A Pivotal Phase 3 Randomized, Placebo-controlled Clinical Study to Evaluate the Efficacy and Safety of the sGC Stimulator Vericiguat/MK-1242 in Adults With Chronic Heart Failure With Reduced Ejection Fraction
Phase: PHASE3
Conditions: Chronic Heart Failure With Reduced Ejection Fraction
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT number:                NCT05093933
Document Date:            25-Jan-2024
A Pivotal Phase 3 Randomized, Placebo-controlled 
Clinical Study to Evaluate the Efficacy and Safety of 
the sGC Stimulator Vericiguat/MK-1242 in Adults With 
Chronic Heart Failure With Reduced Ejection Fraction

PRODUCT: MK-1242
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TITLE PAGE
THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Pivotal Phase 3 Randomized, Placebo-controlled Clinical Study to 
Evaluate the Efficacy and Safety of the sGC Stimulator Vericiguat/MK-1242 in Adults With 
Chronic Heart Failure With Reduced Ejection Fraction 
Protocol Number: 035-03
Compound Number: MK-1242
Sponsor Name: Merck Sharp & Dohme LLC (hereafter called the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
NCT
Not applicable
EU CT
2022-500881-80-00
EudraCT
2020-005941-18
JAPIC-CT
Not applicable
WHO
Not applicable
UTN
Not applicable
IND
116,743
Approval Date: 25 January 2024
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study 
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 03
25-JAN-2024
The purpose of this amendment is to update the 
SAP.
Amendment 02
01-AUG-2022
Merck Sharp & Dohme Corp. underwent an 
entity name and address change to Merck Sharp 
& Dohme LLC, Rahway, NJ, USA. This 
conversion resulted only in an entity change and 
update to the address.
Amendment 01
28-JAN-2022
The purpose of this amendment is to provide 
country-specific adverse event reporting 
requirements for sites in Germany.
Original Protocol
14-JUL-2021
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 03
Overall Rationale for the Amendment:
The purpose of this amendment is to update the SAP.
Summary of Changes Table
Section Number 
and Name
Description of Change
Brief Rationale
Primary Reason for Amendment
Section 9.1,
Statistical Analysis 
Plan Summary 
Modified IA by removing the number of 
required events for primary endpoint and 
triggering IA and final analysis based on 
number of CV deaths.
This change was made to address new data. The 
observed ratio of CV death rate to the primary 
endpoint event rate is lower than projected due 
to the slower than anticipated event rate for CV 
deaths. Therefore, the IA and final analysis 
triggers will be based solely on the number of 
CV death events.
Description of 
Change
Section Number 
and Name
Description of Change
Brief Rationale
Additional Changes
Synopsis, Duration 
of participation
Updated the definition for duration of 
participation.
Refer to rationale for Section 9.1.
Section 1.3.2,
Schedule of 
Activities –
Participants Who 
Prematurely 
Discontinue Study 
Intervention
Specified that study contacts should be 
calculated relative to randomization.
To clarify when to initiate safety follow-up 
contact and how to calculate timing of safety 
follow-up contacts for participants who 
prematurely discontinue study intervention.
Section 4.1, Overall 
Design
Updated timing of Final Visit.
Refer to rationale for Section 9.1.
Section 4.4.2, 
Primary Completion 
Date
Updated definition of Primary Completion 
Date.
Refer to rationale for Section 9.1.
Section 6.4, Study 
Intervention 
Compliance
Rephrased guidance on study intervention 
compliance for instance of protocol-specified 
study intervention interruptions
To clarify range of compliance not considered 
to be a protocol deviation.
Rephrased timing of assessments of 
compliance.
To clarify at which visits compliance will be 
assessed.
Section 6.6, Dose 
Modification 
(Titration)
Added additional guidance for initiation, up-
titration, and restart of study intervention. 
To clarify that mean SBP should be
≥100 mmHg for initiation, up-titration, or 
restarting study intervention.
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Description of 
Change
Section Number 
and Name
Description of Change
Brief Rationale
Section 6.6.1,
Resumption of Study 
Intervention 
Following 
Interruption
Rephrased considerations for restarting study 
intervention.
To clarify procedure for restarting study 
intervention after interruption for reasons other 
than intolerability. 
Section 7.1,
Discontinuation of 
Study Intervention
Clarified discontinuation criteria related to 
eGFR. 
To provide additional guidance for participants 
requiring short-term or chronic dialysis during 
the study.
Added language allowing participants to 
restart study intervention.
To clarify that participants are now allowed to 
restart study intervention after Sponsor 
consultation.
Section 8.4.1, Time 
Period and 
Frequency for 
Collecting AE, SAE, 
and Other 
Reportable Safety 
Event Information
Added a footnote to Table 3.
