A Phase 2b Open-label Clinical Study to Evaluate the Tolerability and Safety of an Initiation Dose of 5 mg of Vericiguat in Participants With Chronic Heart Failure With Reduced Ejection Fraction
Phase: PHASE2
Conditions: Chronic Heart Failure With Reduced Ejection Fraction
Sponsor: Bayer

CONFIDENTIAL 
Clinical Study Protocol  
No. BAY 1021189 / 21683 
29 NOV 2023 
Page:  1 of 44 
 
Title Page 
Protocol Title: A Phase 2b open-label clinical study to evaluate the tolerability and safety of 
an initiation dose of 5 mg of Vericiguat in participants with chronic heart failure with reduced 
ejection fraction 
Protocol Number: 
 
21683 
Protocol Version:  
 
1.0 
Amendment Number: 
Not applicable 
Compound Number: 
BAY 1021189, Vericiguat, Verquvo 
Short Title:   
 
Vericiguat 5 mg initiation study 
Study Phase:  
 
2 
Acronym: 
 
 
VELOCITY HF 
Sponsor Name:  
 
Bayer AG 
Legal Registered Address: 
Non-US: Bayer AG, 51368 Leverkusen, Germany  
US territory: Bayer HealthCare Pharmaceuticals Inc., 100 Bayer Boulevard, P.O. Box 915, 
Whippany NJ 07981-0915, USA 
Regulatory Agency Identifier Numbers:  
 
Registry  
 
 
ID 
EU CT:  
 
 
2023-507682-25-00 
IND:  
 
 
116,743 
 
 
Protocol Date:  
29 NOV 2023 
Name:  
 
  
 
 
Role: 
 
 
This is an electronically generated document that does not bear any sponsor signatures. The 
signature of the sponsor’s medically responsible person is filed in the TMF and available on 
request. 
 
Medical Monitor name and contact information can be found in the Trial Master File.  
 
Confidential 
The information provided in this document is strictly confidential and is intended solely for the performance 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

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Table of Contents 
Title Page ............................................................................................................................... 1 
Table of Tables ..................................................................................................................... 4 
Table of Figures .................................................................................................................... 4 
List of Abbreviations ............................................................................................................ 5 
1. 
Protocol Summary ........................................................................................................ 7 
1.1 
Synopsis ....................................................................................................................... 7 
1.2 
Schema ......................................................................................................................... 8 
1.3 
Schedule of Activities (SoA) ....................................................................................... 9 
2. 
Introduction ................................................................................................................. 10 
2.1 
Study Rationale .......................................................................................................... 10 
2.2 
Background ................................................................................................................ 10 
2.3 
Benefit/Risk Assessment ........................................................................................... 11 
2.3.1 
Risk Assessment ..................................................................................................... 11 
2.3.2 
Benefit Assessment ................................................................................................ 12 
2.3.3 
Overall Benefit: Risk Conclusion ........................................................................... 12 
3. 
Objectives, Endpoints ................................................................................................. 13 
4. 
Study Design ................................................................................................................ 13 
4.1 
Overall Design ........................................................................................................... 13 
4.2 
Scientific Rationale for Study Design ....................................................................... 13 
4.3 
Justification for Dose ................................................................................................. 14 
4.4 
End-of-Study Definition ............................................................................................ 15 
5. 
Study Population ......................................................................................................... 15 
5.1 
Inclusion Criteria ....................................................................................................... 16 
5.2 
Exclusion Criteria ...................................................................................................... 17 
5.3 
Lifestyle Considerations ............................................................................................ 19 
5.4 
Screen Failures ........................................................................................................... 19 
5.5 
Criteria for Temporarily Delaying Study Intervention .............................................. 20 
6. 
Study Intervention and Concomitant Therapy ........................................................ 20 
6.1 
Study Intervention Administered ............................................................................... 20 
6.2 
Preparation, Handling, Storage, and Accountability ................................................. 20 
6.3 
Assignment to Study Intervention ............................................................................. 21 
6.4 
Blinding ..................................................................................................................... 21 
6.5 
Study Intervention Compliance ................................................................................. 21 
6.6 
Dose Modification ..................................................................................................... 22 
6.6.1 
Retreatment Criteria ............................................................................................... 22 
6.7 
Continued Access to Study Intervention after the End of the Study ......................... 22 
6.8 
Treatment of Overdose .............................................................................................. 22 
6.9 
Prior and Concomitant Therapy ................................................................................. 22 
6.9.1 
Rescue Medicine..................................................................................................... 23 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal ...................................................................................... 23 
7.1 
Discontinuation of Study Intervention ....................................................................... 23 
7.1.1 
Temporary Interruption .......................................................................................... 24 

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7.1.2 
Rechallenge ............................................................................................................ 24 
7.2 
Participant Discontinuation/Withdrawal from the Study ........................................... 24 
7.3 
Lost to Follow Up ...................................................................................................... 24 
8. 
Study Assessments and Procedures ........................................................................... 25 
8.1 
Administrative and Baseline Procedures ................................................................... 25 
8.2 
Efficacy Assessments ................................................................................................ 25 
8.3 
Safety Assessments .................................................................................................... 25 
8.3.1 
Physical Examinations ............................................................................................ 25 
8.3.2 
Vital Signs .............................................................................................................. 26 
8.3.3 
Electrocardiograms ................................................................................................. 26 
8.3.4 
Clinical Safety Laboratory Tests ............................................................................ 27 
8.3.5 
Pregnancy Testing .................................................................................................. 27 
8.4 
Adverse Events (AEs), Serious Adverse Events (SAEs) and Other Safety Reporting
 ................................................................................................................................... 27 
8.4.1 
Time Period and Frequency for Collecting AE and SAE Information................... 27 
8.4.2 
Method of Detecting AEs and SAEs ...................................................................... 28 
8.4.3 
Follow-up of AEs and SAEs .................................................................................. 28 
8.4.4 
Regulatory Reporting Requirements for SAEs ...................................................... 28 
8.4.5 
Pregnancy ............................................................................................................... 28 
8.4.6 
Adverse Events of Special Interest ......................................................................... 29 
8.5 
Pharmacokinetics ....................................................................................................... 29 
8.6 
Pharmacodynamics .................................................................................................... 29 
8.7 
Genetics ..................................................................................................................... 29 
8.8 
Biomarkers ................................................................................................................. 29 
8.9 
Immunogenicity Assessments .................................................................................... 29 
8.10 Medical Resource Utilization and Health Economics ............................................... 29 
9. 
Statistical Considerations ........................................................................................... 29 
9.1 
Statistical Hypotheses ................................................................................................ 29 
9.1.1 
Multiplicity Adjustment ......................................................................................... 29 
9.2 
Analysis Sets .............................................................................................................. 30 
9.3 
Statistical Analyses .................................................................................................... 30 
9.3.1 
General Considerations........................................................................................... 30 
9.3.2 
Primary Endpoint Analysis ..................................................................................... 30 
9.3.2.1 
Definition of Endpoint(s). ................................................................................... 30 
9.3.2.2 
Main Analytical Approach .................................................................................. 30 
9.3.2.3 
Sensitivity Analyses ............................................................................................ 30 
9.3.2.4 
Supplementary Analyses ..................................................................................... 30 
9.3.3 
Secondary Endpoints Analysis ............................................................................... 30 
9.4 
Interim Analysis ......................................................................................................... 31 
9.5 
Sample Size Determination ....................................................................................... 31 
10. Supporting Documentation and Operational Considerations ................................ 31 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations .................... 31 
10.1.1 Regulatory and Ethical Considerations .................................................................. 31 
10.1.2 Financial Disclosure ............................................................................................... 32 
10.1.3 Informed Consent Process ...................................................................................... 32 
10.1.4 Recruitment Strategy .............................................................................................. 32 
10.1.5 Data Protection ....................................................................................................... 32 
10.1.6 Committees Structure ............................................................................................. 33 

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10.1.7 Dissemination of Clinical Study Data .................................................................... 33 
10.1.8 Data Quality Assurance .......................................................................................... 34 
10.1.9 Source Documents .................................................................................................. 34 
10.1.10 Study and Site Start and Closure ............................................................................ 35 
10.1.11 Publication Policy ................................................................................................... 35 
10.2 Appendix 2: Clinical Laboratory Tests ...................................................................... 36 
10.3 Appendix 3: AEs and SAEs: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting .......................................................................................... 36 
10.3.1 Definition of AE ..................................................................................................... 36 
10.3.2 Definition of SAE ................................................................................................... 37 
10.3.3 Recording and Follow-Up of AE and/or SAE ........................................................ 38 
10.3.4 Reporting of SAEs .................................................................................................. 40 
10.4 Appendix 4: Contraceptive and Barrier Guidance ..................................................... 40 
10.4.1 Definitions .............................................................................................................. 40 
10.4.2 Contraception Guidance ......................................................................................... 42 
11. References .................................................................................................................... 43 
 
Table of Tables 
Table 6-1: Study Intervention Administered ............................................................................ 20 
Table 10-1: Protocol-required Safety Laboratory Tests ........................................................... 36 
 
Table of Figures 
Figure 1-1: Schema .................................................................................................................... 8 
 
 
 

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List of Abbreviations  
ACCF 
American College of Cardiology Foundation 
ACEI 
angiotensin-converting enzyme inhibitor 
AE 
adverse event 
AESI 
adverse event of special interest 
AHA 
American Heart Association 
ALBI 
albumin to bilirubin ratio 
ALT 
alanine aminotransferase 
APaT 
All-Participants-as-Treated 
ARB 
angiotensin II receptor blocker 
ARNI 
angiotensin receptor-neprilysin inhibitor 
AST 
aspartate aminotransferase 
BP 
blood pressure 
CABG 
coronary artery bypass grafting 
cGMP 
cyclic guanosine monophosphate 
CIOMS 
Council for International Organizations of Medical Sciences 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form  
CRT 
Cardiac resynchronization therapy 
CSR 
Clinical Study Report 
CTFG 
Clinical Trial Facilitation Group  
CTIS 
Clinical Trials Information System 
CV 
cardiovascular 
ECG 
electrocardiogram  
ECI 
event of clinical interest 
eCRF 
electronic Case Report Form 
EF 
ejection fraction 
eGFR 
estimated glomerular filtration rate 
EoS 
end of study 
ESC 
European Society of Cardiology 
EU 
European Union 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone  
GCP 
Good Clinical Practice  
GDMT 
guideline-directed medical therapy for heart failure 
hCG 
human chorionic gonadotropin 
HF 
heart failure 
HFH 
heart failure hospitalization 
HFrEF 
heart failure with reduced ejection fraction 
HRT 
hormone replacement therapy 
ICD 
implantable cardioverter-defibrillator 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
IV 
intravenous 
LAM 
lactational amenorrhea method 
LPLV 
last patient last visit 
LVEF 
Left ventricle ejection fraction 
MRA 
mineralocorticoid receptor antagonist 
NO 
nitric oxide 

