. non-ischemic

Diabetes: yes vs. no

Atrial fibrillation: yes vs. no

Hypertension: yes vs. no

Prior CHF medication:
o
Prior ß-blocker in max tolerated dose: yes vs. no
o
Prior use of ivabradine: yes vs. no
o
Prior use of MRA: yes vs. no
o
Prior use of ACE inhibitor: yes vs. no
o
Prior use of ARB: yes vs. no
o
Prior use of angiotensin receptor-neprilysin inhibitor (ARNI): yes vs. no

Estimated GFR (ml/min/1.73 m2): ≤60 vs. >60
6.1.3
Medical history
Medical history findings will be summarized using medical dictionary for regulatory activities 
(MedDRA, version refers to TS domain) terms for the FAS population by treatment group. 
6.1.4
Prior and Concomitant Medications
All non-study medications taken during the study will be coded using the World Health 
Organization Drug Dictionary (WHO-DD) in its latest version which is specified in the TS 
domain and the Anatomical Therapeutic Chemical (ATC) classification system. Coding will 
include the drug class and preferred drug name.


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Non-study medications taken during the study will be categorized as prior medications, 
concomitant medications during the treatment period, and post treatment medications during 
the safety follow-up.
Prior medications will be defined as a non-study medication with a stop date prior to the first 
dose of study treatment.
Concomitant medications will be defined as:
Non-study medications with a start or stop date on or after the date of the first dose 
of study treatment;
Non-study medications that started prior to the first dose of study treatment and are 
ongoing during the treatment period;
Non-study medications with partial start dates that indicate that the medication could 
be concomitant in relation to the date of the first dose of study treatment;
Non-study medications with completely missing start dates, unless their stop dates 
confirm otherwise (i.e. the stop date is before the first dose of study treatment).
Post treatment medications are defined as non-study medications taken up to 6 weeks after the
last study medication intake.
All concomitant medications will be listed, including verbatim descriptions and coded terms, 
and flags for prior medications. Prior, concomitant, and post treatment medications will be 
summarized using frequencies of subjects reporting each drug category and perferred drug 
name. Additionally 

concomitant medications of interest required by the HF guideline, i.e. 
ACEI/ARB/ARNI, MRA, beta blockers and/or Ivabradine and their combinations

other medications of interest relevant to the cardiovascular system, i.e.digitalis 
glycosides,loop and thiazide diuretics, Potassium sparing agents (excluding MRAs), 
Statins, anticoagulants, antiplatelets, natriuretic peptides,  soluble guanylate cyclase 
stimulators, GLP-1 antagonists, insulins,  and SGLT-2 inhibitors, 
will be summarized using frequencies of subjects reporting each preferred drug name at 
baseline and post-baseline. Frequency of subjects who experienced dose increase, dose 
decrease or no dose change of concomitant medication of interested required in the HF 
guideline will also be summarized. 
For each subject, multiple records of the same concomitant medication will be counted once 
within a drug class and preferred name.


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6.2
Efficacy
6.2.1
Primary efficacy variables and analyses
6.2.1.1
Primary efficacy variables

Absolute change from baseline in left ventricular ejection fraction (LVEF; %) after 20 
weeks measured by echocardiography, i.e., LVEF at week 20 minus LVEF at baseline.

Absolute change from baseline in log-transformed NT-proBNP (pg/mL) after 20 
weeks, i.e., log-transformed NT-proBNP at week 20 minus log-transformed NT-
proBNP at baseline. 
6.2.1.2
Primary analysis of primary efficacy variables
Primary analysis will be performed in PPS LVEF and PPS BNP respectively, a subset of the 
FAS comprising “compliant and adherent” patients (as much as possible, defined via validity 
criteria). To avoid bias, the PPS LVEF and PPS BNP will also include those “compliant and 
adherent” patients who are “censored” due to CV death or a hospitalization for HF preventing 
the assessment of the relevant efficacy endpoints 20 weeks after randomization to take place 
as planned. For missing post-baseline value due to CV death or study drug/study 
discontinuation due to HF, a worst case approach (WOV) will be applied. The worst change 
by treatment group will be calculated.  If the worst change in that treatment group is positive 
for LVEF / negative for NT-proBNP, the worst case in that treatment group is 0. The missing 
change from baseline value will be imputed with a multiple 1.0 of the median of worst 
changes from baseline value among all treatment groups. The post-baseline value at week 20 
will be calculated accordingly as baseline value + imputed change from baseline. If this 
imputed  post-baseline value for LVEF is < 0% in case of CV death preventing the 
measurement, then the post-baseline value will be replaced with 0 and the imputed change 
from baseline will be modified to (- baseline value). Similarly, if the imputed post-baseline 
value is < 5% in case of a hospitalization for HF and no CV death preventing the 
measurement, the post-baseline value will be set to 5% and the corresponding imputed change 
from baseline will be reset to (5 - baseline value).
For both primary efficacy variables, it is planned to perform a test for a dose-response signal,
respectively, under the assumption of a nearly monotone dose-response relationship in the 
dose range considered. The MCP-Mod method (5) combining multiple comparison 
procedures (MCP) principles with modeling techniques will be used for the primary statistical 
analysis of the primary efficacy variables. This method allows the flexibility of modeling for 
dose estimation, while preserving the robustness to model misspecification associated with 
MCP procedures. The MCP-Mod method will be used based on SAS programs provided (9) 
and the results may be validated within R (10) with the actual DoseFinding package (11).
Two primary variables have been defined to better evaluate multiple dimensions of the 
treatment effect, thereby adding a source of multiplicity. The overall outcome of the primary 
efficacy analysis will be considered positive if at least one of the two null hypotheses related 
to the primary efficacy variables can be rejected. The Hochberg (step-up) procedure will be 
applied to control the family-wise error rate (FWER):


