Clinical trial NCT03547583
Conditions: Chronic Heart Failure With Preserved Ejection Fraction
Sponsor: Bayer
Start date: 2018-06-15; Completion date: 2019-11-04
Enrollment: 789 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary hypothesis in this trial is that the treatment with vericiguat 10 mg or 15 mg in patients with HFpEF improves the KCCQ PLS (Kansas City Cardiomyopathy Questionnaire Physical limitation score) compared to placebo after 24 weeks of treatment.

Detailed description:

Arms: arm 1: Subjects will receive vericiguat (BAY1021189) for 24 weeks, starting at 2.5 mg once daily at randomization and up-titrated to 5 mg at week 2, to 10 mg at week 4, with sham titration at week 6. arm 2: Subjects will receive vericiguat (BAY1021189) for 24 weeks, starting at 2.5 mg once daily at randomization and up-titrated to 5 mg at week 2, to 10 mg at week 4, and to 15 mg at week 6. arm 3: Subject will receive placebo for 24 weeks, once daily, starting sham up-titration at weeks 2, 4, and 6.
Interventions: intervention 1: Vericiguat (BAY1021189) 2.5 mg, 5 mg or 10 mg IR tablets intervention 2: Placebo
Intervention descriptions: intervention 1: Oral use. Vericiguat, which will be started at 2.5 mg at randomization and up-titrated to 5 mg at week 2, and to 10 mg at week 4, with sham titration or up-titration to 15 mg at week 6. intervention 2: Placebo and sham up-titration at weeks 2, 4, and 6

Protocol documents:
Prot_000.pdf: 
 
Document Type: 
Study Protocol 
Official Title: 
A randomized parallel-group, placebo-controlled, double-blind, 
multi-center trial to evaluate the efficacy and safety of the oral sGC 
stimulator vericiguat to improve physical functioning in activities of 
daily living in patients with heart failure and preserved ejection 
fraction (VITALITY-HFpEF) 
NCT Number: 
NCT03547583 
Document Date: 
22-Feb-2018 
 


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1.
Title page
A randomized parallel-group, placebo-controlled, double-blind, multi-center trial to eValuate 
the effIcacy and safeTy of the orAL sGC stImulator vericiguaT to improve phYsical 
functioning in activities of daily living in patients with heart failure and preserved ejection 
fraction (VITALITY-HFpEF)
Short title: Patient-reported outcomes in vericiguat-treated patients with HFpEF
Acronym:
VITALITY-HFpEF
Test drug:
Vericiguat / BAY 1021189
Study purpose:
To assess the safety and efficacy of vericiguat in reducing physical 
limitations in patients with heart failure and preserved ejection 
fraction 
Clinical study phase:
Phase IIb 
Date:
22 FEB 2018
Registration:
2018-000298-65
Version no.:
1.0 
Sponsor’s study no.:
19334 
Sponsor:
Bayer AG, D-51368 Leverkusen, Germany 
US territory: Bayer HealthCare Pharmaceuticals Inc., 100 Bayer 
Boulevard, PO box 915, Whippany, NJ 07981-0915 United States
Sponsor’s medical expert:
Bayer SA
Rua Cancioneiro de Évora, 255 - Prédio E1 - 1º andar 
04708-010 São Paulo - SP Brazil
SP Brazil
Phone no.
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


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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.
In the protocol document, this page may remain unsigned.


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2.
Synopsis
Title
A randomized parallel-group, placebo-controlled, double-blind, multi-center 
trial to evaluate the efficacy and safety of the oral sGC stimulator vericiguat to 
improve physical functioning in activities of daily living in patients with heart 
failure and preserved ejection fraction (HFpEF) 
Short title
Patient-reported outcomes in vericiguat-treated patients with HFpEF
Acronym
VITALITY-HFpEF
Clinical study phase
Phase IIb 
Study objectives
Primary objectives:

To evaluate the efficacy of vericiguat 10 mg in comparison to placebo on 
improving physical functioning from baseline to week 24. 

To evaluate the efficacy of vericiguat 15 mg in comparison to placebo on 
improving physical functioning from baseline to week 24. 

To evaluate the safety and tolerability of vericiguat. 
Secondary objectives:

To evaluate the efficacy of vericiguat 10 mg in comparison to placebo on 
improving distance traveled on a 6-minute walk test (6MWT) from 
baseline to week 24

To evaluate the efficacy of vericiguat 15 mg in comparison to placebo on 
improving distance traveled on a 6 MWT test from baseline to week 24. 

To evaluate the efficacy of vericiguat 10 mg in comparison to placebo in 
increasing the proportion of patients with Kansas City Cardiomyopathy 
Questionnaire (KCCQ) physical limitation score (PLS) improvement 
from baseline by >5 points at 24 weeks and other thresholds (e.g. >3, >7, 
>10, >15, >20), and the proportions with these improvements in the other 
KCCQ domains; overall symptom score (OSS), clinical summary score 
(CSS), total symptom score (TSS) and symptom frequency score (SFS).

To evaluate the efficacy of vericiguat 15 mg in comparison to placebo in 
increasing the proportion of patients with KCCQ PLS improvement from 
baseline by >5 points at 24 weeks and other thresholds (e.g. >3, >7, >10, 
>15, >20), and the proportions with these improvements in the other 
KCCQ domains OSS, CSS, TSS and SFS.

To evaluate the efficacy of vericiguat 10 mg in comparison to placebo in 
decreasing the proportion of patients with KCCQ PLS decline from 
baseline by >5 points at 24 weeks and the proportions with decline in the 
other KCCQ domains OSS, CSS, TSS and SFS.

To evaluate the efficacy of vericiguat 15 mg in comparison to placebo in 
decreasing the proportion of patients with KCCQ PLS decline from 
baseline by >5 points at 24 weeks and the proportions with decline in the 
other KCCQ domains OSS, CSS, TSS and SFS.


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Other objectives:

To evaluate the efficacy of vericiguat 15 mg and the efficacy of 
vericiguat 10 mg in comparison to placebo on improving
o
Symptom frequency as measured by the KCCQ SFS
o
Other patient-reported outcomes such as the generic health-related 
quality of life measure EuroQoL five dimensions five levels 
questionnaire (EQ-5D-5L) and the Fried-based frailty score 
o
New York Heart association (NYHA) class
o
Laboratory variables such as N-terminal pro-brain natriuretic 
peptide (NT-proBNP) from baseline to 24 weeks

To collect and summarize death including cardiovascular death, and CV 
hospitalizations including heart failure hospitalizations, myocardial 
infarction and stroke, and outpatient HF events.

To analyze the cumulative distribution function of KCCQ PLS, OSS, 
CSS, TSS and SFS change from baseline at 24 weeks

To evaluate pharmacokinetics of vericiguat in patients with HFpEF.

To evaluate the concentration-QTc relationship of vericiguat at the 15 mg 
dose level.

Optional pharmacogenetic research: To explore the relationship between 
genetic variation and clinical characteristics of patients, independent and 
dependent of the treatment administered. Variations across the human 
genome may be analyzed for association with clinical data collected in 
this study.

To evaluate further biomarkers to investigate the drug (i.e. mode-of-
action-related effect and/or safety) and/or the mechanisms of the disease

Optional accelerometry substudy: To collect exploratory data by activity 
tracking
Test drug
Vericiguat, BAY 1021189
Name of active ingredient
Vericiguat, BAY 1021189 
Doses
2.5 mg, 5 mg, 10 mg, 15 mg
Route of administration
Oral 
Duration of treatment
24 weeks 
Reference drug
Placebo 
Name of active ingredient
N/A 
Doses
N/A
Route of administration
Oral 
Duration of treatment
24 weeks 


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Background treatment
Standard diuretic and comorbidity treatment 
Indication
Treatment of chronic heart failure with preserved ejection fraction
Diagnosis and main criteria 
for inclusion /exclusion
Male and female patients aged 45 years or older, with chronic HF (NYHA 
class II or III), preserved left ventricular ejection fraction (LVEF ≥45%), 
elevated natriuretic peptides, and previous HF decompensation will be 
enrolled in this trial. 
Main inclusion criteria:

Previous diagnosis of chronic HF 

HF decompensation within 6 months prior to randomization, defined as 
hospitalization for HF or intravenous (IV) diuretic treatment for HF 
without hospitalization.

N-terminal pro brain natriuretic peptide (NT-proBNP) ≥300 or brain 
natriuretic peptide (BNP) ≥100 pg/mL in sinus rhythm, or NT-proBNP 
≥600 or BNP ≥200 pg/mL in atrial fibrillation within 30 days prior to
randomization

Diagnostic criteria of HFpEF by echocardiography assessed within 
12 months prior to randomization (most recent measurement must be 
used to determine eligibility with no interim event signaling potential 
deterioration in ejection fraction)
o
Left ventricular ejection fraction (LVEF) ≥45%
and
o
Structural changes indicated by at least one of the following 
parameters:

Left ventricle (LV) hypertrophy (any of the following: 
intraventricular septal or posterior wall thickness ≥1.1 cm, and/or 
LV mass index ≥115 g/m2 in male and ≥95 g/m2 in female), 
or

Left atrium (LA) enlargement (any of the following: left atrial 
volume (LAV) index ≥29 ml/m2, or LAV >58 mL in male 
and >52 mL in female patients, or LA area >20 cm2, or LA 
diameter >40 mm in male and >38 mm in female patients)

NYHA class II or III at randomization
Main exclusion criteria:

Clinical instability at randomization, defined by 
o
Any IV treatment within 24h prior to randomization, and/or
o
SBP ≥160 mmHg 
o
SBP <110 mmHg and/or DBP <40 mmHg and/or symptomatic 
hypotension
o
Resting heart rate (HR) <50 or ≥100 beats per minute (bpm)

Use of IV inotropes at any time between qualifying HF event and 


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randomization 

Previous diagnosis of reduced ejection fraction (EF) (EF <40%)

Hypertrophic obstructive cardiomyopathy, acute myocarditis, 
amyloidosis, sarcoidosis, or pericardial disease 

Primary valvular heart disease requiring surgery or intervention, or 
within 3 months after valvular surgery or intervention, or active 
endocarditis

Acute coronary syndrome, including unstable angina, Non ST-elevation 
myocardial infarction or ST-elevation myocardial infarction, or Coronary 
artery bypass grafting (CABG) within 60 days prior to randomization, or 
indication for Percutaneous coronary intervention or CABG at the time of 
randomization

Symptomatic carotid stenosis, or transient ischemic attack or stroke 
within 60 days prior to randomization

Complex congenital heart disease

Non-cardiac comorbidity (any of the following)
o
Estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m2 
calculated by Modification of Diet in Renal Disease formula
o
Hepatic insufficiency classified as Child-Pugh B or C
o
Morbid obesity with a body mass index >45 kg/m2
o
Malignancy or other non-cardiac condition limiting life expectancy 
to <1 year, per physician judgment
o
Requires continuous home oxygen for severe pulmonary disease or 
has interstitial lung disease
o
Patients with allergies, intolerance or hypersensitivity to 
investigational drug or any of the excipients

Concurrent or anticipated use of nitrates or NO donors, 
phosphodiesterase type V (PDE5) inhibitors, or a Soluble guanylate 
cyclase (sGC) stimulator
Study design
Randomized parallel-group, placebo-controlled, double-blind, multi-center 
trial
Methodology
Patients will be randomized 1:1:1 within 4 weeks after the Screening Visit to 
either:

Placebo arm: placebo and sham up-titration at weeks 2, 4, and 6.

10 mg arm: vericiguat, which will be started at 2.5 mg at randomization 
and up-titrated to 5 mg at week 2 and to 10 mg at week 4, with sham 
titration at week 6.

15 mg arm: vericiguat, which will be started at 2.5 mg at randomization 
and up-titrated to 5 mg at week 2, to 10 mg at week 4, and to 15 mg at 
week 6.


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The first dose of trial treatment will be administered at the trial site at the 
randomization visit. Subsequent dosing will be performed once daily by the 
patient at approximately the same time each day. Patients will be instructed to 
take vericiguat with food. The titration will be based on systolic blood pressure 
(SBP) measurement prior to intake and safety considerations, at the discretion 
of the investigator as follows:

Increase dose: if SBP ≥100 mmHg and ≤20 mmHg decreases from 
previous visit, and not yet on highest dose (sham titration will occur if 
dose increase is chosen from 10 mg in the 10 mg arm)

Maintain dose: if SBP between ≥90 and <100 mmHg or SBP
≥100 mmHg and >20 mmHg decreases from previous visit, or if already 
on highest dose step (after 3 uptitrations)

Decrease the dose: if SBP <90 mmHg without symptoms of hypotension 
if on vericiguat at a blinded dose step >2.5 mg, or temporarily interrupt if 
on 2.5 mg (starting dose or after down titration from a higher dose)

Interrupt the dose: if SBP <90 mmHg with symptoms of hypotension.
Down-titration is possible at any time during the study. In case of temporary 
discontinuation or dose reduction after the titration period, up-titration is also 
possible at scheduled visits. If the period between the scheduled visits is more 
than 17 and less than 11 days, the patient should attend an unscheduled visit.
Type of control
Placebo 
Data Monitoring Committee
Yes 
Number of patients
Approximately 735 patients are planned to be randomized, 245 patients per 
arm.
Primary variable
Change in KCCQ PLS from baseline to week 24
Time point/frame of 
measurement for primary 
variable
KCCQ PLS will be assessed at baseline, at weeks 2, 6, 12, and 24
Plan for statistical analysis
The primary endpoint will be change from baseline to week 24 in physical 
limitations as measured by the KCCQ PLS. The primary analysis of the 
primary endpoint will be performed using a repeated-measures mixed model
(MMRM), including all assessments post baseline, with baseline values, 
region, heart rhythm, treatment group, study visit, and the interaction between 
study visit and treatment group as covariates. The analysis will be performed 
in the Full Analysis Set.
The study is powered at 80% for rejecting either of the primary hypotheses 
(vericiguat 15 mg arm vs. placebo arm and vericiguat 10 mg arm vs. placebo 
arm), with the assumption of a mean difference from placebo in KCCQ PLS of 
5 points for both dose groups and a common SD of 21 points, under two sided 
alpha level of 0.05.
A planned futility analysis will be performed by data monitoring committee 
(DMC) when 50% of patients complete Visit 7 (week 12) and their KCCQ 
data become available. An observed treatment effect of 0.6 point will serve as 


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the boundary for futility for both dose groups, which is approximately 
equivalent to a joint conditional power (CP) of 23%. An observed difference
<0.6 in both comparisons would therefore signal to the DMC that the trial 
should be terminated early. At this futility boundary the trial has a joint 
probability of 9% to observe a >5 point improvement in either of the dose 
groups. 
In addition, a blinded anchor-based interim analysis will be conducted upon 
the completion of the 3-month assessments by all trial participants. A non-
parametric discriminant analysis will be used to determine the discrimination 
point between “no change” and “a little better” categories, which is considered 
to be Minimal clinically important difference (MCID). 
Based on the blinded anchor-based interim analysis, the percentages of 
responders with MCID, moderate, and large differences at each visit will be 
summarized, and nominal p-values will be also provided.
The study uses the graphical method of Maurer and Bretz (2013) to provide 
strong multiplicity control across the primary KCCQ PLS hypotheses and the 
secondary 6 MWT hypotheses. The overall two sided alpha level will be 
controlled at 0.05. The two primary hypotheses will be tested using Bonferroni 
procedure, each at a splitted alpha of 0.025. The two secondary hypotheses 
will be tested based on parallel gatekeeping principle. If both primary 
hypotheses can be rejected, the secondary family will be tested at a full alpha 
level 0.05 (two sided). If only one primary hypothesis has shown to be 
statistically significant, then only the secondary hypothesis based on the same 
dose group can be tested at an alpha level carried forward from the primary 
family testing, i.e., 0.025 (two sided). In this case, if the secondary hypothesis 
is rejected, the alpha spending associated with this dose group (0.025) will be 
re-utilized to test the other failed primary hypothesis again. Overall, the 
primary analysis will be claimed to have a positive outcome if the null 
hypothesis for at least one of the two primary hypotheses can be rejected. 


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Table of contents
1.
Title page............................................................................................................................ 1
Signature of the sponsor’s medically responsible person..................................................... 2
Signature of principal investigator......................................................................................... 3
2.
Synopsis.............................................................................................................................. 4
Table of tables......................................................................................................................... 12
Table of figures....................................................................................................................... 12
List of abbreviations............................................................................................................... 13
3.
Introduction..................................................................................................................... 16
3.1
Background.................................................................................................................... 16
3.2
Previous experience in humans...................................................................................... 17
3.2.1
Dose selection............................................................................................................. 18
3.3
Rationale of the study .................................................................................................... 19
4.
Study objectives............................................................................................................... 20
5.
Study design..................................................................................................................... 22
6.
Study population ............................................................................................................. 23
6.1
Inclusion criteria ............................................................................................................ 23
6.2
Exclusion criteria ........................................................................................................... 24
6.3
Withdrawal of patients from study ................................................................................ 26
6.3.1
Withdrawal ................................................................................................................. 26
6.3.2
Replacement ............................................................................................................... 28
6.4
Patient identification...................................................................................................... 28
7.
Treatments....................................................................................................................... 28
7.1
Treatments to be administered....................................................................................... 28
7.2
Identity of study treatment............................................................................................. 29
7.3
Treatment assignment.................................................................................................... 30
7.4
Dosage and administration............................................................................................. 30
7.5
Blinding ......................................................................................................................... 32
7.6
Drug logistics and accountability................................................................................... 33
7.7
Treatment compliance.................................................................................................... 34
8.
Non-study therapy........................................................................................................... 34
8.1
Prior and concomitant therapy....................................................................................... 34
8.2
Post-study therapy.......................................................................................................... 35
9.
Procedures and variables ............................................................................................... 36
9.1
Tabular schedule of evaluations .................................................................................... 36
9.2
Visit description............................................................................................................. 37
9.2.1
Visit 1 Screening Visit – Day -28-1 ........................................................................... 38
9.2.2
Visit 2 Baseline and Randomization – Day 1............................................................. 39
9.2.3
Visit 3 – Day 14±3 (week 2) ...................................................................................... 40
9.2.4
Visit 4 – Day 28±3 (week 4) ...................................................................................... 40


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9.2.5
Visit 5 – Day 42±3 (week 6) ...................................................................................... 41
9.2.6
Visit 6 – Day 56±3 (week 8) ...................................................................................... 42
9.2.7
Visit 7 – Day 84±3 (week 12) .................................................................................... 43
9.2.8
Visit 8 – Day 126±3 (Week 18).................................................................................. 43
9.2.9
Visit 9 End of treatment – Day 168±7 (week 24)....................................................... 44
9.2.10
Visit 10 Safety follow-up – Day 196±7...................................................................... 45
9.2.11
Premature discontinuation visit – at time of permanent discontinuation ................... 45
9.2.12
Safety follow-up visit after premature discontinuation– 28 ±7 days after last dose .. 46
9.3
Population characteristics .............................................................................................. 46
9.3.1
Demographic .............................................................................................................. 46
9.3.2
Medical history........................................................................................................... 47
9.4
Efficacy.......................................................................................................................... 47
9.4.1
KCCQ......................................................................................................................... 48
9.4.2
EQ-5D-5L................................................................................................................... 50
9.4.3
Patient Global Impression of Change (PGIC), and Severity (PGIS).......................... 50
9.4.4
Fried frailty score........................................................................................................ 50
9.4.5
Assessment of NYHA class........................................................................................ 51
9.4.6
NT-proBNP ................................................................................................................ 51
9.4.7
Clinical outcome events.............................................................................................. 52
9.4.8
Six-minute walk test................................................................................................... 52
9.5
Pharmacokinetics / pharmacodynamics......................................................................... 52
9.6
Safety ............................................................................................................................. 53
9.6.1
Adverse events............................................................................................................ 53
9.6.2
Pregnancies................................................................................................................. 58
9.6.3
Further safety.............................................................................................................. 58
9.7
Other procedures and variables...................................................................................... 59
9.7.1
Laboratory assessments.............................................................................................. 59
9.7.2
Physical examination.................................................................................................. 60
9.7.3
Echocardiography parameters .................................................................................... 60
9.7.4
12-lead ECG ............................................................................................................... 60
9.7.5
Vital signs................................................................................................................... 61
9.7.6
Biomarkers ................................................................................................................. 61
9.7.7
Optional pharmacogenetic research............................................................................ 62
9.7.8
Accelerometry ............................................................................................................ 62
9.8
Appropriateness of procedures / measurements ............................................................ 62
10. Statistical methods and determination of sample size ................................................. 62
10.1
General considerations................................................................................................... 62
10.2
Analysis sets .................................................................................................................. 63
10.3
Variables and planned statistical analyses..................................................................... 63
10.3.1
Efficacy variables ....................................................................................................... 63
10.4
Determination of sample size......................................................................................... 65
10.5
Planned interim analyses ............................................................................................... 66
10.6
PK and PK/QT analyses ................................................................................................ 68
11. Data handling and quality assurance............................................................................ 68
11.1
Data recording................................................................................................................ 68
11.2
Monitoring ..................................................................................................................... 69
11.3
Data processing.............................................................................................................. 70


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11.4
Missing data................................................................................................................... 70
11.5
Audit and inspection ...................................................................................................... 70
11.6
Archiving ....................................................................................................................... 71
12. Premature termination of the study.............................................................................. 71
13. Ethical and legal aspects................................................................................................. 72
13.1
Investigator(s) and other study personnel...................................................................... 72
13.2
Funding and financial disclosure ................................................................................... 73
13.3
Ethical and legal conduct of the study........................................................................... 73
13.4
Patient information and consent .................................................................................... 74
13.5
Publication policy and use of data ................................................................................. 75
13.6
Compensation for health damage of patients / insurance .............................................. 75
13.7
Confidentiality ............................................................................................................... 75
14. Reference list.................................................................................................................... 76
15. Protocol amendments...................................................................................................... 79
16. Appendices....................................................................................................................... 79
16.1
Appendix 1: 6 Minute walk test..................................................................................... 79
16.2
Appendix 2: Borg CR 10 scale and test instructions ..................................................... 80
Table of tables
Table 7–1: Identity of test drug................................................................................................ 29
Table 7–2: Identity of matching placebos................................................................................ 29
Table 7–3: Dosing plan ............................................................................................................ 31
Table 7–4: Resumption of study drug intake ........................................................................... 32
Table 9–1: Tabular schedule of assessments............................................................................ 36
Table 9–2: KCCQ Domains and Summary Scores .................................................................. 49
Table 9–3: KCCQ - Physical Limitation domain item wording .............................................. 50
Table of figures
Figure 5–1 Study design........................................................................................................... 22
Figure 10–1 α-allocation for each hypothesis in the ellipse representing the hypothesis........ 65


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List of abbreviations
6MWT
6 minute walk test
ACE
angiotensin converting enzyme
AE
Adverse event
AESI
Adverse event of special interest
AF
Atrial fibrillation
ALT
Alanine aminotransferase
ANCOVA
Analysis of covariance
aPTT
Partial Thromboplastin time, activated
ARB
Angiotensin receptor blocker
AST
Aspartate aminotransferase
AV
Atrioventricular
BMI
Body mass index
BNP
Brain natriuretic peptide
BP
Blood pressure
bpm
Beats per minute
BUN
Blood urea nitrogen
CABG
Coronary artery bypass grafting
CAD
Coronary artery disease
CCSA
Canadian Cardiovascular Society angina (classification)
CEC
Central clinical events committee
cGMP
Cyclic guanosine monophosphate
CP
Conditional power
CR
Category Ratio
CRO
Clinical research organization
CSR
Clinical study report
CSS
Clinical Summary Score
CV
Cardiovascular
DBP
Diastolic blood pressure
dL
Deciliter
DMC
Data monitoring committee
e.g.
Exempli gratia, for example
ECG
Electrocardiogram
(e)CRF
(Electronic) case report form
EDC
Electronic data collection
EF
Ejection fraction
eGFR
Estimated glomerular filtration rate
EoT
End of treatment
EQ-5D-5L
EuroQoL five dimensions five levels questionnaire
ESC
European Society of Cardiology
EU
European Union
FAS
Full analysis set
FDA
Food and Drug Administration
FSH
Follicle-stimulating hormone
FU
Follow up
GCL
Global clinical lead
GCP
Good clinical practice
GGT
Gamma glutamyl transferase
GMP
Good manufacturing practice
Hb
Hemoglobin
HbA1c
Hemoglobin A1c
Hct
Hematocrit
HDL
High density lipoprotein
HF
Heart failure
HFpEF
Heart failure with preserved ejection fraction


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HFrEF
Heart failure with reduced ejection fraction
HR
Heart rate
i.e.
Id est, in other words
IB
Investigator’s brochure
ICH-GCP
International Conference on Harmonization-Good Clinical 
Practice
IEC
Independent ethics committee
INR
International normalized ratio
IR
Immediate release
IRB
Institutional review board
IV
Intravenous
IxRS
Interactive voice / web response system
K
Potassium
KCCQ
Kansas City Cardiopathy Questionnaire
L
Liter
LA
Left atrium, left atrial
LAE
Left atrial enlargement
LAV
Left atrial volume
lb(s)
Pound(s)
LDH
Lactate dehydrogenase
LDL
Low density lipoprotein
LLOQ
lower limit of quantification
LS
Least squares
LSH
Life Sciences Data Hub
LV
Left ventricle, left ventricular
LVAI
Left volume atrial index
LVEF
Left ventricular ejection fraction
LVH
Left ventricular hypertrophy
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCID
Minimal clinically important difference
MCV
Mean corpuscular volume
MD
Medical doctor
MDRD
Modification of Diet in Renal Disease
mEq
Milliequivalents
mg
Milligram
MDDT
Medical Device Development Tool
mIU
Milli-International Units
MID
Minimally important difference
mL
Milliliters
min
Minute
mmHg
Millimeters of mercury
MMRM
Mixed model repeated-measures
Na
Sodium
NA
Not applicable
NO
Nitric oxide
NSTEMI
Non ST-elevation myocardial infarction
NTG
Nitroglycerin
NT-proBNP
N-terminal pro-brain natriuretic peptide
NYHA
New York Heart Association
o.d.
Once daily
OSS
Overall summary score
PCI
Percutaneous coronary intervention
PD
Pharmacodynamic(s)
PDE5
Phosphodiesterase type V
pg
Picograms
PGIC
Patient’s Global Impression of Change
PGIS
Patient’s Global Impression of Severity


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PH
Pulmonary Hypertension
PID
Patient identification number
PK
Pharmacokinetic(s)
PKS
Pharmacokinetics analysis set
Plc
Placebo
PLS
Physical limitation score
PPS
Per protocol analysis set
PR
PR interval
(e)PRO
(Electronic) patient reported outcome
PTT
Partial thromboplastin time
QC
Quality control
QoL
Quality of Life
QRSD
QRS duration
QT
QT interval
QTc
QT interval corrected for HR
QTcB
Formula of Bazett
QTcF
Formula of Fridericia
RAVE
Electronic data capture system used by the sponsor
RBC
Red blood cells
RDW
Red cell distribution width
SAE
Serious adverse event
SAF
Safety analysis set
SAP
Statistical analysis plan
SBP
Systolic blood pressure
SD
Standard deviation
SFS
Symptom frequency score
sGC
Soluble guanylate cyclase
STEMI
ST-elevation myocardial infarction
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR
Systemic vascular resistance
TIA
Transient ischemic attack
TSS
Total symptom score
US
United States of America
VAS
Visual analogue scale
VO2
Oxygen uptake
WBC
White blood cells


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3.
Introduction
3.1
Background
Heart failure is a leading cause of CV morbidity and mortality, and constitutes a major public 
health problem worldwide. Patients suffering from HFpEF are a large and growing 
population; the relative proportion of HFpEF has increased to more than 50% of all HF 
hospitalizations (1). Predisposing conditions for HFpEF are advanced age, female gender, 
diabetes, obesity, arterial hypertension, and LV hypertrophy. While mortality in outpatient 
cohorts appears to be lower for HFpEF than HFrEF, hospitalizations for HFpEF have 
increased over time. HFpEF patients also have substantially reduced functional capacity and 
quality of life (2), and they need a therapy that addresses these limitations. However, no 
specific therapy has been approved to reduce cardiovascular risk or to improve functional 
status in patients with HFpEF, and recommendations have thus far been limited to 
symptomatic treatment of congestive symptoms by diuretics, and to treating causes and 
comorbidities including hypertension, coronary artery disease, and atrial fibrillation (3). US 
guidelines were recently updated with a new class IIb recommendation stating that 
aldosterone receptor antagonists might be considered to decrease hospitalizations in 
appropriately selected patients with HFpEF (with EF ≥45%, elevated BNP levels or HF 
admission within 1 year, estimated glomerular filtration rate >30 mL/min, creatinine <2.5 
mg/dL, potassium <5.0 mEq/L) (4). ESC guidelines on HF also provide no evidence level A 
recommendations for the treatment of patients with HFpEF and reiterate that no treatment has 
yet been shown, convincingly, to reduce morbidity or mortality in patients with HFpEF (5).
Trials that established the clinical benefits of ACE inhibitors, angiotensin receptor antagonists
and ß-blockers beyond their use in arterial hypertension, CAD or for rate control have all 
selected patients on the basis of their reduced EF. Subsequent trials in patients with HFpEF 
did not confirm equal effectiveness in this patient group (6). Since patients with HFpEF are 
highly symptomatic with a poor quality of life, it is important to find new therapies that can
alleviate symptoms and improve patient well-being (5). Therefore, there is need for new drug 
targets such as cGMP. The nitric oxide-soluble guanylate cyclase-cGMP signaling pathway is 
a relevant mechanism in HF that remains unaffected by neurohumoral antagonists. cGMP 
deficiency causes two important pathophysiologies in HF:
1.
Myocardial dysfunction including impaired relaxation, diastolic stiffening and 
myocardial energy wastage. cGMP is a powerful antihypertrophic mediator in the 
heart (7). It is specifically reduced in myocardial biopsies of patients with HFpEF, 
and bypassing the cGMP deficiency by in vitro protein kinase G administration 
corrects inappropriately high resting tension forces of human cardiomyocytes (8).
In a genetic sGC knockout model sGCα1-/- mice (deficiency in the α1 subunit 
results in decreased enzymatic sGC activity, whereas the total sGC knockout is not 
viable) increased cardiac contractility, arterial elastance and impaired ventricular 
relaxation were observed (9). 
2.
Endothelial dysfunction, i.e. disturbed endothelium-dependent vasotone regulation 
due to a reduced NO bioavailability, including the myocardial microcirculation. 
Endothelial dysfunction contributes to the pathophysiology of HFpEF (10). 
Previous attempts to increase cGMP remain limited. The long-term effects of nitrates and 
exogenous NO donors are limited by tolerance (11), and they also cause endothelial 
dysfunction, oxidative stress, and release of endothelin-1 (12). The venoselectivity of these 