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NSTEMI 
non-ST elevation myocardial infarction 
NT-proBNP 
N-terminal pro-brain natriuretic peptide 
NYHA 
New York Heart Association 
PCI 
percutaneous coronary intervention 
PDE5 
phosphodiesterase type 5 
PD 
pharmacodynamic 
PID 
participant identification number 
PK 
pharmacokinetic 
QD 
once daily 
QTL 
quality tolerance limit 
RAS 
Renin-angiotensin-system 
SAE 
serious adverse event  
SAF 
safety analysis set 
SBP 
systolic blood pressure 
SC 
subcutaneous 
sGC 
soluble guanylate cyclase 
SGLT2i 
sodium-glucose cotransporter 2 inhibitor  
SmPC 
summary of product characteristics 
SoA 
schedule of activities 
SOC 
System Organ Class 
STEMI 
ST elevation myocardial infarction 
SUSAR 
suspected unexpected serious adverse reaction 
TIA 
transient ischemic attack 
UHF 
urgent heart failure 
ULN 
upper limit of normal 
UNS 
unscheduled 
VICTOR 
VerICiguaT GlObal Study in Participants With Chronic Heart Failure With Reduced 
Ejection Fraction 
VICTORIA 
VerICiguaT GlObal Study in Subjects With Heart Failure With Reduced EjectIon 
FrAction 
WOCBP 
woman/women of childbearing potential 
WONCBP 
woman/women of nonchildbearing potential 

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1. 
Protocol Summary 
1.1 
Synopsis 
Protocol Title: 
A Phase 2b open-label clinical study to evaluate the tolerability and 
safety of a starting dose of 5 mg of Vericiguat in participants with chronic heart failure with 
reduced ejection fraction 
Short Title: Vericiguat 5 mg initiation study 
Regulatory Agency Identifier Number(s): 
Registry 
ID 
EU CT: 
2023-507682-25-00 
IND:  
116, 743 
Envisaged indication:  
Chronic heart failure with reduced ejection fraction 
Rationale: 
 
 
The objective of this study is to evaluate the tolerability of a 5 mg starting dose of vericiguat. 
The aim of this study is to generate evidence to support streamlining the titration regimen 
steps from 2 to 1 and enable HFrEF patients to achieve the target dose of 10 mg vericiguat 
daily within 1 titration step. 
Objectives, Endpoints: 
Objectives 
Endpoints  
Primary 
 
• 
To evaluate the tolerability of 5 mg as a 
starting dose of vericiguat  
• 
Treatment tolerability, defined as the 
completion of the two-week 5 mg dose 
without discontinuation of study intervention  
and without moderate to severe 
symptomatic hypotension between Visit 1 
and Visit 2. 
Secondary 
 
• 
To describe safety events of initiation of 
5 mg dose 
• 
To further evaluate the tolerability of 5 mg 
as a starting dose of vericiguat 
• 
Any AE reported between Visit 1 and Visit 
2. 
• 
Absence of AE related to study intervention 
between Visit 1 and Visit 2. 
• 
Continuous intake of study intervention 
between Visit 1 and Visit 2 or restart of 
study intervention after any temporary 
interruption. 
Overall Design Synopsis: 
This is multi-center, a single arm, open label study of vericiguat initiation at 5 mg in HFrEF 
patients with EF <45%. Participants will undergo a screening visit to assess eligibility. 
Eligible participants must wait a mandatory 2 weeks before returning for Visit 1 in order to be 
clinically and hemodynamically stable.  
At Visit 1, participants will receive vericiguat with directions to take a 5 mg tablet once daily 
for 2 weeks. Participants will return for Visit 2 after 2 weeks of treatment.  
Unscheduled visits may be utilized between Visits 1 and 2 at the discretion of the investigator.  

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Number of Participants: 
Approximately 120 participants will be screened to achieve at least 100 participants who are 
assigned to study intervention and complete the treatment period of up to 2 weeks. 
Study Arms and Duration: 
This is a single arm, open label study. The total study duration is approximately 4 weeks, 
including a 2-week screening period and a 2-week treatment period. 
Data Monitoring/Other Committee: 
Yes 
 
1.2 
Schema 
Figure 1-1: Schema 
 
A = assignment to study intervention, D = day, EoS = end of study, S= screening, V = visit 

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1.3 
Schedule of Activities (SoA) 
Visit Number 
Screening  
V1 
V2b 
UNS c 
Notes 
Study Day, Window 
D -14 
D1 
D14 
 
 
Window (Days) 
-4 a 
 
+4 
 
 
Informed consent 
X 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
Recheck clinical status before assignment and/or 1st dose of study intervention. 
Demography 
X 
 
 
 
 
Full physical examination 
including height and weight 
X 
 
 
 
 
Optional: local lab- clinical 
chemistry, hematology  
X 
 
 
 
eGFR, albumin, hemoglobin, total bilirubin, ALT and AST values must be available at 
screening. Values obtained as part of routine management should be used if measured within 
30 days prior to Visit 1. If data is unavailable, values should be determined using a local lab. 
Serum OR urine pregnancy test 
(WOCBP only) 
 
X 
 
 
If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy 
test is required. 
Medical history 
X 
 
 
 
Includes substance usage and family history of premature CV disease 
Current status of heart failure 
medical conditions  
 
X 
X 
 
Collect any changes to heart failure medical condition (hospitalization, worsening of condition).  
Prior and current medications  
X 
X 
X 
X 
Assess at any visit including daily dose, time of intake and dosing regimen 
Local 12-lead ECG 
X 
 
 
 
 
Vital signs 
X 
X 
X 
X 
Vital signs should be measured before study intervention intake. See Section 8.3.2. 
Study Intervention Assignment 
 
X 
 
 
 
Intake of Study Intervention 
 
X 
 
 
Study intervention should be taken orally with food at the same time each day, preferably in the 
morning. Date and time of study intervention intake will be recorded at Visit 1. Participants 
must remain at the site for 2 h after intake of first dose of study intervention. Study intervention 
is self-administered between Visit 1 and Visit 2. See Section 6 for additional details. .  
Study Intervention Accountability  
 
 
X 
X 
 
AE review 
 
X 
X 
X 
See Section 8.4.Includes AESI. At Visit 1, the AE review should be conducted before and 2h 
after dosing. If AE review is suggestive of symptomatic hypotension, date, time, and severity 
will be recorded and vital signs should be re-assessed post dose.  
AE = adverse event, AESI = adverse event of special interest, ALT = alanine transaminase, AST = aspartate aminotransferase, CV = cardiovascular, D = day, 
ECG = electrocardiogram, UNS = unscheduled, V = visit, WOCBP = women of child-bearing potential 
a Screening must be completed 14-18 days before Visit 1. 
b Visit 2 is the end of intervention visit. 
c For Unscheduled Visits for AE review and reporting, assessments indicated in the SoA are mandatory. All other procedures selected and performed at 
unscheduled visits are at the discretion of the investigator and as clinically indicated. 
 

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2. 
Introduction 
Chronic HFrEF is a major source of morbidity and mortality. Clinical outcomes for patients 
with chronic HFrEF remain poor, despite contemporary evidence-based therapies. Therefore, 
drugs are needed that effectively target disease mechanisms not addressed by current standard 
therapy.  
Vericiguat, a novel soluble sGC stimulator, is approved for the treatment of HFrEF. 
Decreased NO availability, sGC desensitization to NO, sGC deficiency, and cGMP signaling 
are potential contributing factors for HF disease progression. Vericiguat works via stimulation 
of sGC in the critical NO-sGC-cGMP pathway. Vericiguat has a novel mode of action that 
targets endothelial dysfunction to improve regulation of vascular tone and myocardial 
function. Pharmacokinetic, pharmacodynamic, safety and efficacy profiles of vericiguat have 
been well characterized in a series of Phase 1 (29 studies), Phase 2 (3 studies) and Phase 3 (1 
study) studies. In the global Phase 3 study, VICTORIA, treatment of 5050 patients with 
chronic HF with reduced ejection fraction with vericiguat on top of the standard of care 
resulted in a 10% reduction in the primary outcome of a composite of death from 
cardiovascular causes or first hospitalization for HF after a median treatment period of 10.8 
months (Armstrong et al. 2020).   
In VICTORIA, vericiguat was generally safe and well tolerated with low incidence of 
symptomatic hypotension and syncope, using a titration regimen (a starting dose of 2.5 mg 
followed by a 2-step up-titration to the target 10 mg dose) guided by symptoms and SBP to 
mitigate the risk of hypotension. Correlation between vericiguat plasma concentrations and 
hemodynamic parameters such as heart rate and SBP has been observed following first dose 
administration but dissipated with repeated dosing. In addition, no meaningful exposure-
response relationship was observed for the incidence of symptomatic hypotension or syncope 
– after first dose and further during the study. This led to the implementation of a symptom- 
and SBP-guided 2-step titration scheme for vericiguat posology. A detailed description of the 
chemistry, pharmacology, efficacy, and safety of vericiguat is provided in the investigator’s 
brochure. 
2.1 
Study Rationale 
The objective of this study is to evaluate the tolerability of a 5 mg starting dose of vericiguat 
in HFrEF patients; the aim of the study is to generate evidence to support streamlining the 
titration regimen from 2 steps to 1 step and enable HFrEF patients to achieve the target 
maintenance dose of 10 mg vericiguat daily. 
2.2 
Background 
In clinical practice, titration of HF medications, including vericiguat, is often compromised by 
limited follow-up opportunities and complexity of care at each follow-up visit. This results in 
under treatment of HFrEF patients due to failure to achieve the maximum efficacious dose for 
treatments with established benefit. Achieving the target dose of HF treatments in a safe and 
fast manner remains a large unmet medical need in HFrEF patients. Keeping drug 
initiation/titration regimens as simple and as safe as possible is critical to HFrEF patients in 
order to achieve optimal doses of GDMT.  
Currently, initiation of vericiguat starts with 2.5 mg, increasing to 5 mg at 2 weeks, then 
10 mg at 4 weeks. Removing the 2.5 mg step has the benefit of patients starting on a more 
efficacious dose and achieving maximal (target) dose with a single titration. In VICTORIA,  