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Consider the null hypotheses for LVEF, H0,LVEF, and for NT-proBNP, H0,NT-proBNP, and their 
associated raw p-values pLVEF and pNT-proBNP.  The Hochberg test is performed using the 
following steps:
1. If max(pLVEF, pNT-proBNP) ≤α = 0.05, both null hypotheses H0,LVEF and H0,NT-proBNP will 
be rejected and the procedure stops. 
2. If max(pLVEF, pNT-proBNP) > α = 0.05 and min(pLVEF, pNT-proBNP) ≤α/2 = 0.025,
we will fail to reject the null hypothesis related to the larger p-value max(pLVEF, pNT-
proBNP) and the null hypothesis related to the smaller p-value min(pLVEF, pNT-proBNP) will 
be rejected. 
3.
Otherwise, we will fail to reject both null hypotheses H0,LVEF  and H0,NT-proBNP .
Assumptions
Five active doses of neladenoson bialanate will be used in this study: 5 mg, 10 mg, 20 mg, 30 
mg, and 40 mg, as well as a placebo arm corresponding to a 0 mg dose. 
The measurements of the primary efficacy variables are assumed to be normally distributed 
with the same standard deviation σ and independent between patients, respectively.
LVEF: The following assumptions were made for the absolute change from baseline in LVEF 
over 20 weeks:

the expected mean effect under the placebo dose is conservatively assumed as an 
absolute increase from baseline of up to = 2% with a standard deviation of = 7%

while the maximum observable mean effect under neladenoson bialanate within the 
dose range considered is assumed as an absolute increase of = 5% with a standard 
deviation of = 7% .
This results in an expected maximum effect size of (5-2)/7 = 3/7 = 0.43 under conservative 
assumptions. Note that the threshold of clinical relevance is an absolute difference of 3% in 
the change from baseline over the placebo control group.
NT-proBNP: The following assumptions were made for the absolute change from baseline in 
the log-transformed NT-proBNP over 20 weeks:

the expected mean effect under the placebo dose is assumed as an absolute decrease 
from baseline of -0.105 log(pg/mL) with a standard deviation of = 0.85 log(pg/mL), 
which is equivalent to a 10% relative reduction from a mean of 2,500 pg/mL at 
baseline.

while the maximum observable mean effect under neladenoson bialanate within the 
dose range considered is assumed as an absolute decrease from baseline of 
-0.357 log(pg/mL) with a standard deviation of = 0.85 log(pg/mL), which is 
equivalent to a 30% relative reduction from a mean of 2,500 pg/mL at baseline.
It is assumed that the respective primary response efficacy variable, denoted as , is observed 
for the 6 parallel groups corresponding to doses levels: (placebo =) 1 < 2 < … < k, where 
k = 6.


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For patient j within treatment group i the response can then be described by the following 
model:
 = 	(, ) + ,       ~(0, ),       = 1, … , ,    = 1,  … ,  ,  
where 	(. ) is parameterized by a vector of parameters  and  is the error term.
A candidate set with M=5 different dose response shapes 	(. ) based on four models was 
chosen for the MCP-Mod method. Table 6–1 displays the response expressions for the shapes 
in the candidate sets for both, change in LVEF and change in log-transformed NT-proBNP. 
Figure 6–1 shows the corresponding dose-response shapes for change in LVEF. The model 
parameters were obtained through discussions with experts in the clinical team, taking prior 
beliefs and uncertainty into account. The dose-response shapes for NT-proBNP are equivalent 
to those for LVEF but with decreasing trends. 
Table 6–1: Dose-response shapes used in the candidate set
Model
Response as function of dose d
LVEF
NT-proBNP
Linear
2 + 0.075d
–0.105 – 0.0063d
Sigmoidal Emax 1
2 + 3.007689d4 / (94 + d4)
–0.105 – 0.2526d4 / (94 + d4)
Sigmoidal Emax 2
2 + 3.375d3 / (203 + d3)
–0.105 – 0.2835d3 / (203 + d3)
Emax
2 + 3.09375d / (1.25 + d)
–0.105 – 0.2599d / (1.25 + d)
Quadratic
2 + 0.2d – 0.00333d²
–0.105 – 0.0168d + 0.00028d²
Figure 6–1: Dose-response shapes used in the candidate set for change in LVEF


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Based on the standardized versions of the models in the candidate set and the sample size 
allocation planned for this study, the optimum contrast coefficients for the 5 contrast tests on 
the dose-response shapes can be derived for both primary variables (Table 6–2). 
These contrast coefficients will be updated based on the actual number of subjects per 
treatment group which are finally available for the analysis.
Table 6–2: Contrast coefficients
Model
Contrast coefficients for dose
0.0
5.0
10.0
20.00
30.00
40.00
Linear
-0.674
-0.159
-0.186
0.077
0.340
0.603
Sigmoidal Emax 1
-0.784
-0.223
0.004
0.315
0.342
0.347
Sigmoidal Emax 2
-0.615
-0.197
-0.290
0.130
0.423
0.550
Emax
-0.901
0.046
0.170
0.215
0.231
0.240
Quadratic
-0.815
-0.129
-0.024
0.288
0.392
0.288
Analysis
Step 1: Detection of dose-response signal
For detecting an overall trend, or a dose-response signal, each of the M=5 dose-response 
shapes in the candidate set will be tested, using a single contrast test based on the updated 
version of contrast coefficients taking the actual sample sizes per treatment group into 
account.
For each model m, m = 1, …, 5, in the candidate set 
the null hypothesis
:  !
 = 0
will be tested against 
the respective 1-sided alternative hypothesis ":  !
 > 0, 
where !
 = (!"
 , … , !$
 )% = (	
(", 
 ), … , 	
($, 
 ))′ and
	 is the standardized version of the dose-response model 	(, ) = ' + '"	(, ). In 
this parameterization, ' is a location parameter and '" is a scale parameter such that only 
 determines the shape of the model function. 
The contrast coefficients cm1 … cmi for the m-th model are chosen such that they maximize the 
power to detect the underlying model. These optimal contrast coefficients depend only on the 
parameters in the standardized model function (, which determine the model shape (5) and 
the actual group sample sizes (which is known after unblinding of the study). The ith member 
of the optimal contrast vector copt,m for testing the shape model m is proportional to
)(!
 , … , !̅),  = 1, … ,6,  
where !̅ = ," ∑
!
 