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drugs may restrict their hemodynamic tolerability (13), as the dependency of nitrates and 
exogenous NO donors on biotransformation to the active, NO-containing compound causes 
different regional responses in the venous vs. arterial system (14, 15). A novel class of sGC 
compounds directly stimulate the NO receptor sGC with a dual mode of action; they sensitize 
sGC to endogenous NO by stabilizing the NO-sGC binding, and also directly stimulate sGC 
via a different binding site, independently of NO. Their regional vasoactivity and potential 
direct myocardial effects are independent of biotransformation and, therefore, might differ 
from nitrates. Due to this unique mode of action direct oral sGC stimulators could provide a
novel, tolerable option to restore cGMP signaling in HFpEF (16). 
The sGC stimulator riociguat has previously been studied in patients with HFpEF and 
secondary pulmonary hypertension. Although the study missed its primary endpoint of 
pulmonary artery pressure reduction, single doses of riociguat increased stroke volume and 
decreased SVR at the highest dose step of 2 mg without changing pulmonary capillary wedge 
pressure, indicating that increases in stroke volume upon afterload reduction could be 
achieved without increasing LV filling pressures (17). These results point at different 
hemodynamic effects of the direct sGC stimulator riociguat compared to the PDE5 inhibitor 
inhibitor sildenafil. Patients with HFpEF in the RELAX-DHF study treated with sildenafil
remained without any effects on SVR at 6 months (17), and in another study 12 weeks of
sildenafil treatment did not improve invasive haemodynamic or clinical parameters in patients 
with HFpEF and PH (18). The hemodynamic effects of single doses of riociguat in the 
DILATE-1 study in patients with PH and diastolic heart failure also differed from sodium 
nitroprusside, which frequently decreased stroke volume upon acute administration in patients 
with HFpEF, potentially owing to excessive preload reduction in line with venodilation (19).
In contrast, a decrease in heart rate upon treatment with the sGC stimulator vericiguat was 
associated with unchanged cardiac output in non-invasive echocardiographic hemodynamic 
measurements in the 10 mg arm of the SOCRATES-PRESERVED study (Study 15829) at 12 
weeks (20).
The NEAT study showed that patients with HFpEF receiving isosorbide mononitrate were 
less active and did not show improvement in QoL or submaximal exercise capacity (21). 
Based on these data, the 2017 ACC/AHA/HFSA guideline update stated that the routine use 
of nitrates or phosphodiesterase-5 inhibitors to increase activity or QoL in patients with 
HFpEF is ineffective (a class III, or “no benefit” recommendation). Limitations specific to the 
mode of action of NO substitution with nitrates and to the dependency on PDE5 
overexpression for PDE5 inhibitor treatment are hypothesized to be the reason for failed 
clinical efficacy. These limitations may be overcome by the different mode of action of direct 
sGC stimulators, and exploratory clinical data suggest potential benefit of oral sGC stimulator 
treatment in heart failure. Therefore, vericiguat, a novel oral sGC stimulator half-life long 
enough for once daily dosing, is currently being developed for the treatment of heart failure.
Further details can be found in the latest available version of the investigator's brochure, 
which contains comprehensive information on the study drug.
3.2
Previous experience in humans
Vericiguat has been evaluated in approximately 65 preclinical studies and has been 
administered to over 500 healthy patients in 19 completed Phase I studies with single- and 
multiple-dose administration, and in approximately 740 heart failure patients in two Phase IIb 
studies that studied vericiguat in worsening chronic heart failure patients with HFrEF and 


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with HFpEF. In the ongoing phase III event-driven outcome trial VICTORIA
(NCT02861534), as of Dec 1 2017, 2279 patients with HFrEF out of a planned total sample 
size of 4872 have been randomized to vericiguat 10 mg target dose or placebo with a median 
study drug treatment duration at that time of 5 months. The study treatment duration is 
planned to continue until 2020 for a median follow-up duration of 18 months.
A detailed description of the properties of vericiguat and the results of the nonclinical and 
clinical pharmacology studies conducted so far are given in the IB.
3.2.1
Dose selection
The starting dose, as well as the dose range in this study, are based on data from the Phase IIb 
study SOCRATES, as well as on the Phase I program in healthy volunteers.
In SOCRATES-PRESERVED 4 different dose regimens of vericiguat were studied in patients 
with chronic HFpEF enrolled within 1 month after a qualifying heart failure decompensation
event (20). Data from SOCRATES-PRESERVED established 2.5 mg vericiguat as the safe 
and well tolerated starting dose. Uptitration by two dose doublings with 14 day intervals each
to a target dose of 10 mg was tolerated in patients with HFpEF without an increase in adverse 
events compared to placebo, with low discontinuation rates in all groups, and no changes in 
blood pressure at 10 mg compared to placebo. Although analyses of the primary efficacy 
variables in SOCRATES-PRESERVED did not demonstrate changes in NT-proBNP and 
LAV at 12 weeks in the vericiguat dose groups compared to placebo, patients receiving 
vericiguat in the 10 mg target dose arm experienced a more pronounced improvement in 
health related QoL, physical limitations, NYHA class, signs and symptoms of congestion and 
trends towards improved diastolic function at 12 weeks (20, 22). These data generate the 
hypothesis that vericiguat improves physical functioning and clinically relevant patient-
reported outcomes in patients with HFpEF. In the parallel SOCRATES-REDUCED study 
(Study 15371) vericiguat treatment of patients with HFrEF in the 10 mg target dose arm was 
safe and well tolerated, and resulted in a large biological effect on the primary endpoint NT-
proBNP when added to standard of care. Based on these data, the currently ongoing 
VICTORIA trial evaluates the efficacy of vericiguat in comparison to placebo on a 
background of standard of care in increasing the time to first occurrence of the composite of 
CV death or HF hospitalization in patients with HFrEF.
Ad hoc application without prior titration of the 15 mg dose step as an oral polyethylene 
glycol solution was not well tolerated, and led to orthostatic reactions and syncope in the 
single dose escalation phase I study 15355 in 3 out of 4 healthy volunteers. Therefore 10 mg 
was chosen as the highest dose in SOCRATES-PRESERVED. In parallel with SOCRATES
studies another phase I study, 15838, was conducted. In this study administration of single 
doses of 15 mg to 14 healthy volunteers in fasted state as three 5 mg IR tablets in the 
formulation used for the clinical development program was generally well tolerated even 
without prior uptitration. Therefore, since no dose limiting intolerabilities were observed 
within the dose range of up to 10 mg studied in SOCRATES-PRESERVED, in this study 
(19334) a higher dose arm with a third uptitration step to 15 mg will be studied in addition to 
the 10 mg arm. The objective of this additional dose arm is to test whether titration to the 
higher target dose of 15 mg is tolerable and safe over 24 weeks, and associated with an even 
greater improvement in physical functioning. As with uptitration to 10 mg, the titration will 
start from 2.5 mg, not in a forced manner but adapted to individual tolerability as objectively 
defined by lack of any decrease in blood pressure below limits established for titration in 
SOCRATES, and in addition to the subjective well-being of patients.


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There is limited ability to add blood pressure lowering doses of vericiguat to the guideline-
recommended regimen for HFrEF patients, given the baseline blood pressures in these 
patients and the fact that these latter agents lower blood pressure (23). In contrast, the higher 
baseline blood pressure in HFpEF and the flexibility of adjusting concomitant risk factor 
controlling therapy that has not been established as life-saving, allow studying doses with 
potential blood pressure reducing potential in this study 19334.
Based on the exploratory improvement of physical functioning measured by the KCCQ PLS
at the 10 mg target dose in SOCRATES-PRESERVED, this dose regimen will also be studied 
in a parallel arm next to the higher 15 mg target dose. This design will allow testing of the 
primary hypothesis that vericiguat will improve KCCQ PLS over the treatment duration of 24 
weeks compared to placebo individually in the 10 mg and in the 15 mg dose titration arms
and to establish the benefit/risk ratio of the 10 mg and of the 15 mg dose titration of vericiguat
in separate arms. 
3.3
Rationale of the study
Vericiguat, an sGC stimulator, was studied in a Phase IIb dose-finding study (SOCRATES-
PRESERVED) in patients with HFpEF. Even though a 10 mg dose of vericiguat over a 12 
week treatment period did not change NT-proBNP or LAV as pre-specified primary endpoints
in this trial, exploratory post-hoc analyses showed an improvement in the patient-relevant 
domains of KCCQ and related patient reported (EQ-5D-5L) and physician assessed (NYHA 
class, clinical congestions score) endpoints (20, 22) in the highest target dose group. 
KCCQ is widely used in HF trials. In SOCRATES-PRESERVED, an improvement in the 
KCCQ OSS as well as the CSS was observed. Consistent changes in other domains of the 
KCCQ were also noted. However, the improvement appeared to be driven primarily by 
improvements in the PLS. KCCQ PLS has previously been validated against the distance 
covered in a 6MWT, NYHA class, and physical limitation domains within other QoL 
instruments including the 36-Item Short Form Survey in patients with HF (24). Improvements 
in physical functioning and reduction in symptom frequency are considered to be direct 
measures of treatment benefit in patients with HFpEF (2). This observation led to the 
hypothesis that vericiguat improves physical functioning in patients with HFpEF.
Benefit-risk assessment
Although in the phase IIb SOCRATES-PRESERVED study vericiguat did not reveal changes
in the two primary efficacy variables (NT-proBNP and LAV at 12 weeks), the exploratory 
finding of clinically meaningful increases (i.e. improvements compared to placebo of equal to 
or larger than 5 points) in KCCQ PLS, CSS and OSS suggest that vericiguat can improve 
physical limitations in patients with HFpEF. 
Daily activities of patients with HFpEF are limited due to common HF symptoms. Patients 
are especially affected by breathlessness and fatigue, which have a major impact on daily 
activities and are central to the patient experience (25). These, in turn, have an impact on 
wider concepts of patient health-related quality of life which are not addressed due to a lack 
of approved medications for the treatment of HFpEF patients. The changes in KCCQ PLS and 
consistent improvements in EQ-5D-5L observed in SOCRATES-PRESERVED together with 
trends in NYHA class and physician-assessed congestion indicate vericiguat’s potential to 
improve functioning in patients with HFpEF.


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The main risk of vericiguat is hypotension. There was only a small increase in the rate of 
hypotension AEs at the starting dose of 2.5 mg (4.4% of patients in the first 2 weeks 
compared to 3.3% with placebo) in SOCRATES-REDUCED, and these occurred only 
transiently upon initiation of vericiguat treatment in the majority of cases (26). In 
SOCRATES-PRESERVED, treatment-emergent hypotension adverse events were similar in
all arms including placebo. Therefore, by using the titration rules from SOCRATES-
PRESERVED, a safe uptitration to the target dose of 10 mg is expected in patients with 
HFpEF. In the absence of existing data with 15 mg vericiguat in patients with heart failure, 
the risks of hypotension and syncope with 15 mg vericiguat require further characterization. 
Based on previous experience from SOCRATES-PRESERVED with doses up to 10 mg 
vericiguat, the risk of hypotension, syncope or any other intolerability is expected to be 
manageable and minimized through a non-forced titration also for the 15 mg dose. 
Given the absence of life-saving drugs and the particular relevance of physical limitations in 
daily activities for patients with HFpEF, the potential for vericiguat to improve physical 
functioning based on exploratory data from SOCRATES-PRESERVED appears to outweigh 
the manageable risks of hypotension and syncope observed with the 10 mg target dose. 
Therefore, before data for the 15 mg dose in patients with HFpEF will become available, there 
is equipoise with respect to the benefit-risk assessment for vericiguat 15 mg for the treatment 
of symptomatic HF in patients with chronic HFpEF, and we expect potential benefit in this 
indication.
4.
Study objectives
The primary hypothesis in this trial is that the treatment with vericiguat 10 mg or 15 mg in 
patients with HFpEF improves the KCCQ PLS compared to placebo after 24 weeks of
treatment.
Primary objectives:

To evaluate the efficacy of vericiguat 10 mg in comparison to placebo on improving 
physical functioning from baseline to week 24. 

To evaluate the efficacy of vericiguat 15 mg in comparison to placebo on improving 
physical functioning from baseline to week 24. 

To evaluate the safety and tolerability of vericiguat. 
Secondary objectives:

To evaluate the efficacy of vericiguat 10 mg in comparison to placebo on improving 
distance traveled on a 6MWT from baseline to week 24. 
o
To evaluate the efficacy of vericiguat 15 mg in comparison to placebo on improving 
distance traveled on a 6MWT from baseline to week 24.
o
To evaluate the efficacy of vericiguat 10 mg in comparison to placebo in increasing 
the proportion of patients with KCCQ PLS improvement from baseline by >5 points at 
24 weeks and other thresholds (e.g. >3, >7, >10, >15, >20), and the proportions with 
these improvements in the other KCCQ domains OSS, CSS, TSS and SFS.
o
To evaluate the efficacy of vericiguat 15 mg in comparison to placebo in increasing 
the proportion of patients with KCCQ PLS improvement from baseline by >5 points at 


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24 weeks and other thresholds (e.g. >3, >7, >10, >15, >20), and the proportions with 
these improvements in the other KCCQ domains OSS, CSS, TSS and SFS.
o
To evaluate the efficacy of vericiguat 10 mg in comparison to placebo in decreasing 
the proportion of patients with KCCQ PLS decline from baseline by >5 points at 
24 weeks and the proportions with decline in the other KCCQ domains OSS, CSS, 
TSS and SFS.
o
To evaluate the efficacy of vericiguat 15 mg in comparison to placebo in decreasing 
the proportion of patients with KCCQ PLS decline from baseline by >5 points at 
24 weeks and the proportions with decline in the other KCCQ domains OSS, CSS, 
TSS and SFS.
Other objectives:
o
To evaluate the efficacy of vericiguat 10 mg and the efficacy of vericiguat 15 mg in 
comparison to placebo on improving:
o
Symptom frequency as measured by the KCCQ SFS 
o
Perceived exertion experienced by patients during 6MWT as measured by 
Borg CR 10.
o
Other patient-reported outcomes such as the generic health-related quality of 
life measure EQ-5D-5L and the Fried-based frailty score
o
NYHA class
o
Laboratory variables such as NT-proBNP from baseline to 24 weeks

To collect and summarize death including cardiovascular death and CV 
hospitalizations including heart failure hospitalizations, MI and stroke, and outpatient 
HF events.

To analyze the cumulative distribution function of KCCQ PLS, OSS, CSS, TSS and 
SFS change from baseline at 24 weeks. 

To evaluate PK of vericiguat in patients with HFpEF, and

To evaluate the concentration-QTc relationship of vericiguat at the 15 mg dose level.

Optional pharmacogenetic research: To explore the relationship between genetic 
variation and clinical characteristics of patients, independent and dependent of the 
treatment administered. Variations across the human genome may be analyzed for 
association with clinical data collected in this study.

To evaluate further biomarkers to investigate the drug (i.e. mode-of-action-related 
effect and / or safety) and / or the mechanisms of the disease

Optional accelerometry substudy: to collect exploratory data by activity tracking


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5.
Study design
Design overview
This is a randomized parallel-group, placebo-controlled, double-blind, multi-center trial of 
vericiguat in patients with HFpEF to be conducted in conformance with GCP. Approximately 
735 patients will be randomized as described in Figure 5–1 to evaluate the efficacy of 
vericiguat 10 mg and 15 mg in comparison to placebo on improving physical functioning
from baseline to week 24. To reduce heterogeneity in the studied population patients younger 
than 45 years of age are not eligible. Patients are expected to be on a background treatment 
for co-morbidities like hypertension (see Section 8.1), and diuretics in the presence of
symptoms due to volume overload. 
Screening may be initiated any time after admission of a patient to the hospital for HF, before 
or after discharge, and up to 6 months after hospitalization for HF. Use of IV diuretic 
treatment for HF, even without hospitalization, is indicative of HF decompensation and 
accepted as a qualifying HF event equivalent to hospitalization. The most recent 
decompensation should be considered for qualifying the patient for the study. In either 
scenario, HF must be the primary reason for hospitalization or IV diuretic treatment. Patients 
will be randomized within up to 4 weeks after the screening visit (see Section 7.3) and within 
up to 6 months after the onset of the qualifying event of hospitalization for HF or treatment 
with IV diuretic for HF (see Figure 5–1), and treated as given in Sections 7.1 and 7.3. 
Primary endpoint assessment is at week 24. All patients will be followed until study 
completion to assess for vital status and all study endpoints.
Figure 5–1 Study design
EF, ejection fraction; FU, follow-up; HF, heart failure; KCCQ, Kansas City Cardiomyopathy 
Questionnaire; LAE, left atrial enlargement; LVH, left ventricular hypertrophy; NT-proBNP, N-terminal 
pro-brain natriuretic peptide; NYHA, New York Heart Association; PLS, physical limitation score; 
V, Visit.
KCCQ as the entire questionnaire is administered, not just the PLS domain.


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Primary variable
Change in KCCQ PLS from baseline to week 24.
Justification of the design
The study is designed to evaluate the safety and efficacy of the 10 mg and of the 15 mg dose 
regimens of vericiguat at 24 weeks in separate parallel arms. Placebo control is used in a 
parallel comparator arm to control for observer and patient bias, and randomization to control 
for assignment bias. 
Rationale of study endpoints
To demonstrate durability of efficacy in improving physical functioning and to study safety 
beyond the previously studied time period of 12 weeks in SOCRATES-PRESERVED, longer 
treatment duration of 24 weeks has been chosen for this study. This endpoint gives a valid and 
appropriate measure of the limitations in activities of daily living that are impacted by HF
symptoms of breathlessness and fatigue, and represent the key burden of patients suffering 
from HFpEF. In SOCRATES-PRESERVED in the 10 mg arm a constant rise in KCCQ PLS 
that did not yet reach a maximum by week 12 was observed. This was opposed to a smaller
improvement in placebo that reached its peak at 8 weeks and subsequently decreased. Based
on the exploratory finding of a clinically meaningful improvement in KCCQ PLS (i.e. an 
improvement compared to placebo larger than 5 points upon 12 weeks treatment with a 10 mg 
target dose regimen) consistent with parallel improvements in EQ-5D-5L in SOCRATES-
PRESERVED, the change in KCCQ PLS from baseline to week 24 is defined as the primary 
endpoint in the present study. This endpoint will serve for confirmatory testing of the 
hypothesis that vericiguat improves KCCQ PLS compared to placebo on top of background 
standard of care in a durable manner upon 24 weeks of treatment. Notably, the parallel 
ongoing event-driven HFrEF outcome trial VICTORIA plans median treatment duration of 18 
months to add long-term safety and tolerability data of the 10 mg target dose in HFrEF.
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 
been reached in all centers in all participating countries (EU and non-EU).
Primary completion
The primary completion event for this study is last patient last treatment.
The primary completion date for this study according to the FDA Amendment Act is specified 
in a separate document (not part of this study protocol).
6.
Study population
6.1
Inclusion criteria
1. Provided written informed consent 
2. Aged 45 years and older
3. Previous history of chronic HF
4. HF decompensation within 6 months prior to randomization, defined as hospitalization 
for HF or IV diuretic treatment for HF without hospitalization.


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5. NT-proBNP ≥300 or BNP ≥100 pg/mL in sinus rhythm, or NT-proBNP ≥600 or BNP 
≥200 pg/mL in atrial fibrillation within 30 days prior to randomization.
The most appropriate natriuretic peptide level cut-off should be guided by the 
investigator’s judgment of the impact of the heart rhythm at the time of blood draw on 
natriuretic peptide levels.
6. Diagnostic criteria of HFpEF by echocardiography assessed within 12 months prior to 
randomization (most recent measurement must be used to determine eligibility with no 
interim event signaling potential deterioration in ejection fraction)
o
LVEF ≥45% and
o
Structural changes indicated by at least one of the following parameters:
LV hypertrophy (any of the following: intraventricular septal or 
posterior wall thickness ≥1.1 cm, and/or LV mass index ≥115 g/m2 in 
male and ≥95 g/m2 in female), or
LA enlargement (any of the following: LAV index ≥29 ml/m2, or LAV 
>58 mL in male and >52 mL in female patients, or LA area >20 cm2, or 
LA diameter >40 mm in male and >38 mm in female patients)
7. NYHA class II or III at randomization
8. Men or women
o
Women of childbearing potential can only be included in the study if a 
pregnancy test is negative and if they agree to use acceptable effective 
contraception when sexually active. This applies for the time period between 
signing of the informed consent form and time point after the last 
administration of study drug. The definition of acceptable effective 
contraception will be based on the judgment of the investigator and on local 
requirements.
o
Women are considered post-menopausal and/or not of childbearing potential if 
they have had 12 months of natural (spontaneous) amenorrhea with an 
appropriate clinical profile (e.g. age appropriate, history of vasomotor 
symptoms) or 6 months of spontaneous amenorrhea with serum FSH levels 
>40 mIU/mL [for US only: and estradiol <20 pg/mL] or have had surgical 
treatment such as bilateral tubal ligation, bilateral ovariectomy, or 
hysterectomy
6.2
Exclusion criteria
1. Clinical instability at randomization, defined by any of the following: 
o
Any IV treatment including IV diuretics or IV fluids within 24h prior to 
randomization
o
SBP ≥160 mmHg 
o
SBP <110 mmHg and/or DBP <40 mmHg and/or symptomatic hypotension
o
Resting HR <50 or ≥100 bpm 
2. Use of IV inotropes at any time between qualifying HF event and randomization 
3. Previous diagnosis of reduced EF (EF <40%)


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4. Hypertrophic obstructive cardiomyopathy, acute myocarditis, amyloidosis, cardiac 
sarcoidosis, or constrictive pericarditis
5. Primary valvular heart disease requiring surgery or intervention, or within 3 months 
after valvular surgery or intervention, or active endocarditis
6. Acute coronary syndrome (unstable angina, NSTEMI or STEMI) or PCI or CABG 
within 60 days prior to randomization, or indication for PCI or CABG at the time of 
randomization
7. Symptomatic carotid stenosis, or TIA or stroke within 60 days prior to 
randomization
8. Complex congenital heart disease
9. Non-cardiac comorbidity (any of the following)
o
eGFR <30 ml/min/1.73 m2 calculated by MDRD formula
o
Hepatic insufficiency classified as Child-Pugh B or C
o
Morbid obesity with a BMI >45 kg/m2
o
Malignancy or other non-cardiac condition limiting life expectancy to <1 year, 
per physician judgment
o
Requires continuous home oxygen for severe pulmonary disease or has 
interstitial lung disease
o
Patients with allergies, intolerance or hypersensitivity to the investigational 
drug or any of the excipients
o
Medical, psychiatric, or other condition or history thereof that in the opinion of 
the investigator would impair the ability to complete the planned study 
procedures
10. Concurrent or anticipated use of PDE5 inhibitors
11. Concurrent or anticipated use of an sGC stimulator 
12. Concurrent or anticipated use of long-acting and short -acting nitrates or NO donors 
for any route, including isosorbide dinitrate, isosorbide 5-mononitrate, 
pentaerythritol tetranitrate, nicorandil, NTG and molsidomine
13. Previous (within 30 days of randomization) or concomitant participation in another 
clinical study with investigational medicinal product(s) 
14. 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) 
15. Previous assignment to treatment during this study to prevent randomizing patients 
twice
16. Illiteracy and /or inability to read the questionnaire for any reason, as the primary 
endpoint is based on data collected from a self-administered patient-reported 
questionnaire
17. Patients who are non-ambulatory or in the view of the investigator are not able to 
perform a 6MWT. For ATS Statement: Guidelines for the 6MWT see Section 16.1).
18. Pregnancy or lactation
19. Previous use of vericiguat
20. Known current alcohol and/or illicit drug abuse that may interfere with the patient’s 
safety and / or compliance at the discretion of the investigator


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6.3
Withdrawal of patients from study
6.3.1
Withdrawal
Withdrawal from study
Unnecessary withdrawal of patients from the study follow-up should be avoided and all 
efforts should be taken to motivate patients to adhere to all study procedures and to be 
followed until the end of the trial.
The investigator should explore all possible options to reach a patient who fails to return to a 
visit or to respond to the site contact attempts. 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 discuss solutions with the patient that would enable the 
patient to continue with follow-up in order to minimize the number of patients who withdraw 
such consent. The vital status will be collected for all randomized patients who have not 
specifically withdrawn consent for further study follow-up by any method (telephone call, 
email etc.), irrespective of completion of study procedures.
Withdrawal from study drug treatment
Withdrawal from study drug treatment does not represent withdrawal from the study. As 
certain data on clinical events beyond study treatment discontinuation may be important to the 
study, they must be collected through the participant’s last scheduled follow-up, even if the 
participant has discontinued study treatment. Therefore, all participants who discontinue study 
treatment prior to completion of the protocol-specified treatment period will still continue to 
participate in the study.
Before permanently discontinuing study drug treatment (either initiated by the patient or the 
investigator) a temporary interruption should be considered. Patients who have temporarily 
discontinued from study drug treatment should resume in line with the temporary interruption
rules as soon as medically justified in the opinion of the investigator (see Section 7.4). In 
addition, patients should not be discontinued from the study drug or withdrawn from the study 
solely for reaching a potential cardiovascular event.
If permanent discontinuation of study drug treatment becomes necessary due to intolerance 
even at the lowest dose step or any other reason, this does not mean that the patient has 
withdrawn from the study follow-up. Participants may be allowed to begin study treatment 
again if deemed medically appropriate, unless the participant’s treatment assignment has been 
unblinded by the investigator/delegate and/or non-study treating physician.
For participants who are discontinued from study treatment but continue to be monitored in 
the study, all visits and procedures, as outlined in the schedule of assessments, should be 
completed. If the patient is unable to attend scheduled study visits, follow-up of clinical 
events specified as exploratory endpoints may continue by phone, unless the patient explicitly 
withdraws his/her consent to any type of follow-up.


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Withdrawal criteria
Patients must be withdrawn from the study drug, while all efforts should be made to continue 
all protocol procedures also upon study drug discontinuation, if any of the following occurs:

In case of pregnancy or breastfeeding. 

If the investigator believes that for safety reasons (i.e., adverse event) it is in the best 
interest of the subject to stop study drug even at the lowest dose.
Patients may be withdrawn from the study drug if any of the following occurs:

If a significant violation of the protocol occurs, as defined by the sponsor and the 
coordinating investigator. 

If the randomization code is broken via IxRS. 
Patients must be withdrawn from the study if any of the following occurs:

At their own request; 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). 
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 the time point used for the definition of “dropout” (see below) is regarded a 
“screening failure”.
Re-starting the defined set of screening procedures to enable the “screening failure” patient’s 
participation at a later time point is not allowed – with the following exceptions:

The patient had successfully passed the screening procedures, but could not be 
randomized to start subsequent treatment on schedule.

Initial screening occurred too early to complete the required washout period after prior 
therapy.

The in- / exclusion criteria preventing the patient’s initial attempt to participate have 
been changed (via protocol amendment).
In any case, the investigator has to ensure that the repeated screening procedures do not 
expose the patient to an unjustifiable health risk. Also, for re-screening, the patient has to re-
sign the informed consent form, even if it was not changed after the patient’s previous 
screening.