To clarify the regulatory reporting 
requirements for events meeting serious criteria 
that have been determined not to meet endpoint 
criteria.
Section 8.6.1, Blood 
Collection for 
Plasma MK-1242
Added that date and time of sample collection 
and last dose of study intervention is 
required.
To clarify documentation requirements are for 
all PK samples. 
Section 8.11.3,
Participants Who 
Prematurely 
Discontinue Study 
Intervention
Clarified follow-up contact scheduling and 
timing.
Refer to rationale for Section 1.3.2.
Section 9.6.1 
Efficacy Analyses
Updated definition of primary completion date
Refer to rationale for Section 9.1.
Section 9.7, Interim 
Analyses
Modified timing of efficacy IA.
Refer to rationale for Section 9.1.
Section 9.8,
Multiplicity
Updated criteria for IA success.
Refer to rationale for Section 9.1.
Section 9.9, Sample 
Size and Power 
Calculations
Clarified the power of the trial is based on the 
CV death endpoint.
The power to detect a difference in the primary 
endpoint is revised to reflect the result of sizing 
the trial based on the CV deaths.
Section 10.8,
Determination of 
ALBI Grade
Corrected ALBI Grade 2 score.
To align ALBI score with previous protocol 
clarification letter correction.
Throughout
Minor administrative, formatting, 
grammatical, and/or typographical changes 
were made throughout the document.
To ensure clarity and accurate interpretation of 
the intent of the protocol.
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TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................14
1.1
Synopsis.................................................................................................................14
1.2
Schema ..................................................................................................................18
1.3
Schedule of Activities...........................................................................................19
1.3.1
Schedule of Activities – All Participants.....................................................19
1.3.2
Schedule of Activities – Participants Who Prematurely Discontinue 
Study Intervention........................................................................................23
2
INTRODUCTION..........................................................................................................25
2.1
Study Rationale....................................................................................................25
2.2
Background ..........................................................................................................25
2.2.1
Pharmaceutical and Therapeutic Background .............................................25
2.3
Benefit/Risk Assessment......................................................................................26
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................27
4
STUDY DESIGN............................................................................................................30
4.1
Overall Design......................................................................................................30
4.2
Scientific Rationale for Study Design.................................................................30
4.2.1
Rationale for Endpoints ...............................................................................31
4.2.1.1
Efficacy Endpoints.............................................................................31
4.2.1.2
Safety Endpoints................................................................................31
4.2.1.3
Pharmacokinetic Endpoints ...............................................................32
4.2.1.4
Planned Exploratory Biomarker Research.........................................32
4.2.1.4.1
Planned Genetic Analysis ........................................................32
4.2.1.5
Future Biomedical Research..............................................................32
4.2.2
Rationale for the Use of Comparator/Placebo .............................................33
4.3
Justification for Dose...........................................................................................33
4.3.1
Rationale for the Dose Selection/Regimen/Modification............................33
4.4
Beginning and End-of-Study Definition ............................................................33
4.4.1
Clinical Criteria for Early Study Termination .............................................34
4.4.2
Primary Completion Date ............................................................................34
5
STUDY POPULATION ................................................................................................35
5.1
Inclusion Criteria.................................................................................................35
5.2
Exclusion Criteria................................................................................................37
5.3
Lifestyle Considerations......................................................................................39
5.3.1
Meals and Dietary Restrictions....................................................................39
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................39
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5.3.3
Activity Restrictions ....................................................................................39
5.4
Screen Failures.....................................................................................................39
5.5
Participant Replacement Strategy......................................................................39
6
STUDY INTERVENTION............................................................................................40
6.1
Study Intervention(s) Administered...................................................................40
6.1.1
Medical Devices...........................................................................................42
6.2
Preparation/Handling/Storage/Accountability .................................................42
6.2.1
Dose Preparation..........................................................................................42
6.2.2
Handling, Storage, and Accountability........................................................42
6.3
Measures to Minimize Bias: Randomization and Blinding..............................43
6.3.1
Intervention Assignment..............................................................................43
6.3.2
Stratification.................................................................................................43
6.3.3
Blinding........................................................................................................43
6.4
Study Intervention Compliance..........................................................................43
6.5
Concomitant Therapy..........................................................................................44
6.5.1
Rescue Medications and Supportive Care ...................................................45
6.6
Dose Modification (Titration).............................................................................45
6.6.1
Resumption of Study Intervention Following Interruption .........................46
6.7
Intervention After the End of the Study............................................................47
6.8
Clinical Supplies Disclosure................................................................................47
6.9
Standard Policies..................................................................................................47
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................48
7.1
Discontinuation of Study Intervention...............................................................48
7.2
Participant Withdrawal From the Study...........................................................49
7.3
Lost to Follow-up .................................................................................................49
8