$
."
. In case of unequal sample sizes per treatment arm, copt,m cannot 
be expressed in closed form and numerical optimization techniques are required (9, 11). The 
copt,m is derived by fulfilling the condition ∑
 
 = 1
$
."
.
The single contrast test for detecting the m-th model shape is defined by


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/ =
∑
012
3
245
672
8 9∑
012
: /<2
3
245
, = = 1, … ,5,     where   ? =
∑
∑
@62A,672B
:
C2
245
3
245
D,$
.
Under the null hypothesis of no dose-response effect, i.e. !E5 = ⋯= !E3, the test statistic 
/ = (/", … , /G)′ follows a central multivariate t distribution with N-6 degrees of freedom and 
correlation matrix  J = (K), where   K = 
∑
02L0AL/<L
3
L45
9∑
02L
:/<L
3
L45
∑
0AL
: /<L
3
L45
 
.
The final test statistic /MN is based on the maximum contrast test and a “proof-of-concept” 
dose-response relationship is detected if this maximum statistic /MN, and thus at least 
one single contrast test, is statistically significant, while controlling the familywise error rate 
at level .  If O",P denotes the multiplicity adjusted critical value, a dose-response signal is 
established if  /MN  ≥O",P.The smallest of the corresponding adjusted p-values will be used 
for the Hochberg test.
This analysis will be performed for the FAS and PPS LVEF, PPS BNP populations
respectively, where the PPS LVEF and PPS BNP analysis is the primary analysis. 
If no candidate model is statistically significant, the procedure stops, indicating that a dose-
response relationship cannot be established from the observed data.
Out of the statistically significant models in the candidate set a best model can be selected for 
the next step: modeling and estimation. 
Step 2: Modeling and estimation of target doses
If a dose-response signal is established, the selected dose-response model(s) will be fitted to 
the observed data to estimate the model parameters. 
The estimated dose-response model will be plotted against the doses including 90% 
confidence bands. Once the dose-response model has been successfully fitted to the data, 
target dose(s) of interest are estimated. Given a clinically relevant effect ∆f, a minimum 
effective dose (TUV∆) associated with model 	(, ) is defined as
TUV∆= argminE∈(E5,E3]{	(, ) ≥	(", ) + ∆}.
Estimates of TUV∆will be calculated for a clinically relevant change in LVEF assumed as 
∆wil% and potentially a plausible range of ∆values which will be defined based on the 
observed data. Estimation for change in log-transformed NT-proBNP will be performed 
analogously, ensuring an adequate back-transformation to allow for better interpretability of 
the results. In addition, estimates considering confidence bounds for the predicted value at a 
certain dose may be used. The final choice of the target dose depends on the evaluation of the 
primary efficacy variables and other efficacy variables, as well as safety considerations.
Additionally LVEF and increasing change from baseline, NT-pro-BNP and decreasing change 
from baseline, and log-transformed NT-proBNP and decreasing change from baseline will be
descriptively summarized by treatment and overall, and visit in PPS LVEF and PPS BNP 
respectively.


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6.2.1.3
Secondary analysis of primary efficacy variables
As a secondary analysis pairwise comparisons of the active neladenoson bialanate dose 
groups with the placebo group will be performed without controlling the family-wise error 
rate, by calculating the 90% confidence interval for the difference in primary efficacy variable 
between each active dose of neladenoson bialanate and placebo.
6.2.1.4
Sensitivity analyses of primary efficacy variables
6.2.1.4.1
Sensitivity analysis of primary efficacy variables in PPS LVEF and PPS 
BNP
As a sensitivity analysis, primary analysis of primary efficacy variables on the “completers 
and treatment adherers” excluding the censored patients in the per-protocol analysis set will 
be repeated. This strategy leads to unbiased estimates only if missing values are “missing 
completely at random” (MCAR), i.e. the missingness – including missing data due to death –
is independent of both observed and unobserved outcomes. This condition is unlikely to hold 
exactly but rather approximately.
Further sensitivity analyses on the PPS LVEF and PPS BNP may be performed if the missing 
data patterns suggest further exploration.
6.2.1.4.2
Sensitivity analysis of primary efficacy variables in FAS
Additional efficacy analyses in the FAS will include the following:

Primary analyses of primary efficacy variables specified in section 6.2.1.2 will be
performed in FAS without any imputation. 

Generally, it will be assumed that missing observations for the respective efficacy 
variables are missing at random. This implies that the behavior of the post dropout 
observations can be predicted from the observed variables using appropriate 
imputation models. Likely exceptions to the missing at random assumption are 
observations which are missing due to a patient’s CV death or HF hospitalization prior 
to the visit in Week 20. These observations can be assumed to be missing not at 
random (MNAR), i.e., that missingness depends both on observed and unobserved 
outcomes and that an explicit model for the patient’s statistical behavior after drop-out 
(or death) is required. Therefore, an analysis based on a pattern mixture framework (6) 
with different imputation rules depending on the reason for missingness will be used 
using a multiple imputation model, followed by a modification of the imputed data 
applying penalties: 
1. First, multiple imputation will be applied to draw sets of completed data, using an 
appropriate imputation model. Baseline characteristics which should be considered 
in the imputation model include but are not restricted to the baseline values of the 
respective efficacy variable, the treatment group, and sex. 
2. The imputed data will be modified by applying penalties. The penalty is chosen as 
the median of the worst changes from baseline across treatment groups (or 0 if the 
median worst change should be positive for LVEF or negative for 
LVESV/LVEDV or log-transformed NT-proBNP/hs-TNT).