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>80% of HFrEF participants were successfully titrated to the 10 mg dose , with minimal 
decrease in blood pressure after placebo adjustment, such that only 10% of patients remained 
on the starting dose of 2.5 mg of vericiguat, similar to 9% remaining on “2.5 mg” after sham 
titration in the placebo arm. Indeed, in VICTORIA, following initiation of the 2.5 mg starting 
dose, 96.1% of participants on vericiguat and 96.4% of those on placebo remained on 
treatment through the day 14 visit without interruption. 
During the first 14 days of treatment with vericiguat, adverse events of clinical interest of 
symptomatic hypotension or syncope occurred in 2.0% of those on vericiguat and 1.2% of 
those on placebo. It was also observed that a slightly higher incidence of hypotensive events 
was seen in vericiguat arm during first 1-2 weeks since initiation but not later in titration.  
Another large clinical trial, VICTOR, currently underway is assessing the efficacy and 
tolerability of vericiguat compared with placebo in stable HFrEF patients treated with current 
GDMT (Heidenreich et al. 2022, McDonagh et al. 2021).  Overall, there is a pertinent need to 
investigate the effects of vericiguat in optimally treated, lower-risk HFrEF patients (i.e. those 
without recently worsening heart failure). 
In a real-world setting, two sets of data on the use of vericiguat are available: one in the US 
and one in Germany.  
In the United States (Victores et al. 2023), among 3,578 patients treated with vericiguat (mean 
age 67.4 years, 68.1% male), only 34% reaching the target dose of 10 mg. This was more 
likely to occur in patients treated by SGLT2i or on both ARNi and SGLT2i. 
In Germany (Kerwagen et al. 2023), during the 16-month study period since the launch of 
vericiguat in September 2021, initiation of vericiguat was observed in n=2,916 (median age 
75 years, 72% male) patients. During a median follow-up of 150 days, 33% of the patients 
reached the 5 mg, and 36% reached the 10 mg dose. 
This real-world data provides background to explore initiating treatment at dose 5 mg to 
achieve the 10 mg target dose of vericiguat in a safe and faster manner. 
2.3 
Benefit/Risk Assessment 
The results of the VICTORIA study showed a favorable benefit-risk profile for the use of 
vericiguat in patients with chronic HFrEF following a recent worsening event.  In 
VICTORIA,  patients were allowed to titrate to the target dose of 10 mg. Vericiguat has a 
clinically meaningful benefit on the endpoints of HF hospitalizations and CV death. The AE 
profile in VICTORIA was predominantly associated with vericiguat’s mechanism of action as 
a sGC stimulator (i.e., relaxation of smooth muscle leading to vasodilation, hemodynamic 
changes and gastrointestinal side effects).  
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of vericiguat may be found in the VERQUVO Investigator’s 
Brochure and approved labeling. 
2.3.1 
Risk Assessment 
The general risks of vericiguat are known. During the VICTORIA study, AEs more frequently 
reported in the vericiguat group compared to placebo included hypotension, dyspepsia, 
nausea, dizziness, and headache. Anemia was also more frequently reported in the vericiguat 
group compared to placebo. Similar results were reported with riociguat, another sGC 

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stimulator. Overall, these events are generally nonserious and manageable (Ghofrani et al. 
2013a, Ghofrani et al. 2013b). 
Pharmacokinetic-pharmacodynamic (PK-PD) analysis of SOCRATES-REDUCED and 
VICTORIA revealed a small but statistically significant linear relationship between the 
change in SBP from baseline to 2 hours post dose and the measured vericiguat Cmax (PH-
38550 2020, R-13340 2020) following initiation of vericiguat treatment. However, no 
statistically significant relationship was observed between Cmax and changes in SBP from 
baseline at later visits, suggesting that subsequent titrations to higher doses had minimal 
hemodynamic effects. 
Based on PK-PD modeling of data from SOCRATES-REDUCED, the mean SBP is predicted 
to decrease from baseline by an additional 2.0 to 2.5 mmHg (i.e., a 4.0 -5.0 mmHg total 
decrease) when the starting dose is increased from 2.5 mg to 5 mg (i.e. when exposure is 
doubled) (PH-38545 2015, PH-38550 2020).  
The pharmacodynamic effects of vericiguat were evaluated after single and multiple-dose 
administrations in healthy participants. All tested doses (up to 15 mg) were administered with 
ad-hoc dosing (without titration). In a pooled analyses across Phase 1 healthy participant 
studies, the most frequent AEs were headache, dyspepsia and dizziness, consistent with the 
predicted effects of an sGC stimulator on smooth muscle relaxation and vasodilation (PH-
40726 2020). Generally, the incidence of AEs decreased after multiple dosing and when taken 
with food as directed (for details, see Section 4.3).  
Overall, the anticipated risks associated with a starting dose of 5 mg of vericiguat are deemed 
in line with the established safety profile of the product. 
In addition, the risk assessment will involve addressing risks related to the use of SGLT2i and 
ARNI in the study population as we foresee an adoption of these classes larger than in 
VICTORIA based on current GDMT. Both VICTORIA and VICTOR included 
recommendations to treat participants to GDMT; however, given the time lapse between the 
two studies, the recommendations were to different standards. VICTORIA included 
approximately 15% of patients on ARNI at randomization and only 3% of patients on SGLT2i 
after randomization, while VICTOR protocol encourages use of ARNI and SGLT2i at 
baseline with goals of at least 30% and 15%, respectively. 
2.3.2 
Benefit Assessment 
The results from the Phase 3 VICTORIA study provide evidence of an important clinical 
benefit of vericiguat in adult patients with symptomatic chronic HF and ejection fraction less 
than 45% following a worsening HF event. Although participants of the present study are 
unlikely to benefit from the study intervention directly due to the short duration of treatment 
with vericiguat not achieving the target dose, reducing the current titration regimen from 2 
steps to 1 step will enable HFrEF patients to achieve the target dose of 10 mg vericiguat daily 
in a shorter period of time while starting on a dose with higher pharmacological activity. 
2.3.3 
Overall Benefit: Risk Conclusion 
Vericiguat is a new therapeutic option to fulfill the unmet medical need in patients with 
chronic HFrEF. Based on current clinical evidence, vericiguat provides an important clinical 
benefit to adult patients with symptomatic chronic HFrEF, and is well tolerated at doses up to 
10 mg daily. The currently known risks associated with the mechanism of action are deemed 
well characterized. With the higher starting dose of 5 mg only a small decrease in blood 
pressure of about 4.0-5.0 mmHg is expected after administration of the first dose. In order to 

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manage potential side effects, participants will be asked to stay at the site for 2 hours after the 
first dose. 
Considering the measures taken to minimize risks to participants in this study and the 
expected clinical benefit in patients with worsening HF, the benefit/risk assessment is 
considered positive and the conduct of the planned study in heart failure patients who will not 
directly benefit from the study intervention is justified. 
3. 
Objectives, Endpoints 
Objectives 
Endpoints 
Primary 
 
• 
To evaluate the tolerability of 5 mg as a 
starting dose of vericiguat 
• 
Treatment tolerability, defined as the 
completion of the two-week 5 mg dose 
without discontinuation of study intervention 
and without moderate to severe symptomatic 
hypotension between Visit 1 and Visit 2. 
Secondary 
 
• 
To describe safety events of initiation of 
5 mg dose  
• 
To further evaluate the tolerability of 5 mg 
as a starting dose of vericiguat 
• 
Any AE reported between Visit 1 and Visit 2. 
• 
Absence of AE related to study intervention 
between Visit 1 and Visit 2. 
• 
Continuous intake of study intervention 
between Visit 1 and Visit 2 or restart of study 
intervention after any temporary interruption. 
4. 
Study Design 
4.1 
Overall Design 
This is a single arm, open label study of vericiguat initiation at 5 mg in HFrEF patients with 
EF <45%. The total study duration is approximately 4 weeks, including a 2-week screening 
period and a 2-week treatment period. 
Screening: Approximately 120 participants will be screened to achieve at least 100 
participants who are assigned to study intervention and complete the treatment period of up to 
2 weeks. Participants will undergo a screening visit to assess eligibility. Eligible participants 
must wait a mandatory 2 weeks before returning for Visit 1 in order to be clinically and 
hemodynamically stable.  
Treatment: At Visit 1, participants will receive vericiguat 5 mg (on top of standard of care) 
with directions to take once daily for 2 weeks. Participants will return for Visit 2 after 2 
weeks of treatment.  
Unscheduled visits may be utilized between Visits 1 and 2 at the discretion of the investigator 
for AE review and reporting.  
4.2 
Scientific Rationale for Study Design 
The objective of this study is to evaluate the tolerability of a 5 mg starting dose of vericiguat. 
The current dosing regimen for vericiguat requires a 2-step titration to the target dose of 
10 mg; the initial dose of the 2-step titration is 2.5 mg. The aim of this study is to generate 
evidence to support streamlining the titration steps from 2 to 1 and ease reaching the target 
dose of 10 mg vericiguat daily.  