STUDY ASSESSMENTS AND PROCEDURES........................................................50
8.1
Administrative and General Procedures ...........................................................50
8.1.1
Informed Consent.........................................................................................50
8.1.1.1
General Informed Consent.................................................................51
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................51
8.1.2
LVEF Assessment........................................................................................51
8.1.3
Inclusion/Exclusion Criteria ........................................................................52
8.1.4
Participant Identification Card.....................................................................52
8.1.5
Medical History ...........................................................................................52
8.1.6
Prior and Concomitant Medications Review...............................................52
8.1.6.1
Prior Medications...............................................................................52
8.1.6.2
Concomitant Medications..................................................................52
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8.1.7
Assignment of Screening Number...............................................................52
8.1.8
Assignment of Treatment/Randomization Number.....................................53
8.1.9
Study Intervention Administration ..............................................................53
8.1.9.1
Timing of Dose Administration.........................................................53
8.1.10
Study Intervention Compliance ...................................................................53
8.1.11
Discontinuation and Withdrawal .................................................................53
8.1.11.1
Withdrawal From Future Biomedical Research ................................54
8.1.12
Participant Blinding/Unblinding..................................................................54
8.1.13
Calibration of Equipment.............................................................................55
8.2
Efficacy Assessments ...........................................................................................55
8.2.1
Clinical Events Assessment.........................................................................55
8.2.2
New York Heart Association Functional Classification of Heart Failure ...55
8.2.3
EuroQol Group 5-Dimension, 5-level Questionnaire..................................55
8.2.4
Kansas City Cardiomyopathy Questionnaire...............................................56
8.2.5
Vital Status Assessment...............................................................................56
8.3
Safety Assessments...............................................................................................56
8.3.1
Physical Examinations.................................................................................57
8.3.2
Vital Signs....................................................................................................57
8.3.3
Dose Assessment and Modification.............................................................58
8.3.4
Electrocardiograms ......................................................................................58
8.3.5
Clinical Safety Laboratory Assessments .....................................................59
8.3.6
Pregnancy Testing........................................................................................59
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................60
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................60
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......63
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...63
8.4.4
Regulatory Reporting Requirements for SAE .............................................63
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................64
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................64
8.4.7
Events of Clinical Interest............................................................................65
8.5
Treatment of Overdose........................................................................................65
8.6
Pharmacokinetics.................................................................................................66
8.6.1
Blood Collection for Plasma MK-1242 .......................................................66
8.7
Pharmacodynamics..............................................................................................66
8.8
Biomarkers ...........................................................................................................66
8.8.1
Planned Genetic Analysis Sample Collection..............................................67
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8.8.2
Exploratory Biomarker Sample Collection..................................................67
8.9
Future Biomedical Research Sample Collection...............................................67
8.10
Health Economics, Medical Resource Utilization and Health Economics......67
8.11
Visit Requirements...............................................................................................67
8.11.1
Screening Period ..........................................................................................68
8.11.1.1
Target Screening (Optional) ..............................................................68
8.11.1.2
Screening Visit...................................................................................68
8.11.2
Treatment Period..........................................................................................68
8.11.2.1
Randomization Visit ..........................................................................68
8.11.2.2
Unscheduled Visits ............................................................................68
8.11.3
Participants Who Prematurely Discontinue Study Intervention..................69
8.11.4
14-day Safety Contact..................................................................................69
8.11.5
Primary Completion Date Requirements.....................................................69
8.11.5.1
Final Visit...........................................................................................69
8.11.5.2
Final Contact......................................................................................69
9
STATISTICAL ANALYSIS PLAN .............................................................................70
9.1
Statistical Analysis Plan Summary.....................................................................70
9.2
Responsibility for Analyses/In-house Blinding .................................................72
9.3
Hypotheses/Estimation ........................................................................................72
9.3.1
Estimands.....................................................................................................72
9.4
Analysis Endpoints...............................................................................................73
9.4.1
Efficacy Endpoints.......................................................................................73
9.4.2
Safety Endpoints..........................................................................................73
9.5
Analysis Populations............................................................................................73
9.6
Statistical Methods...............................................................................................74
9.6.1
Efficacy Analyses ........................................................................................74
9.6.2
Safety Analyses............................................................................................76
9.6.3
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses.......................................................................................................77
9.7