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3. After modifying the completed data sets, the primary analysis specified in section 
6.2.1.2 will be applied to the multiple imputed datasets and the point estimate and 
variance of the contrast from multiple imputed datasets will be combined based on 
Rubin’s rule (8). For more details see Appendix 9.4.

Primary analyses where for each patient without an observation at the visit in Week 20 
the missing value will be imputed according to a last observation carried forward 
approach, including the baseline value. 
For reproducibility, the SAS seed number for creating the random numbers for the multiple 
imputation will be set to the study number. 
6.2.1.5
Additional analysis of primary efficacy variables
Adjusted primary analysis of primary efficacy variables specified in section 6.2.1.2 (dose-
response test) will performed in PPS LVEF and PPS BNP respectively. Baseline values of 
atrial fibrillation, eGFR (≤60 mL/min/1.73m2 , >60 mL/min/1.73m2), gender , age group
(<50, 50-75 and >75), and BMI > 30 kg/m2 will be used as covariates. In exploratory manner, 
the absolute change in LVEF (%) from baseline to week 20 will be categorized into four 
groups (≤-5, > -5 to <5, 5 to <10, ≥10). The number (%) of patients in each category of 
LVEF will be displayed by treatment group and overall. For further details including further 
categorization see the TLF Specification document.
6.2.2
Secondary efficacy variables and analyses
6.2.2.1
Secondary efficacy variables
Secondary efficacy variables across different domains are: 

Key echocardiographic parameters, measured values and absolute change from 
baseline at 20 weeks:
o
Left ventricular end-systolic volume (LVESV; mL) 
o
Left ventricular end-diastolic volume (LVEDV; mL)

High sensitivity troponin T (hs-TNT; ng/L), measured values (log transformed) and 
absolute / relative change from baseline at 20 weeks as a biomarker of myocardial 
injury

Time from randomization to clinical outcomes: CV mortality, HF hospitalization and 
urgent visits for HF (separate and composite)
6.2.2.2
Primary analyses of secondary efficacy variables
The primary analysis of key echocardiographic parameters will be performed in PPS LVEF 
and other secondary efficacy variables will be performed in PPS BNP. The missing values of 
post baseline of LVESV and LVEDV will be imputed by WOV if the baseline values are not 
missing and the subjects have CV death or HF hospitalization, otherwise remains missing.  
Similarly The missing values of post baseline of hs-TNT will be imputed by WOV if the 
baseline values are not missing and the subjects have CV death or HF hospitalization, 
otherwise remains missing. The secondary efficacy variables, except for the clinical 
outcomes, will be analyzed using similar statistical methods as for the primary efficacy 


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variables, i.e. the MCP-Mod method with the same standardized candidate dose-response 
shapes (with the proper direction: decreasing trend for change of LVESV,  LVEDV and log-
transformed hs-TNT) and corresponding coefficients as for the primary variables. 
Time to adjudicated clinical outcome event since randomization (using both separate and 
composite outcomes) will be described by means of Kaplan-Meier (KM) estimates by 
treatment group. The subjects who do not have the corresponding clinical outcomes until 
week 26 visit (upper time limit, i.e. 182+7days) will be considered as right-censored at the 
minimum of date of last visit, date of week 26 visit, study day 189, and date of death (in case 
death is non CV death). KM estimates for each visit will be tabulated.
Additionally time to adjudicated on-treatment clinical outcome events since randomization 
(using both separate and composite outcomes) will also described up to 6 weeks after last 
dose in each treatment arm respectively. The subjects who do not have the corresponding 
clinical outcomes until 6 weeks after last dose will be considered right censored at minimum 
of 6 weeks after last dose, date of last visit and date of death (in case death is non CV death).  
6.2.2.3
Sensitivity analyses of secondary efficacy variables
Sensitivity analyses of secondary variables except for clinical events will be performed in the 
FAS using the same methods as for the primary efficacy variables. If the baseline values of 
secondary endpoints are missing, then only multiple imputation will be applied for those 
subjects. Please see the details in section 6.2.1.4. In addition clinical events will be analyzed 
by using life table statistics and Kaplan-Meier estimates in FAS (only time scope up to week 
26) and SAF.
6.2.2.4
Additional analyses of secondary efficacy variables
Percentage change in hs-TNT from baseline to week 20 will be summarized by treatment 
group and overall in PPS BNP. In addition to analyses comparing population means in the 
different dose groups, the number of patients in whom the individual change from baseline 
value crossed clinically meaningful thresholds will be reported in post-hoc analysis 
separately.
6.2.3
Exploratory efficacy variables and analyses
Exploratory efficacy variables include:

Activity (duration, intensity) reported values and absolute change from baseline at 20 
weeks. Variables as specified in appendices 9.1

Echocardiographic parameters, as described in Section 9.4.1 of Clinical Study 
Protocol, measured values and absolute / relative change from baseline at 20 weeks

Left ventricular ejection fraction (LVEF; %), measured values, number of patients in 
whom absolute change from baseline after 20 weeks is > 5%

Mandatory biomarkers, measured values and absolute / relative change from baseline 
at 20 weeks, including 
o
NT-proBNP (pg/mL), measured values and relative change from baseline at 20 
weeks to assess elevated filling pressures
o
UACR, cystatin-C, NGAL for the evaluation of kidney function 