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The proposed study aims at providing evidence of tolerability of initiating treatment with a 
starting dose of 5 mg vericiguat. Tolerability of the subsequent up-titration step from 5 mg to 
10 mg has been extensively investigated in VICTORIA and is currently being investigated in 
VICTOR. Thus, in this respect, a 2-week study is considered to provide the additional 
evidence for the evaluation of 5 mg as a starting dose with the aim to support a 1-step titration 
regimen. 
The target population for this study is adults with chronic HFrEF with EF < 45% with and 
without a recent (<6 months) worsening HF event. This study population therefore is 
representative of the patient populations of both VICTORIA and VICTOR. Vericiguat was 
shown to improve outcomes in patients with HFrEF in the VICTORIA trial, which included 
patients with recent worsening HF. VICTOR is evaluating the efficacy and safety of 
vericiguat in lower-risk HFrEF patients. Indeed, all key HFrEF medications have been 
evaluated in both higher- and lower-risk populations, and the treatment effect was not always 
consistent across the risk spectrum. Furthermore, post-hoc analyses of the VICTORIA trial 
have suggested that sGC stimulators may have cardioprotective effects that may be more 
apparent when the medication is initiated earlier in the disease process. Finally, the effect of 
vericiguat on cardiovascular mortality was uncertain in VICTORIA and a trial of vericiguat 
with a longer follow-up in a lower-risk HFrEF population such as VICTOR may shed light on 
its effect on cardiovascular mortality.  
The present study will support initiation of vericiguat at 5 mg dose, streamlining the titration 
regimen from 2 steps to 1 step and enabling all HFrEF patients to achieve the target dose of 
10 mg vericiguat daily within 1 titration step. In order to support the posology section change 
in the current (worsening HF) and the expanded (stable HFrEF) label, conditional to a 
positive outcome of VICTOR, there is a pertinent need to investigate the effects of vericiguat 
in both optimally treated, high-risk (with a recent worsening heart failure event) and low-risk 
(without a recent worsening heart failure event) HFrEF patients. These two subpopulations in 
this study are intended to be comparable to those addressed in VICTORIA and VICTOR, in 
terms of demographics, severity of disease and comorbidities, with the potential difference 
stemming from a better background treatment compared with VICTORIA, based on the latest 
standards of GDMT.  
Vericiguat’s mechanism of action results in increased intracellular cGMP levels in cardiac 
myocytes and smooth muscle cells. These changes are associated with smooth muscle 
relaxation and a reduction in vascular tone. Throughout the clinical development of 
vericiguat, dose up-titration was dependent upon maintaining adequate SBP and the presence 
or absence of hypotensive symptoms. Tolerability and safety monitoring during this study 
will focus on continuation of study intervention and absence of symptomatic hypotension of 
moderate to severe intensity. 
4.3 
Justification for Dose 
The study will assess the tolerability of a starting dose of 5 mg vericiguat, once daily.  
In the initial clinical pharmacology studies in healthy volunteers, 5 mg (and 10 mg) of 
vericiguat were administered as an initial dose and were well tolerated (Boettcher et al. 2021). 
The approved target dose and titration regimen for vericiguat are based on data from the 
Phase 1 program in healthy volunteers, the Phase 2b study SOCRATES-REDUCED in 
HFrEF, and the Phase 3 VICTORIA study in HFrEF. The goal of the present study is to 
provide tolerability and safety evidence to enable starting treatment on dose 5 mg. 

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Several stepwise titration schemes were assessed in the Phase 2 SOCRATES-REDUCED 
trial, with titration guided by clinic-based BP measurements in each scheme. Comparison of 
NT-proBNP reduction from baseline at 12 weeks across titration schemes demonstrated a 
clear trend of larger reductions in NT-proBNP in those titrated to higher target vericiguat 
doses. The greatest reduction occurred in those titrated to a target dose of 10 mg with this 
target also having an acceptable safety profile. This led to the 2.5 mg to 5.0 mg to 10 mg 
titration scheme being adopted for the VICTORIA trial. In VICTORIA, up- and down-
titration at the study visits was guided by SBP and the presence or absence of symptomatic 
hypotension. Overall, this titration regimen was well tolerated and a total of 74% of 
participants reached the 10 mg target by the end of the titration period (73% of those 
randomized to vericiguat; 75% of those randomized to placebo;); for participants followed for 
up to one year, 90% reached 10 mg (89% of those randomized to vericiguat; 91% of those 
randomized to placebo).  
Over the course of VICTORIA, the effect of vericiguat on BP was small, with mean SBP 
generally < 2 mmHg lower in those treated with vericiguat compared to placebo. The main 
blood pressure effect was observed early after the first 2.5 mg dose of vericiguat (SBP 
reduction of about 3 mmHg) in participants who received vericiguat compared with placebo. 
This small vericiguat-induced decrease in BP did not translate into a meaningful exposure-
response relationship for the incidence of symptomatic hypotension or syncope – after first 
dose and during the further study.  
PK-PD analysis of SOCRATES-REDUCED and VICTORIA revealed a small hemodynamic 
effect (2.0-2.5 mmHg SBP reduction) following initiation of vericiguat treatment, but 
subsequent titrations to higher doses had minimal hemodynamic effects. Based on PK/PD 
modeling of data from SOCRATES-REDUCED, an additional 2.0-2.5 mmHg (i.e., 4.0-
5.0 mmHg total) decrease in SBP is predicted when the starting dose is increased from 2.5 mg 
to 5 mg. 
Finally, symptomatic hypotension and syncope events were collected as events of clinical 
interest in VICTORIA. Randomization to vericiguat resulted in a 1.8 percentage point 
increase of reported events of clinical interest of symptomatic hypotension or syncope 
compared to placebo over the duration of the study. These ECIs were more frequent during 
the earlier phases of the titration, though no clustering of symptomatic hypotension events 
was observed following the very first dose, or immediately following each titration step. 
4.4 
End-of-Study Definition 
The end of the study and primary completion date are defined as the date of the last visit of 
the last participant in the study globally.  
A participant is considered to have completed the study if he/she has completed Visit 2 (end 
of intervention visit).  
5. 
Study Population 
The study will enroll participants with chronic heart failure with ejection fraction <45%, with 
and without recent worsening HF. Enrollment caps will be applied to ensure enrollment of the 
desired proportion of participants with (group 1) and without (group 2) recent HF event 
(approximately 50% in each group). These two groups will also reflect contemporary 
standards of care in HF, with a goal of enrolling at least 30% of participants receiving an 
ARNI and 30% a SGLT2 inhibitor. The desired proportion of participants on GDMT may be 

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achieved by capping the number of participants not on ARNI or SGLT2i therapy. These 
enrollment caps will be managed in the IRT. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Participants (male and female) must be ≥18 years of age at the time of signing the 
informed consent. 
Type of Participant and Disease Characteristics 
2. Has an LVEF of <45% assessed within 12 months before Visit 1 by local any 
imaging method, and no subsequent LVEF measurement  > 45%. The most recent 
measurement must be used to determine eligibility. 
NOTE: Participants who have undergone a coronary revascularization (PCI or 
CABG), valve repair/replacement, or implantation of CRT device or any 
other surgical, device, or pharmacological intervention (i.e., initiation of a 
GDMT) that might improve LVEF, must have a measurement of LVEF 
<45% at least 3 months after the intervention to be eligible. 
3. SBP ≥ 100 mmHg at screening and Visit 1 (pre-treatment). 
4. No changes in GDMT dosing (including beta blockers, ACEI/ARBs, ARNI, MRAs, 
hydralazine-nitrate combinations, SGLT2 inhibitors, ivabradine, or oral diuretics)  
• Within 4 weeks of screening for participants without a HF event ≤6 months 
prior to screening 
• within 2 weeks of screening for participants with a HF event ≤6 months prior 
to screening 
• planned during study participation 
5. No expected medical procedures to occur 2 weeks before screening or during study 
participation.  
6. Participants with ( group 1) OR without (group 2) recent worsening HF event  
Group 1: History of chronic HF (NYHA class II symptomatic-IV) on GDMT with 
recent HF event within 6 months of screening or outpatient IV / SC diuretic use 
within 3 months before screening. 
 
OR 
 
Group 2: History of chronic HF (NYHA class II symptomatic-IV) on GDMT 
without recent HF event within 6 months of screening or outpatient IV / SC 
diuretic use within 3 months before screening. 
Sex and Contraceptive/Barrier Requirements 
7. Male or female 

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Contraceptive use by men and women should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies. 
Male participants: No measures. 
Female participants:  
• A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and one of the following conditions applies: 
• Is a woman of nonchildbearing potential (WONCBP) as defined in Section 
10.4. 
OR 
• Is a WOCBP and using a contraceptive method that is highly effective 
(with a failure rate of < 1% per year), with low user dependency, as 
described in Section 10.4 during the study intervention period and for at 
least 1 month after the last dose of study intervention. The investigator 
should evaluate the potential for contraceptive method failure (e.g., 
noncompliance, recently initiated) in relationship to the first dose of study 
intervention. 
• A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as 
required by local regulations) within 24h before the first dose of study intervention, 
see Section 8.3.5.  
• If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a 
serum pregnancy test is required. In such cases, the participant must be 
excluded from participation if the serum pregnancy result is positive.  
• Additional requirements for pregnancy testing during and after study intervention are 
located in Section 8.3.5. 
• The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy. 
Informed Consent 
8. Capable of giving signed informed consent as described in Section 10.1.3 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. 
5.2 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Cardiac conditions 
1. 
History of symptomatic hypotension 4 weeks before screening. 
2. 
Primary valvular heart disease requiring surgical procedure or intervention or has 
undergone a valvular surgical procedure or intervention within 3 months before 
Visit 1. 
3. 
Hypertrophic cardiomyopathy. 
4. 
Acute myocarditis or Takotsubo cardiomyopathy. 