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Dropout
A patient who discontinues study participation prematurely for any reason is defined as a 
“dropout” if the patient has already been randomized.
General procedures
In all cases, the reason for discontinuation from the study drug and / or withdrawal from the 
study 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.
Any patient removed from the trial will remain under medical supervision until discharge or 
transfer is medically acceptable.
Details for the premature termination of the study as a whole (or components thereof) are 
provided in Section 12.
Patients may be allowed to begin treatment again if deemed medically appropriate, unless 
he/she has been unblinded.
6.3.2
Replacement
Randomized patients who withdraw prematurely will not be replaced. 
6.4
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 be randomized 1:1:1 within 4 weeks after the Screening Visit to either:
1.
Placebo arm: placebo and sham up-titration at weeks 2, 4, and 6
2.
10 mg arm: vericiguat, which will be started at 2.5 mg at randomization and up-titrated to 
5 mg at week 2, and to 10 mg at week 4, with sham titration at week 6.
3.
15 mg arm: vericiguat, which will be started at 2.5 mg at randomization and up-titrated to
5 mg at week 2, to 10 mg at week 4, and to 15 mg at week 6.
Study drug treatment will be initiated after clinical stabilization, within 6 months after the
onset of the qualifying HF decompensation, defined as HF hospitalization or IV diuretic 
treatment for HF without hospitalization. End of treatment is reached at visit 9 after 24 weeks 
of treatment. 


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Dose modification will depend on mean sitting SBP and the absence of symptoms indicative 
of hypotension before intake of the dose as described in Section 7.4. The intention of the 
protocol is to reach and maintain the target study drug dose upon uptitration. If the patient
does not reach the 15 mg dose step by the time of the week 6 visit (42±3 days after 
randomization), or the dose is temporarily interrupted and when the investigator feels it is 
medically appropriate to resume it afterwards, uptitration should be considered at any 
subsequent visit at the discretion of the investigator according to the SBP criteria in Section 
7.4.
If in the opinion of the investigator the patient does not tolerate the target dose of the study 
drug and presents symptoms of orthostatic hypotension, in addition to considering the 
reduction of the study drug the investigator should also consider the volume status, and 
whether there is a necessity to change the dose of diuretics. If such adjustment or 
discontinuation of concomitant diuretic or other medications (such as anti-hypertensive 
therapy, in the case of excessive blood pressure lowering) is not possible or does not resolve 
signs and symptoms of intolerability, the investigator may at any time during the course of the 
trial reduce the dose or interrupt study treatment in patients who no longer tolerate the current 
study drug dose.
Down-titration is possible at any time during the study if the investigator feels this is justified 
for safety reasons. Reasons for dose modifications (maintenance, increase, decrease, or 
interruption) will be collected at all planned or unscheduled visits. In case of temporary 
discontinuation or dose reduction after the titration period, up-titration is also possible at 
scheduled visits.
7.2
Identity of study treatment
Table 7–1: Identity of test drug
INN 
vericiguat
Substance code number
BAY 1021189
Formulation
IR tablets
Strength
2.5 mg, 5 mg or 10 mg BAY 1021189
Table 7–2: Identity of matching placebos
INN 
N/A
Substance code number
N/A
Formulation
Tablets
Strength
N/A
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
Following a screening visit, eligible patients stabilized after a HF decompensation will be 
randomly allocated 1:1:1 via block randomization to one of the 3 equally sized groups (2 
vericiguat groups, 1 placebo group) using IxRS and will receive treatment with study drug or 
placebo for 24 weeks. The IxRS will determine the kit number for the study site investigator 
or designee to select for the subject. Patients are to take 2 tablets once daily, preferably in the 
morning with food, throughout study drug treatment. In case patient is randomized in the 
afternoon first tablets can be taken then and should be continued the next day in the morning.
Patients will be randomized within 4 weeks of the screening visit and within up to 6 months
after the date of hospitalization for HF or treatment with IV diuretic for HF, and 
randomization will be stratified according to region and heart rhythm at baseline ECG.
Region

Americas

Europe (incl. Israel and South Africa)

Asia/Pacific (including Australia)
Heart rhythm

Atrial fibrillation (defined as atrial fibrillation or atrial flutter in baseline ECG)

Sinus rhythm (defined as no atrial fibrillation and no atrial flutter in baseline 
ECG)
To avoid over-representation of patients with atrial fibrillation (AF) in the trial, randomization 
of patients with AF on their baseline ECG may be stopped at the discretion of the Steering 
Committee when this randomized cohort comprises approximately 40% of the total planned 
randomized population. The exact proportion of patients randomized with AF will be 
determined by the Steering Committee following a review of the blinded baseline clinical 
characteristics of this group compared to those without AF.
7.4
Dosage and administration
Patients will take two tablets once daily preferably in the morning with food. The starting 
dose will be 2.5 mg of vericiguat or matching placebo.
Titration steps at 2, 4 and 6 weeks include sham titration in placebo arm. Titration step at 6 
weeks includes sham titration in10 mg arm. The maximal dose of vericiguat is 10 mg o.d. in 
the 10 mg treatment arm, and 15 mg (5 mg + 10 mg tablet) o.d. in the 15 mg arm (Table 7–3).
For justification of dose selection see Section 3.2.1.


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Table 7–3: Dosing plan
Dose step
Arm
Placebo
10 mg target dose
15 mg target dose
1
placebo
2.5 mg
2.5 mg
2
placebo
5 mg
5 mg
3
placebo
10 mg
10 mg
4
placebo
10 mg
15 mg
Titration will be based on systolic blood pressure (SBP) measurement, before intake of the 
study drug as follows:

Increase dose: if SBP ≥100 mmHg and SBP decrease is ≤20 mmHg from previous 
visit, and not yet on highest dose 

Maintain dose: if SBP is between 90 mmHg and <100 mmHg, or SBP ≥100 mmHg 
and SBP decrease is >20 mmHg from previous visit, or if already on highest dose step 
(after 3 uptitrations)

Decrease the dose: if SBP <90 mmHg without symptoms of hypotension if on dose 
steps 2-4 (see Table 7–3) >2.5 mg, or temporarily interrupt if on 2.5 mg (starting dose 
or after down titration from a higher dose)

Interrupt the dose: if SBP <90 mmHg with symptoms of hypotension
Dose decrease is possible at any time if the physician feels this is necessary for safety reasons.
The first dose of trial treatment will be administered at the trial site at the randomization visit. 
Subsequent dosing will be performed once daily preferably in the morning by the patient at 
approximately the same time each day. Patients will be instructed to take vericiguat with food.
Resumption of study drug after temporary interruption
Upon temporary interruption of the study drug due to intolerability, intake should be resumed 
as soon as medically justified at the discretion of the investigator. There is no defined 
maximum time limit for temporary treatment interruption. In all cases, the reason for study 
drug interruption or permanent study drug discontinuation must be recorded in the eCRF and 
in the patient's medical records. Titration rules following restart of study drug after temporary 
interruption of study drug are as follows:

If restart before visit 5 (week 6): Restart at a scheduled visit and titrate according to 
the intervals in Table 7–4.

If restart after visit 5 (week 6) restart as soon as possible (with an unscheduled visit if 
required) and up-titrate according to Table 7–4. Patient will then resume the planned 
visit schedule. Unscheduled clinic and/or phone contacts can be conducted at the 
discretion of the investigator. The titration steps must be at least 11 days apart, and if 
the period between resumption and the next scheduled visit is more than 17 (14+3) 
days, the patient can attend an unscheduled visit. 


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Table 7–4: Resumption of study drug intake 
Dose step 
at time of 
interruption
(mg) at time of 
interruption
Length of 
interruption
Restart 
dose
1st titration
(14±3 days
after 
resumption)
2nd titration
(28±3 days
after 
resumption)
3rd titration
(42±3 days
after 
resumption)
1
Plc or 2.5
Any
Plc or 2.5
Plc or 5
Plc or 10
Plc or 10 or 15
2
Plc or 5
Any
Plc or 2.5
Plc or 5
Plc or 10
Plc or 10 or 15
3
Plc or 10
>5 days
Plc or 2.5
Plc or 5
Plc or 10
Plc or 10 or 15
≤5 days
Plc or 5
Plc or 10
Plc or 10 or 15
NAa
4
Plc or 10 or 15
>5 days
Plc or 2.5
Plc or 5
Plc or 10
Plc or 10 or 15
≤5 days
Plc or 5
Plc or 10
Plc or 10 or 15
NAa
a
highest dose achieved in the second titration
NA, not applicable; Plc, placebo
For follow-up of patients after discontinuation see Section 9.1
7.5
Blinding
Tablets containing 2.5 mg and 5 mg vericiguat and the respective matching placebo tablets 
will be identical in appearance. 10 mg vericiguat and matching placebo to 10 mg tablets will 
be identical in appearance. The packaging and labeling are designed to maintain the blinding 
of the investigator’s team and to the patients. The study data will remain blinded for each 
treatment group, until database lock and authorization of data release.
Unblinding
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. Notifications of ethic committees and investigators will be 
done according to all applicable regulations (see Section 9.6.1.4).
In this study, the following events are outcome events and will be considered as disease 
related in the defined study population. For the purposes of this trial, these events will not be 
subject to systematic unblinding and expedited reporting process, if reported as serious 
adverse drug reactions.

Acute heart failure

Chronic heart failure 

Worsening chronic heart failure 

Cardiac arrest

Myocardial Infarction 

Stroke

CV death 


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These events will be captured in the eCRF, and will undergo regular central adjudication by 
central CEC, and unblinded DMC review. If an event submitted for adjudication is 
determined by the CEC not to meet the endpoint criteria in the CEC charter and meets 
seriousness criteria, it will then be subject to expedited reporting (as appropriate, based upon 
both investigator and Bayer company causality assessment of drug relationship, as required 
by local legislation).
Emergency unblinding by the investigator
In case of emergency or any finding that requires unblinding, the investigator will be able to 
break the blind for an individual patient via IxRS according to the unblinding procedure 
implemented. This will allow breaking the blind for an individual patient without impairing 
the study as a whole unless safety findings required unblinding.
The code can be broken by the investigator, or other responsible person, when knowledge of 
the patient's treatment is required for the clinical management of the patient. Whenever 
possible, the sponsor is to be contacted to discuss the case before the code is broken. If it 
becomes necessary to know the individual treatment during the study and thus to break the 
code for that patient, the date, time, and reason are to be recorded in the patient’s medical
notes and relevant eCRF page. The investigator is required to promptly document and explain 
to the sponsor any premature unblinding (e.g. unblinding due to a serious adverse event) of 
the study treatment.
Unblinding for ongoing safety monitoring
To allow ongoing safety monitoring during the conduct of the study by an external DMC, 
members of the Committee will receive unblinded safety data. The involvement of an external 
Statistical Analysis Center in this process will ensure that unblinded information is not 
available for third parties. Details of the process are described in the DMC charter.
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/contract research organization), 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.
If performing drug accountability implies a potential risk of contamination, a safety process/ 
guidance for handling returned study drug will be provided.


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7.7
Treatment compliance
To monitor compliance, completing a drug dispensing log for each patient will be required. 
Overall compliance with study drug intake should be between 80% and 120% of the 
scheduled study drug intake 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 at Visit 2, Visit 3, Visit 4, Visit 5, Visit 6, Visit 7 and Visit 8. 
Patients should return all remaining unused study drug at each visit.
Accountability will be determined by tablet count at each visit. 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 as well as in the eCRF.
8.
Non-study therapy
8.1
Prior and concomitant therapy 
Permitted background treatment

Diuretics are recommended in congested patients in order to alleviate symptoms and 
signs (5).

Treatment of comorbidities like hypertension, coronary and vascular diseases, 
hyperlipidemia, diabetes, atrial fibrillation and other arrhythmias should follow the 
local/regional Guidelines. Any dose adaptations, addition, changed or added route of 
administration, omission or cessation of concomitant therapy including diuretics, anti-
hypertensives such as ACE inhibitors, ARB, or rate control such as ß blockers and 
digoxin are possible whenever deemed necessary by the investigator irrespective of 
blinded titration of the study drug.
Prohibited prior and concomitant medications:

Nitrates or NO donors including isosorbide dinitrate, isosorbide 5-mononitrate, 
pentaerythritol tetranitrate, nicorandil, NTG and molsidomine: all routes are not 
allowed during study drug treatment; IV therapy with nitrates or NO donors is only 
allowed until 24 h prior to randomization.
It is recommended that nitrates should not be administered to any patient previously 
on study drug earlier than 3 days after the last dose of study drug. Should there be an 
urgent need for nitrate administration, they should be administered in a monitored 
inpatient setting. 

PDE5 inhibitors: Sildenafil and Vardenafil are allowed only until 24 h prior to
randomization, Tadalafil until 48 h prior to randomization.

sGC stimulators other than the study drug are not allowed during study drug treatment


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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.


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9.
Procedures and variables
9.1
Tabular schedule of evaluations
Table 9–1: Tabular schedule of assessments
Trial Periods
Screeninga
Base-
line
Titration / 
Sham 
titration
Treatment
End of 
treatment
Safety 
Follow-
Upb
Premature 
Treatment 
Discontinuation
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
Week
2
4
6
8
12 18
24
28
Visit Window (Days)
-28-1
1
14±3
28±3
42±3
56±3
84±3
126±3
168±3
196±7
At time of 
permanent 
treatment 
discon
28±7 days 
after last 
dose
Informed consent main study
Demographic data
Medical and surgical history
●
Optional - Informed consent for 
pharmacogenetic research
●c
Optional - Informed consent for 
accelerometry
●
Concomitant medication 
●
●
●
●
●
●
●
●
●
●
●
●
Inclusion / exclusion criteria
●
●
Urine pregnancy test (local)q
●
●
●
Randomization (IxRS)
●
ePRO: KCCQ, PGICd, PGIS, EQ-5D-5L
●
●
●
●
●
●
●e
●
●e
Fried Frailty score
●
●
●
NYHA class
●
●
●
●
●
●
●
●
●
●
●
●
Blood pressure, pulse rate f
●
●
●
●
●
●
●
●
●
●
●
●
ECG
●g
●h
●r
Only in patients 
eligible for PK/QT 
assessment j
ECG
●i
●i
●i
PK sample predose 
●
●
PK sample 1-2 h, 
and 3-6h post
●k
●
●
6 MWT
●
●
●
●
●
●
●
Local lab blood sample l
●
Central lab blood sample m
●
●
●s
●
Optional pharmacogenetic research 
blood sample
●c
Physical exam, weight, height n
●
●
●
●
●
●
●
●
●
●
●
Adverse events
●
●
●
●
●
●
●
●
●
●
●
●
Drug accountability o
●
●
●
●
●
●
●
●
Dispense study drug
●
●
●
●
●
●
●
Optional uptitration p
●
●
●
Optional accelerometry
●t
●u
●t ●u ●t
●u
Footnotes:
a.
Can start as early as at time of hospitalization or IV diuretic treatment for HF or up to 6 months after. Should start no more 
than 4 weeks before randomization. Screening visit and baseline visit can take place on the same day.
b.
In case of premature discontinuation of study treatment, vital status will be collected at week 28 by any method (e.g. via 
telephone call or e-mail), unless the patient has specifically withdrawn consent for further study follow-up.
c.
Optional pharmacogenetic informed consent and blood collection may also be performed at a later visit. Blood sample for 
genetic analysis will only be taken if the patient signed the separate consent for the pharmacogenetic research study.
d.
Not performed at baseline visit.
e.
Only KCCQ and EQ-5D-5L performed at visit 10 and 12.
f.
3 measurements, 2 min apart; measurements are taken prior to study drug intake. Additional measurement at 2h ± 15 min 
post study drug intake will be performed only at visit 2, and at visits 5-8 if dose is uptitrated from dose step 3 to step 4.
g.
Assessment of eligibility for PK/QT assessment.


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h.
Only for patients not eligible for QT assessment
i.
Central 12-lead ECGs should be recorded only in patients eligible for PK/QT assessment, just before the collection of the 
blood sample for PK, to enable PK/QT assessments. Exact date and time of the ECG recording and date and time of last 
study drug intake (either at home on the day before the sample or at site) must be documented.
j.
In case the PK sample at the specified visits cannot be obtained at a specified time point, 12-lead ECG and the PK
sample can be taken at the subsequent (scheduled or unscheduled) visits. Exact collection date and time of the PK 
samples and date and time of last study drug intake before PK sampling (either at home on the day before the sample or 
at site) must be documented.
k.
Only PK sample 1-2h post study drug will be collected at this visit.
l.
Only if not available within 30 days prior to randomization for eligibility, creatinine and NT-proBNP or BNP (or both if 
available)
m. NT-proBNP, clinical chemistry, hematology, coagulation, biomarker testing, and other laboratory tests (for full list see 
Section 9.7.1.2)
n.
Full physical examination to be performed at Visit 1 and 2. Focused cardiovascular examination to be performed in all 
other visits. Height will be only measured once at the screening visit. Automatic calculation of body mass index (BMI) in 
the electronic case report form (eCRF) will use this result.
o.
Collect unused study drug.
p.
In case of temporary discontinuation or dose modification after the titration period. An unscheduled visit is possible if the 
period between resumption and the next scheduled visit is more than 17 days. Time between uptitration steps must be no 
less than 11 days.
q.
A local lab urine or serum pregnancy test will be conducted for women of childbearing potential according to local 
procedures. If required by national / institutional regulations, a serum or urine pregnancy test in patients of childbearing 
potential should be performed more often (e.g. at every visit).
r.
In case of premature discontinuation, ECG is performed as a safety measure.
s.
PK sample predose will be collected together with the central lab sample for all patients.
t.
Only for patients participating in the optional accelerometry substudy, activity tracking devices are planned to be handed 
out as specified in the accelerometry procedure manual.
u.
Activity tracking devices are planned to be collected from patients participating in the optional accelerometry substudy as 
specified in the accelerometry procedure manual.
Abbreviations: 6MWT, 6-minute walk test; BMI, body mass index; BNP, brain natriuretic peptide; ECG, electrocardiogram; 
eCRF, electronic case report form; ePRO, electronic patient reported outcome; EQ-5D-5L, EuroQoL Group 5-dimension, 
5-level questionnaire; HF, heart failure; IxRS, interactive voice/web response system; IV, intravenous; KCCQ, Kansas City 
Cardiomyopathy Questionnaire; NT-proBNP, N-terminal pro-brain natriuretic peptide; NYHA, New York Heart Association; 
PGIC, Patient Global Impression of Change questionnaire; PGIS, Patient Global Impression of Severity questionnaire;
PK, pharmacokinetics
9.2
Visit description
Before any screening examination takes place, potentially eligible patients will be given a full 
explanation as to what the study would involve. This will be done both verbally and in writing 
in the form of a written patient information leaflet. Patients will be given sufficient time to 
consider their participation in the study and to ask any questions. Patients who are willing to 
take part in the study will then be asked to sign a patient information / informed consent form. 
This signature must be collected prior to the screening visit.
Screening examinations will only be performed after having received the patient’s written 
informed consent. If not stated otherwise, the measures listed in the following sections will be 
performed by or under the supervision of a study site investigator.
Procedures for the screening visit can be performed on several days. Alternatively, screening 
visit and Visit 1 including randomization of patients can take place on the same day.
All visits from Visit 1 to Visit 9 must be started in the morning. Patients will be instructed to 
take their daily dose at the study site (not taken at home) as indicated in the study procedures.


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9.2.1
Visit 1 Screening Visit – Day -28-1
Screening can start as early as at time of hospitalization for HF, before or after discharge, or 
upon intravenous diuretic treatment for heart failure without hospitalization, and up to 6 
months after hospitalization for HF or intravenous diuretic treatment for HF. 
The following procedures will be performed within 4 weeks before randomization of the 
patient. 

Confirm signed informed consent is available

Confirm signed informed consent for optional pharmacogenetic research is available, 
for those who wish to participate in pharmacogenetic research (Informed consent for 
pharmacogenetic research may also be performed at later visit)

Confirm signed informed consent for optional accelerometry substudy is available, for 
those who wish to participate in the optional accelerometry substudy at sites 
participating in the optional accelerometry substudy (see Section 9.7.8)

Allocation of unique PID number (see Section 6.4)

Demographic data and other population characteristics (see Section 9.3.1)

Medical and surgical history (see Section 9.3.2)

Prior and concomitant medications (see Section 8.1)

Urine pregnancy test, if applicable.

Physical examination including height and weight (BMI will be calculated 
automatically in the eCRF) (see Section 9.7.2)

Vital signs (BP and pulse rate) in sitting position after resting for at least 10 min, 3 
measurements, 2 min apart; means will be calculated in the eCRF (See Section 9.7.5).

Continuous assessment of AEs will start immediately after signing the informed 
consent until the follow-up visit (if applicable)

Assess inclusion and exclusion criteria (see Sections 6.1 and 6.2), including previously 
recorded local laboratory and echocardiography results for entry in the eCRF:
•
NT-proBNP or BNP or both within 30 days prior to randomization 
•
Serum creatinine to calculate eGFR
•
LVEF
•
Intraventricular or posterior wall thickness
•
LVAI or LAV or LA area or LA diameter

6MWT (familiarization test if screening is done on a separate day from randomization, 
perform only once if screening and randomization are on the same day) 

Only for patients participating in the optional accelerometry substudy: activity 
tracking devices are planned to be handed out with instructions to use as specified in 
the accelerometry procedure manual.

Schedule Visit 2 (Baseline) within 4 weeks after screening 


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9.2.2
Visit 2 Baseline and Randomization – Day 1
Randomization occurs latest within 4 weeks after informed consent.

Before randomization:
•
Assess patient eligibility (see Sections 6.1 and 6.2; for echo criteria see below)
•
KCCQ, EQ-5D-5L, PGIS (see Section 9.4)
•
Frailty assessment based on the Fried score 
•
Assessment of NYHA class
•
Concomitant medications, record new or ongoing medication or changes in 
dosage (see Section 8.1)
•
Urine pregnancy test, if applicable.
•
Adverse events (see Section 9.6.1)
•
Only for patients participating in the optional accelerometry substudy: Activity 
tracking devices are planned to be collected (see accelerometry manual).
•
Physical examination including height and weight (BMI will be calculated 
automatically in the eCRF) (see Section 9.7.2)
•
Vital signs (BP and pulse rate), See Section 9.7.5.
•
12-lead ECG to evaluate the eligibility of the patient for PK/QT assessment
(see Section 9.7.4)
•
6MWT 

Randomization to vericiguat once daily or placebo (see Section 7.3)

Central lab blood samples for NT-proBNP, hematology, clinical chemistry, 
coagulation and biomarkers (see Section 9.7.1)

Only to be collected for patients who signed the optional pharmacogenetics research 
informed consent: Central lab blood sample for pharmacogenetics (obtaining the 
informed consent for optional pharmacogenetics research and blood collection may 
also be performed at a later visit).

Dispense study drug for the first 2 week interval until Visit 3 and instruct the patient
on how to take the study drug

Patient to take first dose of study drug (exact time of intake must be documented)

Only in patients eligible for PK/QT assessment (all patients assessed as eligible based 
on the baseline ECG, see Section 9.7.4) – ECG and PK sample should be collected 
time-matched, first ECG, subsequently PK sample: 
•
12-lead ECG (to be performed just before the PK sample is taken) 1-2h after 
study drug intake (exact collection times must be documented)
•
Blood sample for PK 1-2h after study drug intake (exact collection time must 
be documented)


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
2 h 15 min after study drug intake: Vital signs (BP and pulse rate) in sitting position 
after resting for at least 10 min, 3 measurements, 2 min apart. See Section 9.7.5.

Schedule Visit 3 for Day 14±3
Visit 1 (Screening visit) and Visit 2 (Day1) including randomization of patients can take place 
on the same day. In this case, procedures listed for both visits need to be performed only once.
9.2.3
Visit 3 – Day 14±3 (week 2)
Patients need to come for this visit without taking the morning dose of the study drug (this 
applies only for the study drug. All others medications shall be taken as scheduled).

Before titration / sham titration
•
KCCQ, EQ-5D-5L, PGIC/S
•
Assessment of NYHA class
•
Concomitant medications (see Section 8.1) 
•
Adverse events (see Section 9.6.1) 
•
Physical examination 
•
Vital signs (BP and pulse rate). See Section 9.7.5.
•
Drug accountability, and collect unused study drug

Titration/sham titration in accordance with dosing regimen in Section 7.3 and dispense 
study drug accordingly for the 2 week interval until Visit 4 and instruct the patient on 
how to take the study drug

Patient to take first dose of titrated / sham titrated study drug (exact time of intake 
must be documented)

Schedule Visit 4 for Day 28±3
9.2.4
Visit 4 – Day 28±3 (week 4)
Patients need to come for this visit without taking the morning dose of the study drug (this 
applies only for the study drug. All others medications shall be taken as scheduled)

Before titration / sham titration
•
Assessment of NYHA class
•
Concomitant medications (see Section 8.1) 
•
Adverse events (see Section 9.6.1) 
•
Physical examination 
•
Vital signs (BP and pulse rate). See Section 9.7.5.
•
Drug accountability, and collect unused study drug


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
Titration/sham titration in accordance with dosing regimen in Section 7.4 and dispense 
study drug accordingly for the 2 week interval until Visit 5 and instruct the patient on 
how to take the study drug

Patient to take first dose of titrated / sham titrated study drug (exact time of intake 
must be documented)

Schedule Visit 5 for Day 42±3

For PK sampling at visit 5: Remind the patient to report the date and time of the last 
study drug intake the day before visit 5.
9.2.5
Visit 5 – Day 42±3 (week 6)
Patients need to come for this visit without taking the morning dose of the study drug (this 
applies only for the study drug. All others medications shall be taken as scheduled)

Before titration / sham titration
•
KCCQ, EQ-5D-5L, PGIC/S (see Section 9.4)
•
Assessment of NYHA class
•
Concomitant medications (see Section 8.1) 
•
Adverse events (see Section 9.6.1) 
•
Physical examination 
•
Vital signs (BP and pulse rate). See Section 9.7.5.

Only in patients eligible for PK/QT assessment (all patients assessed as eligible based 
on the baseline ECG, see Section 9.7.4) – ECG and PK sample should be collected 
time-matched, first ECG, subsequently PK sample::
•
12-lead ECG (to be performed just before the PK sample is taken) prior to 
study drug intake (exact collection times must be documented)
•
Blood sample for PK prior to study drug intake (exact collection time to be 
documented)
•
Drug accountability, incl. exact time of last dose intake the day before, and 
collect unused study drug

Titration/sham titration in accordance with dosing regimen in Section 7.4 and dispense 
study drug accordingly for the 2 week interval until Visit 6 and instruct the patient on 
how to take the study drug

Patient to take first dose of titrated / sham titrated study drug (exact time of intake 
must be documented)

Only in case of uptitration from dose step 3 to dose step 4, at 2 h 15 min after study
drug intake: Vital signs (BP and pulse rate). See Section 9.7.5.


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
Only in patients eligible for PK/QT assessment (all patients assessed as eligible based 
on the baseline ECG, see Section 9.7.4) – ECG and PK sample should be collected 
time-matched, first ECG, subsequently PK sample:
•
12-lead ECG (to be performed just before the PK sample is taken) to be taken 
1-2 h after study drug intake, exact collection times must be documented)
•
Blood sample for PK 1-2 h after study drug intake (exact collection time must 
be documented)
•
12-lead ECG (to be performed just before the PK sample is taken) to be taken 
within the time interval of 3-6 h study drug intake (exact collection times must 
be documented)
•
Blood sample for PK within the time interval of 3-6 h after study drug intake 
(exact collection time must be documented)

Schedule Visit 6 for Day 56±3
9.2.6
Visit 6 – Day 56±3 (week 8)
Patients need to come for this visit without taking the morning dose of the study drug (this 
applies only for the study drug. All others medications shall be taken as scheduled)

Assessment of NYHA class

Concomitant medications (see Section 8.1) 

Adverse events (see Section 9.6.1) 

Physical examination 

Vital signs (BP and pulse rate). See Section 9.7.5. 

Central lab blood samples for NT-proBNP, hematology, clinical chemistry,
coagulation and biomarkers prior to study drug intake (exact collection time to be 
documented; see Section 9.7.1)

Drug accountability, incl. exact time of last dose intake the day before, and collect 
unused study drug

Optional uptitration/sham titration if not yet on target dose, dispense study drug in 
accordance with dosing regimen for the 6 week interval until Visit 7 and instruct the 
patient on how to take the study drug.

Patient to take the study drug (exact time of intake must be documented)

Only in case of uptitration from dose step 3 to dose step 4, 2 h 15 min after study
drug intake: Vital signs BP and pulse rate). See Section 9.7.5.

Schedule Visit 7 for Day 84±3

Only for patients participating in the optional accelerometry substudy: activity 
tracking devices are planned to be handed out with instructions to use as specified in 
the accelerometry procedure manual.


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9.2.7
Visit 7 – Day 84±3 (week 12)
Patients need to come for this visit without taking the morning dose of the study drug (this 
applies only for the study drug. All others medications shall be taken as scheduled)

KCCQ, EQ-5D-5L, PGIC/S (see Section 9.4)

Assessment of NYHA class

Concomitant medications (see Section 8.1) 

Adverse events (see Section 9.6.1) 

Only for patients participating in the optional accelerometry substudy: Activity 
tracking devices are planned to be collected (see accelerometry manual).

Physical examination 

Vital signs in sitting position (BP and pulse rate). See Section 9.7.5.

6 MWT 

Drug accountability, incl. exact time of last dose intake the day before, and collect 
unused study drug

Optional uptitration/sham titration if not yet on target dose, dispense study drug in 
accordance with dosing regimen for the 6 week interval until Visit 8 and instruct the 
patient on how to take the study drug.