Interim Analyses ..................................................................................................78
9.8
Multiplicity ...........................................................................................................79
9.9
Sample Size and Power Calculations .................................................................80
9.9.1
Rationale for Incidence Rate Assumption ...................................................80
9.10
Subgroup Analyses...............................................................................................81
9.11
Compliance (Medication Adherence).................................................................82
9.12
Extent of Exposure...............................................................................................82
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................83
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........83
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10.1.1
Code of Conduct for Interventional Clinical Trials .....................................83
10.1.2
Financial Disclosure.....................................................................................86
10.1.3
Data Protection.............................................................................................87
10.1.3.1
Confidentiality of Data ......................................................................89
10.1.3.2
Confidentiality of Participant Records...............................................89
10.1.3.3
Confidentiality of IRB/IEC Information............................................89
10.1.4
Committees Structure...................................................................................90
10.1.4.1
Steering Committee ...........................................................................90
10.1.4.2
Executive Oversight Committee........................................................90
10.1.4.3
External Data Monitoring Committee ...............................................90
10.1.4.4
Clinical Events Committee (CEC).....................................................91
10.1.4.5
National Leader Committee...............................................................91
10.1.5
Publication Policy........................................................................................91
10.1.6
Compliance with Study Registration and Results Posting Requirements ...91
10.1.7
Compliance with Law, Audit, and Debarment ............................................92
10.1.8
Data Quality Assurance ...............................................................................92
10.1.9
Source Documents .......................................................................................93
10.1.10
Study and Site Closure.................................................................................94
10.2
Appendix 2: Clinical Laboratory Tests..............................................................95
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................97
10.3.1
Definitions of Medication Error, Misuse, and Abuse..................................97
10.3.2
Definition of AE ..........................................................................................97
10.3.3
Definition of SAE ........................................................................................99
10.3.4
Additional Events Reported.......................................................................100
10.3.5
Recording AE and SAE .............................................................................100
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................104
10.4
Appendix 4: Medical Device and Drug–Device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................105
10.5
Appendix 5: Contraceptive Guidance..............................................................106
10.5.1
Definitions..................................................................................................106
10.5.2
Contraceptive Requirements......................................................................107
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................108
10.7
Appendix 7: Country-specific Requirements..................................................112
10.7.1
Country-specific Requirements for Germany............................................112
10.7.2
Country-specific Requirements for China .................................................112
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10.7.3
Country-specific Requirements for South Korea.......................................112
10.8
Appendix 8: Determination of ALBI Grade....................................................113
10.9
Appendix 9: Abbreviations ...............................................................................114
11
REFERENCES.............................................................................................................118
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LIST OF TABLES
Table 1
NT-proBNP Inclusion Criteria.....................................................................36
Table 2
Study Interventions......................................................................................41
Table 3
Systolic Blood Pressure Criteria for Study Intervention Dose 
Modification.................................................................................................................46
Table 4
Instructions for Resumption of Study Intervention After Interruption 
due to Intolerability......................................................................................................47
Table 5
New York Heart Association Functional Classification..............................55
Table 6
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events...................................................................................62
Table 7
Primary Analysis Strategy for Efficacy Variables.......................................76
Table 8
Analysis Strategy for Safety Parameters......................................................77
Table 9
Protocol-required Laboratory Assessments.................................................96
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LIST OF FIGURES
Figure 1
Study Design................................................................................................18
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Pivotal Phase 3 Randomized, Placebo-controlled Clinical Study to 
Evaluate the Efficacy and Safety of the sGC Stimulator Vericiguat/MK-1242 in Adults With 
Chronic Heart Failure With Reduced Ejection Fraction 
Short Title: Vericiguat Outcomes Study in HFrEF 
Acronym: VICTOR
Hypotheses, Objectives, and Endpoints:
In adults with chronic heart failure with reduced ejection fraction receiving guideline-
directed medical therapy for heart failure: 
Primary Objective
Primary Endpoint
Objective: To evaluate the efficacy of 
vericiguat compared with placebo on 
reducing the risk of cardiovascular death or
heart failure hospitalization
Hypothesis (H1): Vericiguat is superior to 
placebo in reducing the risk of 
cardiovascular death or heart failure 
hospitalization.
Time from randomization to the first event 
of cardiovascular death or heart failure 
hospitalization
Secondary Objectives
Secondary Endpoints
Objective: To evaluate the efficacy of 
vericiguat compared with placebo on 
reducing the risk of cardiovascular death
Hypothesis (H2): Vericiguat is superior to 
placebo in reducing the risk of 
cardiovascular death.
Time from randomization to cardiovascular 
death
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Objective: To evaluate the efficacy of 
vericiguat compared with placebo in 
reducing the risk of heart failure 
hospitalization
Hypothesis (H3): Vericiguat is superior to 
placebo in reducing the risk of the first 
event of heart failure hospitalization.
Hypothesis (H4): Vericiguat is superior to 
placebo in reducing the risk of all heart 
failure hospitalization events.