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5. 
Awaiting heart transplantation (United Network for Organ Sharing Class 1A /1B 
or equivalent) or has or anticipates receiving an implanted ventricular assist 
device, or has received a heart transplant. 
6. 
Tachycardia-induced cardiomyopathy and/or uncontrolled tachyarrhythmia. 
7. 
Acute coronary syndrome (unstable angina, NSTEMI, or STEMI), undergone 
CABG or PCI within 3 months before Visit 1, or indication for coronary 
revascularization at the time of treatment assignment. 
8. 
Symptomatic carotid stenosis, TIA, or stroke within 3 months before Visit 1. 
9. 
History of repaired or unrepaired simple congenital heart disease (e.g., atrial or 
ventricular septal defects, or patent ductus arteriosus) with ongoing 
hemodynamically significant residual lesions, or any history of complex 
congenital heart disease (e.g. tetralogy of Fallot, transposition of the great arteries, 
single ventricle disease) regardless of repair status. 
10. 
Active endocarditis or constrictive pericarditis. 
11. 
Hemodynamic instability or hypovolemia within 4 weeks of screening and during 
the screening period.  
Medical Conditions 
12. 
Currently hospitalized. 
13. 
eGFR based on the CKD-EPI Creatinine Equation of <15 mL/min/1.73 m2 within 
30 days before Visit 1 or on chronic dialysis. For participants with multiple eGFR 
results during screening, the most recent value will be used to determine 
eligibility. 
14. 
Severe hepatic insufficiency defined as ALBI Grade 3 or hepatic encephalopathy, 
or has hepatic laboratory abnormalities (ALT or AST ≥3 × ULN or total bilirubin 
≥2 × ULN). Exceptions for Gilbert’s syndrome will be considered.  Albumin, 
ALT, AST, and total bilirubin results within 30 days before Visit 1 may be used 
for assessment of laboratory abnormalities or the calculation of the ALBI score. 
For participants with multiple albumin and/or total bilirubin results during 
screening, the most recent value for each test will be used to calculate ALBI 
score.  
15. 
Malignancy or other noncardiac condition limiting life expectancy to <3 years. 
16. 
Requires continuous home oxygen for severe pulmonary disease. 
17. 
Interstitial lung disease. 
18. 
Known allergy or hypersensitivity to vericiguat, any of its constituents, or any 
other sGC stimulator. 
19. 
Amyloidosis or sarcoidosis. 

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Prior/Concomitant Therapy 
20. 
Concurrent or anticipated concomitant use of PDE5 inhibitors such as vardenafil, 
tadalafil, and sildenafil during the study. 
21. 
Concurrent use of an sGC stimulator such as riociguat or vericiguat.  
22. 
Prior (within 2 weeks prior to screening) or anticipated concomitant 
administration of IV / SC diuretics or inotropes.  
Prior/Concurrent Clinical Study Experience 
23. 
Participated in another interventional clinical study or has been treated with 
another investigational product ≤30 days before Visit 1 or plans to participate in 
any other study or study intervention during this study. 
Other Exclusion Criteria 
24. 
Recent history (within the last year) of drug or alcohol abuse or dependence. 
25. 
Is pregnant or breastfeeding or plans to become pregnant or to breastfeed during 
the study. 
26. 
Medical disorder, condition, or history thereof that in the opinion of the 
investigator would impair the participant’s ability to participate in or complete the 
study. 
27. 
Is or has an immediate family member (e.g., spouse, parent/legal guardian, 
sibling, or child) who is investigational site or Sponsor staff directly involved with 
this study. 
5.3 
Lifestyle Considerations 
No restrictions required.  
5.4 
Screen Failures 
A screen failure occurs when a participant who has consented to participate in the clinical 
study but is not subsequently assigned to study intervention (vericiguat). A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure 
participants to meet the CONSORT publishing requirements and to respond to queries from 
regulatory authorities. Minimal information includes demography, screen failure details, last 
visit date and SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once. The following conditions are pre-requisites of re-screening: 
• A minimum of 1 month between the initial Screening visit and re-screening.  
• Before re-screening, new documented informed consent must be obtained.  
• Allocation of a new participant identification number. 
• All screening assessments for the study must be repeated. 

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5.5 
Criteria for Temporarily Delaying Study Intervention 
Not applicable. 
6. 
Study Intervention and Concomitant Therapy 
Study interventions are all pre-specified, investigational and non-investigational medicinal 
products, medical devices and other interventions (e.g., surgical and behavioral) intended to 
be administered to the study participants during the study conduct. 
Refer to the approved labeling / most recent investigator’s brochure for vericiguat for more 
details regarding study intervention properties and formulation. 
6.1 
Study Intervention Administered 
Study intervention should be taken orally with food at the same time each day, preferably in 
the morning.  If a dose is missed, it should be taken as soon as the participant remembers on 
the same day of the missed dose. But there should be consistency with respect to dosing 
intervals (the recommendation is to have at least a 20-hour interval between doses). 
Participants should not take 2 doses of study intervention on the same day. The investigator 
should be informed if the dose of Vericiguat taken has exceeded the scheduled dose. 
 
Table 6-1: Study Intervention Administered 
Intervention Label 
Vericiguat 
Intervention Name 
Vericiguat  
Intervention Description 
Tablet 5 mg/day 
Type  
Small molecule drug 
Dose Formulation 
Tablet 
Unit Dose Strength(s) 
5 mg 
Dosage Level(s) 
1 x 5 mg daily for 14 (+4) days 
Route of Administration 
Oral 
Use 
Experimental 
Sourcing 
Vericiguat will be provided centrally by the Sponsor. 
Packaging and Labeling 
Vericiguat tablets are available in high density 
polyethylene (HDPE) bottles with a white child 
resistant closure and induction seal. The packaging 
configuration is 18 tablets Vericiguat 5 mg per bottle. 
The bottles will be labelled as required per country 
requirement. 
Current/Former Name(s) or Alias(es) 
VERQUVO®, BAY 1021189 
 
6.2 
Preparation, Handling, Storage, and Accountability 
1. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply, prepare or administer study intervention.  
2. All study intervention must be stored in a secure, environmentally controlled, and 
monitored (manual or automated) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff. 

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3. The investigator is responsible for study intervention accountability, reconciliation, 
and record maintenance (i.e., receipt, reconciliation, and final disposition records). 
Study intervention returns, reconciliation and destruction return information will be 
captured in IRT. 
4. Further guidance and information for the final disposition of unused study 
interventions are provided in the site file.  
Handling/Storage/Accountability at the participant’s home 
Participants will follow the instructions provided by authorized site staff for storage and 
administration of study intervention at home, as well as for return of unused study 
intervention to the site. 
6.3 
Assignment to Study Intervention 
Randomization is not applicable for the study. All participants will receive the same study 
intervention. 
All participants will be centrally assigned to the study intervention using an IRT.  Enrollment 
caps defined in Section 5 will be managed by the IRT. Participants  will be given a unique 
PID (9 digit number) at the start of screening. The PID consists of a unique country number 
(digits 1 to 2), unique center number (digits 3 to 5) and the participant number within the 
center (digits 6 to 9). Participants who meet the entry criteria will be sequentially assigned to 
a treatment allocation number (TNR) in ascending order.  
6.4 
Blinding 
Not applicable. This is an open label study. For details on ensuring data integrity, see Section 
9.4. 
6.5 
Study Intervention Compliance 
A participant will receive exactly one bottle of vericiguat 5 mg tablets containing 18 tablets 
for any unforeseen events (e.g. loss or damage of single tablets or to allow for visit window). 
Compliance with study intervention (vericiguat) self-administered at home between Visit 1 
and Visit 2, will be assessed at Visit 2 (Day 14). Compliance will be assessed by counting 
returned tablets during the site visit and documented in the source documents and relevant 
form.  
Deviation(s) from the prescribed dosage regimen should be recorded. Any discrepancies 
between actual and expected amount of returned study intervention must be discussed with 
the participant at the time of the visit, and any explanation must be documented in the source 
records. An adequate record of receipt, distribution, and return/destruction of all study 
intervention must be kept. 
A record of the quantity of vericiguat tablets dispensed to and administered by each 
participant must be maintained and reconciled with study intervention and compliance 
records. An adequate record of receipt, distribution, and return/destruction of all study 
intervention must be captured on the dispensing log and/or in the IRT. Intervention start and 
stop dates, including dates for intervention delays will also be recorded in the CRF/ eCRF.  
Participants will be instructed to take study intervention as scheduled, and to return all of the 
study intervention packaging including unused study intervention and empty packaging. 

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Study intervention tablets not returned will be considered to have been taken unless otherwise 
specified. At the end of the study, any remaining study intervention will be collected and 
destroyed as per local regulations. Any discrepancies between the returned and expected 
returned study intervention should be explained. 
6.6 
Dose Modification 
The intention of the protocol is to maintain participants on the 5 mg dose of study intervention 
for the 2-week treatment period. Dose modifications are not planned within the scheme of this 
study. See Section 7.1.1 for details on temporary discontinuation of study intervention. 
6.6.1 
Retreatment Criteria  
All participants entered into the study will be treated from Day 1 to Day 14 inclusive. See 
Section 7.1.2 for details on treatment resumption after temporary interruption of study 
intervention. 
6.7 
Continued Access to Study Intervention after the End of the Study 
No continued access to the study intervention is planned following the end of the study. 
Participants may continue treatment on commercially available vericiguat at the discretion of 
their treating physician.  
6.8 
Treatment of Overdose 
In this study, an overdose is any dose higher than 5 mg vericiguat QD. 
Limited data are available with regard to overdosage in patients treated with vericiguat. In the 
event of an overdose, hypotension may result. Symptomatic treatment should be provided. 
Vericiguat is unlikely to be removed by hemodialysis because of high protein binding. 
In the event of an overdose, the investigator should: 
• 
Evaluate the participant to determine, in consultation with the medical monitor, if 
possible, whether study intervention should be interrupted or whether the dose should 
be reduced. 
• 
Closely monitor the participant for any AE/SAE and laboratory abnormalities  
• 
Document the quantity of the excess dose as well as the duration of the overdose. 
Decisions regarding dose interruptions or modifications following a suspected overdose will 
be made by the investigator in consultation with the medical monitor based on the clinical 
evaluation of the participant. 
 