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
KCCQ and EQ-5D-5L, as described in Section 9.4.4.1 and 9.4.4.2 of Clinical Study 
Protocol. Frequencies of answers to individual questions will be displayed by 
treatment group and overall by visit. In addition, changes from baseline for the single 
questions will be categorized into the categories improvement / no change / 
worsening. Frequencies of the different categories will be displayed by treatment 
group and overall by visit.
The 7 individual domain scores and 3 summary scores of the KCCQ and their changes 
to baseline will be summarized by treatment group and overall by visit as continuous 
variables. The symptom stability domain (a measure of change in symptoms over the 
previous two weeks) and self-efficacy domain (a measure of patient knowledge how to 
prevent heart failure exacerbations and management of complications when they 
arise), will be reported and summarized but will not be considered measures of 
treatment efficiency. Change from baseline to week 20 of KCCQ domains of Physical 
Limitation Score, Symptom Frequency Score, Symptom Burden Score, Total 
Symptom Score, Clinical Summary Score and Overall Summary Score will be 
categorized into groups by 5 points and the number (%) of patients in each category of 
KCCQ domains respectively will be displayed by treatment group and overall. For 
scoring see Appendix, Section 9.3. The EQ visual analogue scale (VAS) values of the 
EQ-5D-5L and their changes to baseline will be summarized by treatment group and 
overall by visit as continuous variable.

Time from randomization to all-cause mortality, non-fatal myocardial infarction, non-
fatal stroke

Change in NYHA class
Time to adjudicated clinical outcome events since randomization (using both separate and 
composite outcomes) will be described by means of life table statistics and Kaplan-Meier 
estimates in FAS. Other than time to event variables will be analyzed descriptively in FAS
without missing data. In addition, percentage change in NT-proBNP from baseline to week 20 
will be summarized by treatment group and overall. The percentage change of NT-proBNP 
from baseline to week 20 will be categorized into four groups (≤-20, > -20 to ≤+20, >20 and 
≤+30, > +30) . The number (%) of patients in each category of NT-proBNP respectively will 
be displayed by treatment group and overall. 
6.3
Safety
The summaries of the safety data will be completed for the safety analysis population (SAF). 
No formal statistical test will be performed for the safety variables.
6.3.1 Extent of exposure
Study medication will be summarized for the safety population by treatment group, using 
descriptive statistics such as frequency and proportion (for categorical variables), mean, 
median, and standard deviation (for continuous variables).
All summaries related to intake of study medication will be by treatment group based on SAF:

The treatment duration (date of last study medication- date of first study medication+1 
day) will be summarized descriptively. Additionally the number of subjects by 


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treatment duration category will be given (≤28 days, >28-≤56 days, >56-≤84 days,
>84-≤140 days).

The time on study medication (treatment duration excluding days off study 
medication) will be calculated and summarized descriptively.

The number of tablets taken will be summarized descriptively, as well as 
corresponding extent of exposure (total amount of intake in mg).  
6.3.2
Treatment Compliance
Compliance is defined as 100*number of tablets taken / number of tablets planned. 
The compliance will be summarized descriptively by treatment group and overall.  In 
addition, compliance will be categorized into three groups (<80%, 80-120%, >120%) and 
summarized by treatment group and overall.
6.3.3
Adverse events
All adverse events (AEs) will be coded according to the Medical Dictionary for Regulatory 
Activities (MedDRA) in its latest version which is specified in the TS domain. 
A treatment-emergent AE is defined as any event arising or worsening after the start of study 
drug administration until 6 weeks after the last study medication intake.
Summary statistics (frequency and percentage of subjects) will be presented by treatment 
group using MedDRA for the following:

Incidence rate of treatment-emergent AEs.

Incidence rate of drug-related treatment-emergent AEs.

Incidence rate of treatment-emergent AEs leading to death.

Incidence rate of treatment-emergent AEs leading to permanent withdrawal of 
medication. 

Incidence rate of treatment-emergent AEs leading to interruption of medication. 

Incidence rate of treatment-emergent serious adverse events.

Incidence rate of treatment-emergent drug-related serious adverse events.

Incidence rate of adverse events of special interest:
o
Symptomatic bradycardia (HR < 50 bpm)
o
Findings in ECG and / or AVIVO device as follows:
Mobitz type I AV-block leading to withdrawal or interruption of study 
drug 
Mobitz type II AV block leading to withdrawal or interruption of study 
drug or leading to any change in therapy 
Third degree AV blocks


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
Listing of treatment-emergent AEs leading to withdrawal: subject ID, investigator AE 
term, SOC, preferred term, start and stop date of study drug administration, start and 
stop date(relative days) of AE, drug related (yes/no), serious (yes/no), intensity, 
outcome.

Listing of treatment-emergent serious AEs: subject ID, investigator AE term, SOC, 
preferred term, start and stop dates of study treatment, start and stop date of AE, drug 
related (yes/no), outcome, action taken. 
6.3.4
Deaths
Deaths reported during the study period will be tabulated by treatment group.

Summary table of deaths (all deaths, all deaths during treatment and up to 6 weeks
after last dose of study drug, all deaths later than 6 weeks after last dose of study 
medication)

Listing of subjects who died during treatment and up to 6 weeks after last dose: 
subject ID, start and stop date of study medication, date of death, relative day and 
cause of death.
6.3.5
Clinical laboratory evaluations
All laboratory evaluations will be done by central laboratory. 
Hematology: erythrocytes, hemoglobin, hematocrit, MCV, MCH, MCHC, reticulocytes, 
leukocytes, differential blood count, platelets
Clinical chemistry: aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
alkaline phosphatase (AP), gamma glutamyl transpeptidase (GGT), lactate dehydrogenase 
(LDH), creatine kinase (CK), amylase, lipase, glucose, cholesterol (HDL, LDL, total), 
triglycerides, creatinine, urea, uric acid, bilirubin, total protein, albumin, sodium, potassium, 
calcium, chloride, magnesium, anorganic phosphate 
Coagulation: partial thromboplastin time (PTT), international normalized ratio (INR)
The safety evaluation of laboratory data will include:

Descriptive analysis of continuous laboratory parameters, and their changes from 
baseline by visit and treatment group.