-Time from randomization to the first event 
of heart failure hospitalization
-Time from randomization to all heart 
failure hospitalization events
Objective: To evaluate the efficacy of 
vericiguat compared with placebo in 
reducing the risk of all-cause mortality or 
heart failure hospitalization
Hypothesis (H5): Vericiguat is superior to 
placebo in reducing the risk of all-cause 
mortality or heart failure hospitalization.
Time from randomization to the first event 
of all-cause mortality or heart failure 
hospitalization
Objective: To evaluate the efficacy of 
vericiguat compared with placebo in 
reducing the risk of all-cause mortality
Hypothesis (H6): Vericiguat is superior to 
placebo in reducing the risk of all-cause 
mortality.
Time from randomization to all-cause 
mortality
Objective: To evaluate the safety and 
tolerability of vericiguat compared with 
placebo
-Selected nonserious adverse events
-Serious adverse events
-Events of clinical interest
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Overall Design:
Study Phase
Phase 3
Primary Purpose
Treatment
Indication
Ejection fraction abnormal
Population
Participants with chronic HRrEF
Study Type
Interventional
Intervention Model
Parallel
This is a multi site study.
Type of Control
Placebo
Study Blinding
Double-blind with in-house blinding
Blinding Roles
Participants or Subjects, Care Provider, 
Investigator, Outcomes Assessor, and 
Sponsor
Estimated Duration of Study
The Sponsor estimates that the study will
require approximately 43 months from the 
time the first participant (or their legally 
acceptable representative) provides 
documented informed consent until the last 
participant’s last study-related contact.
Number of Participants:
Approximately 6000 participants will be randomized.
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Intervention Groups and Duration:
Arm Name
Intervention 
Name
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
Vericiguat
MK-1242 
(vericiguat)
2.5 mg, 5 mg, 
and 10 mg
2.5 mg, 5 mg, 
or 10 mg QD
Oral
Titration:
2.5 mg 
titrated to 
5 mg titrated 
to 
10 mg / 
Day 1 until 
end of 
treatment
Test Product
Placebo
Placebo for 
MK-1242 
(vericiguat)
0 mg
matching 
placebo for 
2.5 mg, 5 mg, 
and 10 mg
0 mg QD
Oral
Sham Titration:
0 mg / 
Day 1 until 
end of 
treatment
Placebo
Other current or former name(s) or alias(es) for study intervention(s) are as follows: MK-
1242 and BAY 1021189.
Total Number of Intervention Groups/Arms
2
Duration of Participation
Study participants will participate in the 
study for a median follow-up of 
approximately 25 months from the time the 
participant provides documented informed 
consent through the Final Contact. After a 
screening phase of up to 30 days, each 
participant will receive assigned 
intervention until the required number of 
CV deaths (approximately 590) are 
observed in this study. All participants will 
be followed for efficacy endpoints until the 
end-of-study. After the end of treatment, 
each participant will be followed for 
14 days for safety.
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Study Governance Committees:
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Events Committee
Yes
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Participants: No
A list of abbreviations is in Appendix 9.
1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Design
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1.3
Schedule of Activities
1.3.1
Schedule of Activities – All Participants
Study Period:
Screening
Intervention
Follow-up Notes
Visit Number/Title:
1
Screening
2 
Random
ization
3
4
5
n
Final 
Visit
14-day 
Safety 
Contact
Visits 1 and 2 may occur on the same day 
(see Sec. 8.11.1.2 and 8.11.2.1).
Visit dates should be calculated relative to 
Randomization (Day 1).
For participants who prematurely 
discontinue study intervention, see 
Sec. 1.3.2.
Scheduled Hour, Day, 
Week, etc, and 
Window:
Days
-30 to 1
Day 1
Day 14 
±4 days
Day 28 
±4 days
Week 24 
±14 days
Q24W
±14 days
After 
Primary 
Complet
ion Date
14 days 
After 
Last Dose
Administrative Procedures
Informed Consent
X
Participants may provide documented 
consent for an optional Target Screening 
blood draw before the Screening Visit
(Sec. 8.11.1.1).
Informed Consent for 
Future Biomedical 
Research
X
Participation in FBR is optional. 
Echocardiogram
X
If needed for inclusion criterion No.6 
(Sec. 5.1).
Inclusion/Exclusion 
Criteria
X
X
Participant Identification 
Card
X
X
Visit 2: Add randomization number.
Medical History
X
X
Screening: Collect participant 
demographics.
Visit 2: Update with any changes since 
screening.
Prior/Concomitant 
Medication Review
X
X
X
X
X
X
X
X
See Sec. 6.5 for reporting requirements.