Patient to take the study drug (exact time of intake must be documented)

Only in case of uptitration from dose step 3 to dose step 4, 2 h 15 min after study
drug intake: Vital signs (BP and pulse rate). See Section 9.7.5.

Schedule Visit 8 for Day 126±3
9.2.8
Visit 8 – Day 126±3 (Week 18)
Patients need to come for this visit without taking the morning dose of the study drug (this 
applies only for the study drug. All others medications shall be taken as scheduled)

KCCQ, EQ-5D-5L, PGIC/S (see Section 9.4)

Assessment of NYHA class

Concomitant medications (see Section 8.1)

Adverse events (see Section 9.6.1

Physical examination 

Vital signs in sitting position (BP and pulse rate). See Section 9.7.5

Drug accountability, and collect unused study drug.

Optional uptitration/sham titration if not yet on target dose, dispense study drug in 
accordance with dosing regimen for the 6 week interval until Visit 9 and instruct the 
patient on how to take the study drug.


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
Patient to take the study drug (exact time of intake must be documented)

Only in case of uptitration from dose step 3 to dose step 4, 2 h 15 min after study
drug intake: Vital signs (BP and pulse rate). See Section 9.7.5.

Schedule Visit 9 for Day 168±7

For PK sampling at visit 9: Remind the patient to report the date and time of the last 
study drug intake the day before visit 9.

Only for patients participating in the optional accelerometry substudy: activity 
tracking devices are planned to be handed out with instructions to use as specified in 
the accelerometry procedure manual.
9.2.9
Visit 9 End of treatment – Day 168±7 (week 24)
Patients need to come to site without taking the morning dose of the study drug (this applies 
only for the study drug. All other medications shall be taken as scheduled).
The end of treatment visit should be scheduled at Day 168±7 also in case of premature 
discontinuation of study drug. All other visits and procedures should continue also if the study 
drug has been permanently discontinued.

KCCQ, EQ-5D-5L, PGIC/S (see Section 9.4)

Frailty assessment based on the Fried score

Assessment of NYHA class

Concomitant medications (see Section 8.1)

Adverse events (see Section 9.6.1

Only for patients participating in the optional accelerometry substudy: Activity 
tracking devices are planned to be collected (see accelerometry manual).

Physical examination 

Vital signs in sitting position (BP and pulse rate). See Section 9.7.5.

6MWT

12-lead ECG in patients not eligible for PK/QT assessment, see Section 9.7.4

Only in patients eligible for PK/QT assessment (all patients assessed as eligible based 
on the baseline ECG, see Section 9.7.4) – ECG and PK sample should be collected 
time-matched, first ECG, subsequently PK sample:
•
12-lead ECG (to be performed just before the PK sample is taken) to be taken 
prior to study drug intake (exact collection time must be documented)
•
Blood sample for PK prior to study drug intake (exact collection time to be 
documented)

Central lab blood samples for NT-proBNP, hematology, clinical chemistry, 
coagulation and biomarkers 9.7.1 and blood sample for PK prior to study drug intake 
(exact collection time to be documented) in all patients, see Section 9.7.4


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
Drug accountability, incl. exact time of last dose intake the day before, and collect 
unused study drug

Patient to take study drug (exact time of intake must be documented)

Only in patients eligible for PK/QT assessment (all patients assessed as eligible based 
on the baseline ECG, see Section 9.7.4) – ECG and PK sample should be collected 
time-matched, first ECG, subsequently PK sample:
•
12-lead ECG (to be performed just before the PK sample is taken) to be taken 
1-2 h after study drug intake, exact collection times must be documented)
•
Blood sample for PK 1-2 h after study drug intake, exact collection time must 
be documented)
•
12-lead ECG in supine position, after resting for at least 10 min (to be 
performed just before the PK sample is taken) to be taken within the time 
interval of 3-6 h study drug intake (exact collection times must be 
documented)
•
Blood sample for PK within the time interval of 3-6 h after study drug intake 
(exact collection time must be documented)

Schedule Follow-Up visit for Day 196±7
9.2.10
Visit 10 Safety follow-up – Day 196±7

KCCQ and EQ-5D-5L (see Section 9.4)

Assessment of NYHA class

Adverse events (see Section 9.6.1)

Physical examination incl. weight

Vital signs (BP and HR). See Section 9.7.5.

6MWT 

Vital status will be collected for all randomized patients, including those who did not 
attend the visit or were permanently discontinued, by any method (e.g. via telephone 
call or e-mail), unless the patient has specifically withdrawn consent for further study 
follow-up.
9.2.11
Premature discontinuation visit – at time of permanent discontinuation
This visit is applicable only for patients who prematurely discontinue the study drug intake 
(Either by decision of the investigator or by the patient.)

KCCQ, EQ-5D-5L, PGIC/S (see Section 9.4)

Frailty assessment based on the Fried score

Assessment of NYHA class

Concomitant medications (see Section 8.1)


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
Adverse events (see Section 9.6.1) 

Physical examination incl. weight

Vital signs (BP and pulse rate). See Section 9.7.5.

12-lead ECG (see Section 9.7.4)

6MWT 

Central lab blood sample for NT-proBNP, hematology, clinical chemistry, coagulation
and biomarkers.

Drug accountability, incl. exact time of last dose intake the day before, and collect 
unused study drug

Schedule Visit 12 for 30±7 days after last dose
9.2.12
Safety follow-up visit after premature discontinuation– 28 ±7 days after 
last dose
This visit is applicable only for patients who prematurely discontinue the study drug intake
(Either by decision of the investigator or by the patient.)

KCCQ and EQ-5D-5L (see Section 9.4)

Assessment of NYHA class

Adverse events (see Section 9.6.1)

Physical examination incl. weight

Vital signs (BP and pulse rate). See Section 9.7.5.

6MWT 
9.3
Population characteristics
9.3.1
Demographic
The following demographic characteristics will be collected:

Year of birth

Age at Informed Consent

Gender

Race (as allowed by local regulation) and 

Ethnicity (as allowed by local regulation)


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9.3.2
Medical history
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 

Considered relevant for the patient’s study eligibility.

Previous diagnosis of HFpEF

Number of previous hospitalizations for HF prior to the qualifying event (these are not 
mandatory for inclusion but recorded as clinical characteristics)

Angina pectoris (CCSA class in patients with a medical history of angina)

Medical history related to concomitant medication

Comorbidities (medical history of atrial fibrillation is collected in addition to 
collection of atrial fibrillation in local baseline ECG before randomization for 
stratification: arterial hypertension, hyperlipidemia, CAD, diabetes mellitus, chronic 
kidney disease, chronic obstructive pulmonary disease, sleep apnea, anemia, erectile 
dysfunction

Smoking history

Alcohol consumption
Detailed instructions on the differentiation between (i) medical history and (ii) adverse events 
can be found in Section 9.6.1.1.
9.4
Efficacy

The primary efficacy variable is the change in KCCQ PLS from baseline to week 24, 
for the 10 and 15 mg vericiguat arms compared to placebo.

The secondary efficacy variable is the change in the 6MWT from baseline to week 24, 
for the 10 and 15 mg vericiguat arms when compared to placebo

Exploratory efficacy variables:

KCCQ domains of PLS, Symptom Frequency, Symptom Burden, Social 
limitation, QoL and the summary scores TSS, CSS and OSS measured values 
and change from baseline, by visit. 

Cumulative distribution function of – and proportions of patients with –
change from baseline at 24 weeks for the KCCQ domains of PLS, Symptom 
Frequency, Symptom Burden, and summary scores TSS, CSS and OSS.

EQ-5D-5L domain and Visual Analogue Scale responses and change from 
baseline, by visit.

PGIS response level and change from baseline, by visit

PGIC response level, proportion with response of important improvement from 
baseline, proportion with response of important deterioration, by visit.

Change in Fried-based frailty assessment at 24 weeks

Change in NYHA class from baseline at 24 weeks


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
NT-proBNP 

Incidences of cardiovascular death and total heart failure hospitalizations, as 
well as all-cause mortality, CV hospitalizations including MI and stroke, and 
outpatient HF events.

Time to first occurrence of the composite of CV death or heart failure 
hospitalization.

Time to first occurrence of the composite of CV death, HF hospitalization, 
worsening from baseline in NYHA class, or worsening from baseline in PGIC 

Time to first occurrence of the composite of CV death, heart failure 
hospitalization, worsening from baseline in NYHA class, or worsening from 
baseline in KCCQ CSS

Other efficacy variables:

Planned Genetic analysis
9.4.1
KCCQ
KCCQ, is a widely used 23-item, disease-specific health status measure intended for the 
assessment of heart failure patients’ perspectives of how their disease impacts their lives (24). 
It is a self-administered PRO instrument and requires, on average, 4–6 minutes to complete.
Patients are asked to recall how their heart failure impacted their life over a 2-week recall 
period. Response options are on a 5- to 7-point Likert-type scale with varying response 
options depending on the question.
The KCCQ measures the impact of patients’ heart failure, or its treatment, on 6 domains; Physical 
Limitation, Symptom (with subscores for frequency and burden), Quality of Life, Social 
Limitations, Symptom Stability and Self-Efficacy. Scores are calculated by summing domain 
responses and then transforming scores to a 0-100 unit scale with higher scores indicating better 
health status. In addition, the KCCQ includes 2 summary scores, CSS an equally weighted 
composite of Physical limitation and Total Symptom domain scores, and OSS which additionally 
combines the social limitation and quality of life domain scores to the CSS (Table 9–2).


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Table 9–2: KCCQ Domains and Summary Scores
KCCQ 
Domain
Descriptiona
Efficacy Domains
Physical 
Limitationb
The limitations patients’ experience, due to their heart failure symptoms, in 
performing routine activities. Activities are common, gender-neutral, and 
generalizable across cultures, while also capturing a range of exertional 
requirements.
Symptomc
The frequency and burden of clinical symptoms in heart failure, including fatigue, 
shortness of breath, paroxysmal nocturnal dyspnea and patients’ edema/swelling. 
An overall symptom score is generally used in analyses; subscale scores for both 
frequency and severity are also available.
Quality of 
Life
Designed to reflect patients’ assessment of their quality of life, given the current 
status of their heart failure.
Social 
Limitation
The extent to which heart failure symptoms impair patients’ ability to interact in a 
number of gender-neutral social activities.
Non-Efficacy Domains
Symptom 
Stability
Measures recent changes in patients’ symptoms; their shortness of breath, fatigue 
or swelling. It is compares patients frequency of heart failure symptoms at the time 
of completing the KCCQ with their frequency 2 weeks ago. This domain is not 
included in the summary scores.
Self-efficacy
Patient perceptions of how to prevent heart failure exacerbations and manage 
complications when they arise. This scale is not included in the summary scores. 
Summary Scores
Clinical 
Summary
Includes total symptom and physical function scores to correspond with NYHA 
Classification.
Overall 
Summary
Includes the total symptom, physical function, social limitations and quality of life 
scores
a
Descriptions of KCCQ Domain and summary scores are taken from the FDA document Medical 
Device Development Tool (MDDT) Qualification Decision Summary for Kansas City 
Cardiomyopathy Questionnaire (KCCQ) (27) with minor editing for brevity. 
b
‘Physical Function’ also used as domain name. 
c
Often reported as ‘Total Symptom Score’.
KCCQ Physical Limitation Score (PLS) has been selected as the primary endpoint in the trial 
as it is a direct measure of the hypothesized treatment effect; improvement in functional 
capacity in activities of daily life limited by the symptoms of heart failure. PLS measures the 
limitations patients’ experience, due to their heart failure symptoms (shortness of breath or 
fatigue), in performing routine activities of daily life (Table 9–3). The PLS is calculated 
through an algorithm applying equal weighting to each of the items and a transformation to a 0-
100 scale. Other KCCQ domains including Symptom (frequency, burden and overall), Quality 
of life and Social limitation together with the Clinical and Overall summary scores will be 
reported as exploratory endpoints. The KCCQ domains of Symptom Stability and Self-
efficacy will be reported but will not be considered measures of treatment efficacy. 


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Table 9–3: KCCQ - Physical Limitation domain item wording
Item activity descriptiona
Response scale (for all items)
(a) Dressing his/herself
1. Extremely limited
(b) Showering / bathing
2. Quite a bit limited
(c) Walking 1 block on level ground
3. Moderately limited
(d) Doing yard work, housework or 
carrying groceries
4. Slightly limited
(e) climbing a flight of stairs without 
stopping
5. Not at all limited
(f) Hurrying or jogging (as if to catch a 
bus)
6. Limited for other reasons or did not do 
the activity
a
The patient is asked to indicate how much he/she is limited by heart failure 
(shortness of breath or fatigue) in his/her ability to do the described activities over 
the past 2 weeks.
9.4.2
EQ-5D-5L
The EQ-5D-5L is a self-administered generic measure of health-related quality of life which 
includes five dimensions: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression. Patients provide a rating for each question on a five-level Likert scale: 
having no problems, having slight problems, having moderate problems, having severe 
problems and being unable to do/having extreme problems. In addition, patients are asked to 
self-rate their own health today on a vertical 0-100 unit visual analogue scale (VAS), with 0 
corresponding to "the worst health you can imagine", and 100 corresponding to "the best 
health you can imagine".
9.4.3
Patient Global Impression of Change (PGIC), and Severity (PGIS) 
PGIC contains one question (1a) asking the patient to assess the degree of change in physical 
limitation due to heart failure compared to the start of the treatment using the following 
response options: “much better”, “better”, “a little better”, “the same”, “a little worse”, 
“worse”, or “much worse”. A subsequent question (1b) then asks the patient to indicate 
whether he/she feels the degree of change reported is important or not (yes/no). 
PGIS contains one question asking the patient to assess the current severity of their physical 
limitations due to heart failure using the following response options: “No limitations”, 
“Mild”, “Moderate”, “Severe”, or “Very severe”
It is anticipated to take approximately 2-3 minutes to complete both the PGIC and PGIS 
questions. Data from these questions will be used to provide anchors for estimating minimally 
important differences in physical limitations in heart failure.
9.4.4
Fried frailty score
The Fried frailty phenotype defines 5 key domains for frailty (28) weakness, low energy, 
slowed walking speed, decreased physical activity, and weight loss. It quickly garnered 
attention in the CV community (29). Fried’s frailty score is on the basis of an integrated 
biological perspective, without focus on a single aspect of decline but the overall context of 
homeostasis. The Fried score differentiates frailty from multimorbidity and disability, 


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articulating that frailty predisposed to the other conditions, but frailty was a distinct biologic 
syndrome (30).
The questions patterned from the Fried Frailty score domains are assessed at baseline and at 
24 weeks (31). The questions address five domains of the frailty phenotype: (a) shrinking 
(weight loss of ⩾10 pounds in the prior year); (b) weakness (decreased or weakened grip 
strength); (c) exhaustion (fatigue or declining endurance); (d) slowness (slower walking 
pace); and (e) low activity (decline in physical activity). The 5 questions are as follows:
Questions at baseline:
Within the last 12 months has the patient experienced any of the following?
∀
Unintentional weight loss ( 5 kg/10 lbs).
∀
Developed decreased grip strength.
∀
Developed increasing fatigue/lethargy or declining endurance.
∀
Walks a distance of 5 m/15 feet at a slower pace.
∀
Decline in typical activity level.
Questions at 24 weeks:
Within the last 6 months has the patient experienced any of the following?
∀
Unintentional weight loss ( 5 kg/10 lbs).
∀
Developed decreased grip strength.
∀
Developed increasing fatigue/lethargy or declining endurance.
∀
Walks a distance of 5 m/15 feet at a slower pace.
∀
Decline in typical activity level.
9.4.5
Assessment of NYHA class
NYHA class will be assessed according to the classification below:
∀
Class I: No limitation of physical activity
∀
Class II: Slight limitation of physical activity in which ordinary physical activity leads 
to fatigue, palpitation, dyspnea, or anginal pain; the person is comfortable at rest
∀
Class III: Marked limitation of physical activity in which less-than-ordinary activity 
results in fatigue, palpitation, dyspnea, or anginal pain; the person is comfortable at 
rest
∀
Class IV: Inability to carry on any physical activity without discomfort but also 
symptoms of heart failure or the anginal syndrome even at rest, with increased 
discomfort if any physical activity is undertaken 
9.4.6
NT-proBNP
NT-proBNP measurements will be assessed by the central lab. NT-proBNP or BNP 
measurements for screening will be assessed locally.


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9.4.7
Clinical outcome events
Potential pre-specified clinical outcome events will be submitted for adjudication to an 
independent CEC. The following events will be collected and analyzed to explore the efficacy 
of study drug treatments on clinical outcomes:

All deaths (CV and non-CV, including outpatient death)

CV hospitalizations including HF and non-HF hospitalizations and non-HF CV 
hospitalizations (i.e. myocardial infarction and stroke)

Outpatient HF events, such as IV diuretic use for HF or urgent HF visits 
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 outcomes 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.
9.4.8
Six-minute walk test
The 6MWT is designed to evaluate a patient’s exercise capacity while performing an 
everyday activity (32). During this study, a 6MWT including Borg CR 10 Scale will be 
conducted at different time points as specified in Section 9.2, for further details on assessment 
refer to Section 16.1. A familiarization 6MWT will be performed during the run-in phase. To 
avoid any interactions, it is not permitted to perform the familiarization test on the same day 
as the baseline 6MWT. 
9.5
Pharmacokinetics / pharmacodynamics
For the investigation of systemic exposure to vericiguat and its relationship with efficacy, the 
plasma concentrations of vericiguat will be determined at different time points using a sparse 
sampling approach mainly in patients eligible for PK/QT assessment. EoT PK predose sample 
should be collected for all patients.
Blood samples will be collected at the time points indicated in Study Flow Chart in Section 
9.1 and described in the visit description in Section 9.2. PK samples obtained at additional 
time points based on the investigator’s discretion and/or from patients not eligible for PK/QT 
assessment will not qualify as a protocol deviation and will be analyzed. Deviations from the 
specified time points will be documented and taken into account. Date and time of the PK 
sample collection and date and time of last study drug intake (either at home on the day before 
the sample or at site) must be documented. 
Details about the collection, processing, storage and shipment of samples will be provided 
separately (e.g. sample handling sheets or lab manual).
Plasma concentrations of vericiguat will be measured using validated methods. QC and 
calibration samples will be analyzed concurrently with study samples. Concentrations are 
calculated from the chromatographic raw data in accordance with current Bayer guidelines. 
The results of calibration samples and QC samples will be reported in the Bioanalytical 


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Reports which will be included in the Clinical Study Report for this study. The bioanalyst will 
be unblinded for analysis of study samples.
The PK calculations will be based on the actual sampling and dosing times. Therefore, it is of 
importance to have this data thoroughly documented in the eCRF. Deviations from the 
specified time points will be documented and taken into account when calculating the PK 
parameters. Those deviations do not qualify as protocol violations.
Pharmacokinetics and, if applicable, pharmacokinetics/pharmacodynamics (PK/PD) modeling 
using population approaches to describe vericiguat PK including potential influence of 
relevant patient co-variables (e.g., age, gender, body weight, etc.) or potentially to relate 
parameters of clinical safety and efficacy response (e.g. primary, secondary and/or 
exploratory variables) with vericiguat plasma concentrations will be investigated under a 
separate detailed PK/PD evaluation and analysis plan.
9.6
Safety
Safety and tolerability will be assessed by clinical review of all relevant parameters including:
Primary safety variable:

The incidence of treatment-emergent AEs
Exploratory safety variables:

Vital signs

Laboratory data

12- lead ECG data
9.6.1
Adverse events
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 patient 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 e.g. physical examination findings, symptoms, diseases, laboratory, ECG.


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
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. This includes intercurrent illnesses.
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
(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
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.


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9.6.1.2.2
Intensity
The intensity of an AE is classified according to the following categories:
-
Mild
-
Moderate
- Severe
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 eCRF.
Causality should be assessed separately for each study treatment as detailed in the eCRF. If 
the investigator feels that the event cannot be firmly attributed to one of the study treatments 
(e.g. owing to a suspected underlying interaction), the same assessment will be documented 
for each study treatment.
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:
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.
Important 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: Clinical/preclinical


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- 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 procedures
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”
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 reduced
- Dose not changed
- Dose increased
- Not applicable
- Unknown
9.6.1.2.5
Other specific treatment(s) of adverse events
- None
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 eCRF 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. 


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“Death” should not be recorded as an AE on the AE page. Instead, “death” is the outcome of 
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.
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 in the CRF as well as the complementary SAE pages provided 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, suspected, unexpected, 
serious adverse reactions [SUSARs]) will be performed by the sponsor and/or by the 
investigator according to all applicable regulations.
In addition, adverse events related to study endpoints or underlined diseases may not be 
considered as SUSAR in this study (see Section 7.5).
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.
9.6.1.5 Expected adverse events
For this study, the applicable reference document is the most current version of the IB.
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.


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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 safety interest
For this trial, the following safety related event of special interest has been defined:

Symptomatic hypotension (all hypotension AEs will be captured, only symptomatic 
hypotension is considered an AESI)

Syncope
The DMC will monitor with special attention to these AESIs as defined in the DMC charter.
Any of these events have to be reported as an “important medial event” (see Section 9.6.1.6) 
and therefore as a SAE to the sponsor within 24 hours of becoming aware of the events. 
In any case, adverse events of special interest fulfilling any seriousness criterion should be 
reported as SAE (see also Section 9.6.1.1).
9.6.2
Pregnancies
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 followed up until up to 4 weeks after discharge.
For a pregnancy in the partner of a male study patient, all efforts will be made to obtain 
similar information on course and outcome, patient 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. 
9.6.3
Further safety
Safety assessments will include adverse events (AEs), physical examination findings, and 
vital signs including pulse rate and blood pressure assessment. Laboratory safety studies will 
include blood chemistry, hematology, and urine pregnancy testing (performed in women of 
childbearing potential) (see Section 9.7).
Adverse events may occur during clinical trials from overdose (whether accidental or 
intentional), from abuse and from withdrawal. In this trial, any dose higher than the maximal 
target dose prescribed in the study protocol will be considered an overdose. If an adverse 
event(s) is resulted from the overdose, the adverse event(s) is reported as a non-serious 
adverse event, unless other serious criteria are met.
In the event of an overdose, the investigator/treating physician should contact the Medical 
Monitor immediately and closely monitor the participant for any AE/SAE and laboratory 
abnormalities for at least 4 days. Sponsor does not recommend specific treatment for an 
overdose.
Medical devices:
The following is Japan specific guidance for reporting medical device failures:


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The investigator must report immediately all non-approved medical device failures which 
could cause health damage, as well as any health damage that may be causally associated with 
a non-approved medical device failure. For this reporting, the forms provided are to be used 
and sent to the designated recipient.
9.7
Other procedures and variables
9.7.1
Laboratory assessments
9.7.1.1
Local laboratory
At the screening visit, local laboratory results from routine clinical examinations will be 
assessed to check the eligibility of the patient.
At least the following parameters must be measured at the screening visit and entered in the 
eCRF to check the patient’s eligibility for the study:

NT-proBNP or BNP for screening (see Section 9.7.7 for further details)

Serum creatinine for screening (eGFR will be calculated automatically in the eCRF 
using the MDRD formula)

urine pregnancy test, and Serum β-human chorionic gonadotropin (unless requested by 
local authorities, serum β-human chorionic gonadotropin will only be conducted if 
urine pregnancy test is positive)
Urine or serum pregnancy test will also be conducted on visits 2 and 7 for women of 
childbearing potential, according to the local regulations. If required by national / institutional 
regulations, a serum or urine pregnancy test in patients of childbearing potential should be 
performed more often (e.g. at every visit).
9.7.1.2
Central Laboratory
Only centrally analyzed blood samples will be considered for analysis.
The name and address for the central lab service provider can be found in the documentation 
supplied by the vendor. The following laboratory tests will be performed centrally:
Hematology: Hct, Hb, MCV, MCH, MCHC, Platelet count, RBC, RDW, Reticulocytes, and 
WBC.
Chemistry: ALT, AST, LDH, Bilirubin (Total), Blood glucose, cholesterol (HDL, LDL, 
total), triglycerides, BUN, creatinine, GGT, K, Na, and Uric acid, high-sensitivity troponin t, 
HbA1c.
Biomarker: NT-proBNP.
Coagulation: aPTT, INR
In the event of implausible results, the laboratory may measure additional parameters to 
assess the quality of the sample (e.g. clotted or hemolyzed) and to verify the results. The 
results from such additional analyses may neither be included in the clinical database of this 
study nor evaluated further. If the results are relevant, the investigator will be informed to 
determine follow-up activities outside of this protocol.


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9.7.2
Physical examination
Full physical examination should be performed by the investigator at Screening and 
randomization. Physical exams focused on CV assessment will be performed at the other 
visits. Abnormal physical examination findings are recorded either as medical history or as 
adverse events (see Section 9.6.1.1).
9.7.3
Echocardiography parameters
Echocardiography data from routine clinical exam will be assessed at screening to determine 
eligibility, according to the following criteria: 

LVEF ≥45% and

Structural changes indicated by at least one of the following parameters:
o
LV hypertrophy (any of the following: intraventricular septal or posterior wall 
thickness ≥1.1 cm) and/or LV mass index ≥115 g/m2 in male and ≥95 g/m2 in 
female)
o
LA enlargement (any of the following: LAV index ≥29 ml/m2, or LAV 
>58 mL in male and >52 mL in female patients, or LA area >20 cm2, or LA 
diameter >40 mm in male and >38 mm in female patients)
9.7.4
12-lead ECG
ECGs will be transferred and analyzed centrally. The reading will be done in a standard way. 
Standard electrocardiogram (12-lead ECG) in supine position will be recorded after resting 
for at least 10 min as follows:
1. ECG at baseline in all patients to evaluate the eligibility of the patient for PK/QT 
assessment. The eligibility for PK/QT will be defined by the investigator in the 
baseline ECG.
The ECG is invalid for QT assessment if at least one of the following is fulfilled:

QRS-Prolongation >120 ms, e.g. in the presence of complete bundle branch 
block 

Pacemaker stimulation 

Arrhythmia and conduction abnormalities such as atrial fibrillation or flutter, 
2nd - 3rd degree AV block with ventricular escape rhythm etc.

Marked sinus arrhythmia
2. ECG matched with PK
The ECG will only be performed for patients who are eligible for PK/QT assessment. 
It will be recorded at visits 2, 5 and 9 just before collection of the blood sample for PK 
analysis. Non-concordance with subsequent assignment as evaluable or non-evaluable 
upon central processing by the ECG core lab using different methods for QT 
assessment will be descriptively summarized and not be considered as deviation.
3. ECG at the end of treatment and in case of premature discontinuation as a safety 
measure in all patients (for patients who are eligible for PK/QT, assessment as part of 
PK/QT collection).


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Only the results of the central evaluation will be used for statistical evaluation of ECG data. 
The following ECG parameters will be analyzed: HR, PR, QRS duration (QRSD), QT, and 
QTc (QTcB and QTcF).
The ECGs must be recorded with a paper velocity of 25 mm per second. The ECG print-outs 
will be identified with the PID as well as date and time of recording and will be attached to 
the patient’s file.
All ECGs will be examined by the investigator, and any new clinically relevant abnormality 
will be documented as an AE.
9.7.5
Vital signs
BP and pulse rate measurements will be performed at specific visits. For details see Section 
9.2.
Accurate measurement of blood pressure is essential to guide dose titration management and 
to detect potential safety signals during the trial. A number of factors related to the patient can 
cause significant deviations in measured blood pressure. These include room temperature, 
exercise, alcohol or nicotine consumption, positioning of the arm, muscle tension, bladder 
distension, talking, and background noise.
Blood pressure and pulse rate should be measured under the following conditions:

Measurement of pulse rate and blood pressure must be conducted after 10 minute 
resting period with patient comfortably seated in a chair with the legs uncrossed and 
the back and arm supported. Measurements should not be made while the patient is on 
an examining table. The patient should be instructed to relax as much as possible and 
to not talk during the measurement procedure

The examiner should ensure that the middle of the cuff on the upper arm is at the level 
of the right atrium (the mid-point of the sternum).

The patient should be asked to remove all clothing that covers the location of cuff 
placement.

The same examiner should assess the patient at all subsequent visits and use the same 
device under same external conditions.

The protocol requires 3 measurements – approximately 2 min apart (means will be 
calculated in the eCRF). Please record the time, positioning and arm used for each 
measurement
9.7.6
Biomarkers
NT-proBNP will be determined at the time points indicated in Section 9.1. 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)
Other biomarkers deemed relevant to gain further knowledge about the mechanisms 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 
but only in countries where it is not excluded by local guidelines.