Incidence rates of treatment-emergent laboratory values outside of normal range by 
treatment group.

Listings of laboratory data out of normal range.
Laboratory abnormalities will be summarized in table of change from baseline by visit and 
treatment:

Change in renal function measured by eGFR change from baseline

Change in liver function measured by bilirubin (total and fractions), AST and ALT 
from baseline


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6.3.6
AVIVO/HealthPatch monitoring
AVIVO Mobile Patient Management System is intended to continuously measure, record and 
periodically transmit ECG data. 
Notifiable ECG-findings (like AV-conduction abnormalities) triggered by system/patients 
based, as well as reportable ECG finding according to AVIVO will be summarized in 
frequency tables by treatment group. ECG-findings according to HealthPatch will also be 
summarized in frequency tables by treatment group . A table displaying the number of 
patients with AV-block > I° according to AVIVO/HealthPatch will be provided by treatment 
group. All patients with significant ECG-finding will be listed. The definition of the findings 
that trigger a notifiable report is in Appendices 9.1.
6.3.7 Other safety measures
The last pre-treatment safety measurement, i.e., SBP(systolic blood pressure), DBP(diastolic
blood pressure), weight, body temperature, heart rate, respiration rate and electrocardiogram 
(12 lead ECG) will be used as “baseline value.”
When more than one value is collected at the same post-baseline visit, the value retained at 
that particular visit for summary statistics will be the average of the different measures 
reported for that visit.
For each treatment group, vital signs will be tabulated and summarized by visit for observed 
values and changes from baseline using descriptive statistics, as appropriate. 
The incidence rates of treatment-emergent 12-lead ECG abnormalities will be tabulated by 
treatment group.  A descriptive analysis of continuous ECG parameters and their changes 
from baseline by visit and treatment group will also be presented.  PR interval will be 
summarized by visit and treatment group.
6.4
Subgroup Analysis
6.4.1
Subgroups
Subgroups are specified in Section 4.5.4.
6.4.2
Subgroup analysis of efficacy variables
Primary, secondary and sensitivity analyses (without imputed values) of primary efficacy 
variables will be performed based on key subgroups. Additionally primary efficacy variables 
will be descriptively summarized based on exploratory subgroups.
Secondary efficacy variables will be descriptively summarized based on key subgroups and 
exploratory efficacy variables will be descriptively summarized based on LVEF(%) at 
baseline: ≤40 vs. >40.
6.4.3
Subgroup analysis of safety variables
Incidence rate of treatment-emergent AEs and treatment-emergent ECG abnormalities not 
presented at baseline (by AVIVO and HealthPatch, Japan only) will be summarized based on 
key and exploratory subgroups.


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6.5
Pharmacokinetics/pharmacodynamics
Pharmacokinetic analyses will be performed on the population valid for pharmacokinetics.
For the investigation of systemic exposure to BAY 84-3174 and its relationship with 
treatment effects, the plasma concentrations of BAY 84-3174 will be determined at different 
time points using a sparse sampling approach in all participating patients (see Clinical Study 
Protocol Section 9.5). The plasma concentration vs. time data will be evaluated descriptively 
separated by dose and visit. Plots will be prepared pooling all individual plasma 
concentrations (naive pooling) vs. actual relative study times (time of sample collection after 
time of study drug administration).
Furthermore, the pharmacokinetic data and the relationship of markers of BAY 84-3174 
exposure (e.g. Cmax, AUC) with treatment effects will be evaluated using non-linear mixed 
effect modeling (NONMEM). The latter evaluation will be described in a separate analysis 
plan and will be reported under separate cover.
The PK bioanalysis will be performed under the responsibility of the Sponsor’s Bioanalytics 
Laboratory.
6.6
Biomarker analyses
Biomarker data will be described by the following summary statistics: arithmetic mean, 
standard deviation, median, quantiles, minimum, and maximum.
Box plots and line plots of means of biomarkers over visits, by treatment group will be 
provided. Additional analyses of safety and efficacy biomarkers and their results will be 
provided in a separate report.
7.
Document history and changes in the planned statistical analysis
Version
Date
Action
Version 1.0
13Nov2017
Version 2.0
19 April 2018

Change the wording in section 
6.3.6

Add more detailed description of 
plots we plan to provide in section 
6.6
Version 3.0
29 May 2018

Add one more key subgroup: 
LVEF(%) at baseline: ≤45 vs. >45 

Add more details of worst case 
imputation and censoring rule of 
time to event variables in section 
6.2

Some minor changes in subgroup 


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analyses in section 6.4

Remove some unused variables 
from Appendix 9.1
8.
References
1. McCullough PA, Philbin EF, Spertus JA, Kaatz S, Sandberg KR, Weaver WD, et al. 
Confirmation of a heart failure epidemic: findings from the Resource Utilization 
Among Congestive Heart Failure (REACH) study. Journal of the American College of 
Cardiology. 2002;39(1):60-9.
2. Stewart S, MacIntyre K, Hole DJ, Capewell S, McMurray JJ. More 'malignant' than 
cancer? Five-year survival following a first admission for heart failure. European 
journal of heart failure. 2001;3(3):315-22.
3. Executive summary: HFSA 2006 Comprehensive Heart Failure Practice Guideline. J 
Card Fail. 2006;12(1):10-38.
4. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, et al. 
Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 
2014;371(11):993-1004.
5. Bretz F, Pinheiro JC, Branson M. Combining multiple comparisons and modeling
techniques in dose-response studies. Biometrics. 2005;61(3):738-48.
6. Carpenter JR, Kenward MG. Missing data in randomized controlled trials - a practical
guide. Chapter 6.2008.
7. Kelly RP, Ting CT, Yang TM, Liu CP, Maughan WL, Chang MS, et al. Effective 
arterial elastance as index of arterial vascular load in humans. Circulation. 
1992;86(2):513-21.
8. Rubin DB. Multiple imputation for nonresponse in surveys. New York: Wiley; 1987.
9. Menon S, Zink RC. Modern Approaches to Clinical Trials Using SAS: Classical, 
Adaptive, and Bayesian Methods. SAS Institute; December 2015
10. R Core Team (2017). R: A language and environment for statistical computing. R 
Foundation for Statistical Computing, Vienna, Austria. URL https://www.R-
project.org/.
11. Bjoern Bornkamp, Jose Pinheiro and Frank Bretz (2016). DoseFinding: Planning and 
Analyzing Dose Finding Experiments. R package version 0.9-15. URL https://cran.r-
project.org/web/packages/DoseFinding
12. The Kansas City Cardiomyopathy Questionnaire Scoring Instructions (2000-2003), 
John Spertus MD MPH [http://cvoutcomes.org/ (6th September 2013)].
13. C. Patrick G, et al. Development and Evaluation of the Kansas City Cardiomyopathy 
Questionnaire: A New Health Status Measure for Heart Failure, Journal of the 
American College of Cardiology, 2000; 35(5):1245-55 