Intervention
Randomization
X
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Study Period:
Screening
Intervention
Follow-up Notes
Visit Number/Title:
1
Screening
2 
Random
ization
3
4
5
n
Final 
Visit
14-day 
Safety 
Contact
Visits 1 and 2 may occur on the same day 
(see Sec. 8.11.1.2 and 8.11.2.1).
Visit dates should be calculated relative to 
Randomization (Day 1).
For participants who prematurely 
discontinue study intervention, see 
Sec. 1.3.2.
Scheduled Hour, Day, 
Week, etc, and 
Window:
Days
-30 to 1
Day 1
Day 14 
±4 days
Day 28 
±4 days
Week 24 
±14 days
Q24W
±14 days
After 
Primary 
Complet
ion Date
14 days 
After 
Last Dose
Vericiguat/Placebo 
Administration/
Dispensing
X
X
X
X
X
Complete after Vital Signs and Dose 
Assessment and Modification.
Study Intervention 
Compliance
X
X
X
X
X
Efficacy Procedures
Clinical Events 
Assessment
X
X
X
X
X
X
Can be requested at any time during the 
study.
NYHA Classification
X
X
X
X
X
X
X
EQ-5D-5L
X
X
Q48W
X
Perform EQ-5D-5L before KCCQ.
Complete the QoL questionnaires prior to 
performing any visit procedure.
Visit 2: Complete after IRT randomization
and before any other procedures.
After V5, EQ-5D-5L, and KCCQ will be 
performed at every other visit (ie, every 
48 weeks).  
KCCQ
X
X
Q48W
X
Vital Status
X
Can be done at any time when vital 
status is in question.
Safety Procedures
Full physical 
examination including 
height
X
X
Height is not required at the Final Visit.
Directed Physical 
Examination
X
X
Vital Signs (pulse rate, 
sitting BP, weight)
X
X
X
X
X
X
X
Visit 2: BP and pulse rate measurements 
are required before and 2 h ± 0.5 h after 
dosing. See Sec. 8.3.2.
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Study Period:
Screening
Intervention
Follow-up Notes
Visit Number/Title:
1
Screening
2 
Random
ization
3
4
5
n
Final 
Visit
14-day 
Safety 
Contact
Visits 1 and 2 may occur on the same day 
(see Sec. 8.11.1.2 and 8.11.2.1).
Visit dates should be calculated relative to 
Randomization (Day 1).
For participants who prematurely 
discontinue study intervention, see 
Sec. 1.3.2.
Scheduled Hour, Day, 
Week, etc, and 
Window:
Days
-30 to 1
Day 1
Day 14 
±4 days
Day 28 
±4 days
Week 24 
±14 days
Q24W
±14 days
After 
Primary 
Complet
ion Date
14 days 
After 
Last Dose
Dose Assessment and 
Modification
X
X
X
X
X
Perform at any visit when BP is 
assessed. See Sec. 8.3.3.
12-lead ECG
X
Visit 2: Perform predose.
AE/SAE review
X
X
X
X
X
X
X
X
See Sec. 8.4 for limitations to AE 
reporting.
Clinical Laboratory Assessments
Urine or Serum hCG 
(WOCBP only; per local 
requirements)
X
X
In addition to site testing at every visit, urine pregnancy 
testing will be performed Q4W at home using site-
provided kits until 1 month after the last dose of study 
intervention
Serum test is required if urine test cannot 
be confirmed as negative
See Sec. 8.3.6.
Serum Follicle-
Stimulating Hormone 
(FSH) -
(WONCBP only)
X
Perform 2 tests 2-3 weeks apart if 
required to confirm menopause status 
(Appendix 5).
Creatinine (eGFR)
X
A historical result collected within 
30 days before randomization is 
acceptable. ALBI score must be 
calculated at Screening Visit (Appendix 
8). 
Albumin
X
Total bilirubin
X
ALT
X
AST
X
Hematology
X
X
X
X
X
Chemistry
X
X
X
X
X
Liver Function Tests
X
X
X
X
NT-proBNP
X
X
X
X
X
Screening: A historical result collected 
within 30 days before randomization is 
acceptable.
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Study Period:
Screening
Intervention
Follow-up Notes
Visit Number/Title:
1
Screening
2 
Random
ization
3
4
5
n
Final 
Visit
14-day 
Safety 
Contact
Visits 1 and 2 may occur on the same day 
(see Sec. 8.11.1.2 and 8.11.2.1).
Visit dates should be calculated relative to 
Randomization (Day 1).
For participants who prematurely 
discontinue study intervention, see 
Sec. 1.3.2.