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The additional biomarker results may be reported separately.
9.7.7
Optional pharmacogenetic research
Understanding genetic determinants of drug response is an important endeavor during medical 
research. This research will evaluate whether genetic variation within the studied clinical trial 
population correlates with baseline clinical characteristics and the course of disease for the 
studied outcomes and/or ii) response to the study drug treatment. If genetic variation is found 
to correlate with clinical characteristics and outcomes, the data might point to novel pathways 
involved in the disease and thereby inform development of novel medicines. If genetic 
variation is found to predict efficacy or adverse events, the data might inform optimal use of 
therapies in the patient population. This research contributes to understanding genetic 
determinants of the disease in general, as well as efficacy and safety associated with the 
treatments in this study.
A whole blood sample will be obtained from those patients, who have signed a separate 
informed consent form for pharmacogenetic research, but only in countries where it is not 
excluded by local guidelines. The participation in this part of the study is voluntary and has 
no influence on the participation in this study.
Results will be reported under separate cover, if the evaluations are performed.
9.7.8
Accelerometry
At sites participating in the accelerometry substudy, it is planned that up to approximately 150
patients may consent to undergo activity tracking before randomization, before visit 7, and 
before visit 9 (end of treatment at 24 weeks).
Subjects are not required to participate in the accelerometry substudy in order to participate in 
the main trial. In addition, subjects must provide separate informed consent in order to 
participate in this substudy. 
Additional details will be specified in separate site accelerometry procedure manuals and 
accelerometry substudy analysis plans.
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 analysis will be performed using Statistical Analysis Software; the version used 
will be specified in the statistical analysis plan.


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10.2
Analysis sets
FAS: All subjects randomized and treated (at least one dose of the study treatment), and have 
at least one observed outcome measure, will be valid for the FAS. The patients will be 
analyzed based on the planned treatment. The primary analysis for all efficacy endpoints will 
be based on FAS.
SAF: All patients that received at least one dose of study treatment (vericiguat or placebo). 
Analyses will be based on actual treatment received, and patients who did not reach maximum 
titration or received both vericiguat and placebo by mistake will be assigned to the planned 
treatment. All safety analyses will be based on the SAF.
PPS: All patients who meet the major inclusion and exclusion criteria at randomization that 
may affect efficacy, who are not taking excluded concomitant medications during the study 
that could have an effect on efficacy, have the KCCQ assessed at baseline and at least once 
during the main treatment phase and who are at least 80% compliant with study medication
and show no major protocol deviations. The detailed criteria will be described in the SAP. 
The PPS will only be used in the supportive analysis.
PKS: All subjects with at least one valid pharmacokinetic concentration will be included in 
the statistical evaluation of pharmacokinetics.
10.3
Variables and planned statistical analyses
10.3.1
Efficacy variables
Primary efficacy variable: The primary endpoint will be change in KCCQ PLS from 
baseline to week 24.
The estimand of interest is the de facto or treatment policy estimand.
Population: Defined through appropriate inclusion/exclusion criteria (see Section 6.1 and 6.2) 
to reflect the targeted patient population.
Variable: Change from baseline in KCCQ PLS from baseline to Week 24.
Measurement of intervention effect: Regardless of stopping study treatment or adherence to 
study treatment.
Summary measure: Difference of LS means at Week 24.
The analysis will include all assessments post-baseline. Graphical method of Maurer and 
Bretz (33) will be applied for multiplicity control. The two primary hypotheses will be tested
with an equally splitted two sided alpha level of 0.025.
The primary analysis of the primary endpoint will be performed using a MMRM, including 
treatment group (vericiguat versus placebo), study visit as fixed effects, patient as a random 
effect, interaction between study visit and treatment group, and adjustment for the baseline 
PLS values as covariates. The model will assume an unstructured covariance matrix for 
within-patient variability. 
The analysis will be performed in the Full Analysis Set. For patients who drop out of the 
study, a pattern-mixture model with control-based pattern imputation will be implemented. 
After the patient drops out from the study, it is assumed that patients from the vericiguat arm 


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will show the same future trend as those on the placebo arm. Patients that discontinue from 
the placebo arm are assumed to evolve in the same way as placebo patients that remain in the 
study. For those patients who had died during the study, they will be imputed with the worst 
case outcome, i.e., a zero score for missing KCCQ PLS. 
The model statement is:
Yijklm = μ + βxi + tk + rl + hm +vj+ (tv)jk + si + εi j
where Yijklm is the change from baseline in PLS to visit j for patient i; μ is the intercept, β is 
the baseline covariate effect, xi is the baseline PLS for patient i, tk is the fixed effect of 
treatment k, rl is the fixed effect of region l, hm is the fixed effect of heart rhythm m (atrial 
fibrillation and sinus rhythm), vj is the fixed effect of visit j, (tv)jk is the interaction effect of 
treatment k by visit j, si is the random effect of patient i and εi j  ~ Normal(0, σ2) represents the 
residual variance component with corr(ε i j, ε i j’) = ρjj’,  j ≠ j’
Further, based on the anchor-based interim analysis (see Section 10.5), the percentages of 
responders with MCID, moderate, and large differences at each visit will be summarized and 
nominal p-values will also be provided. In addition, cumulative distribution function of 
change from baseline at 24 weeks for the KCCQ PLS domain will be plotted to compare the 
proportion of patients who are meeting certain threshold from vericiguat and placebo arms
(see Section 10.5).
As a supportive analysis, the MMRM using the above model will be applied to all 
assessments post-baseline prior to study drug termination.
Additional sensitivity analyses will be performed. Analysis using data imputation approaches 
based on different missing data mechanisms will be investigated, including tipping point 
analysis. Details of such methods will be described in the SAP. 
Secondary efficacy variable:
The secondary endpoint is change from baseline in the 6 MWT at 24 weeks.
The estimand of interest is the de facto or treatment policy estimand.
Population: Defined through appropriate inclusion/exclusion criteria (see Section 6.1 and 
Section 6.2) to reflect the targeted patient population and restricted to those who are able to 
perform the 6 MWT at baseline.
Variable: Change from baseline in 6 MWT from baseline to Week 24.
Measurement of intervention effect: Regardless of stopping study treatment or adherence to 
study treatment.
Summary measure: Difference of LS means at Week 24.
The secondary endpoint will be analyzed in the same manner as the primary endpoint. For 
those patients who are too sick to perform the test at any post baseline visit, a score of 0 will 
be assumed. further sensitivity analyses will be specified in SAP. 
Other efficacy variables:
Other continuous variables including change from baseline to week 24 in other KCCQ 
domains, EQ-5D-5L, fried frailty score and NT-proBNP, will be analyzed using the MMRM


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model. For categorical variables such as NYHA class, PGIC, PGIS, the relative response level 
change will be summarized by each visit. Incidences of cardiovascular death and total heart 
failure hospitalizations, as well as all-cause mortality and CV hospitalizations, MI and stroke 
will be summarized. Kaplan Meier curves of the composite endpoints (see Section 9.4) will be 
presented.
Details on any descriptive subgroup analyses will be specified in the SAP. These will include 
region, gender, atrial fibrillation status, patient randomization time (before or after discharge 
from HF hospitalization, or post IV diuretic treatment without hospitalization), and the time 
from HF hospitalization or IV diuretic treatment to randomization (<3 month vs. ≥3 month).
Multiplicity adjustment:
The study uses the graphical method of Maurer and Bretz (33) to provide strong multiplicity 
control across the primary KCCQ PLS hypotheses and the secondary 6 MWT hypotheses.
The overall two sided alpha level will be controlled at 0.05. The two primary hypotheses will 
be tested using Bonferroni procedure, each at a splitted level of alpha 0.025. The two 
secondary hypotheses will be tested based on parallel gatekeeping principle. If both primary 
hypotheses can be rejected, the secondary family will be tested at a full alpha level 0.05 (two 
sided). If only one primary hypothesis is shown to be statistically significant, then only the 
secondary hypothesis based on the same dose group can be tested at an alpha level carried 
forward from the primary family testing, i.e., 0.025 (two sided). In this case, if the secondary 
hypothesis is rejected, the alpha spending associated with this dose group (0.025) will be re-
utilized to test the other failed primary hypothesis again. Figure 10–1 shows the α-allocation 
for each hypothesis in the ellipse representing the hypothesis.
Figure 10–1 α-allocation for each hypothesis in the ellipse representing the 
hypothesis
Overall, the primary analysis will be claimed to have a positive outcome if the null hypothesis 
for at least one of the two primary hypotheses can be rejected. 
10.4
Determination of sample size
The sample size estimation for this study will be based on the analysis of the primary 
endpoint of KCCQ PLS at 24 weeks comparing vericiguat 15 mg versus placebo and 10 mg 
versus placebo, to achieve 80% power with two-sided alpha level of 0.05 to detect a treatment 
difference from placebo in one or both of the dose groups. A mean difference from placebo in 
KCCQ PLS of 5 points for both dose groups and a common SD of 21 points are assumed.
Under the same assumption of treatment effect and standard deviation, the power to detect 


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difference for any single comparison will be 65%. The 80% power was based on an “either 
or” success criterion, i.e., if at least one of the primary null hypotheses is rejected. The 
marginal power to reject any single comparison is 65%.
The given sample size provides 97% power to detect +30 m placebo-corrected increase in the 
secondary endpoint 6MWT (assumed SD 80 m) for any one dose group, and 80% power to 
detect an increase by +22.3 m, which is below the 35 m increase associated with a 6.2 point 
improvement in KCCQ PLS at 24 weeks in FAIR-HF and greater than the 15 m increase at 3-
months that was associated with a 2.3 point improvement in KCCQ PLS in ACTION-HF
(34).
A 5 point improvement in KCCQ OSS in patients with HFrEF is considered to represent a 
clinically significant change in heart failure status (35). Similarly, a change of +6.4 and -5.1 
points in KCCQ PLS were associated with either small improvements or small deteriorations 
in clinical status, as determined by a cardiologist, in the Cardiovascular Outcomes Research 
Consortium study cohort in patients with HFrEF (35, 36). In addition, baseline KCCQ PLS 
score has also been associated with peak VO2 and distance traveled on the 6 minute walk test 
(6 MWT), with 6.4 and 7.5 point differences in PLS being associated with 1SD changes for 
peak VO2 and 6 MWT respectively (37). Furthermore, both anchor-based and distribution-
based analyses of the SOCRATES-PRESERVED data support an improvement of 5 points in 
KCCQ PLS as MCID. This effect size has been proposed to the US FDA during a Type C 
meeting and was considered preliminarily acceptable pending additional data analyses (see 
Section 10.5) per Agency correspondence following the meeting. As such, this study will be 
powered to detect a placebo-corrected change of at least 5 point improvement in KCCQ PLS 
from baseline to 24 weeks. An SD of 21 points was assumed based on studies in which 
KCCQ PLS has been reported in the literature (38-43). The patients will also be followed 
until the end of the study regardless of stopping study treatment or not, hence the drop-out 
rate is considered negligible. Based on these considerations, the total sample size will be 
N=735 with N=245 each in the placebo, 10 mg vericiguat arm and 15 mg vericiguat arm in a 
1:1:1 randomization. 
10.5
Planned interim analyses
Futility interim analysis
A single interim assessment by the DMC to evaluate futility is planned for when 50% of the 
patients complete Visit 7 (week 12) and their KCCQ data become available. Although the 
effects of 24 weeks of treatment with vericiguat have not been evaluated in patients with 
HFpEF, prior data in this population suggest that the 12 week timepoint will be sufficiently 
predictive of the 24 week data to allow for an adequate interim assessment of efficacy. 
Furthermore, in view of the expected timeline for trial conduct, a sufficiently large proportion 
of data at the 24 week timepoint will only become available shortly before completion of the 
trial. Based on a careful analysis of the operating characteristics of a range of futility criteria, 
an observed treatment effect of 0.6 point difference in KCCQ PLS (vericiguat vs placebo) was 
chosen to serve as the boundary for futility for both dose groups; this is approximately 
equivalent to a joint conditional power (CP) of 23% (under the assumption of a true difference 
of 5 points). An observed treatment effect <0.6 in both comparisons would therefore signal to 
the DMC to consider their potential recommendation that the trial should be terminated early. 
The type II error rate spent with this futility rule will be <0.01. Assuming the true treatment 


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effect is a 5 point difference as expected, the probability of stopping at the interim is 
approximately 1.3%. Under the null hypothesis, i.e., assuming 0 treatment effect for both 
vericiguat vs. placebo comparisons, the probability of stopping at the interim for futility for 
both doses is approximately 43%. Stopping for futility will only be done if both arms are 
futile. If only one arm is futile then it will not be dropped as enrollment is expected to be 
completed at the time of the futility analysis. At this futility boundary the trial has a 
probability of 9% to observe a >5 point improvement in either of the comparison in KCCQ 
PLS. Details of the futility analysis will be specified in the SAP and in the DMC charter. No 
formal interim report will be written.
Anchor-based interim analysis
The PGIC will be used to support an anchor-based approach to estimate KCCQ PLS MCID 
values. These analyses will be performed upon completion of the 3-month assessment by all 
trial participants and therefore at the time point at which approximately 70% of patients have 
completed the week 24 visit assessment. The analysis will take place before unblinding and 
without knowledge of the treatment received by the participants,
Participants will be categorized according to their responses to the PGIC as follows:

Participant who report “A little better” to PGIC Question #1 as well as “Yes” to 
Question #1b (Was this improvement in your physical limitations an important change 
for you?).

Participants who report “A little worse” to PGIC Question #1 as well as “Yes” to 
Question #1b (Was this worsening in your physical limitations an important change 
for you (by important we mean did it bother you?); 
Mean KCCQ PLS change scores from baseline will be calculated for each group above to 
define an anchor-based MID.
In addition, further analysis including non-parametric discriminant analysis will be conducted 
to explore the MCID using all patient response data available (44). Patients who respond 
“much better” and “better” will be aggregated to the new category “Much improved”. Patients 
who respond “the same”, “a little worse”, “worse”, or “much worse” will be combined into 
the new category “Not improved”. Given sufficient sample size for category responses (at 
least 20 patients in each of the categories), the KCCQ PLS score densities for each category
will be estimated and the intersection point of these density curves will be considered as the 
discrimination points. The discrimination point between the two categories “a little better” 
and “Not improved” is considered to be MCID. Similarly, the discrimination point for PGIS 
categories will be used to inform anchor-based approaches for MID estimates for the KCCQ 
PLS mean change from baseline.
The blinded information obtained from the above described anchor-based approaches, will 
have no impact on the trial conduct. These analyses serve to support responder definitions that 
will be further detailed in the statistical analysis plan prior to unblinding the trial. Therefore, 
no correction of the family wise error rate of the trial is necessary. No formal interim report 
will be written.


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10.6
PK and PK/QT analyses
PK analysis will be performed in the PKS (see Section 10.2). Vericiguat peak and trough 
plasma concentrations will be summarized per visit and separated according to assigned dose. 
The following statistics will be calculated for each of the sampling points: arithmetic mean, 
standard deviation and coefficient of variation, geometric mean, geometric standard deviation 
(re-transformed standard deviation of the logarithms) and geometric coefficient of variation, 
minimum, median, and maximum value and the number of measurements.
Means at any time will only be calculated if at least 2/3 of the individual data were measured
and were above the LLOQ. For the calculation of the mean value a data point below LLOQ 
will be substituted by one half of this limit. In tables showing mean values, where values 
below LLOQ are included in the calculation of mean values, these means will be marked.
PK/QT analyses
The time-matched placebo-corrected change from baseline of the QT interval corrected 
according to QTcF after 10 mg vericiguat and after 15 mg vericiguat at steady state will be 
analyzed. 
The individual change from baseline of QTcF after 24 weeks will be analyzed by ANCOVA, 
including treatment as fixed effects, the subject as random effect and the baseline value as 
covariate. Based on these analyses, point estimates (LS-Means) and confirmatory two-sided 
90% confidence intervals of the true mean difference will be calculated for each time point on 
week 24.
Further analyses to explore the relationship between PK concentration and QTc will be 
specified in the SAP.
For further details of other standard PK/PD analyses, see Section 9.5.
11.
Data handling and quality assurance
11.1
Data recording
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 (LSH).
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 
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 


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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
(e.g. patient file, local laboratory report, etc.). 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. Race, ethnic 
group, age and gender may be entered directly into the CRF, without availability of
corresponding source documentation. Thus, these CRF data will be the source and no
additional source documentation needs to be available. For all other data, source 
documentation must be 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 applicable race / 
ethnicity)

Date of informed consent

Relevant inclusion/exclusion criteria

Reason for premature discontinuation

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:

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, 


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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 applicable sponsor’s/CRO’s standards and data cleaning 
procedures. This is applicable for data recorded on CRF as well as for data from other sources 
(e.g. IxRS, laboratory, adjudication committees).
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. 
11.4
Missing data 
We expect a low number of missing data since investigators and patients are encouraged to 
complete the visit schedule with all assessments irrespective of whether study drug treatment 
is completed per protocol or after premature permanent study drug discontinuation.
All missing or partial data will be presented in the data listing as they are recorded on the 
CRF.
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.


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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, 
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 all regulations relevant for the study 
center.
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 any interim analysis
- 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 6.3.1.


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13.
Ethical and legal aspects
13.1
Investigator(s) and other study personnel
Sponsor’s medical expert
Name: 
Title: 
Address:
Bayer SA
Rua Cancioneiro de Évora, 255 - Prédio E1 - 1º andar 
04708-010 São Paulo - SP Brazil 
SP Brazil
Phone no. 
Coordinating investigator for the study
Name:
Title:
Address:
Phone:
Fax:
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 have received 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.
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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External data evaluation bodies
Independent data monitoring committee
Ongoing safety monitoring during the conduct of the study will be performed by an external 
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.
Steering committee
The conduct of this study will be overseen by the steering committee which is made up of a 
panel of experts in the field.
Central independent blinded clinical events committee (CEC)
Blinded adjudication of all cardiovascular hospitalizations and all deaths will be performed by 
a central CEC as described in the CEC manual. The committee will be provided with all 
relevant documentation related to the event. The committee will also adjudicate all events 
listed in Section 7.5. The procedures followed by the committee will be described in the CEC 
manual. Adjudication results will be the basis for the final analysis. Further details will be 
documented in the CEC manual.
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 
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 
IEC/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.


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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 patients 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.
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 / legal representative (if the patient is under legal 
protection), 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 / legal representative 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 9.2.11 to be conducted after withdrawal of consent. 
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 / legal representative will have ample time and opportunity to ask questions.
Only if the patient / legal representative 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 / legal representative will receive a copy of the signed and 
dated form.


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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.
If the patient is not capable of providing a signature, a verbal statement of consent can also be 
given in the presence of an impartial witness (independent of the sponsor and the 
investigator). This is to be documented by a signature from the informing physician as well as 
by a signature from the witness.
The informed consent form and any other written information provided to patients / legal 
representatives 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 / legal representative 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.
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. 
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 


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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.
14.
Reference list 
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Steinberg BA, Zhao X, Heidenreich PA, Peterson ED, Bhatt DL, Cannon CP, et al. 
Trends in patients hospitalized with heart failure and preserved left ventricular ejection 
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Butler J, Hamo CE, Udelson JE, Pitt B, Yancy C, Shah SJ, et al. Exploring New 
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Shah SJ, Gheorghiade M. Heart failure with preserved ejection fraction: treat now by 
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Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Jr., Colvin MM, et al. 2017 
ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the 
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/American Heart Association Task Force on Clinical Practice Guidelines and the Heart 
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Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et al. 2016 ESC 
Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task 
Force for the diagnosis and treatment of acute and chronic heart failure of the 
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200.
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Borlaug BA, Redfield MM. Diastolic and systolic heart failure are distinct phenotypes 
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7.
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van Heerebeek L, Hamdani N, Falcao-Pires I, Leite-Moreira AF, Begieneman MP, 
Bronzwaer JG, et al. Low myocardial protein kinase G activity in heart failure with 
preserved ejection fraction. Circulation. 2012 Aug 14;126(7):830-9.
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Buys ES, Sips P, Vermeersch P, Raher MJ, Rogge E, Ichinose F, et al. Gender-
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Cardiovascular research. 2008 Jul 01;79(1):179-86.
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Lam CS, Brutsaert DL. Endothelial dysfunction: a pathophysiologic factor in heart 
failure with preserved ejection fraction. J Am Coll Cardiol. 2012 Oct 30;60(18):1787-
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Oelze M, Knorr M, Kroller-Schon S, Kossmann S, Gottschlich A, Rummler R, et al. 
Chronic therapy with isosorbide-5-mononitrate causes endothelial dysfunction, 
oxidative stress, and a marked increase in vascular endothelin-1 expression. Eur Heart 
J. 2013 Nov;34(41):3206-16.


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Schwartzenberg S, Redfield MM, From AM, Sorajja P, Nishimura RA, Borlaug BA. 
Effects of vasodilation in heart failure with preserved or reduced ejection fraction 
implications of distinct pathophysiologies on response to therapy. J Am Coll Cardiol. 
2012 Jan 31;59(5):442-51.
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Kurz MA, Lamping KG, Bates JN, Eastham CL, Marcus ML, Harrison DG. 
Mechanisms responsible for the heterogeneous coronary microvascular response to 
nitroglycerin. Circ Res. 1991 Mar;68(3):847-55.
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Bassenge E, Zanzinger J. Nitrates in different vascular beds, nitrate tolerance, and 
interactions with endothelial function. Am J Cardiol. 1992 Sep 24;70(8):23b-9b.
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Gheorghiade M, Marti CN, Sabbah HN, Roessig L, Greene SJ, Bohm M, et al. Soluble 
guanylate cyclase: a potential therapeutic target for heart failure. Heart Fail Rev. 2013 
Mar;18(2):123-34.
17.
Bonderman D, Pretsch I, Steringer-Mascherbauer R, Jansa P, Rosenkranz S, Tufaro C, 
et al. Acute hemodynamic effects of riociguat in patients with pulmonary hypertension 
associated with diastolic heart failure (DILATE-1): a randomized, double-blind, 
placebo-controlled, single-dose study. Chest. 2014 Nov;146(5):1274-85.
18.
Redfield MM, Chen HH, Borlaug BA, Semigran MJ, Lee KL, Lewis G, et al. Effect of 
phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure 
with preserved ejection fraction: a randomized clinical trial. JAMA. 2013 Mar 
27;309(12):1268-77.
19.
Hoendermis ES, Liu LC, Hummel YM, van der Meer P, de Boer RA, Berger RM, et 
al. Effects of sildenafil on invasive haemodynamics and exercise capacity in heart 
failure patients with preserved ejection fraction and pulmonary hypertension: a 
randomized controlled trial. Eur Heart J. 2015 Oct 07;36(38):2565-73.
20.
Pieske B, Maggioni AP, Lam CSP, Pieske-Kraigher E, Filippatos G, Butler J, et al. 
Vericiguat in patients with worsening chronic heart failure and preserved ejection 
fraction: results of the SOluble guanylate Cyclase stimulatoR in heArT failurE 
patientS with PRESERVED EF (SOCRATES-PRESERVED) study. Eur Heart J. 2017 
Apr 14;38(15):1119-27.
21.
Redfield MM, Anstrom KJ, Levine JA, Koepp GA, Borlaug BA, Chen HH, et al. 
Isosorbide Mononitrate in Heart Failure with Preserved Ejection Fraction. N Engl J 
Med. 2015 Dec 10;373(24):2314-24.
22.
Filippatos G, Maggioni AP, Lam CSP, Pieske-Kraigher E, Butler J, Spertus J, et al. 
Patient-reported outcomes in the SOluble guanylate Cyclase stimulatoR in heArT 
failurE patientS with PRESERVED ejection fraction (SOCRATES-PRESERVED) 
study. Eur J Heart Fail. 2017 Jun;19(6):782-91.
23.
Chang C-L, Song X, Willson T, Duffy C. Abstract 220: Early Assessment of Real-
world Utilization and Dosing of Sacubitril/Valsartan in the US. Circulation: 
Cardiovascular Quality and Outcomes. 2017;10(Suppl 3):A220-A.
24.
Green CP, Porter CB, Bresnahan DR, Spertus JA. Development and evaluation of the 
Kansas City Cardiomyopathy Questionnaire: a new health status measure for heart 
failure. J Am Coll Cardiol. 2000 Apr;35(5):1245-55.
25.
Gwaltney CJ, Slagle AF, Martin M, Ariely R, Brede  Y. Hearing the voice of the heart 
failure patient: key experiences identified in qualitative interviews. Br J Cardiol. 
2012;19:25.
26.
Gheorghiade M, Greene SJ, Butler J, Filippatos G, Lam CS, Maggioni AP, et al. 
Effect of Vericiguat, a Soluble Guanylate Cyclase Stimulator, on Natriuretic Peptide 
Levels in Patients With Worsening Chronic Heart Failure and Reduced Ejection 


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Fraction: The SOCRATES-REDUCED Randomized Trial. Jama. 2015 Dec 
1;314(21):2251-62.
27.
FDA. Medical Device Development Tool (MDDT) qualification decision summary for 
Kansas City Cardiomyopathy Questionnaire (KCCQ). Submission number 
MDDT020. 2016; available online: 
https://www.fda.gov/downloads/MedicalDevices/ScienceandResearch/MedicalDevice
DevelopmentToolsMDDT/UCM581761.pdf.
28.
Forman DE, Alexander KP. Frailty: A Vital Sign for Older Adults With 
Cardiovascular Disease. Can J Cardiol. 2016 Sep;32(9):1082-7.
29.
Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, et al. Frailty 
in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001 
Mar;56(3):M146-56.
30.
Newman AB, Boudreau RM, Naydeck BL, Fried LF, Harris TB. A physiologic index 
of comorbidity: relationship to mortality and disability. J Gerontol A Biol Sci Med 
Sci. 2008 Jun;63(6):603-9.
31.
White HD, Westerhout CM, Alexander KP, Roe MT, Winters KJ, Cyr DD, et al. 
Frailty is associated with worse outcomes in non-ST-segment elevation acute coronary 
syndromes: Insights from the TaRgeted platelet Inhibition to cLarify the Optimal 
strateGy to medicallY manage Acute Coronary Syndromes (TRILOGY ACS) trial. 
European heart journal Acute cardiovascular care. 2016 Jun;5(3):231-42.
32.
American Thoracic Society. ATS statement: guidelines for the six-minute walk test. 
American journal of respiratory and critical care medicine. 2002 Jul 1;166(1):111-7.
33.
Maurer W, Bretz F. Multiple Testing in Group Sequential Trials Using Graphical 
Approaches. Statistics in Biopharmaceutical Research. 2013 2013/11/01;5(4):311-20.
34.
Flynn KE, Lin L, Moe GW, Howlett JG, Fine LJ, Spertus JA, et al. Relationships
between changes in patient-reported health status and functional capacity in 
outpatients with heart failure. Am Heart J. 2012 Jan;163(1):88-94.e3.
35.
Spertus J, Peterson E, Conard MW, Heidenreich PA, Krumholz HM, Jones P, et al. 
Monitoring clinical changes in patients with heart failure: a comparison of methods. 
Am Heart J. 2005 Oct;150(4):707-15.
36.
Dreyer RP, Jones PG, Kutty S, Spertus JA. Quantifying clinical change: discrepancies 
between patients' and providers' perspectives. Qual Life Res. 2016 Sep;25(9):2213-20.
37.
Flynn KE, Lin L, Ellis SJ, Russell SD, Spertus JA, Whellan DJ, et al. Outcomes, 
health policy, and managed care: relationships between patient-reported outcome 
measures and clinical measures in outpatients with heart failure. Am Heart J. 2009 
Oct;158(4 Suppl):S64-71.
38.
Ekman I, Chassany O, Komajda M, Bohm M, Borer JS, Ford I, et al. Heart rate 
reduction with ivabradine and health related quality of life in patients with chronic 
heart failure: results from the SHIFT study. Eur Heart J. 2011 Oct;32(19):2395-404.
39.
Comin-Colet J, Lainscak M, Dickstein K, Filippatos GS, Johnson P, Luscher TF, et al. 
The effect of intravenous ferric carboxymaltose on health-related quality of life in 
patients with chronic heart failure and iron deficiency: a subanalysis of the FAIR-HF 
study. Eur Heart J. 2013 Jan;34(1):30-8.
40.
O'Connor CM, Whellan DJ, Lee KL, Keteyian SJ, Cooper LS, Ellis SJ, et al. Efficacy 
and safety of exercise training in patients with chronic heart failure: HF-ACTION 
randomized controlled trial. Jama. 2009 Apr 8;301(14):1439-50.


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41.
Veazie PJ, Noyes K, Li Q, Hall WJ, Buttaccio A, Thevenet-Morrison K, et al. Cardiac 
resynchronization and quality of life in patients with minimally symptomatic heart 
failure. J Am Coll Cardiol. 2012 Nov 6;60(19):1940-4.
42.
Lewis EF, Claggett BL, McMurray JJV, Packer M, Lefkowitz MP, Rouleau JL, et al. 
Health-Related Quality of Life Outcomes in PARADIGM-HF. Circ Heart Fail. 2017 
Aug;10(8).
43.
Flynn KE, Pina IL, Whellan DJ, Lin L, Blumenthal JA, Ellis SJ, et al. Effects of 
exercise training on health status in patients with chronic heart failure: HF-ACTION 
randomized controlled trial. JAMA. 2009 Apr 08;301(14):1451-9.
44.
Gerlinger C, Schmelter T. Determining the non-inferiority margin for patient reported 
outcomes. Pharm Stat. 2011 Sep-Oct;10(5):410-3.
15.
Protocol amendments
Not applicable
16.
Appendices
16.1
Appendix 1: 6 Minute walk test
The 6MWT test must be performed in accordance with the American Thoracic Society 
Guideline (81). In case of absolute contraindication (i.e. unstable angina and myocardial 
infarction during the previous month), the 6MWT test must not be performed.
According to the guideline, the 6MWT test should be carried out indoors, along a long, flat, 
straight, enclosed corridor with hard surface that is seldom traveled. The walking course 
should be preferably 30 m in length, but not less than 25 m (longer walking courses should be 
shortened to 30 m). The length of the corridor and turnaround points should be marked. 
Patients will be instructed to walk alone, not run, from one end to the other end of the walking 
course, at their own pace, while attempting to cover as much ground as possible in 6 minutes. 
During the walk, patients are allowed to stop, lean against the wall and rest, but should 
resume walking as soon as they feel able to do so. The resting time will be included in the 
6 minutes.
A “warm-up” period before the test should not be performed. The patients should sit at rest in 
a chair, located near the starting position, for at least 10 minutes before the test starts. 
Investigators should not walk with the patients. Moreover, only standardized phrases for 
encouragement must be used during the test. To allow reproducibility, standardized phrases 
should be used every minute according to the following pattern:

After the first minute, tell the patient the following (in even tones): “You are doing 
well. You have 5 minutes to go.”