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14. Barnard J, Rubin DB. Small-Sample Degrees of Freedom with Multiple Imputation.
Biometrika 1999; 86: 948–955.
15. Rubin, D. B. (1996), "Multiple Imputation after 18+ Years," Journal of the American 
Statistical Association, 91, 473–489.
9.
Appendices
9.1
AVIVO device variable specification
In the following, we describe the variables which will be analyzed 

Activity
Variable
Summary 
measure(s)
Unit
Length of 
intervals
activity duration
duration
seconds
daily
activity intensity
mean
mG
1 hour
activity intensity
mean, max
%
daily

Notifiable findings
These should be the findings that trigger a notifiable report, definitions as below: 
Finding
Notification criteria
Ventricular fibrillation
always notified
ICD discharge
always notified
Ventricular Tachycardia
any rate and ≥10 beats
Wide complex Tachycardia
any rate and ≥10 beats
PVCs
never notified
Sinus Bradycardia
≤30bpm
Sinus Tachycardia
≥ 180bpm
Supraventricular tachycardia
≥ 150 bpm AND ≥ 30 sec
A. Fibrillation or A. flutter
≥ 150 bpm AND ≥ 30 sec
A. Fibrillation or A. flutter
≤30bpm and ≥ 30 sec
A. Fibrillation or A. flutter
when notification criteria are met
pause
≥ 3.0 sec
AV block 2nd (Mobitz I)
≤ 50bpm
AV block 2nd (Mobitz II)
always notified
Isolated 2nd degree AV block (2:1)
≤ 50bpm
High degree AV block
always notified


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3rd Degree AV block
always notified
other
Patient triggered Events
when notification criteria are met
Technicians discretion
any
9.2
Echocardiography parameters
The list of parameters is

LV ejection fraction (LVEF, %)

LV end-diastolic volume (LVEDV), LVEDV index (LVEDVI, calculated as 
LVEDV/BSA)

LV end-systolic volume (LVESV), LVESV index (LVESVI, calculated as 
LVESV/BSA)

LA size (LA diameter, area, volume index [LAVI, calculated as LAV/BSA])

Lateral e' (early diastolic mitral annular relaxation velocity at the lateral mitral annulus 
by Tissue Doppler, TD)

Septal e' (early diastolic mitral annular relaxation velocity at septal mitral annulus by 
TD), including calculation of average e'

Global longitudinal strain (%)

Pulmonary artery systolic pressure (PASP), estimated by tricuspid regurgitation 
velocity and inferior vena cava diameter, including its change with respiration, and 
hepatic vein flow in patients with tricuspid regurgitation

Tricuspid annular plane systolic excursion (TAPSE), right ventricular (RV) s' (velocity 
of the tricuspid annular systolic excursion at the RV free wall by TD)

Mitral regurgitation

LV mass, LV mass index (calculated as LV mass/BSA)

Wall thicknesses, incl. interventricular septum diameter (IVSD), posterior wall 
thickness (PWT), anteroseptal wall thickness (ASWT)

E, A (if in sinus rhythm), calculation of E/A and E/e' (using lateral, septal, average e') 
ratios

E-wave deceleration time (EWDT)

Stroke volume (SV, calculated by LVEDV - LVESV) and derived parameters, 
including SV index (SVI, calculated as SV/BSA), cardiac output (CO, calculated as 
SV*HR), cardiac index (CI, calculated as CO/BSA), systemic arterial compliance 
(SAC, calculated as SV/PP), total peripheral resistance (TPR, calculated as 
MAP/CO*80)


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
Effective arterial elastance (Ea), estimated as end-systolic pressure (Pes) [Pes 
calculated as SBP times 0.9 (7)] divided by SV (SBP*0.9/SV)
Final details of all echocardiography parameters to be measured and analyzed will be included 
in a separate echocardiography manual.
9.3
KCCQ Scoring
As described in the KCCQ Scoring instruction [12][13], the following derivations will be 
used.
Generally only questions actually answered are used for derivation of the scores in the 
following way:
If there are n questions in a scale, and the subject must answer m to score the scale, but the 
subject answers only n-i, where n-i ≥ m, calculate the mean of those questions as
(sum of the responses to those n-i questions) / (n-i)
not
(sum of the responses to those n-i questions) / n
The 7 individual domain scores and 3 summary scores will be calculated as follows:
9.3.1
Physical Limitation
Code responses to each of Questions 1a-f as follows:
Extremely limited = 1
Quite a bit limited = 2
Moderately limited = 3
Slightly limited = 4
Not at all limited = 5
Limited for other reasons or did not do = <missing value>
If at least three of Questions 1a-f are not missing, then compute
Physical Limitation Score = 100*[(mean of Questions 1a-f actually answered) – 1]/4
9.3.2
Symptom Stability
Code the response to Question 2 as follows:
Much worse = 1
Slightly worse = 2
Not changed = 3
Slightly better = 4
Much better = 5
I’ve had no symptoms over the last 2 weeks = 3
If Question 2 is not missing, then compute