Scheduled Hour, Day, 
Week, etc, and 
Window:
Days
-30 to 1
Day 1
Day 14 
±4 days
Day 28 
±4 days
Week 24 
±14 days
Q24W
±14 days
After 
Primary 
Complet
ion Date
14 days 
After 
Last Dose
Pharmacokinetics/Biomarkers
Blood for Genetic 
Analysis
X
Visit 2: Collect predose.
See Sec. 8.8.1.
Blood for Exploratory 
Biomarker Research
X
X
Visit 2: Collect predose. See Sec. 8.9 for 
use of leftover sample.
PK sample collection
X
X
X
Q48W
X
Visit 2: Collect predose.
After Visit 5, PK samples will be 
collected at every other visit (ie, every 
48 weeks).
AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BP=blood pressure; DNA=deoxyribonucleic acid; ECG=electrocardiogram; 
EQ-5D-5L=EuroQol Group 5-Dimensional, 5-level Questionnaire; FBR=future biomedical research; FSH=follicle-stimulating hormone; hCG=human chorionic 
gonadotropin; IEC=Independent Ethics Committee; IRB=Institutional Review Board; KCCQ=Kansas City Cardiomyopathy Questionnaire; NYHA=New York Heart 
Association; NT-proBNP=N-terminal pro-brain natriuretic peptide; PK=pharmacokinetic; Q24W=every 24 weeks; Q4W=every 4 weeks; Q48W=every 48 weeks;
SAE=serious adverse event; V=Visit; WOCBP=women of childbearing potential; WONCBP=women of nonchildbearing potential.
Country-specific requirements are noted in Appendix 7.
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1.3.2
Schedule of Activities – Participants Who Prematurely Discontinue Study Intervention
Study Period: Premature Discontinuation
Follow-up
Notes
Visit Number/Title:
Study Intervention 
Discontinuation
14-day Safety 
Contact
Follow-up
Contact
Final Contact
Scheduled Hour, Day, Week, etc., 
and Window:
Premature Discontinuation
of Study Intervention
14 Days After 
Last Dose
Q24W
±14 days
After Primary 
Completion 
Date
Visit/Contact dates should be 
calculated relative to 
Randomization (Day 1).
Administrative Procedures
Prior/Concomitant Medication Review
X
X
X
X
See Sec. 6.5 for reporting 
requirements.
Study Intervention Compliance
X
Efficacy Procedures
Clinical Events Assessment
X
X
X
X
Can be requested at any time during 
the study.
NYHA Classification
X
EQ-5D-5L
X
Perform EQ-5D-5L before KCCQ.
Complete the QoL questionnaires 
prior to performing any visit 
procedure.
KCCQ
X
Vital Status
X
Can be conducted at any time when 
vital status is in question.
Safety Procedures
Full physical examination 
X
Vital Signs 
(pulse rate, sitting BP, and weight)
X
See Sec. 8.3.2.
AE/SAE review
X
X
Clinical Laboratory Assessments
Urine or Serum hCG 
(WOCBP only; per local 
requirements)
X
Use home 
pregnancy kit 
1 month after 
last dose
Serum test is required if urine test 
cannot be confirmed as negative.
Perform urine pregnancy testing at 
home using site-provided kit 
1 month after the last dose of study 
intervention. See Sec. 8.3.6.
Hematology
X
Chemistry
X
Liver Function Tests
X
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Study Period: Premature Discontinuation
Follow-up
Notes
Visit Number/Title:
Study Intervention 
Discontinuation
14-day Safety 
Contact
Follow-up
Contact
Final Contact
Scheduled Hour, Day, Week, etc., 
and Window:
Premature Discontinuation
of Study Intervention
14 Days After 
Last Dose
Q24W
±14 days
After Primary 
Completion 
Date
Visit/Contact dates should be 
calculated relative to 
Randomization (Day 1).
NT-proBNP
X
Pharmacokinetics/Biomarkers
Blood for Exploratory Biomarker 
Research
X
Required only if participant 
discontinues study intervention 
before Visit 5.
PK sample collection
X
Required only if participant has 
received study intervention within 
the previous 2 weeks.
AE=adverse event; BP=blood pressure; DNA=deoxyribonucleic acid; ECG=electrocardiogram; EQ-5D-5L=EuroQol Group 5-Dimensional, 5-level Questionnaire; hCG=human 
chorionic gonadotropin; KCCQ=Kansas City Cardiomyopathy Questionnaire; NT-proBNP=N-terminal pro-brain natriuretic peptide; NYHA=New York Heart Association; 
PK=pharmacokinetic; Q24W=every 24 weeks; SAE=serious adverse event; V=Visit; WOCBP=women of childbearing potential.