When the timer shows 4 minutes remaining, tell the patient the following: “Keep up 
the good work. You have 4 minutes to go.”

When the timer shows 3 minutes remaining, tell the patient the following: “You are 
doing well. You are halfway done.”


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
When the timer shows 2 minutes remaining, tell the patient the following: “Keep up 
the good work. You have only 2 minutes left.”

When the timer shows only 1 minute remaining, tell the patient: “You are doing well. 
You have only 1 minute to go.”
To reduce the variability of the 6MWT tests, it is of utmost importance that familiarization-
6MWT test, baseline-test and all following tests are performed under the same conditions.

Wheelchair or scooter dependent / supplemental oxygen patients or those on 
continuous oxygen for severe pulmonary disease are excluded from the study.

The use of a cane is allowed in cane dependent patients, but then these patients need to 
use the same cane at every 6MWT test throughout the study. If the need for walking 
aids should arise at the baseline visit, the same walking aids should also be used at 
every subsequent test.

If a supplemental oxygen therapy should be implemented already at baseline, all 
subsequent 6MWT tests have to be performed under the same “baseline” conditions 
(same flow of oxygen, same application route, and same way of carrying the oxygen 
bottle).

Even if a supplemental oxygen therapy is implemented or modified during the trial 
(e.g. increase of oxygen flow), it is not permitted to perform the subsequent 6MWT
tests under conditions other than the baseline conditions.
However, a change of test conditions should be avoided, if reasonably possible at least after 
baseline, to have the same conditions in all 6MWT tests. For quality reasons, the inhalation of 
supplemental oxygen and the use of walking aids during the 6MWT tests must be documented 
in the eCRF.
16.2
Appendix 2: Borg CR 10 scale and test instructions
Use this rating scale to report how strong your perception of exertion is. First look at the 
verbal expressions. Start with them and then the numbers. Of these ten (10) or “Extremely 
strong – Maximal” is a very important intensity level. This is the most intense perception or 
feeling you have ever had. 
If your experience or feeling is “Very weak”, you should say “1”, if it is “Moderate”, say “3”. 
Note that “Moderate” is “3” and thus weaker than “Medium”, “Mean” or “Middle”. If the 
experience is “Strong” or “Heavy” (it feels “Difficult”) say “5”. Note that “Strong” is about 
half of “Maximal”. Is your feeling “Very strong”, choose a number from 6 to 8. If your 
perception or feeling is stronger than “10”, “Extremely strong – Maximal” you can use a 
larger number, e.g. 12 (that’s why “Absolute maximum” is marked with a dot “●”). It is very 
important that you report what you actually experience or feel, not what you think you should 
report. Be as spontaneous and honest as possible and try to avoid under- or overestimating. 
Look at the verbal descriptors and then choose a number. 
When rating your exertion give a number (in principle any kind of decimal number is 
allowed) that corresponds to how hard and strenuous you perceive the work to be. The 
perception of exertion is mainly felt as strain and fatigue in your muscles and as 
breathlessness or any aches.


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0 
“Nothing at all”, means that you don’t feel any exertion whatsoever, no muscle 
fatigue, no breathlessness or difficulties breathing.
0.3
0.5 
“Extremely weak”, “Just noticeable”
0.7
1 
“Very weak” means a very light exertion. As taking a shorter walk at your own pace.
1.5
2 
“Weak”, “Light”
2.5
3 
“Moderate” is somewhat but not especially hard. It feels good and not difficult to go 
on
4
5 
“Strong – Heavy”. The work is hard and tiring, but continuing isn't terribly difficult.
The effort and exertion is about half as intense as “Maximal”.
6
7 
“Very strong” is quite strenuous. You can still go on, but you really have to push 
yourself and you are very tired.
8
9
10 
“Extremely strong – Maximal” is an extremely strenuous level. For most people this is 
the most strenuous exertion they have ever experienced previously in their lives.
11
⸗
● Is “Absolute maximum – Highest possible” for example “12” or even more.

SAP_001.pdf: 
 
Document Type: 
Study Analysis Plan 
Official Title: 
A randomized parallel-group, placebo-controlled, double-blind, 
multi-center trial to evaluate the efficacy and safety of the oral sGC 
stimulator vericiguat to improve physical functioning in activities of 
daily living in patients with heart failure and preserved ejection 
fraction (VITALITY-HFpEF) 
NCT Number: 
NCT03547583 
Document Date: 
21-Nov-2019 
 


Statistical Analysis Plan
Protocol No.: BAY 1021189 /19334
Page:
1
of
40
Reference Number: RD-OI-0119
Supplement Version: 9.0
Title Page
A randomized parallel-group, placebo-controlled, double-blind, multi-center 
trial to eValuate the effIcacy and safeTy of the orAL sGC stImulator 
vericiguaT to improve phYsical functioning in activities of daily living in 
patients with heart failure and preserved ejection fraction (VITALITY-
HFpEF) 
Bayer study drug
BAY 1021189 / Vericiguat / sGC stimulator vericiguat
Study purpose:
efficacy, safety, pharmacokinetics
Clinical study 
phase:
2b
Date:
21 NOV 2019
Study No.:
19334
Version:
2.0
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 1021189 /19334
Page:
2
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Reference Number: RD-OI-0119
Supplement Version: 9.0
Table of Contents
Title Page................................................................................................................................... 1
Table of Contents ..................................................................................................................... 2
List of Tables............................................................................................................................. 3
List of Figures........................................................................................................................... 3
Abbreviations............................................................................................................................ 4
1.
Introduction....................................................................................................................... 6
2.
Study Objectives................................................................................................................ 7
3.
Study Design ...................................................................................................................... 9
4.
General Statistical Considerations ................................................................................ 11
4.1
General Principles.......................................................................................................... 11
4.2
Handling of Missing Data.............................................................................................. 12
4.3
Interim Analyses and Data Monitoring ......................................................................... 12
4.3.1
Futility interim analysis.............................................................................................. 13
4.3.2
Anchor-based analysis and responder definitions ...................................................... 14
4.4
Data Rules...................................................................................................................... 17
4.4.1
Compliance................................................................................................................. 17
4.4.2
Baseline and Change from Baseline........................................................................... 17
4.4.3
Laboratory Data Handling.......................................................................................... 18
4.4.4
Subgroup analyses ...................................................................................................... 18
5.
Analysis Sets .................................................................................................................... 19
5.1
Assignment of analysis sets ........................................................................................... 19
5.1.1
Full analysis set (FAS) ............................................................................................... 19
5.1.2
FAS (KCCQ).............................................................................................................. 19
5.1.3
FAS (6MWT) ............................................................................................................. 19
5.1.4
Pre-specified supportive efficacy analysis set (PEAS)............................................... 19
5.1.5
Safety analysis set (SAF)............................................................................................ 20
5.1.6
Per protocol set (PPS)................................................................................................. 20
5.1.7
Pharmacokinetics analysis set (PKS) ......................................................................... 20
5.1.8
Validity Review.......................................................................................................... 20
6.
Statistical Methodology .................................................................................................. 20
6.1
Population characteristics .............................................................................................. 20
6.1.1
Disposition.................................................................................................................. 20
6.1.2
Demography and Baseline Characteristics................................................................. 21
6.1.3
Protocol deviations ..................................................................................................... 22
6.1.4
Medical History.......................................................................................................... 22
6.1.5
Concomitant Medication ............................................................................................ 22


Statistical Analysis Plan
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Reference Number: RD-OI-0119
Supplement Version: 9.0
6.1.6
Treatment Duration and Exposure.............................................................................. 24
6.1.7
Treatment Compliance ............................................................................................... 24
6.1.8
Completer definition................................................................................................... 25
6.2
Efficacy.......................................................................................................................... 25
6.2.1
Patient Reported Outcomes ........................................................................................ 25
6.2.2
Clinician Reported Outcomes..................................................................................... 27
6.2.3
Primary efficacy variable............................................................................................ 28
6.2.4
Secondary efficacy variable........................................................................................ 30
6.2.5
Multiplicity adjustment .............................................................................................. 31
6.2.6
Other KCCQ domains ................................................................................................ 32
6.2.7
EQ-5D-5L................................................................................................................... 32
6.2.8
Fried frailty score........................................................................................................ 32
6.2.9
Clinical outcome events.............................................................................................. 32
6.2.10
NYHA Class............................................................................................................... 33
6.2.11
PGIC and PGIS........................................................................................................... 33
6.3
Safety ............................................................................................................................. 33
6.3.1
Adverse events............................................................................................................ 33
6.3.2
Adverse events of special safety interest.................................................................... 34
6.3.3
Further safety parameters ........................................................................................... 34
7.
Document history and changes in the planned statistical analysis............................. 35
7.1
Document history........................................................................................................... 35
7.1.1
Changes from the protocol ......................................................................................... 35
8.
References ........................................................................................................................ 36
9.
Appendix.......................................................................................................................... 38
9.1
Pattern-mixture modeling approach............................................................................... 38
9.2
Tipping point analysis approach .................................................................................... 39
9.3
Region Definition .......................................................................................................... 39
List of Tables
Table 4-1: Visit windows for KCCQ ....................................................................................... 12
Table 4-2: Operating characteristics for futility boundaries .................................................... 13
Table 6-1: Equivalence doses for different diuretics ............................................................... 24
List of Figures
Figure 3-1 Study design ............................................................................................................. 9
Figure 6-1 α-allocation for the primary and secondary hypotheses......................................... 31


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Abbreviations
ACE
Angiotensin converting enzyme
ACIR
Assessment Criteria Identification Requirement
AE
Adverse event
ALT
Alanine aminotransferase
AN(C)OVA
Analysis of (Co-)Variance
ARB
Angiotensin receptor blocker
ATC
Anatomical Therapeutic Chemical
BMI
Body mass index
CAD
Coronary artery disease
CDF
Cumulative distribution function
cGMP
Cyclic guanosine monophosphate
CKD
Chronic kidney disease
COPD
Chronic obstructive pulmonary disease
CSR
Clinical Study Report
CSS
Clinical Summary Score
CV
Cardiovascular
DSMC
Data Safety Monitoring Committee
DBP
Diastolic blood pressure
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EF
Ejection fraction
eGFR
Estimated glomerular filtration rate
e.g.
exempli gratia, for example
FAS
Full analysis set
GCP
Good Clinical Practice
HEOR
Health Economics, Outcomes & Reimbursement
HF
Heart failure
HFrEF
Heart failure with reduced ejection fraction
HFpEF
Heart failure with preserved ejection fraction
HR
Heart rate
ICH
International Committee on Harmonization
i.e.
id est, that is
IV
Intravenous
KCCQ
Kansas City Cardiomyopathy Questionnaire
LAV
Left atrial volume
LLOQ
Lower limit of quantification
LVEF
Left ventricular ejection fraction
MACE
Major adverse cardiovascular event
MAP
Mean arterial pressure
MAR
Missing at random
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed-effects model for repeated measures
MNAR
Missing not at random
MRA
Mineralocorticoid receptor antagonist
NO
Nitric oxide
NT-proBNP
N-terminal pro-brain natriuretic peptide
NYHA
New York Heart Association
o.d.
omni die, once daily
OSS
Overall Summary Score
PD
Pharmacodynamics


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PDF
PLS
Probability Density Function
Physical Limitation Score
PK
Pharmacokinetics
PKS
Pharmacokinetic analysis set
PP
Pulse pressure
PPS
Per protocol set
PT
Preferred term
QoL
Quality of Life
ROC
Receiver operating characteristics
SAC
Statistical Analysis Center
SAE
Serious adverse event
SAF
Safety analysis set
SAP
Statistical Analysis Plan
SBP
Systolic blood pressure
SFS
Symptom Frequency Score
sGC
Soluble guanylate cyclase
SMQ
Standard MedDRA query
SOC
System organ class
TEAE
Treatment emergent adverse event
TLF
Tables, listings, and figures
TSS
Total Symptom Score
ULN
Upper limit of normal
VAS
Visual analogue scale
WCHF
Worsening chronic heart failure
WHO-DD
World Health Organization Drug Dictionary


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1.
Introduction
Patients hospitalized with heart failure (HF) with preserved ejection fraction (HFpEF) are a 
large and growing population. The relative proportion of HFpEF has increased to more than 
50% of all HF hospitalizations [1]. Event rates after hospitalization in patients with HFpEF 
are as high as in patients with HF with reduced ejection fraction (HFrEF). Since patients with 
HFpEF are highly symptomatic with a poor quality of life, it is important to find new therapies 
that can alleviate symptoms and improve patient well-being [2].
No specific therapy has been currently established for HFpEF patients, and recommendations 
are limited to symptomatic treatment of congestive symptoms by diuretics, and to treating 
causes and comorbidities including hypertension, coronary artery disease, and atrial 
fibrillation [3]. Trials that established the clinical benefits of angiotensin converting enzyme 
(ACE) inhibitors, angiotensin receptor antagonists, and β-blockers have all selected patients 
on the basis of reduced EF. Subsequent trials in patients with HFpEF did not confirm equal 
effectiveness in this subgroup [4]. Therefore, there is need for new drug targets such as cyclic 
guanosine monophosphate (cGMP).
Vericiguat has been evaluated in approximately 65 preclinical studies and has been 
administered to over 500 healthy patients in 19 completed Phase I studies with single- and 
multiple-dose administration, and in approximately 740 heart failure patients in two Phase IIb 
studies (SOCRATES- REDUCED and SOCRATES- PRESERVED) that studied vericiguat in 
worsening chronic heart failure patients with HFrEF and with HFpEF. In the ongoing phase 
III event-driven outcome trial VICTORIA (NCT02861534), as of Aug 31 2018, 3791 patients 
with HFrEF out of a planned total sample size of 4872 have been randomized to vericiguat 10 
mg target dose or placebo with a median study drug treatment duration at that time of 5 
months. The study treatment duration is planned to continue until 2020 for a median follow-
up duration of 18 months.
In SOCRATES-PRESERVED 4 different dose regimens of vericiguat were studied in patients 
with chronic HFpEF enrolled within 1 month after a qualifying heart failure decompensation 
event [5]. Data from SOCRATES-PRESERVED established 2.5 mg vericiguat as the safe and 
well tolerated starting dose. Uptitration by two dose doublings with 14 day intervals each to a 
target dose of 10 mg was tolerated in patients with HFpEF without an increase in adverse 
events compared to placebo, with low discontinuation rates in all groups, and no changes in 
blood pressure at 10 mg compared to placebo. Although analyses of the primary efficacy 
variables in SOCRATES-PRESERVED did not demonstrate changes in NT-proBNP and 
LAV at 12 weeks in the vericiguat dose groups compared to placebo, patients receiving 
vericiguat in the 10 mg target dose arm experienced a more pronounced improvement in 
health related QoL, physical limitations, NYHA class, signs and symptoms of congestion and 
trends towards improved diastolic function at 12 weeks [5,6]. 
The Kansas City Cardiomyopathy Questionnaire (KCCQ) has been widely used in HF trials. 
In SOCRATES-PRESERVED, improvements in the KCCQ overall summary score (OSS) as 
well as the clinical summary score (CSS) were observed. Consistent changes in other domains 
of the KCCQ were also noted. However, the improvement appeared to be driven primarily by 
improvements in the physical limitation score (PLS). KCCQ PLS has previously been 


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validated against the distance covered in a 6MWT, NYHA class, and physical limitation 
domains within other quality of life (QoL) instruments including the 36-Item Short Form 
Survey in patients with HF [7]. Improvements in physical functioning and reduction in 
symptom frequency are considered to be direct measures of treatment benefit in patients with 
HFpEF, and have been shown to be associated with subsequent reductions in mortality and 
hospitalizations [8]. These data generate the hypothesis that vericiguat improves physical 
functioning and clinically relevant patient-reported outcomes in patients with HFpEF. Based 
on these data, the VITALITY phase 2 trial (study 19334) has been designed to study whether 
in patients with HFpEF vericiguat 10 mg or 15 mg improves the KCCQ PLS compared to 
placebo after 24 weeks of treatment.
This statistical analysis plan (SAP) is based on the study protocol (Version 1.0 dated 22 FEB 
2018) and describes the interim and final analyses of study 19334.
2.
Study Objectives
The primary hypothesis is treatment with vericiguat 10 mg or 15 mg in patients with HFpEF
improves physical functioning measured by the KCCQ PLS compared to placebo after 24 
weeks of treatment. The secondary hypothesis is treatment with vericiguat 10 mg or 15 mg in 
patients with HFpEF improves walking distance as measured by the 6MWT compared to 
placebo after 24 weeks of treatment. The study is designed to have enough power for the 
primary and secondary hypotheses testing. Other objectives are listed only for descriptive 
purposes. 
Primary objectives:

To evaluate the efficacy of vericiguat 10 mg in comparison to placebo on improving 
physical functioning as measured by KCCQ PLS from baseline to week 24. 

To evaluate the efficacy of vericiguat 15 mg in comparison to placebo on improving 
physical functioning as measured by KCCQ PLS from baseline to week 24. 

To evaluate the safety and tolerability of vericiguat. 
Secondary objectives:

To evaluate the efficacy of vericiguat 10 mg in comparison to placebo on improving 
distance traveled on a 6MWT from baseline to week 24. 

To evaluate the efficacy of vericiguat 15 mg in comparison to placebo on improving 
distance traveled on a 6MWT from baseline to week 24.

To evaluate the efficacy of vericiguat 10 mg in comparison to placebo in increasing 
the proportion of patients with KCCQ PLS improvement from baseline by >5 points at 
24 weeks and other thresholds (e.g. >3, >7, >10, >15, >20), and the proportions with 
these improvements in the other KCCQ domains OSS, CSS, TSS and SFS.


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
To evaluate the efficacy of vericiguat 15 mg in comparison to placebo in increasing 
the proportion of patients with KCCQ PLS improvement from baseline by >5 points at 
24 weeks and other thresholds (e.g. >3, >7, >10, >15, >20), and the proportions with 
these improvements in the other KCCQ domains OSS, CSS, TSS and SFS.

To evaluate the efficacy of vericiguat 10 mg in comparison to placebo in decreasing 
the proportion of patients with KCCQ PLS decline from baseline by >5 points at 
24 weeks and the proportions with decline in the other KCCQ domains OSS, CSS, 
TSS and SFS.

To evaluate the efficacy of vericiguat 15 mg in comparison to placebo in decreasing 
the proportion of patients with KCCQ PLS decline from baseline by >5 points at 
24 weeks and the proportions with decline in the other KCCQ domains OSS, CSS, 
TSS and SFS.
Other objectives:

To evaluate the efficacy of vericiguat 10 mg and the efficacy of vericiguat 15 mg in 
comparison to placebo on improving:
o
Symptom frequency as measured by the KCCQ SFS 
o
Perceived exertion experienced by patients during 6MWT as measured by 
Borg CR 10.
o
Other patient-reported outcomes such as the generic health-related quality of 
life measure EQ-5D-5L and the Fried-based frailty score
o
NYHA class
o
Laboratory variables such as NT-proBNP from baseline to 24 weeks

To collect and summarize death including cardiovascular death and CV 
hospitalizations including heart failure hospitalizations, MI and stroke, and outpatient 
HF events. 

To create the cumulative distribution function of KCCQ PLS, OSS, CSS, TSS and 
SFS change from baseline to 24 weeks. 

To evaluate PK of vericiguat in patients with HFpEF, and

To evaluate the concentration-QTc relationship of vericiguat at the 15 mg dose level.

Optional pharmacogenetic research: To explore the relationship between genetic 
variation and clinical characteristics of patients, independent and dependent of the 
treatment administered. Variations across the human genome may be analyzed for 
association with clinical data collected in this study.

To evaluate further biomarkers to investigate the drug (i.e. mode-of-action-related 
effect and / or safety) and / or the mechanisms of the disease


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
Optional accelerometry substudy: to collect exploratory data by activity tracking
Note: Analyses for PK, biomarker, and optional objectives (including accelerometry) will be 
specified in a separate supplementary SAP. 
3.
Study Design
This is a randomized, parallel-group, placebo-controlled, double-blind, multi-center trial of 
vericiguat in patients with HFpEF to be conducted in conformance with GCP. Approximately 
735 patients will be randomized as described in Figure 3-1 to evaluate the efficacy of 
vericiguat 10 mg and 15 mg in comparison to placebo on improving physical functioning 
from baseline to week 24. To reduce heterogeneity in the studied population patients younger 
than 45 years of age are not eligible. Patients are expected to be on a background treatment 
for concurrent conditions including hypertension (anti-hypertensives) and volume overload
(diuretics). 
Screening may be initiated any time after admission of a patient to the hospital for HF, before 
or after discharge, and up to 6 months after hospitalization for HF. Use of IV diuret ic 
treatment for HF, even without hospitalization, is indicative of HF decompensation and 
accepted as a qualifying HF event equivalent to hospitalization. The most recent 
decompensation should be considered for qualifying the patient for the study. In either 
scenario, HF must be the primary reason for hospitalization or IV diuretic treatment. Patients 
will be randomized within up to 4 weeks after the screening visit and within up to 6 months 
after the onset of the qualifying event of hospitalization for HF or treatment with IV diuretic 
for HF (see Figure 3-1). 
Primary endpoint assessment is at week 24. All patients will be followed until study 
completion to assess for vital status and all study endpoints until week 28.
Figure 3-1 Study design


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EF, ejection fraction; FU, follow-up; HF, heart failure; KCCQ, Kansas City Cardiomyopathy 
Questionnaire; LAE, left atrial enlargement; LVH, left ventricular hypertrophy; NT-proBNP, N-terminal 
pro-brain natriuretic peptide; NYHA, New York Heart Association; PLS, physical limitation score; 
V, Visit. KCCQ as the entire questionnaire is administered, not just the PLS domain.
Stratification
Patients will be randomized within 4 weeks of the screening visit and within up to 6 months 
after the date of hospitalization for HF or treatment with IV diuretic for HF, and 
randomization will be stratified according to region and heart rhythm at baseline ECG.
Region

Americas

Europe (incl. Israel and South Africa)

Asia/Pacific 
Heart rhythm

Atrial fibrillation (defined as atrial fibrillation or atrial flutter in baseline ECG)

Sinus rhythm (defined as no atrial fibrillation and no atrial flutter in baseline 
ECG)
Treatment
Patients will be randomized 1:1:1 within 4 weeks after the Screening Visit to either:
1.
Placebo arm: placebo and sham up-titration at weeks 2, 4, and 6
2.
10 mg arm: vericiguat, which will be started at 2.5 mg at randomization and up-titrated to 
5 mg at week 2, and to 10 mg at week 4, with sham titration at week 6. 
3.
15 mg arm: vericiguat, which will be started at 2.5 mg at randomization and up-titrated to 
5 mg at week 2, to 10 mg at week 4, and to 15 mg at week 6.
Withdrawal from study
Unnecessary withdrawal of patients from the study follow-up should be avoided and all 
efforts should be taken to motivate patients to adhere to all study procedures and to be 
followed until the end of the trial. All patients will be followed until study completion to 
assess for vital status and all study endpoints until week 28.
The investigator should explore all possible options to reach a patient who fails to return to a 
visit or to respond to the site contact attempts. 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 


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efforts should therefore be made to discuss solutions with the patient that would enable the 
patient to continue with follow-up in order to minimize the number of patients who withdraw 
such consent. The vital status will be collected for all randomized patients who have not 
specifically withdrawn consent for further study follow-up by any method (telephone call, 
email etc.), irrespective of completion of study procedures.
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 
been reached in all centers in all participating countries (EU and non-EU).
4.
General Statistical Considerations
4.1
General Principles
The statistical analyses will be performed using the software package SAS release 9.2 or 
higher (SAS Institute Inc., Cary, NC, USA) [9].
All variables will be analyzed by descriptive statistical methods.  For continuous data, the 
summary statistics including mean, standard deviation, minimum, median, quartiles, and 
maximum, and the number of missing data will be provided.  For categorical data, frequency 
count and percentages will be generated. 
All patients will be analyzed according to the assigned treatment group if not specified 
otherwise.  Each treatment group will comprise all patients within one randomized titration 
scheme regardless of the individual subject’s actual titration, i.e. in case a subject could not be 
uptitrated or was down-titrated during the study.  
On treatment
A measurement is considered to be "on-treatment," if it was taken during treatment or up to 5 
days after end of treatment with study medication.
Analysis time point and visit window
Based on the randomization date, each scheduled visit date will be computed and a midpoint 
between two adjacent scheduled visit dates will be identified as the boundary of two visit 
windows. For example, Day 28 will be used to label the boundary between week 2 and week 
6 windows. Table 4-1 shows an example of the visit window for each analysis time point for 
KCCQ. Each visit date will be mapped to one visit window. For any particular window, if 
there are multiple measurements within the window then the one that is closest to the 
scheduled visit date will be used. In case there are multiple measurements on the same day, 
the latest one will be selected. Also note that the baseline is defined as the last non-missing 
measurement before first intake of study treatment (Section 4.4.2). In case KCCQ assessments 
may simultaneously be considered as baseline and follow up, for example if a patient takes 
first study treatment 14 days after randomization, under such scenario these measurements 
will be assigned as baseline only.


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Table 4-1: Visit windows for KCCQ
Analysis time point
Scheduled visit date
Scheduled visit window
Baseline
Day 1
Day 1
Week 2
Day 14
Day 2 – Day 27
Week 6
Day 42
Day 28 – Day 62
Week 12
Day 84
Day 63 – Day 104
Week 18
Day 126
Day 105 – Day 146
Week 24
Day 168
Day 147 – Day 181
Safety follow-up*
Day 196
Day 182 – Day 209
*If patients have completed all scheduled doses. In case of premature discontinuation, safety 
follow-up will be scheduled at 28 ± 7 days after the last dose, and the visit window will span 
from two weeks before the scheduled safety follow-up visit to two weeks after.
4.2
Handling of Missing Data
All missing or partial data will be presented in the subject data listings as they are recorded on 
the electronic Case Report Form (eCRF) or electronic PRO diary (ePRO).
For missing components in KCCQ domains, the algorithm for score calculation will follow 
the KCCQ scoring instructions [10]. For example in the PLS domain, if a patient answers 
“Limited for other reasons or did not do the activity”, the response will be considered as 
missing. KCCQ scoring instructions specify that at least 3 out of 6 non-missing components 
are needed for the domain to be evaluable.
Non-evaluable domains will be treated the same way as missing domains and will be handled 
based on missing data imputation rules specified in Appendix 9.1.  
4.3
Interim Analyses and Data Monitoring
An independent Data Safety Monitoring Committee (DSMC) has been established for this 
study. The DSMC will review safety and tolerability regularly, and conduct the futility 
interim analysis during the course of the study. Members of the DSMC will receive unblinded 
safety data. The involvement of an external Statistical Analysis Center in this process will 
ensure that unblinded information is not available to anyone except the DSMC. The study 
team and study committees (steering committee and the PRO sub-committee, see below) will 
be kept blinded in this process.  There are no predefined stopping conditions for the ongoing 
safety monitoring of this trial. However, the DSMC may recommend termination, temporary 
suspension of the study, and intervention of treatment arm or modification of the study. 
Details on DSMC responsibilities and decisions, as well as a detailed plan for DSMC
meetings will be described in the DSMC Charter.
A sub-committee of the study steering committee will be focused on PROs (called PRO sub-
committee The PRO sub-committee is made up of an additional panel of experts in the field
acting in support of the steering committee. Steering committee and PRO sub-committee will 
review and monitor the blinded PRO data regularly to ensure data quality and completeness.
The PRO sub-committee will also contribute to the interpretation of the analyses to evaluate 
important within patient change which will be used to determine the responder definitions for 


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the KCCQ-PLS. Details on PRO sub-committee membership, roles, responsibilities and 
operational aspects will be described in the PRO sub-committee charter.
4.3.1
Futility interim analysis
A single interim assessment by the DSMC to evaluate futility is planned for when 50% of the 
patients complete Visit 7 (week 12) and their KCCQ data become available. Although the 
effects of 24 weeks of treatment with vericiguat have not been evaluated in patients with 
HFpEF, prior data in this population suggest that the 12 week timepoint will be sufficiently 
predictive of the 24 week data to allow for an adequate interim assessment of efficacy. 
Furthermore, in view of the expected timeline for patient recruitment, a sufficiently large 
proportion of data at the 24 week timepoint will only become available shortly before 
completion of the trial. Based on the operating characteristics of a range of futility criteria
(Table 4-2), an observed mean treatment effect of 0.6 point difference in KCCQ PLS 
(vericiguat vs placebo) was chosen to serve as the boundary for futility for both dose groups; 
this is approximately equivalent to a joint conditional power (CP) of 23% at week 24 (under 
the assumption of a true difference of 5 points and a SD of 21 points).
Table 4-2: Operating characteristics for futility boundaries
Equivalent 
treatment 
effect 
boundary 
(points)
Conditional 
power [1]
Joint 
conditional 
power 
[2]
Probability of meeting 
futility criterion
(Observed treatment 
difference < boundary for 
both arms)
Joint probability [3]
of observing a >7/5/3 
point treatment effect  
on any dose at final 
analysis
True effect 
= 0
True effect 
= 5
1.2
20%
31%
53%
2.5%
0.004 / 0.134 / 0.696
0.7
15%
24%
44%
1.4%
0 / 0.095 / 0.621
0.6
14%
23%
43%
1.3%
0 / 0.089 / 0.605
0.5
13%
21%
40%
1.1%
0 / 0.082 / 0.590
0.4
12%
20%
38%
1.0%
0 / 0.077 / 0.574
0
10%
16%
34%
0.7%
0 / 0.056 / 0.509
[1] Probability of rejecting any individual hypothesis at the end of the study based on 
observed interim value (under the assumption of a true difference of 5 points).
[2] Joint probability of rejecting at least one of the hypotheses at the end of the study based 
on observed interim value (under the assumption of a true difference of 5 points).
[3] Joint probability of observing a treatment effect larger than certain threshold in either of 
the comparisons at the end of the study based on observed interim value (under the 
assumption of a true difference of 5 points).