6.9 
Prior and Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, recreational 
drugs, vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrollment or receives during the study must be recorded along with: 
• Reason for use 
• Dates of administration including start and end dates 

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• Dosage information including dose and frequency 
All participants should receive GDMT based on locally relevant guidelines such as ESC and 
ACC/AHA Guidelines for Management of Heart Failure applied individually to the discretion 
of the treating investigator and in line with individual tolerability, aiming at reflecting the 
current standard of care in the largest proportion of patients (Heidenreich et al. 2022, 
McDonagh et al. 2021). This includes medications such as beta blockers, ACEIs, ARBs, 
ARNI, MRAs, hydralazine-nitrate combinations, SGLT2 inhibitors, ivabradine, and cardiac 
device therapies such as ICDs and biventricular pacemakers. At least 30% of participants 
receiving an ARNI and 30% a SGLT2i should be enrolled in the study in order for the study 
to meet contemporary GDMT standards. Dose changes in GDMT medications (RAS 
blockade, Beta-blocker, MRA, or SGLT2i) or oral diuretics should be discouraged, except 
when mandated by known side-effects for individual drug classes (e.g., hyperkalemia for 
MRA or angioedema for ACE-inhibitors / ARNI).  Use of short and long-acting nitrates is 
permitted.  
Medications specifically prohibited in the exclusion criteria are not allowed for concomitant 
use with study intervention. In particular, the following are prohibited: 
• Use of IV diuretic or inotropes  
• PDE5i such as vardenafil, tadalafil, and sildenafil  
• sGC stimulators (e.g., riociguat or vericiguat) 
If there is a clinical indication for any medications specifically prohibited, discontinuation 
from study intervention may be required. This would result in not meeting criteria for the 
primary endpoint treatment tolerability. The investigator should discuss any questions 
regarding this with the medical monitor. The final decision on any medical therapy rests with 
the investigator and/or the participant’s primary physician. However, the decision to continue 
the participant on study intervention requires the mutual agreement of the investigator and the 
participant and the information of the Sponsor. 
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.9.1 
Rescue Medicine 
No rescue or supportive medications are specified for use in this study. 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal  
Discontinuation of specific sites or of the study as a whole are detailed in Section 10.1. 
7.1 
Discontinuation of Study Intervention  
Discontinuation is defined as the inability to complete treatment between Visit 1 and Visit 2. 
One missing/forgotten dose is permitted. All cases exceeding one missing dose will not be 
counted for the analysis of the primary endpoint. 
Participants may discontinue study intervention or be discontinued from the study at the 
discretion of the investigator should any untoward effect occur. In addition, a participant may 
be discontinued from study intervention by the investigator or the Sponsor if study 
intervention is inappropriate, the study plan is violated, or for administrative and/or other 
safety reasons. If study intervention is permanently discontinued, the participant should 

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remain in the study to be evaluated at Visit 2 (Day 14). Discontinuation of study intervention 
does not represent withdrawal from the study. 
A participant must be discontinued from study intervention, but continue to be monitored in 
the study for any of the following reasons: 
• The participant experiences symptomatic hypotension of moderate to severe intensity 
(Section 10.3.3) during the treatment period.  
• The participant or participant’s legally acceptable representative requests to 
discontinue study intervention. 
• The participant has a medical condition or personal circumstance, which in the opinion 
of the investigator and/or Sponsor, placed the participant at unnecessary risk from 
continued administration of study intervention. 
• The participant has a confirmed positive serum pregnancy test. 
7.1.1 
Temporary Interruption  
Temporary interruption of study intervention is permitted at any time during the study at the 
investigator’s discretion.  
7.1.2 
Rechallenge 
Upon temporary interruption of the study intervention, resumption of treatment at 5 mg is 
allowed if the interruption was not related to symptomatic hypotension of moderate to severe 
intensity. Intake should be resumed as soon as medically acceptable at the discretion of the 
investigator. In all cases, the reason for study intervention interruption must be recorded in the 
eCRF and the participant’s medical records.  
7.2 
Participant Discontinuation/Withdrawal from the Study 
• A participant may withdraw from the study at any time at the participant’s own 
request, for any reason (or without providing any reason).  
• A participant may be withdrawn at any time at the discretion of the investigator for 
safety, behavioral, or compliance reasons.  
• At the time of discontinuing from the study, if possible, an unscheduled visit should be 
conducted, as shown in the SoA. See SoA for the data to be collected at the time of 
study discontinuation and follow-up and for any further evaluations that need to be 
completed. 
• The participant will be permanently discontinued from the study intervention and the 
study at that time. 
• If the participant withdraws consent for disclosure of future information, the sponsor 
may retain and continue to use any data collected before such a withdrawal of consent. 
7.3 
Lost to Follow Up 
A participant will be considered lost to follow-up if the participant fails to return for Visit 2 
and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 

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• The site must attempt to contact the participant and reschedule the missed visit as soon 
as possible, counsel the participant on the importance of maintaining the assigned visit 
schedule, and ascertain whether the participant wishes to and/or should continue in the 
study. 
• Before a participant is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls, and if necessary, a certified letter to the participant’s last known mailing address 
or local equivalent methods). These contact attempts should be documented in the 
participant’s medical record. 
• Should the participant continue to be unreachable, the participant will be considered 
lost to follow up. 
8. 
Study Assessments and Procedures 
• Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed. 
• Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.  
• Procedures conducted as part of the participant’s routine clinical management (e.g., 
local laboratory) and obtained before signing of the ICF may be utilized for screening 
or baseline purposes provided the procedures met the protocol-specified criteria and 
were performed within the timeframe defined in the SoA.  
• In the event of a significant study-continuity issue (e.g. caused by a pandemic), 
alternate strategies for participant visits, assessments, medication distribution and 
monitoring may be implemented by the sponsor or the investigator, as per local health 
authority/ethics requirements.  
8.1 
Administrative and Baseline Procedures 
Administrative and baseline procedures are summarized in the SoA (Section 1.3). 
8.2 
Efficacy Assessments  
There are no efficacy assessments in this study. 
8.3 
Safety Assessments  
Planned timepoints for all safety assessments are provided in the SoA (Section 1.3). 
Participants will be assessed to determine tolerability as described in Section 9.3.2.  
8.3.1 
Physical Examinations 
• A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal and neurological systems. Height and 
weight will also be measured and recorded. 
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 

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8.3.2 
Vital Signs 
Skin temperature, and respiratory rate will be recorded at screening. 
BP and pulse rate will be assessed at the timepoints defined in Section 1.3. Measurements will 
be done in triplicate, and the average value will be recorded in the CRF.  
Accurate measurement of BP is essential to assess tolerability and to detect potential safety 
signals during the study. Several factors related to the participant can cause significant 
deviations in measured BP. These include room temperature, exercise, alcohol or nicotine 
consumption, positioning of the arm, muscle tension, bladder distension, talking, and 
background noise. 
• No other procedures may be performed during the BP and pulse rate measurements. 
• The participant should be asked to remove all clothing that covers the location of cuff 
placement. 
• BP and pulse rate measurements should be preceded by at least 10 minutes of rest with 
the participant comfortably seated in a chair with the legs uncrossed and the back and 
arm supported in a quiet setting without distractions. Measurements should not be 
made while the participant is on an examining table. The participant should be 
instructed to relax as much as possible and to not talk during the measurement 
procedure. 
• BP and pulse rate measurements will be assessed with the participant in a seated 
position with a completely automated device. Manual techniques will be used only if 
an automated device is not available. Whenever possible, BP measurements should be 
obtained using the same arm, same BP monitoring device, and same examiner at each 
visit. 
• The examiner should ensure that the middle of the cuff on the upper arm is at the level 
of the right atrium (the midpoint of the sternum). 
• 3 consecutive BP measurements will be recorded at intervals of approximately 2 
minutes apart. Record the time, positioning, and arm used for each measurement. 
• Assessment of pulse rate can be manual (rather than using an automated device). 
When performed manually, pulse rate must be measured in the brachial/radial artery 
for at least 30 seconds. 
8.3.3 
Electrocardiograms 
Single 12-lead ECG will be obtained at screening visit as outlined in the SoA and reviewed by 
an investigator or medically qualified designee (consistent with local requirements) using an 
ECG machine that automatically calculates the heart rate and measures pulse rate, QRS, QT, 
and QTc intervals, estimated by formulas Bazett - QTcB - and Fridericia – QTcF calculated 
by data management in the eCRF. 
Participants will refrain from nicotine-containing products and/or ingesting caffeine for at 
least 30 minutes preceding the procedure. 
12-lead ECGs should be performed after the participant has rested quietly for approximately 
10 minutes. 

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8.3.4 
Clinical Safety Laboratory Tests 
There are no clinical laboratory tests planned during this study, with the exception of the 
following: 
1. select clinical labs in the event that historical values are not available at screening  
2. serum pregnancy tests  in the event of an ambiguous urine result at Visit 1 
See Section 10.2 for details. 
8.3.5 
Pregnancy Testing 
• Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at Visit 1.  
• Additional serum or urine pregnancy tests may be performed, as determined necessary 
by the investigator or required by local regulation, to establish the absence of 
pregnancy at any time during the subject's participation in the study. 
NOTE: If a urine test cannot be confirmed as negative (e.g. an ambiguous result), a serum 
pregnancy test is required.  
8.4 
Adverse Events (AEs), Serious Adverse Events (SAEs) and Other Safety 
Reporting 
The definitions of adverse events (AEs) and serious adverse events (SAEs) can be found in 
Section 10.3. 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for 
following up all AEs (see Section 7). This includes events reported by the participant (or, 
when appropriate, by a caregiver, surrogate, or the participant’s legally authorized 
representative). 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3. 
8.4.1 
Time Period and Frequency for Collecting AE and SAE Information 
(S)AEs will be collected from the start of study intervention until the end-of-study visit (Visit 
2) at the timepoints specified in the SoA (Section 1.3). (S)AEs which are related to protocol-
required study procedures (e.g., (S)AE related to invasive study procedures or adjustment of 
therapy to comply with inclusion or exclusion criteria of the study) will be recorded as 
(S)AEs from the signing of the ICF. 
Any medical occurrences/conditions that begin in the period between signing ICF and the 
start of study intervention, and which are not related to a protocol-required study procedure, 
will be recorded as medical history/current medical conditions, not as AEs.  
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours of learning of the event, as indicated in 
Section 10.3. The investigator will submit any updated SAE data to the sponsor within 24 
hours of it being available. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion 
of the study participation. However, if the investigator learns of any SAE, including a death, 
at any time after a participant has been discharged from the study, and the investigator 

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considers the event to be reasonably related to vericiguat, the investigator must promptly 
notify the sponsor. 
8.4.2 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.4.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, and AEs of special interest (as defined in 
Section 8.4.6), will be followed until resolution, stabilization, the event is otherwise 
explained, or the participant is lost to follow-up (as defined in Section 7.3). Further 
information on follow-up procedures is provided in Section 10.3.  
8.4.4 
Regulatory Reporting Requirements for SAEs 
• Prompt notification by the investigator to the sponsor of an SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.  
• The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, institutional review boards 
(IRBs)/independent ethics committees (IECs), and investigators. 
• An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor will 
review and then file it along with the investigator’s brochure and will notify the 
IRB/IEC, if appropriate according to local requirements. 
• For all studies except those using medical devices, investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSARs) according to 
local regulatory requirements and sponsor policy and forwarded to investigators as 
necessary. 
8.4.5 
Pregnancy 
• Details of all pregnancies in female participants will be collected after the start of 
study intervention. The time period for reporting pregnancies should align with the 
time period for post-intervention contraception determined in Section 5.1. 
• If a pregnancy is reported, the investigator will record pregnancy information on the 
appropriate form and submit it to the sponsor within 24 hours of learning of the female 
participant pregnancy. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE. 
• Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs, and will be reported as 
such. 