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Symptom Stability Score = 100*[(Question 2) – 1]/4
9.3.3
Symptom Frequency
Code responses to Questions 3, 5, 7 and 9 as follows:
Question 3
Every morning = 1
3 or more times a week but not every day = 2
1-2 times a week = 3
Less than once a week = 4
Never over the past 2 weeks = 5
Questions 5 and 7
All of the time = 1
Several times a day = 2
At least once a day = 3
3 or more times a week but not every day = 4
1-2 times a week = 5
Less than once a week = 6
Never over the past 2 weeks = 7
Question 9
Every night = 1
3 or more times a week but not every day = 2
1-2 times a week = 3
Less than once a week = 4
Never over the past 2 weeks = 5
If at least two of Questions 3, 5, 7 and 9 are not missing, then compute:
S3 = [(Question 3) – 1]/4
S5 = [(Question 5) – 1]/6
S7 = [(Question 7) – 1]/6
S9 = [(Question 9) – 1]/4
Symptom Frequency Score = 100*(mean of S3, S5, S7 and S9)
9.3.4
Symptom Burden
Code responses to each of Questions 4, 6 and 8 as follows:
Extremely bothersome = 1
Quite a bit bothersome = 2
Moderately bothersome = 3
Slightly bothersome = 4
Not at all bothersome = 5
I’ve had no swelling/fatigue/shortness of breath = 5


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If at least one of Questions 4, 6 and 8 is not missing, then compute
Symptom Burden Score = 100*[(mean of Questions 4, 6 and 8 actually answered) –
1]/4
9.3.5
Self-Efficacy
Code responses to Questions 10 and 11 as follows:
Question 10
Not at all sure = 1
Not very sure = 2
Somewhat sure = 3
Mostly sure = 4
Completely sure = 5
Question 11
Do not understand at all = 1
Do not understand very well = 2
Somewhat understand = 3
Mostly understand = 4
Completely understand = 5
If at least one of Questions 10 and 11 is not missing, then compute
Self-Efficacy Score = 100*[(mean of Questions 10 and 11 actually answered) – 1]/4
9.3.6
Quality of Life
Code responses to Questions 12, 13 and 14 as follows:
Question 12
It has extremely limited my enjoyment of life = 1
It has limited my enjoyment of life quite a bit = 2
It has moderately limited my enjoyment of life = 3
It has slightly limited my enjoyment of life = 4
It has not limited my enjoyment of life at all = 5
Question 13
Not at all satisfied = 1
Mostly dissatisfied = 2
Somewhat satisfied = 3
Mostly satisfied = 4
Completely satisfied = 5
Question 14
I felt that way all of the time = 1
I felt that way most of the time = 2
I occasionally felt that way = 3


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I rarely felt that way = 4
I never felt that way = 5
If at least one of Questions 12, 13 and 14 is not missing, then compute
Quality of Life Score = 100*[(mean of Questions 12, 13 and 14 actually answered) –
1]/4
9.3.7
Social Limitation
Code responses to each of Questions 15a-d as follows:
Severely limited = 1
Limited quite a bit = 2
Moderately limited = 3
Slightly limited = 4
Did not limit at all = 5
Does not apply or did not do for other reasons = <missing value>
If at least two of Questions 15a-d are not missing, then compute
Social Limitation Score = 100*[(mean of Questions 15a-d actually answered) – 1]/4
9.3.8
Total Symptom Score
= mean of the following available summary scores:
Symptom Frequency Score
Symptom Burden Score
9.3.9
Overall Summary Score
= mean of the following available summary scores:
Physical Limitation Score
Total Symptom Score
Quality of Life Score
Social Limitation Score
9.3.10
Clinical Summary Score
= mean of the following available summary scores:
Physical Limitation Score
Total Symptom Score
9.4
Combining inferences from multiple imputed data sets
With m imputations, m different sets of the point and variance estimates for a parameter 
(in 
our case the contrast estimate) can be computed (see SAS version 9.2 Help for Proc 
Mianalyze). Suppose that 
and 
  are the point and variance estimates, respectively, from 
the ith imputed data set, i= 1, 2, ..., m. Then the combined point estimate for 
from multiple 
imputation is the average of the m complete-data estimates: 


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Suppose that 
is the within-imputation variance, which is the average of the m complete-
data estimates: 
And suppose that 
is the between-imputation variance: 
Then the variance estimate associated with 
is the total variance [8]
The statistic 
is approximately distributed as t with νm degrees of freedom [14], 
where 
The degrees of freedom νm depend on m and the ratio 
The ratio r is called the relative increase in variance due to nonresponse [8].When there is no 
missing information about 
, the values of r and B are both zero. With a large value of m or a 
small value of r, the degrees of freedom νm will be large and the distribution of 
will be approximately normal. 
Another useful statistic is the fraction of missing information about : 
Both statistics r and λ are helpful diagnostics for assessing how the missing data contribute to 
the uncertainty about . 
When the complete-data degrees of freedom ν0 are small, and there is only a modest 
proportion of missing data, the computed degrees of freedom, νm, can be much larger than ν0, 
which is inappropriate. For example, with m=5 and r=10%, the computed degrees of freedom 


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νm =484, which is inappropriate for data sets with complete-data degrees of freedom less than 
484. 
[14] recommend the use of adjusted degrees of freedom 
where   
  and   
. 
We will specify the complete-data degrees of freedom ν0 with the EDF= option, the 
MIANALYZE procedure uses the adjusted degrees of freedom, c
∗, for inference.