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An observed mean treatment effect <0.6 in both comparisons (vericiguat 10 mg vs. placebo 
and vericiguat 15 mg vs. placebo) would therefore signal to the DSMC to consider their non-
binding 
recommendation that the trial should be terminated early. Assuming the true 
treatment effect is a 5-point difference, as expected, the probability of stopping at the interim 
is approximately 1.3%. Under the null hypothesis, i.e., assuming 0 treatment effect for both 
vericiguat vs. placebo comparisons, the probability of stopping at the interim for futility is 
approximately 43%. If only one arm is futile then it will not be dropped as enrollment is 
expected to be almost completed at the time of the futility analysis. Stopping for futility will 
only be done if both arms meet the futility criterion.  Under this observed interim value (0.6 
point difference) and assuming the alternative hypothesis is true, the trial has a probability of 
8.9% to observe a >5 point improvement and a probability of 60.5% to observe a >3 point 
mean improvement in either of the comparisons in KCCQ PLS at week 24. Details of the 
futility interim analysis will be specified in the DSMC charter. No formal interim report will 
be written.
4.3.2
Anchor-based analysis and responder definitions
The main analyses to aid the interpretation and definition of a responder threshold for the 
KCCQ PLS change scores will be based on an anchor-based approach by categorizing 
patients according to their responses from baseline to Visit 7 (week 12) to the Patient Global 
Impression of Change (PGIC) (see Section 6.2.1).  A responder definition represents the 
threshold for meaningful within-patient change,  and it can be used to categorize patients as 
responders or non-responders based on the KCCQ PLS scores.
Supportive anchor-based analyses will be conducted by categorizing patients according to 
their change in Patient Global Impression of Severity (PGIS) (see Section 6.2.1) responses
from baseline to Visit 7 (week 12) (e.g. unchanged, improved by 1 response category, 
deteriorated by 1 response category, etc.) and additionally, change in PGIS response between 
week 18 and 24 (when more subjects are expected to rate themselves in the same severity 
category).  In addition to anchor-based approaches, supportive distribution-based approaches 
will also be used, i.e. 0.5 standard deviation and standard error of measurement (SEM). These 
methods provide an indication of the smallest score that would exceed measurement error.
Graphical displays via empirical cumulative distribution function (CDF) and probability 
density function (PDF), receiver operating characteristics (ROC) and non-parametric 
discriminant analyses will also be created to support the above estimations.
These analyses will serve to support the interpretation of study results relative to thresholds 
for meaningful within-patient change in addition to the established thresholds of clinically 
meaningful between group changes for the KCCQ PLS [11,12,13]. They will be performed on 
blinded data, with all treatments combined, from an interim dataset prior to study unblinding. 
These analyses are planned for when 100% of the patients complete Visit 7 (week 12) and 
their KCCQ data become available. Only patients with actual data (not imputed data) on the 
KCCQ PLS, PGIC, PGIS at baseline and the relevant post-baseline date (collected on the 
same day) will be included. The blinded analysis results will be reviewed by the PRO sub-
committee which will propose an appropriate responder definition estimate for within-patient 


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improvement and/or worsening in KCCQ PLS scores. Correlations between KCCQ-PLS and 
anchors will be calculated to assess the level of confidence in the interpretation of results. 
Correlations >0.35 are generally considered acceptable, and confidence in an individual 
analysis is increased between KCCQ-PLS and the anchor if the correlation is moderate to 
strong (0.4 – 0.6) [11].    
Anchor-based approach
The anchor-based approach will be applied by categorizing patients according to their 
responses to the PGIC questions at Visit 7 (week 12).  
The PGIC contains two questions (i.e. Q1 and Q1a or Q1b): 
1. Compared to the start of your treatment, how would you describe your physical limitations 
due to heart failure today? 
o
Response options: “Much better”, “Better”, “A little better”, “The same”, “A
little worse”, “Worse”, or “Much worse”; 

If a subject responds “Much better”, “Better”, or “A little better”, then he/she is asked:
o
1a. Was this improvement in your physical limitations an important change for 
you?
o
Response options: “Yes”, “No”.

If a subject responds “Much worse”, “Worse”, or “A little worse”, then he/she is 
asked:
o
1b. Was this worsening in your physical limitations an important change for 
you (by important we mean did it bother you)?
o
Response options: “Yes”, “No”.
Patients will be categorized according to their responses to the PGIC as follows:

Group 1: Patients who report “A little better” to PGIC #1 as well as “Yes” to 1a;

Group 2: Patients who report “A little worse” to PGIC #1 as well as ‘Yes’ to 1b
KCCQ PLS Mean (SD) change scores from baseline to Visit 7 (week 12) will be calculated 
for each group above to estimate a meaningful within-patient threshold. 
KCCQ PLS mean (SD) change scores from baseline to Visit 7 (week 12) will also be 
calculated for the all PGIC response categories separately, to assess trends in change scores. 
In addition, KCCQ PLS mean (SD) change scores from baseline to Visit 7 (week 12) will be 
calculated  by overall improvement or  worsening in PGIC response categories. 
Distribution-based approaches
Distribution-based approaches will also be performed to supplement the anchor-based 
approaches. These will be based on 0.5 SD and standard error of measurement (SEM) of the 
KCCQ-PLS at baseline. The SEM is calculated as the standard deviation at baseline 
multiplied by the square root of one minus the reliability of the instrument [SD * (2(1-r))1/2 ].  


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The reliability coefficient will be estimated by calculating correlation (Intraclass Correlation 
Coefficient; ICC [14, 15]) between the baseline and Week 6 KCCQ-PLS scores among stable 
patients. Stable patients will be defined as patients who respond ‘the same’ to the PGIC at 
Week 6. KCCQ-PLS mean scores for baseline and week 6, and differences between the two 
assessments and respective standard deviations will be reported for this stable subgroup. 
Empirical Cumulative Distribution Function (CDF) and Probability Density Function 
(PDF)
Empirical cumulative distribution functions of the change from baseline in KCCQ-PLS scores 
for each PGIC anchor category will be created to show the distribution of change scores 
among subjects who experienced different levels of change. Examining the distribution of 
change scores via empirical cumulative distribution function (CDF) and probability density 
function (PDF) plots provides supporting evidence for the chosen responder threshold [16].
Receiver Operating Curves (ROC) 
ROC curves will be used to assess the ability of change in KCCQ PLS to discriminate 
between patients responding  “a little better” with “yes” to PCIG question 1a, “better” or 
“much better” on the PGIC question at Visit 7 (week 12) and those with other responses.  The 
point(s) on the curve that optimizes sensitivity and/or specificity will be considered the 
optimal threshold in differentiating between the two groups.
Non-Parametric Discriminant Analysis
Non-parametric discriminant analysis will be conducted to explore the responder definitions 
[17] further. Given sufficient sample size (at least 20 patients in each of the response groups:
Patients who report “A little better” to PGIC #1 as well as “Yes” to 1a; or “A little worse” to 
PGIC #1 as well as “Yes” to 1b; or “The same” to PGIC #1), the KCCQ PLS score density
curve will be estimated for each group and the intersection points of these density curves will 
be considered as the discrimination points. The discrimination point between the two groups
“A little better” with response “Yes” to 1a and “The same” is considered to be an estimate of 
the responder definition for improvement. Similarly, the estimate of the responder definition 
for worsening is calculated based on those who report “A little worse” with response “Yes” to 
1b and “The same” to PGIC #1. In case there is not sufficient sample size in each group, 
patients who respond “A little better”, “Better” or “Much better” will be aggregated to the 
new category “Improved”. Patients who respond “A little worse”, “Worse” or “Much worse” 
will be combined into the new category “Worsened”. Discriminant point analysis will be 
performed based on these new categories in a similar way.  
4.3.2.1
Updates from FDA Type C meeting
The proposed KCCQ-PLS thresholds for meaningful within-patient changes determined 
during the interim and blinded dataset analysis of 8.33 and 12.5 for improvement and -4.17 
for worsening will be added to the pre-specified thresholds (e.g. >3, >7, >10, >15, >20) for 
exploratory responder analysis already included in the SAP version 1.0. Following an FDA 
request made during the Type C meeting held on 6th November 2019, the anchor-based 
analysis will be additionally run on the full trial dataset prior to unblinding to further inform 
interpretation of the primary endpoint of KCCQ-PLS change from baseline to week 24. 


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Supportive analyses, including distributional-based approaches, receiver-operating 
characteristic curves and non-parametric discriminant methods will not be re-evaluated on the 
full trial dataset prior to unblinding.
4.4 Data Rules
4.4.1
Compliance
The patient drug intake compliance is calculated as percent of planned tablet intake: 
100 * Number of taken tablets / Number of planned tablets. 
The number of planned tablets is calculated as: Treatment duration (days) * Number of 
planned tablets per day. The number of planned tablets per day is two.
To derive treatment duration, the start and stop dates of tablet intake are derived from the 
collected study treatment exposure (dataset EX).  The number of taken tablets is derived from 
the drug accountability (dataset DA). 
For patients who withdraw prematurely from the study treatment, compliance will be 
calculated up to the time of last dose.
4.4.1.1
Imputation rules for partially missing end dates for study medication 
In case of (partially) missing end dates for study medication intake the following approach 
will be applied to impute end of study medication intake:

In case the subject stopped treatment due to death: impute partially missing end dates 
by the 'maximum study medication end date' defined as the maximal possible date (i.e. 
last month of the year, and last day of the month, respectively). Take the minimum of 
death date and, if available, imputed maximum study medication end date as the 
imputed study medication end date.

In case the subject completed treatment or stopped due to reasons other than death: 
impute partially missing end dates by the 'minimum study medication end date' 
defined as the minimal possible date (i.e. first day of month and first month of year, 
respectively). Take the maximum of the last available study medication intake date 
(i.e. largest non-missing study medication start or stop date) and, if available, imputed 
minimum study medication end date as the imputed study medication end date.
4.4.2
Baseline and Change from Baseline
Baseline is defined as the last non-missing measurement before or on randomization date. If 
more than one measurement was taken for a scheduled time point (i.e. blood pressure 
measurements and heart rate), the average value is used
Change from baseline will be displayed as the difference to baseline defined as:
Change = Post baseline value – baseline value.


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4.4.2.1
Vital Signs
Three measurements of vital signs parameters will be taken at time intervals of about 2 
minutes.  Averages of non-missing values of these three measurements will be calculated and 
used for the statistical analysis.  If only one of the planned measurements is available, this 
value will be used.
4.4.3
Laboratory Data Handling
Only the data provided by the central laboratory will be used for analysis, values from local 
laboratories will not be used.  
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 below the LLOQ will be 
assigned values of 0. 
4.4.4
Subgroup analyses
The following subgroups will be considered for descriptive and exploratory analyses. To 
determine whether the treatment effect is consistent across various subgroups, the estimate of 
the between-group treatment effect (with a nominal 95% CI) for the primary endpoint will be 
estimated and plotted within each category of the following classification variables in all 
subjects:

Gender: Male, Female

Region:
o
Americas
o
Europe (incl. Israel and South Africa)
o
Asia/Pacific 

Heart rhythm: Atrial fibrillation (defined as atrial fibrillation or atrial flutter in 
baseline ECG), Sinus rhythm (defined as no atrial fibrillation and no atrial flutter in 
baseline ECG)

Randomization time: 
o
Before discharge from HF hospitalization 
o
After discharge from HF hospitalization
o
Post IV diuretic treatment without hospitalization

Time from qualifying event (HF hospitalization or IV diuretic) to randomization: <3 
month, ≥3 month

Baseline Body Mass Index (BMI; kg/m2): ≤30, >30

Baseline Estimated Glomerular Filtration Rate (eGFR; mL/min/1.73m2): ≤60, >60 

Diabetes: Yes, No


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
COPD: Yes, No

Anemia: Yes, No

NYHA class: II, III

Baseline KCCQ-PLS: <45, 45 – <75, ≥75

Baseline subgroups defined by combined KCCQ-PLS and NYHA class criteria, as 
follows: KCCQ-PLS <65 and NYHA II; KCCQ-PLS <65 and NYHA III; KCCQ-PLS 
≥65 and NYHA II; KCCQ-PLS ≥65 and NYHA III
5.
Analysis Sets
5.1
Assignment of analysis sets
Final decisions regarding the assignment of patients to analysis sets will be made during the 
validity meeting (see Section 5.1.8).
Data from all patients who signed informed consent, regardless of their assignment to certain 
analysis sets, will be presented in individual subject data listings.  In addition, t he following 
analysis sets will be used for this study:
5.1.1
Full analysis set (FAS)
All patients randomized  will be valid for the FAS. The patients will be analyzed based on the 
planned treatment. The population characteristics (such as disposition, demographic and 
baseline characteristics etc.) will be based on FAS.
5.1.2
FAS (KCCQ)
All patients randomized and treated (at least one dose of the study treatment), and have at 
least one observed KCCQ-PLS assessment at both baseline and post-baseline (excluding 
safety follow-up), will be valid for this analysis set. The primary analysis for the primary 
efficacy endpoint will be based on FAS (KCCQ).
5.1.3
FAS (6MWT)
All patients randomized and treated (at least one dose of the study treatment), and who are 
able to perform at least one 6MWT assessment at both baseline and post-baseline (excluding 
safety follow-up), will be valid for this analysis set. The primary analysis for the secondary 
efficacy endpoint will be based on FAS (6MWT).
5.1.4
Pre-specified supportive efficacy analysis set (PEAS)
All patients randomized and treated (at least one dose of the study treatment), and have at 
least one observed KCCQ-PLS assessment at both baseline and post-baseline (excluding 
safety follow-up), excluding those with no physical limitation at baseline (baseline KCCQ 
PLS = 100 or baseline PGIS as “no limitation”), will be valid for this supportive efficacy
analysis set. The primary efficacy analysis will be repeated on PEAS as a supportive analysis.


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5.1.5
Safety analysis set (SAF)
All patients that received at least one dose of study treatment (vericiguat or placebo). 
Analyses will be based on actual treatment received, and patients who received both 
vericiguat and placebo by mistake will be assigned to the planned treatment. All safety 
analyses will be based on the SAF.
5.1.6
Per protocol set (PPS)
All patients who meet the major inclusion and exclusion criteria at randomization that may 
affect efficacy, who are not taking excluded concomitant medications during the study that 
could have an effect on efficacy, have the KCCQ assessed at baseline and at least once during 
the treatment phase and who are at least 80% compliant with study medication and show no 
major protocol deviations. The PPS will only be used in the supportive analysis. 
Major protocol deviations leading to exclusion from PPS include:

Overall compliance with study treatment intake of <80% or >120%.

Study medication was interrupted for more than 10 consecutive days

No history of chronic heart failure.
A complete list of all validity findings and important protocol deviations leading to exclusion 
from the PPS will be specified in the Assessment Criteria Identification Requirement (ACIR).  
5.1.7
Pharmacokinetics analysis set (PKS)
All patients with at least one valid pharmacokinetic concentration will be included in the 
statistical evaluation of pharmacokinetics.
5.1.8
Validity Review
A validity meeting will be held before final database closure where subject validity for the 
individual analysis sets will be decided. The results of the validity meeting will be
documented and may comprise decisions and details relevant for statistical evaluation.  Any 
changes to the statistical analysis prompted by the results of the validity review meeting will 
be documented in an amendment or in a supplement to this SAP, as applicable.
6.
Statistical Methodology
6.1
Population characteristics
Population characteristics will be summarized overall and by treatment group. Analyses will 
be performed in the FAS unless otherwise noted.
6.1.1
Disposition
The number of patients enrolled, randomized, and valid for the FAS, FAS-KCCQ, FAS-
6MWT, SAF, PPS and PKS will be summarized overall and by treatment groups.  The 
number of patients discontinuing the screening phase together with the primary reason for 
discontinuation will be presented.  The number of patients discontinuing the treatment and 


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follow-up phases together with the primary reason for discontinuation will be presented by 
treatment groups and overall in separate tables.  
6.1.2
Demography and Baseline Characteristics
Demographic variables and baseline characteristics will be summarized by treatment group 
and overall. Summary statistics will be presented for metric variables. Frequency tables will 
be presented for categorical variables. 
Demography includes age, gender, race, ethnicity, region, body height, body weight, body 
mass index (BMI), smoking history, and alcohol consumption. Age and BMI will each be 
given as continuous variable and categorized with the following categories:

Age (years): <65, 65-75, >75

BMI (kg/m2): ≤30, >30.
The following additional baseline characteristics will be analyzed:

Time from the qualifying HF event  to randomization (days, continuous)

Qualifying HF event: Hospitalization, IV diuretic

LVEF (%) at baseline: 45% - <50%, 50% - <60%, ≥60%

NT-proBNP (pg/mL) at baseline (continuous)

eGFR (mL/min/1.73m2) at baseline (continuous)

eGFR (mL/min/1.73m2) at baseline: ≤60, >60 

Heart rhythm: Atrial fibrillation, Sinus rhythm

SBP (mmHg) at baseline (continuous)

SBP (mmHg) at baseline: <120, ≥120

Diastolic blood pressure (DBP; mmHg) at baseline (continuous)

Heart rate (HR; beats/min) at baseline (continuous)

NYHA class at baseline: Class II, III

Medical history of coronary artery disease (CAD): present, not present

Medical history of diabetes mellitus: diabetes, no diabetes

Medical history of atrial fibrillation: yes, no

Medical history of arterial hypertension: present, not present

Medical history of chronic kidney disease (CKD): present, not present

Medical history of chronic obstructive pulmonary disease (COPD): present, not 
present

Medical history of anemia: present, not present


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Demographics and baseline characteristics tables will also be presented by the subgroups 
defined in Section 4.4.4.
6.1.3
Protocol deviations
The number of patients with validity findings and important deviations will be presented 
overall and by investigator and country for each treatment group and in total.  The frequencies 
of each major protocol deviation will be presented by treatment group and total. 
6.1.4
Medical History
Medical history findings will be coded by Medical Dictionary for Regulatory Activities 
(MedDRA) codes.
Medical history will be presented for each MedDRA Primary System 
Organ Class (SOC) and Preferred Term (PT) by treatment group and overall.
6.1.5
Concomitant Medication
Prior and concomitant medications will be coded by Anatomical Therapeutic Chemical (ATC) 
classification system according to the World Health Organization Drug Dictionary (WHO-
DD). 
6.1.5.1
Selected Concomitant Medication of Special Interest
Concomitant medication of special interest, derived via ATC codes, Bayer Drug Grouping 
(BDG), or combinations of both ATCs and BDGs, will be summarized by class and corrected 
generic name. Of special interest are the drug groups:

diuretics

β-blockers

ACE inhibitors

Angiotensin receptor blockers (ARB)

Mineralocorticoid receptor antagonists (MRA)

SGLT-2 inhibitors

Calcium channel blockers
Diuretics will be categorized into the subcategories loop diuretics, thiazides, and potassium 
sparing diuretics. In addition the combined drug group ACE inhibitor and/or ARB will be 
analyzed.
The number of patients taking a medication in a drug group of special interest or combination 
of concomitant medications of special interest at any time during the study will be given. In 
addition, the number of patients taking a medication in a drug group of special interest at 
baseline and week 24 will be given. Medication start and stop date information will be used to 
assess, if a medication was taken at the respective visits. In addition, the tables with number 
of patients taking a medication in a drug group of special interest at baseline (Day 1) will be 
provided for the subgroups specified in Section 4.4.4.


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A cross-tabulation comparing the number of patients taking a combination of concomitant 
medications of special interest at baseline 1 and the number of patients taking individual drug 
groups of interest at week 24 will be presented by treatment group.
Analysis of diuretics
An analysis of percentage of equivalence dose taken will be performed. Percentage of 
equivalence dose is calculated individually per subject and medication as:
Percentage of equivalence dose = actual dose / equivalence dose * 100
In case of missing dose and/or frequency information, the respective medication will be 
omitted from the analysis.  Percentage of equivalence dose will be calculated for medications 
taken at baseline and week 24.  
In case a subject takes several medications from one diuretics subcategory at a visit, the sum 
of the percentages of equivalence dose of the different medications will be used for the 
subject for the respective visit.
For each diuretics subcategory, summary statistics will be provided for percentages of 
equivalence dose as well as changes from baseline in percentages of equivalence dose by 
treatment group and overall.
In addition, patients will be grouped into 'below 50% of equivalence dose', '50% to 100% of 
equivalence dose', 'more than 100% of equivalence dose' and 'no respective medication 
intake'.  For each diuretics subcategory, number and percentage of patients within each 
percentage group will be given by treatment group and overall at baseline and week 24.
Changes from baseline to week 24 will be categorized into the categories 'dose increased', 
'dose not changed', 'dose reduced', 'new drug started', 'drug intake stopped'.


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Table 6-1: Equivalence doses for different diuretics
Diuretic (ingredient)
Daily Equivalence* Dose (mg)
Loop diuretics
Bumetanide
1
Furosemide
40
Torasemide
10
Thiazides
Bendroflumethiazide
2.5
Hydrochlorothiazide
12.5
Indapamide
2.5
Metolazone
2.5
Potassium-sparing diuretics
Amiloride
5# or 10†
Spironolactone/eplerenone
50# or 100†
Triamterene
100# or 200†
#in combination with ACEi and/or ARB. †without ACEi and ARB.
*Equivalence does not mean bio-equivalence.
Daily equivalence doses are taken from table 16 in the ESC HF Guideline 2012 [18].
6.1.6
Treatment Duration and Exposure
Treatment duration (number of days with study treatment intake, calculated based on the start 
and stop dates of tablet intake, not including interruptions of drug) will be summarized using 
descriptive statistics by treatment group and overall. In addition, treatment duration will be 
categorized to ≤7 days, >7-42 days, >42-84 days, >84-126 days, >126-168 days, and 
presented with the corresponding number and percentage of patients by treatment group and 
overall.  A table will be presented with the absolute and relative frequencies of patients still in 
the study at each visit. Kaplan-Meier plots for time-to end of study treatment will be provided 
for each treatment group. The extent of exposure to study treatment (total amount of intake in 
mg) will be summarized using descriptive statistics and by 200-mg intervals by treatment 
group and overall.
Gaps as well as interruptions will not be counted towards duration calculations. Overlaps will 
be handled by setting the first record with overlap as the day before the start of the following 
record. The exposure will be computed as the total dose assumed record by multiplying the 
treatment days by the relative dose and summing them across days on treatment for each 
individual patient.
6.1.7
Treatment Compliance
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.
Compliance will be calculated as the number of tablets taken divided by the number of tablets 
dispensed * 100. In addition:


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1) If the patient is missing return tablets or missing dispensing tablets then those 
tablets are not counted toward the number of tablets taken for the compliance 
calculation. 
2) If the dispensing or return dates are missing but the number of return and
dispensing tablets are present, the number of tablets taken will be considered for 
the compliance calculation. 
3) Missing compliance will be noted as missing instead of 0.
6.1.8
Completer definition
A patient is defined as a completer if the following criteria is met:

On the “End of Treatment” form page of the eCRF, the box corresponding to the 
question of “Did the subject complete treatment?” is checked off as “Yes.” 
6.2
Efficacy
All analyses will be performed according to ITT principle, i.e., including all patients 
randomized, if not otherwise specified (Section 5.1).
6.2.1
Patient Reported Outcomes 
Kansas City Cardiomyopathy Questionnaire (KCCQ)
The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a self-administered disease-
specific measure comprised of 23 items grouped into seven domains (Physical Limitation, 
Symptom Stability, Symptom Frequency, Symptom Burden, Self Efficacy, Quality of Life 
and Social Limitations). The following five domains will be considered measures of treatment 
efficacy:

Physical Limitation (PLS) (questions 1a to 1f), 

Symptom Frequency (SFS) (questions 3,5,7,9), 

Symptom Burden (question 4,6,8), 

Quality of Life (questions 12,13,14),

Social limitations (questions 15a to 15d).
The following two KCCQ domains are not considered measures of treatment efficacy and are 
not included in algorithms for summary scores, these domains will be reported for 
completeness; 

Symptom Stability (question 2), referred to as ‘change in symptoms’ in the protocol ,
assesses patient perceived change in symptoms over previous two weeks, 

Self-Efficacy (question 10,11), referred to as ‘self-efficacy and knowledge’ in the 
protocol, is a quality of care metric assessing patient perceived knowledge of disease 
management.  
For each item, options are on a 5- to 7-point Likert-type scale with varying response options 
depending on the question. Domain scores are calculated by summing item scores and then 


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transforming scores to a 0-100 unit scale with higher scores indicating better health status, as 
described in the KCCQ scoring instruction [10], reproduced in protocol appendix 8.
The individual domain scores will additionally be summarized to three summary scores:

The Total Symptom Score (TSS) is the mean of the Symptom Burden and the 
Symptom Frequency scores.

The Clinical Summary Score (CSS) is the mean of the Total Symptom score and the 
Physical Limitation score.

The Overall Summary Score (OSS) is the mean of the Total Symptom score, and the  
Physical Limitation, Quality of Life, and Social Limitation scores.
The KCCQ will be administered at baseline (visit 2), 2 weeks (visit 3),  6 weeks (visit 5), 12 
weeks (visit 7), 18 weeks (visit 8), 24 weeks (visit 9), and safety follow-up (week 28, visit 
10); and following premature discontinuation: at time of discontinuation (visit 11) and at 28 
+/-7 days following premature discontinuation (visit 12). 
EQ-5D-5L
The EQ-5D-5L is a self-administered generic measure of health-related quality of life which 
includes five dimensions: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression. Patients provide a rating for each question on a five-level Likert scale: 
having no problems, having slight problems, having moderate problems, having severe 
problems and being unable to do/having extreme problems. In addition, patients are asked to 
self-rate their own health today on a vertical 0-100 unit visual analogue scale (VAS), with 0 
corresponding to "the worst health you can imagine", and 100 corresponding to "the best 
health you can imagine." For the EQ-5D-5L, summary scores will be calculated out of the 
five dimensions using the preference weighting derived by Craig et al from a representative 
US general population[19].  
The EQ-5D-5L will be administered at baseline (visit 2), 2 weeks (visit 3), 6 weeks (visit 5), 
12 weeks (visit 7), 18 weeks (visit 8), 24 weeks (visit 9), and at safety follow-up (week 28, 
visit 10); and following premature discontinuation: at time of discontinuation (visit 11) and at 
28 +/-7 days following premature discontinuation (visit 12).  
Patient Global Impression of Change (PGIC) and Patient Global Impression of Severity
(PGIS) Questions
The PGIC contains two questions (i.e. Q1 and Q1a or Q1b): 
1. Compared to the start of your treatment, how would you describe your physical limitations 
due to heart failure today? 
o
Response options: “much better”, “better”, “a little better”, “the same”, “a little 
worse”, “worse”, or “much worse”; 

If a subject responds “much better”, “better”, or “a little better”, then he/she is asked:


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o
1a. Was this improvement in your physical limitations an important change for 
you?
o
Response options: “Yes”, “No”.