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• The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate and 
the information will be forwarded to the sponsor. 
• Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
Section 8.4.4. While the investigator is not obligated to actively seek this information 
in former study participants, he or she may learn of an SAE through spontaneous 
reporting. 
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention or be withdrawn from the study. 
8.4.6 
Adverse Events of Special Interest  
Symptomatic hypotension is an AESI as assessed by the investigator. 
8.5 
Pharmacokinetics 
Pharmacokinetics are not evaluated in this study. 
8.6 
Pharmacodynamics 
Pharmacodynamics are not evaluated in this study. 
8.7 
Genetics 
Genetics are not evaluated in this study. 
8.8 
Biomarkers 
Biomarkers are not evaluated in this study. 
8.9 
Immunogenicity Assessments 
There are no immunogenicity assessments planned in this study. 
8.10 
Medical Resource Utilization and Health Economics 
Medical resource utilization and health economics parameters are not evaluated in this study. 
9. 
Statistical Considerations  
A statistical analysis plan will be prepared and will include a more technical and detailed 
description of the statistical analyses described in this section. This section is a summary of 
the planned statistical analyses of the most important endpoints including primary and 
secondary endpoints. The analysis and reporting will be done on all data from all participants 
at the time the study ends.  
9.1 
Statistical Hypotheses 
The analyses presented here will be descriptive in nature and thus no statistical hypothesis 
tests will be performed.  
9.1.1 
Multiplicity Adjustment 
There will be no multiplicity adjustment performed as it is not applicable to this study. 

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9.2 
Analysis Sets 
For the purposes of analysis, the following analysis set is defined: 
Participant Analysis Set 
Description 
Safety analysis set (SAF) 
• 
All participants assigned to investigational intervention who 
were exposed to study intervention at least once. 
9.3 
Statistical Analyses 
9.3.1 
General Considerations 
No hypothesis testing will be performed. Instead, given the nature of the trial, descriptive 
statistics will be provided for data collected. All analyses will be performed on the  safety 
analysis set (SAF).  
9.3.2 
Primary Endpoint Analysis 
9.3.2.1 
Definition of Endpoint(s).  
The primary endpoint of tolerability will be defined as the completion of the two-week 5 mg 
dose without discontinuation of study intervention and without symptomatic hypotension of 
moderate to severe intensity (Section 10.3.3) between Visit 1 and Visit 2. Participants with 
discontinuation of study intervention (described in Section 7.1) or symptomatic hypotension 
of moderate to severe intensity would not meet criteria for the primary endpoint of treatment 
tolerability. 
9.3.2.2 
Main Analytical Approach 
Participants who meet the criteria for tolerability as defined in Section 9.3.2.1 will be 
considered for the numerator in the proportion of participants reaching tolerability. The 
denominator will contain all participants who were included in the SAF. Thus in the case of 
100 participants included in the SAF, all 100 will be included as part of the denominator and 
the numerator will only include the number of participants who completed the two week 5 mg 
dose without any study intervention discontinuation and without symptomatic hypotension of 
moderate to severe intensity. There will be no imputation of missing data. A similar approach 
will be taken for the derivation of the proportion for the secondary endpoint analyses.  
9.3.2.3 
Sensitivity Analyses 
Additional proportions will be derived as sensitivity analyses. These analyses will be 
described in detail in the statistical analysis plan.   
9.3.2.4 
Supplementary Analyses 
There will be no supplementary analyses.  
9.3.3 
Secondary Endpoints Analysis  
Analysis of secondary endpoints will include tabulation of the following using descriptive 
statistics: 
• Any AE reported between Visit 1 and Visit 2  
• Proportion of participants who did not have an AE related to study intervention 
between Visit 1 and Visit 2 

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• Proportion of participants who took study intervention continuously between Visit 1 
and Visit 2 or were able to restart of study intervention after any temporary 
interruption  
9.4 
Interim Analysis 
No interim analysis is planned.  
Due to the nature of this study, participant-level treatment assignment information is available 
during study conduct.  
However, manual interim calculations of tolerability rates will not be done in order to protect 
the integrity of the study.  
9.5 
Sample Size Determination 
Based on the evidence of a strong safety profile of vericiguat and the 
 
, the sample size of approximately 100 participants is considered appropriate 
to assess the tolerability of the 5 mg initiation dose for vericiguat. 
10. 
Supporting Documentation and Operational Considerations 
10.1 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 
Regulatory and Ethical Considerations 
 
• This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) international ethical 
guidelines 
• Applicable ICH Good Clinical Practice (GCP) guidelines 
• Applicable laws and regulations 
• The protocol, protocol amendments, ICF, investigator’s brochure, and other relevant 
documents (e.g., advertisements) must be submitted, reviewed and approved in 
accordance with national legislation and undergo scientific and ethical assessment 
before the study is initiated.  
• Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study participants. Any substantial modification of 
the protocol will be submitted to the competent authorities as substantial amendments 
for approval, in accordance with ICH Good Clinical Practice and national and 
international regulations. 
• Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate 
hazard to study participants. 
• The investigator will be responsible for the following, as applicable: 
• Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/IEC 
CCI

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• Notifying the IRB/IEC of SAEs or other significant safety findings as 
required by IRB/IEC procedures 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of ICH guidelines, the IRB/IEC, and all other applicable local 
regulations 
10.1.2 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study. 
10.1.3 
Informed Consent Process 
• The investigator or the investigator’s representative will explain the nature of the 
study, including the risks and benefits, to the potential participants or their legally 
authorized representative and answer all questions regarding the study.  
• Potential participants must be informed that their participation is voluntary. 
Participants or their legally authorized representatives will be required to sign a 
statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
(HIPAA), where applicable, and the IRB/IEC or study center.  
• The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must also 
sign the ICF. 
• Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study.  
• A copy of the ICF(s) must be provided to the participants or their legally authorized 
representative.  
• Participants who are rescreened are required to sign a new ICF 
10.1.4 
Recruitment Strategy 
Detailed description of the recruitment strategy will be provided in country-specific 
documentation as required. 
10.1.5 
Data Protection 
• Participants will be assigned a unique identifier by the sponsor. Any participant 
records, datasets or biological samples that are transferred to the sponsor will contain 
the identifier only; participant names or any information which would make the 
participant identifiable will not be transferred. 
• Participants must be informed that their personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also 
be explained to the participant who will be required to give consent for their data to be 
used as described in the informed consent.  

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• Participants must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
• The contract between sponsor and study sites specifies responsibilities of the parties 
related data protection, including handling of data security breaches and respective 
communication and cooperation of the parties. 
• Information technology systems used to collect, process, and store study-related data 
are secured by technical and organizational security measures designed to protect such 
data against accidental or unlawful loss, alteration, or unauthorized disclosure or 
access. 
10.1.6 
Committees Structure 
Steering Committee  
The Steering Committee, which consists of external experts in the area of heart failure, will 
ensure the overarching integrity of the study, including: 
• Consultation on study-related activities, including guidance and support on study 
enrollment  
• Provision of recommendations regarding amendments to the protocol  
• Contribution to and oversight of publications and communication of study results 
• Participant safety: this will be continuously monitored by the Steering Committee and 
the sponsor, and include safety signal detection at any time during the study 
• All safety data collected will be summarized and reviewed by the Steering Committee 
and the sponsor for agreement of next steps. 
10.1.7 
Dissemination of Clinical Study Data 
Bayer fulfills its commitment to publicly disclose study results through posting the result of 
its studies on public registries in accordance with applicable law and regulations. 
Result Summaries of Bayer's sponsored clinical studies in drug development Phases 2, 3 and 
4 and Phase 1 studies in patients are provided in the Bayer Trials Explorer application after 
marketing authorization approval in line with the position of the global pharmaceutical 
industry associations laid down in the "Joint Position on the Disclosure of Clinical Trial 
Information via Clinical Trial Registries and Databases". In addition, results of clinical drug 
trials will be provided on the publicly funded websites, ClinicalTrials.gov, and EU Clinical 
Trials Information System (CTIS) in line with the applicable regulations. 
In accordance with the current EU regulations, result summaries will be submitted within one 
year from the end of the study in all participating countries for studies in adult populations, or 
within 6 months from the Last Patient Last Visit (LPLV) date for studies in pediatric 
populations. No preliminary data analysis based on regional requirements (e.g., on EU data 
only) will be performed, as this might compromise data integrity and the scientific validity of 
the study. Bayer commits to sharing upon request from qualified scientific and medical 
researchers patient-level clinical trial data, study-level clinical trial data, and protocols from 
clinical trials in patients for medicines and indications approved in the United States and 
European Union (EU) on or after January 01, 2014 as necessary for conducting legitimate 
research. 