If a subject responds “much worse”, “worse”, or “a little worse”, then he/she is asked:
o
1b. Was this worsening in your physical limitations an important change for 
you (by important we mean did it bother you)?
o
Response options: “Yes”, “No”.
The PGIS contains 1 question: 

How would you rate your physical limitations due to heart failure today?
o
Response options: “No Limitations”, “Mild”, “Moderate”, “Severe”, “Very 
Severe”
These questions will be used to support interpretation of the KCCQ PLS mean change scores.
The PGIC will be administered at 2 weeks (visit 3), 6 weeks (visit 5), 12 weeks (visit 7), 18 
weeks (visit 8), 24 weeks (visit 9), and also at safety follow-up (visit 10) and following 
premature discontinuation; at time of discontinuation (visit 11) and at 28 +/-7 days following 
premature discontinuation (visit 12). 
The PGIS will be administered at the same timepoints as the PGIC but will be additionally 
administered at baseline (visit 2).
6.2.2
Clinician Reported Outcomes
Fried frailty score
The Fried frailty phenotype defines 5 key domains for frailty: weakness, low energy, slowed 
walking speed, decreased physical activity, and weight loss. 
The questions patterned from the Fried Frailty score domains are assessed at baseline and at 
24 weeks. The questions address five domains of the frailty phenotype: (a) shrinking (weight 
loss of ⩾10 pounds in the prior year); (b) weakness (decreased or weakened grip strength); (c) 
exhaustion (fatigue or declining endurance); (d) slowness (slower walking pace); and (e) low 
activity (decline in physical activity). The 5 questions are as follows:
Within the last 12 months has the patient experienced any of the following?

Unintentional weight loss (≥5 kg/10 lbs).

Developed decreased grip strength.

Developed increasing fatigue/lethargy or declining endurance.

Walks a distance of 5 m/15 feet at a slower pace.


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
Decline in typical activity level.
The Fried frailty score will be completed at baseline (visit 2), 24 weeks (visit 9) and at time of 
premature discontinuation (visit 11).
Assessment of NYHA class
NYHA class will be assessed according to the classification below:

Class I: No limitation of physical activity

Class II: Slight limitation of physical activity in which ordinary physical activity leads 
to fatigue, palpitation, dyspnea, or anginal pain; the person is comfortable at rest

Class III: Marked limitation of physical activity in which less-than-ordinary activity 
results in fatigue, palpitation, dyspnea, or anginal pain; the person is comfortable at 
rest

Class IV: Inability to carry on any physical activity without discomfort but also 
symptoms of heart failure or the anginal syndrome even at rest, with increased 
discomfort if any physical activity is undertaken 
The NYHA class will be completed at baseline and all following visits.
6.2.3
Primary efficacy variable 
6.2.3.1
Primary Analysis of the Primary Efficacy Variable 
The primary endpoint will be change in KCCQ PLS from baseline to week 24. 
The estimand of interest is the de facto or treatment policy estimand.
Population: Defined through study inclusion/exclusion criteria (see protocol Section 6.1 and 
6.2).
Variable: Change from baseline in KCCQ PLS from baseline to Week 24.
Approach of intervention effect: Regardless of stopping study treatment or adherence to study 
treatment.
Summary measure: Difference of LS means at Week 24.
The primary analysis will be performed on the FAS (KCCQ) (Section 5.1.2). Missing data 
will be imputed based on a pattern-mixture model with control-based pattern imputation 
(Appendix 9.1). The main idea of this method was introduced by Little and Yau (1996) [ 20]
and later refined by Ratitch and O’Kelly (2011) [21]. In this control-based pattern imputation, 
PROC MI is called in such a way that it builds its imputation model only on data from the 
control arm, while it imputes missing data in both control and experimental treatment arms 
using a single control-based imputation model. In other words, the methods will be 
implemented using copy reference approach. For those patients who had died during the 
study, they will be imputed with the worst case outcome, i.e., a zero score from the time of 
death onward. 


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The analysis of each imputed dataset will be performed using mixed-effects model for 
repeated measures (MMRM), including treatment, region, heart rhythm, study visit as fixed 
effects, interaction between study visit and treatment group, and adjustment for the baseline 
PLS values as covariates. The model will assume an unstructured covariance matrix for 
within-patient variability. 
The model statement is:
Yijklm = μ + βxi + tk + rl + hm +vj+ (tv)jk + εi j
where Yijklm is the change from baseline in PLS to visit j for patient i; μ is the intercept, β is 
the baseline covariate effect, xi is the baseline PLS for patient i, tk is the fixed effect of 
treatment k, rl is the fixed effect of region l, hm is the fixed effect of heart rhythm m (atrial 
fibrillation or sinus rhythm from ECG baseline), vj is the fixed effect of visit j, (tv)jk is the 
interaction effect of treatment k by visit j, and εi j  ~ Normal(0, σ2) represents the residual 
variance component with corr(ε i j, ε i j’) = ρjj’,  j ≠ j’.
The core SAS-code to be used is the following:
proc mixed data=imputed_pls_data;
    by _imputation_;
    class subjidn
trt01pn cntygr1n ATRFIBN avisitn;
    model chg= trt01pn
cntygr1n ATRFIBN base avisitn avisitn*trt01pn /ddfm=kr outp=resid s 
covb;
    repeated avisitn/ subject=subjidn type=un group=trt01pn;
        lsmeans
avisitn*trt01pn/e
cl diff;
    estimate 'Vericiguat10-Placebo'
trt01pn -1 1 0 ;
    estimate 'Vericiguat10-Placebo at Week 2' trt01pn -1 1 0 avisitn*trt01pn -1 0 0 0 0 1 0 0
0 0/e cl;
    estimate 'Vericiguat10-Placebo at Week 6' trt01pn -1 1 0 avisitn*trt01pn
0 -1 0 0 0 0 1
0 0 0/cl;
    estimate 'Vericiguat10-Placebo at Week 12' trt01pn -1 1 0 avisitn*trt01pn 0 0 -1 0 0 0 0
1 0 0/cl;
    estimate 'Vericiguat10-Placebo at Week 18' trt01pn -1 1 0 avisitn*trt01pn 0 0 0 -1 0 0 0
0 1 0/cl;
    estimate 'Vericiguat10-Placebo at Week 24' trt01pn -1 1 0 avisitn*trt01pn 0 0 0 0 -1 0 0
0 0 1/cl;
     estimate 'Vericiguat15-Placebo'
trt01pn -1 0 1;
    estimate 'Vericiguat15-Placebo at Week 2' trt01pn -1 0 1 avisitn*trt01pn -1 0 0 0 0 0 0 0
0 0 1 0 0 0 0/e cl;
    estimate 'Vericiguat15-Placebo at Week 6' trt01pn -1 0 1 avisitn*trt01pn
0 -1 0 0 0 0 0
0 0 0 0 1 0 0 0/cl;
    estimate 'Vericiguat15-Placebo at Week 12' trt01pn -1 0 1 avisitn*trt01pn 0 0 -1 0 0 0 0
0 0 0 0 0 1 0 0/cl;
    estimate 'Vericiguat15-Placebo at Week 18' trt01pn -1 0 1 avisitn*trt01pn 0 0 0 -1 0 0 0
0 0 0 0
0 0 1 0/cl;
    estimate 'Vericiguat15-Placebo at Week 24' trt01pn -1 0 1 avisitn*trt01pn 0 0 0 0 -1 0 0
0 0 0 0 0 0 0 1/cl;
RUN;


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Results of the MMRM analysis on 100 separately imputed datasets can now be combined to 
derive an overall result. This is done by applying PROC MIANALYZE with the following 
generic code:
ods output parameterestimates=mi_lsmean;
proc mianalyze parms=lsmean;
    by trt01pn avisitn;
    modeleffects trt01pn*avisitn;
RUN;
Based on the responder definitions obtained from anchor-based analysis (Section 4.3.2), a 
responder is defined as a patient whose improvement from baseline in KCCQ PLS is greater 
than or equal to responder definition. The number of responders at each visit will be 
summarized and tested using a chi-square test. Note that missing data will not be imputed in 
the responder analysis. In addition, the number of patients with KCCQ PLS improvement 
from baseline by >5 points at 24 weeks and other thresholds (e.g. >3, >7, >10, >15, >20) will 
be summarized for each arm and assessed using a chi-square test. The number of patients with 
KCCQ PLS decline from baseline by >5 points and other thresholds (>3, >7, >10, >15, >20) 
at 24 weeks will be summarized by each arm and examined using a chi-square test as well.
Further, PDF and CDF of change from baseline at 24 weeks for KCCQ PLS domain will be 
plotted to compare the proportion of patients who are meeting certain threshold from 
vericiguat and placebo arms. The Kolmogorov–Smirnov test will be performed to determine if 
the curves are significantly different.
6.2.3.2
Supportive Analysis of the Primary Efficacy Variables
A tipping point analysis will be performed as the sensitivity analysis under missing not at 
random (MNAR) assumption. Based on the primary analysis model, we will vary assumptions 
about the missing outcomes to assess how severe departures from the control-based 
imputation model it can be to overturn the statistical significance conclusions. The procedure 
will impute the missing data with observations only from placebo arm, and adjust the imputed 
values for observations in the vericiguat treatment arm for a specified sequence of shift 
parameters. Multiple imputation will be done using SAS PROC MI under missing not at 
random (MNAR) assumption (Appendix 9.2).
Also, the same primary efficacy model will be repeated on PEAS (Section 5.1.4) as a 
supportive efficacy analysis. 
In addition, the primary analysis model will be applied to all assessments post-baseline prior 
to study treatment discontinuation on FAS and PPS.  
Furthermore, the same primary analysis model will be repeated under missing at random 
(MAR) assumption, which means no missing data imputations will be performed.
6.2.4
Secondary efficacy variable
The secondary endpoint is change from baseline
in the 6 MWT at 24 weeks.
The estimand of interest is the de facto or treatment policy estimand.


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Population: Defined through study inclusion/exclusion criteria (see protocol Section 6.1 and 
6.2).
Variable: Change from baseline in 6 MWT from baseline to Week 24.
Approach of intervention effect: Regardless of stopping study treatment or adherence to study 
treatment.
Summary measure: Difference of LS means at Week 24.
The secondary endpoint will be analyzed in the same manner as the primary endpoint and on 
the KCCQ (6MWT) (Section 5.1.3). Missing data will be imputed based on a pattern-mixture 
model with control-based pattern imputation (Appendix 9.1). For those patients who had died 
during the study, a score of 0 will be assumed from the time of death onward. 
A supportive analysis will be repeated using the MMRM model without any missing data 
imputations. Also, the same model will be applied to all assessments post-baseline prior to 
study treatment termination.  
6.2.5
Multiplicity adjustment
The study uses the graphical method of Maurer and Bretz [22] to provide strong multiplicity 
control across the primary KCCQ PLS hypotheses and the secondary 6 MWT hypotheses. 
The overall two-sided alpha level will be controlled at 0.05. The two primary hypotheses will 
be tested using the Bonferroni procedure, each at a splitted level of alpha 0.025. The two 
secondary hypotheses will be tested based on a parallel gatekeeping principle. As shown in 
Figure 6-1, if the test of both primary and secondary endpoints at one of the dose groups is 
significant at the alpha level of 0.025, the primary and secondary endpoint at the other dose 
group can be tested at the alpha level of 0.05, in an ordered manner. Figure 6-1 shows the α-
allocation for each hypothesis in the circle representing the hypothesis.
Figure 6-1 α-allocation for the primary and secondary hypotheses
Overall, the primary analysis will be claimed to have a positive outcome if the null hypothesis 
for at least one of the two primary hypotheses can be rejected. 


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6.2.6
Other KCCQ domains 
Change from baseline in other KCCQ domains (Symptom Frequency, Symptom Burden, 
Social limitation, Quality of Life), KCCQ summary scores (TSS, CSS and OSS) will be 
summarized by visit. Cumulative distribution functions will be plotted to compare the 
proportion of patients who are meeting certain thresholds from vericiguat and placebo arms. 
The variables will be analyzed using the MMRM model with no missing data imputation. The 
proportion of patients with changes from baseline by >5 points at 24 weeks and other 
thresholds (e.g. >3, >7, >10, >15, >20) in the other KCCQ domains as well as OSS, CSS, TSS 
and SFS will be summarized. The proportion of patients with decline from baseline by >5 
points at 24 weeks, as well as other thresholds (e.g. >3, >7, >10, >15, >20) in the other 
KCCQ domains and summary scores will also be summarized.
6.2.7
EQ-5D-5L 
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 classified
into the following categories: Improvement by two or greater Likert points, Improvement by 
one Likert point, No change, Worsening by one Likert point, Worsening by two or greater  
Likert points. Frequencies of the different categories will be displayed by assigned treatment 
group and overall by visit.
The EQ-5D Visual Analogue Scale (VAS), the preference weighted summary score and the 
corresponding changes from baseline will be described by treatment group and visit.
The summary scores of EQ-5D-5L (UK and US) as well as the EQ Visual Analogue Scale 
(VAS) and the corresponding changes from baseline will be described by treatment group and 
visit.
6.2.8
Fried frailty score
Frequencies of patients with each response option for each question will be presented by 
treatment group and overall by visit. Proportions of patients with one or more responses 
characteristic of frailty and those with three or more characteristics will be summarized.
6.2.9
Clinical outcome events
All patients will be followed until study completion to assess for vital status. Potential pre-
specified clinical outcome events will be submitted for adjudication to an independent CEC. 
The following events will be collected and analyzed to explore the efficacy of study drug 
treatments on clinical outcomes:

All deaths (CV and non-CV, including outpatient death)

CV hospitalizations including HF and non-HF hospitalizations (i.e. myocardial 
infarction and stroke)

Outpatient HF events, such as IV diuretic use for HF or urgent HF visits 
Incidences of events, including all deaths, CV deaths and non-CV deaths, total CV 
hospitalizations, HF hospitalizations, non-HF hospitalizations (i.e. myocardial infarction and 


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stroke), as well as outpatient HF events will be summarized. Patients without an event will be 
censored at their last contact date (the latest date among all known assessments or follow-up 
dates).
In addition, Kaplan Meier curves of the composite endpoints will be presented by treatment:

Time to first occurrence of the composite of CV death or heart failure hospitalization.

Time to first occurrence of the composite of CV death, HF hospitalization, worsening 
from baseline in NYHA class, or worsening from baseline in PGIC 

Time to first occurrence of the composite of CV death, heart failure hospitalization, 
worsening from baseline in NYHA class, or worsening from baseline in KCCQ CSS
6.2.10
NYHA Class
Frequencies of patients in the different NYHA classes will be presented by treatment group 
and overall by visit.
Frequencies of patients with change in NYHA class from baseline (e.g. unchanged, improved 
by 1 category, deteriorated by 1 category, etc.) will be presented by treatment group and visit.  
The number of patients with transitions from baseline with respect to categories (class I, class 
II, class III, class IV) will be provided by baseline value, treatment group and visit. 
6.2.11
PGIC and PGIS
Frequencies of patients in the different PGIC/S categories will be presented by treatment 
group and overall by visit.
Frequencies of patients with change in PGIC/S class from baseline (e.g. unchanged, improved 
by x categories, deteriorated by x categories, etc.) will be presented by treatment group and 
visit.  
6.3
Safety
Safety analyses will be performed in the SAF.
6.3.1
Adverse events
Adverse events (AEs) will be coded using MedDRA terminology. The version number of 
MedDRA used for the analyses will be stored in the clinical database. A listing will be 
provided linking the original investigator terms and the coded terms.
AEs are considered to be treatment-emergent if they have started or worsened after first 
application of study medication up to 5 calendar days after end of treatment with study 
medication.
An overall summary of AEs and treatment-emergent (TE) AEs will be generated by treatment 
group and overall.  
Incidences of patients with TEAEs, drug-related and/or serious TEAEs, TEAEs causing
discontinuation of study treatment will be summarized by treatment group and overall 


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grouped by MedDRA Primary System Organ Class (SOC) and Preferred Term (PT).  In 
addition, the incidence of pre-treatment AEs and AEs during the follow-up (more than 5
calendar days after end of treatment with study medication) will be tabulated. Serious adverse 
events (SAEs), deaths, and AEs leading to discontinuation will be listed.  The date, relative 
day (to study medication) and phase of the study (pre-treatment, during treatment, post-
treatment) will be included.
6.3.2
Adverse events of special safety interest
For this trial, the following adverse events are considered of special interest:

Symptomatic hypotension
events
(Bayer 
SMQ "Hypotension (Riociguat)" 
(code=SMQ_1388)). 
Hypotension 
events 
will 
be 
categorized 
in 
symptomatic/asymptomatic as captured in the eCRF.

Syncope (Bayer SMQ “Syncope Riociguat”( code=SMQ_1389))
For each of the SMQs, the following tables will be provided: overall summary of TEAEs, 
incidences of patients with TEAEs, and with serious TEAEs grouped by SOC and PT. 
A listing of all hypotension and syncope events will be provided, including date, relative day 
(to study medication), dose group, preferred term and phase of the study (pre-treatment, 
during treatment, post-treatment).
6.3.3
Further safety parameters
6.3.3.1
Laboratory parameters
Summary statistics including changes from baseline will be calculated by treatment group and
visit for all quantitative laboratory parameters. The summary statistics for troponin T and 
eGFR will also be provided by treatment group.
The number of patients with transitions from baseline with respect to reference range 
categories (low, normal, high) will be provided by treatment group and visit.  In addition, the 
number of patients with treatment-emergent abnormal laboratory values above or below the 
normal range will be tabulated by treatment group and overall.
To assess acute renal failure, the number and incidence of patients with increase in serum 
creatinine >0.3 mg/dL, >0.5 mg/dL, and ≥ ×2 from baseline, as well as the number and 
incidence of patients with decrease in eGFR >50% or to <15 mL/min/1.73m² will be 
presented by visit and treatment group.
The number and incidence of patients with ALT > 3× upper limit of normal (ULN), and total 
bilirubin > 2×ULN will be presented by visit and treatment group.
6.3.3.2
Vital signs
The absolute values and the changes from baseline values at each visit will be summarized by 
treatment group using descriptive statistics for systolic blood pressure (SBP), diastolic blood 
pressure (DBP), heart rate (HR).


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The change in vital signs parameters from baseline to week 24 will be analyzed by two-sided 
two-sample t-tests comparing each individual vericiguat treatment group with the placebo 
treatment group at the 5% level in an explorative setting. 
The number of patients with systolic blood pressure below 90 mmHg, based on the individual 
measurements rather than the mean value, will be displayed by visit and by treatment group. 
A frequency listing of all patients with systolic blood pressure below 90 mmHg post baseline 
will be provided.
6.3.3.3
Electrocardiogram (ECG)
The incidence rates of treatment-emergent 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.
Prolongations of QT interval will be summarized by visit and treatment group based on the
PKS. At every time point the 90% Confidence Intervals (CI) for the mean change from 
baseline in QTcF will be calculated.
7.
Document history and changes in the planned statistical analysis
7.1
Document history

Version 1.0 

Version 2.0
o
Added updates per the FDA Type C meeting held on 11/6/2019
o
Added definition of completer
o
Updated definition of baseline, treatment compliance calculation , and 
treatment duration calculation
o
Updated with latest SAS code
o
Included imputation rules for partially missing end dates for study medication 
7.1.1
Changes from the protocol
None


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8.
References
1. Steinberg BA, Zhao X, Heidenreich PA, et al. Trends in patients hospitalized with 
heart failure and preserved left ventricular ejection fraction: prevalence, therapies, and 
outcomes. Circulation. 2012; 126 (1): 65-75.
2. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et al. 2016 ESC 
Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task 
Force for the diagnosis and treatment of acute and chronic heart failure of the 
European Society of Cardiology (ESC)Developed with the special contribution of the 
Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016 Jul 14;37(27):2129-
200.
3. Shah SJ, Gheorghiade M. Heart failure with preserved ejection fraction: treat now by 
treating comorbidities. JAMA. 2008; 300 (4): 431-3.
4. Borlaug BA, Redfield MM. Diastolic and systolic heart failure are distinct phenotypes 
within the heart failure spectrum. Circulation. 2011; 123 (18): 2006-13; discussion 
2014.
5. Pieske B, Maggioni AP, Lam CSP, Pieske-Kraigher E, Filippatos G, Butler J, et al. 
Vericiguat in patients with worsening chronic heart failure and preserved ejection 
fraction: results of the SOluble guanylate Cyclase stimulatoR in heArT failurE 
patientS with PRESERVED EF (SOCRATES-PRESERVED) study. Eur Heart J. 2017 
Apr 14;38(15):1119-27.
6. Filippatos G, Maggioni AP, Lam CSP, Pieske-Kraigher E, Butler J, Spertus J, et al. 
Patient-reported outcomes in the SOluble guanylate Cyclase stimulatoR in heArT 
failurE patientS with PRESERVED ejection fraction (SOCRATES-PRESERVED) 
study. Eur J Heart Fail. 2017 Jun;19(6):782-91.
7. Green CP, Porter CB, Bresnahan DR, Spertus JA. Development and evaluation of the 
Kansas City Cardiomyopathy Questionnaire: a new health status measure for heart 
failure. J Am Coll Cardiol. 2000 Apr;35(5):1245-55.
8. Butler J, Hamo CE, Udelson JE, Pitt B, Yancy C, Shah SJ, et al. Exploring New 
Endpoints for Patients With Heart Failure With Preserved Ejection Fraction. Circ 
Heart Fail. 2016; 9(11).
9. SAS Institute Inc. SAS/STAT® 9.2 User's Guide. Cary, NC: SAS Institute Inc. 2008.
10. The Kansas City Cardiomyopathy Questionnaire Scoring Instructions (2000-2003), 
John Spertus MD MPH [http://cvoutcomes.org/ (6th September 2013)]
11. Spertus J, Peterson E, Conard MW, et al. Monitoring clinical changes in patients with 
heart failure: a comparison of methods. Am Heart J 2005;150:707 - 15.
12. Dreyer RP, Jones PG, Kutty S, Spertus J. Quantifying clinical change: discrepancies 
between patients’ and providers’ perspectives. Qual Life Res. 2016; 25: 2213-2220. 


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13. Revicki D, Hays RD, Cella D, Sloan J. Recommended methods for determining 
responsiveness and minimally important differences for patient-reported outcomes. J
Clin Epidemiol. 2008; 61(2), 102–109.
14. Shrout PE, Fleiss JL. Intraclass correlations: uses in assessing rater reliability. 
Psychological Bulletin. 1979; 86 (2), 420-428.
15. Haywood KL, Garratt AM, Dziedzic K, Dawes PT. Generic measures of health-related 
quality of life in ankylosing spondylitis: reliability, validity and responsiveness. 
Rheumatology. 2002; 41: 1380-1387.
16. Coon CD, Cook KF. Moving from significance to real-world meaning: methods for 
interpreting change in clinical outcome assessment scores. Qual Life Res. 2018; 27: 
33-40.
17. Gerlinger C, Schmelter T. Determining the non-inferiority margin for patient reported 
outcomes. Pharm Stat. 2011;10(5):410-3.
18. McMurray JJV, Adamopoulos S, Anker SD, et al. ESC Guideline for the diagnosis 
and treatment of acute and chronic heart failure 2012. The Task Force for the 
Diagnosis and Treament of Acute and Chronic Heart Failure 2012 of the European 
Society of Cardiology. Developed in collaboration with the Heart Failure Association 
(HFA) of the ESC. European Heart Journal. 2012; 33:1787-1847.
19. Craig BM, Rand K. Choice Defines QALYs: A US Valuation of the EQ-5D-5L. 
Medical Care. 2018; 56(6):529-536
20. Little, R, Yau.L. Intent-to-Treat Analysis for Longitudinal Studies with Drop-Outs. 
Biometrics. 1996; 52: 1324-1333.
21. Ratitch, B, O’Kelly, M. Implementation of Pattern-Mixture Models Using Standard 
SAS/STAT Procedures. Proceedings of PharmaSUG2011 Conference – Paper SP04. 
http://www.pharmasug.org/proceedings/2011/SP/PharmaSUG-2011-SP04.pdf
22. Maurer W, Bretz F. Multiple Testing in Group Sequential Trials Using Graphical 
Approaches. Statistics in Biopharmaceutical Research. 2013;5(4):311-20.


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9.
Appendix
9.1
Pattern-mixture modeling approach
The main idea of this method was introduced by Little and Yau (1996) [20] and later refined 
by Ratitch and O’Kelly (2011) [21]. The Ratitch and O’Kelly (2011) approach suggests using 
sequential regression and multiple imputation methodology to impute missing values after a 
subject’s discontinuation from the trial based on “as treated” model, using actual dose after 
drop-out if it is known, or based on some plausible assumptions if unknown. In most clinical 
trials, patients stop taking experimental medication after discontinuation. In this case, the “as 
treated” model for discontinued patients would be based on the idea that patients are taking a 
zero dose of the experimental treatment. 
In this control-based pattern imputation, the intent is to make no direct use of observed data 
from the experimental treatment arm for estimating the imputation model. Hence, PROC MI 
is called in such a way that it builds its imputation model only on data from the control arm, 
while it imputes missing data in both control and experimental treatment arms using a single 
control-based imputation model. This is achieved with a sequence of calls to PROC MI.
The general procedure for control-based pattern imputation is the following:
(a) Impute the non-monotone data with the MCMC method and store the result of this 
partial imputation. In this study, the non-monotone data would represent those patients 
that discontinued study treatment prematurely, but was able to comeback at a later 
visit for assessment (e.g., dropped out at week 2 and missed assessments for week 6, 
then came back and completed week 12 visit).
(b) Next, impute the monotone data with control based pattern imputation. Here it implies 
that the patients who were in the treatment group and no longer received the treatment
will assume the same conditional distribution as those in the control group. We start 
with imputing missing data at the first time-point that has some missing data (defined 
as time-point 1).
(c) Repeat (b) for all other time-points sequentially. Patients whose missing values were 
imputed in the last call to PROC MI will be included in the input dataset f or the next 
call to PROC MI. Thus data for time-point t, filled in during the last call, will be used 
for predictor variables in the next call to PROC MI (for time point t + 1), which is 
consistent with the internal workings of a single call to PROC MI to impute all time-
points automatically.
This procedure is illustrated below by the following example code:
proc mi data = DATAIN out = DATAIN_MONO nimpute =100  seed = 123;
    var SCORE_0 SCORE_1 SCORE_2 SCORE_3 SCORE_4 SCORE_5;
    mcmc chain = multiple impute = monotone;
run;
proc mi data=DATAIN_Mono out = DATAIN_REG_IMP1 seed=123 nimpute=1;
   
class Trt;
   
monotone reg ;


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mnar model( SCORE_1 SCORE_2 SCORE_3 SCORE_4 SCORE_5 / modelobs= (Trt='0'));
   
var SCORE_0 SCORE_1 SCORE_2 SCORE_3 SCORE_4 SCORE_5 ;
run;
where SCORE_0 , SCORE_1, SCORE_2, SCORE_3, SCORE_4, SCORE_5 represent KCCQ 
PLS scores at baseline and post-baseline visits week 2, 6, 12, 18 and 24. 
The same procedure is then repeated until all time-points are imputed.
9.2
Tipping point analysis approach
We intend to perform multiple imputation analysis for a specified sequence of shift 
parameters, which only adjust the imputed values for observations in the treatment group 
(TRT=1). Multiple imputation will be done using SAS PROC MI under MNAR assumption 
using the following generic code:
proc mi data=PLS_data seed=19334 nimpute=1 out=PLS_mi;
  
class Trt;
monotone reg (/details);
mnar model( SCORE_1 SCORE_2 SCORE_3 SCORE_4 SCORE_5 / modelobs= (Trt='0'))
    adjust (SCORE_1 SCORE_2 SCORE_3 SCORE_4 SCORE_5 /shift=sj adjustobs=(Trt=’1’));
  
var SCORE_0 SCORE_1 SCORE_2 SCORE_3 SCORE_4 SCORE_5;
run;
Each imputed observation (missing KCCQ PLS scores) will be modified  according to the 
required delta shift. Assuming there is no penalty in KCCQ PLS score in the placebo group, 
then for those with missing outcomes in vericiguat treatment arm, we decrease the score 
gradually until a p-value of 0.025 or higher is produced (beyond the tipping point). The actual 
penalty (to 1 decimal place) that gives a p-value above and closest to 0.025 will then be 
identified.
9.3
Region Definition
CNTYGR1
Pooled Country/Geographic 
Region 1
COUNTRY
Country
Americas
ARGENTINA
Americas
CANADA
Americas
COLOMBIA
Americas
UNITED STATES
Asia/Pacific
JAPAN


Statistical Analysis Plan
Protocol No.: BAY 1021189 /19334
Page:
40
of
40
Reference Number: RD-OI-0119
Supplement Version: 9.0
Asia/Pacific
MALAYSIA
Asia/Pacific
SINGAPORE
Asia/Pacific
TAIWAN (PROVINCE OF 
CHINA)
Europe (incl. Israel and South 
Africa)
AUSTRIA
Europe (incl. Israel and South 
Africa)
BELGIUM
Europe (incl. Israel and South 
Africa)
BULGARIA
Europe (incl. Israel and South 
Africa)
GERMANY
Europe (incl. Israel and South 
Africa)
SPAIN
Europe (incl. Israel and South 
Africa)
GREECE
Europe (incl. Israel and South 
Africa)
HUNGARY
Europe (incl. Israel and South 
Africa)
ISRAEL
Europe (incl. Israel and South 
Africa)
ITALY
Europe (incl. Israel and South 
Africa)
POLAND
Europe (incl. Israel and South 
Africa)
PORTUGAL
Europe (incl. Israel and South 
Africa)
RUSSIAN FEDERATION
Europe (incl. Israel and South 
Africa)
SOUTH AFRICA