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All Bayer-sponsored clinical trials are considered for publication in scientific literature, 
irrespective of whether the results of the clinical trials are positive or negative. 
10.1.8 
Data Quality Assurance 
• All participant data relating to the study will be recorded on printed or electronic 
CRFs unless transmitted to the sponsor or designee electronically (e.g., laboratory 
data). The investigator is responsible for verifying that data entries are accurate and 
correct by physically or electronically signing the CRF.  
• Guidance on completion of CRFs will be provided in CRF Completion Guidelines  
• The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source documents.  
• QTLs will be predefined in the integrated data review plan to identify systematic 
issues that can impact participant safety and/or reliability of study results. These 
predefined parameters will be monitored during the study and important deviations 
from the QTLs and remedial actions taken will be summarized in the clinical study 
report.  
• Monitoring details describing strategy, including definition of study critical data items 
and processes (e.g., risk-based initiatives in operations and quality such as risk 
management and mitigation strategies and analytical risk-based monitoring), methods, 
responsibilities and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are provided in the 
monitoring plan. 
• The sponsor or designee is responsible for the data management of this study 
including quality checking of the data.  
• The sponsor assumes accountability for actions delegated to other individuals (e.g., 
contract research organizations). 
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 15 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may 
be destroyed during the retention period without the written approval of the sponsor. 
No records may be transferred to another location or party without written notification 
to the sponsor.  
10.1.9 
Source Documents 
• Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 
• Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
• Definition of what constitutes source data and its origin can be found in the Source 
Data Location List  
• The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
• The sponsor or designee will perform monitoring to confirm that data entered into the 
CRF by authorized site personnel are accurate, complete, and verifiable from source 

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documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.  
10.1.10 
Study and Site Start and Closure 
Study Start 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The start of a clinical study in the EU is defined as the date on which the first site is declared 
by the sponsor to be ready to enroll in a country and clinical study will be open for 
recruitment of participants.  
Study/Site Termination 
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
For study termination: 
• Discontinuation of further study intervention development 
For site termination: 
• Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator 
• Total number of participants included earlier than expected. 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The investigator shall promptly inform the participant 
and should assure appropriate participant therapy and/or follow-up. 
 
10.1.11 
Publication Policy 
• The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments.  
• The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual 

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site data. In this case, a coordinating investigator will be designated by mutual 
agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
 
10.2 
Appendix 2: Clinical Laboratory Tests 
• The tests detailed in Table 10-1 may be performed by the local laboratory.  
• Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol. 
• Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. 
Table 10-1: Protocol-required Safety Laboratory Tests 
Laboratory 
Tests 
Parameters 
Pregnancy 
testing 
• 
Highly sensitive urine hCG pregnancy test (as needed for women of 
childbearing potential) 
Clinical 
Chemistry 
• 
eGFR, albumin, total bilirubin, , ALT and AST (as needed for screening if 
not available based on routine measurements [see Section 1.3]) 
Hematology 
• 
Hemoglobin 
ALT = alanine aminotransferase, AST = aspartate aminotransferase, eGFR = estimated 
glomerular filtration rate, HCG = human chorionic gonadotropin 
NOTES: 
Local urine pregnancy testing will be standard for the protocol unless serum testing is required by 
local regulation or IRB/IEC 
eGFR, albumin, hemoglobin, total bilirubin, ALT and AST values must be available at screening. Values 
obtained as part of routine management should be used if measured within 30 days prior to Visit 1. If 
data is unavailable, values should be determined using a local lab. 
Investigators must document their review of each laboratory safety report. 
10.3 
Appendix 3: AEs and SAEs: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
10.3.1 
Definition of AE 
AE Definition 
• An AE is any untoward medical occurrence in a clinical study participant, associated 
with the use of study intervention, whether or not considered related to the study 
intervention. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) associated 
with the use of study intervention. 
Events Meeting the AE Definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 

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medical and scientific judgment of the investigator (i.e., not related to progression of 
underlying disease). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae. 
• Sign, symptoms, or the clinical sequelae of suspected medication errors, misuse and 
abuse of either study intervention or a concomitant medication. Medication errors, 
misuse and abuse per se will not be reported as an AE/SAE, unless it is resulting in 
AE/SAE. Such medication errors, misuse and abuse should be reported regardless of 
sequelae. 
Events NOT Meeting the AE Definition 
• Any abnormal laboratory findings or other abnormal safety assessments that are 
associated with the underlying disease, unless judged by the investigator to be more 
severe than expected for the participant’s condition 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition 
• Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital) 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen 
 
10.3.2 
Definition of SAE 
An SAE is defined as any untoward medical occurrence that, at any dose, meets the one or 
more of the criteria listed: 
a. Results in death 
b. Is life threatening 
• The term life threatening in the definition of serious refers to an event in which the 
participant 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 

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• In general, hospitalization signifies that the participant has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether hospitalization occurred or was necessary, the 
AE should be considered serious. 
• Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
d. Results in persistent or significant disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e. Is a congenital anomaly/birth defect 
f. Other situations: 
• Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations such as significant medical 
events that that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the participant or may require medical or surgical 
intervention to prevent one of the other outcomes listed in the above definition. These 
events should usually be considered serious. 
o Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias, convulsions, or development of intervention dependency or 
intervention abuse. 
10.3.3 
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
• When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event. 
• The investigator will then record all relevant AE/SAE information. 
• It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the sponsor in lieu of completion of the required form. 
• There may be instances when copies of medical records for certain cases are requested 
by the sponsor. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to the sponsor. 
• The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE. 

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Assessment of Intensity  
• The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to one of the following categories:  
• Mild: A type of adverse event that is usually transient and may require only 
minimal treatment or therapeutic intervention. The event does not generally 
interfere with usual activities of daily living. 
• Moderate: A type of adverse event that is usually alleviated with additional 
specific therapeutic intervention. The event interferes with usual activities of daily 
living, causing discomfort but poses no significant or permanent risk of harm to 
the research participant.   
• Severe: A type of adverse event that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic 
intervention.   
Assessment of Causality 
• The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. The investigator will use clinical judgment to 
determine the relationship. 
• A reasonable possibility of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• For causality assessment, the investigator will also consult the investigator’s brochure 
and/or product information, for marketed products. 
• The investigator must review and provide an assessment of causality for each AE/SAE 
and document this in the medical notes. There may be situations in which an SAE has 
occurred and the investigator has minimal information to include in the initial report to 
the sponsor. However, it is very important that the investigator always make an 
assessment of causality for every event before the initial transmission of the SAE 
data to the sponsor. 
• The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
Follow-up of AEs and SAEs 
• The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
sponsor to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
• If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide the sponsor with a copy of any postmortem 
findings including histopathology, if available. 

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• New or updated information will be recorded in the originally submitted documents. 
• The investigator will submit any updated SAE data to the sponsor within 24 hours of 
receipt of the information. 
 
10.3.4 
Reporting of SAEs 
SAE Reporting to the sponsor via an Electronic Data Collection Tool 
• The primary mechanism for reporting an SAE to the sponsor will be the electronic 
data collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data 
transmission (see next section) to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see next 
section) or to the medical monitor by telephone. 
• Contacts for SAE reporting can be found in Investigator Site File. 
SAE Reporting to the Sponsor via Paper Data Collection Tool 
• Email transmission of the SAE paper data collection tool is the preferred method to 
transmit this information to the sponsor. 
• In rare circumstances and if email transmission is not feasible, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service. 
• Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE data collection tool within the designated reporting 
timeframes. 
• Contacts for SAE reporting can be found in the Investigator Site File. 
10.4 
Appendix 4: Contraceptive and Barrier Guidance  
10.4.1 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below). 

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Women in the following categories are considered WOCBP (fertile) 
1. Following menarche 
2. From the time of menarche until becoming postmenopausal unless permanently sterile (see 
below): 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
• A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using 
hormonal contraception or hormonal replacement therapy (HRT). 
However, in the absence of 12 months of amenorrhea, confirmation with 
more than one FSH measurement > 40 mIU/mL (for United States only: 
FSH levels > 40 mIU/mL and estradiol < 20 pg/mL) is required.  
• Females on HRT and whose menopausal status is in doubt will be required 
to use one of the non-estrogen hormonal highly effective contraception 
methods if they wish to continue their HRT during the study. Otherwise, 
they must discontinue HRT to allow confirmation of postmenopausal status 
before study enrollment. 
• Permanent sterilization methods (for the purpose of this study) include: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
• For individuals with permanent infertility due to an alternate medical cause 
other than the above, (e.g., Mullerian agenesis, androgen insensitivity, 
gonadal dysgenesis), investigator discretion should be applied to 
determining study entry. 
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered. 
Woman of Nonchildbearing Potential (WONCBP) 
Women in the following categories are considered WONCBP: 
1. Premenopausal female with permanent infertility due to one of the following: 
a) 
Documented hysterectomy 
b) 
Documented bilateral salpingectomy 
c) 
Documented bilateral oophorectomy 
d) 
For individuals with permanent infertility due to an alternate medical cause other 
than the above, (e.g., Mullerian agenesis, androgen insensitivity, gonadal 
dysgenesis), investigator discretion should be applied to determining study entry. 
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 

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2. 
Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
• A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using 
hormonal contraception or hormonal replacement therapy (HRT). 
However, in the absence of 12 months of amenorrhea, confirmation with 
more than one FSH measurement >40 mIU/mL (for United States only: 
FSH levels >40 mIU/mL and estradiol <20pg/mL) is required.   
• Females on HRT and whose menopausal status is in doubt must 
discontinue HRT to allow confirmation of postmenopausal status before 
study enrollment. 
 
10.4.2 
Contraception Guidance 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
Highly Effective Methodsb That Have Low User Dependency Failure rate of < 1% per year when used 
consistently and correctly. 
• Implantable progestogen-only hormone contraception associated with inhibition of ovulationc 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS)c 
• Bilateral tubal occlusion 
• Azoospermic partner (vasectomized or due to a medical cause) 
Azoospermia is a highly effective contraceptive method provided that the partner is the sole sexual partner 
of the woman of childbearing potential and the absence of sperm has been confirmed. If not, an additional 
highly effective method of contraception should be used. Spermatogenesis cycle is approximately 90 days. 
Note: documentation of azoospermia for a male participant can come from the site personnel’s review of 
the participant’s medical records, medical examination, or medical history interview. 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant. 
a) Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies. 
b) Failure rate of < 1% per year when used consistently and correctly. Typical use failure rates differ from 
those when used consistently and correctly. 
c) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
contraceptive methods are limited to those which inhibit ovulation as the primary mode of action.  
Note: Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception for 
this study.  Male condom and female condom should not be used together (due to risk of failure from 
friction). 
 

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11. 
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