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2
INTRODUCTION
Vericiguat is a novel oral sGC stimulator indicated in the US to reduce the risk of CV death 
and HFH following a hospitalization for HF or need for outpatient IV diuretics in adults with 
symptomatic chronic HF and ejection fraction less than 45%. This study will evaluate the 
efficacy of vericiguat in participants with chronic HFrEF, specifically those with 
symptomatic chronic HF with an ejection fraction of 40% or less who have not had a recent 
hospitalization for HF or need for outpatient IV diuretics.
2.1
Study Rationale
Heart failure is a leading cause of CV morbidity and mortality and constitutes a major public 
health problem worldwide. Despite treatment with GDMT, patients with chronic HFrEF 
remain at high risk for progressive decline with recurrent HFHs and CV death. In 
well-treated populations of generally stable HFrEF participants in both the PARADIGM-HF 
and DAPA-HF studies, for example, there was ongoing residual risk in both treatment arms
with incidence rates ranging from 10.5 to 15.3 participants with an event per 
100 patient-years of follow-up for the composite of CV death or HFH, highlighting this 
unmet medical need [McMurray, J. J., et al 2014] [Srivastava, P. K., et al 2018] [McMurray, 
J. J. V., et al 2019].
The VICTORIA study demonstrated that vericiguat reduces the risk of CV death and HFH in 
a well-treated, but very high-risk population of adults with chronic HFrEF who have 
experienced a recent worsening HF event, specifically an HFH or need for IV diuretic 
therapy [Armstrong, P. W., et al 2020]. The benefit-risk of initiating vericiguat in a chronic 
HFrEF population (ie, patients without a recent worsening event and with lower NT-proBNP 
levels) remains is not known, although extrapolation from VICTORIA data suggests that this 
population may derive even greater benefit. Furthermore, vericiguat targets a critical 
molecular pathway in HF that is not addressed by other GDMT including beta-blockers, 
ACEIs, ARBs, MRAs, and an ARNI, or by SGLT2is.
2.2
Background
Refer to the IB/approved labeling for detailed background information on vericiguat.
2.2.1
Pharmaceutical and Therapeutic Background
Vericiguat is an sGC stimulator. HF is associated with impaired synthesis of NO and 
decreased activity of its receptor, sGC. Soluble guanylate cyclase catalyzes synthesis of 
intracellular cGMP, an important signaling molecule that regulates critical physiological 
processes such as cardiac contractility, vascular tone, and cardiac remodeling. Deficiency in 
sGC-derived cGMP contributes to myocardial and vascular dysfunction. Vericiguat restores 
the relative deficiency in this signaling pathway by directly stimulating sGC, independently 
of and synergistically with NO, to augment the levels of intracellular cGMP, which may 
improve both myocardial and vascular function. The complementary CV benefits of 
vericiguat in HF patients are therefore attributed to the active restoration of the deficient 
NO-sGC-cGMP pathway driving HF progression.
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2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
Chronic HF is a major source of morbidity and mortality. Clinical outcomes for patients with 
chronic HF remain poor, despite contemporary evidence-based therapies. Therefore, drugs 
are needed that effectively target disease mechanisms not addressed by current standard 
therapy. Vericiguat has a novel mode of action that targets endothelial dysfunction to 
improve regulation of vascular tone and myocardial function.
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. Vericiguat has 
a clinically meaningful benefit on the endpoints of HFH and CV death. The AE profile in 
VICTORIA was predominantly associated with vericiguat’s mechanism of action (eg, 
dyspepsia, nausea, headache) or similar to that reported with another sGC stimulator 
(anemia), and these events are generally nonserious and manageable even in this high-risk 
population. Slightly higher proportions of participants with anemia AEs were observed in the 
vericiguat group (9.6%) compared with the placebo group (7.4%). There was no increased 
risk of bleeding associated with vericiguat. The effect on BP during the study was small; 
there was an approximately 1 to 2 mm Hg greater mean reduction in SBP in participants who 
received vericiguat compared with placebo over the course of the study. The 
pharmacodynamic effects of vericiguat were evaluated after single and multiple-dose 
administrations in healthy participants and in participants with HF and are consistent with the 
predicted effects of an sGC stimulator on smooth muscle relaxation and vasodilation. 
Titrated up to a target dose of 10 mg vericiguat, the current risks are manageable. Vericiguat 
is a new therapeutic option to fulfill the unmet medical need in patients with chronic HFrEF.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
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3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
In adults with chronic heart failure with reduced ejection fraction receiving guideline-
directed medical therapy for heart failure: 
Primary Objective
Primary Endpoint
Objective: To evaluate the efficacy of 
vericiguat compared with placebo on 
reducing the risk of cardiovascular death or
heart failure hospitalization
Hypothesis (H1): Vericiguat is superior to 
placebo in reducing the risk of 
cardiovascular death or heart failure 
hospitalization.
Time from randomization to the first event 
of cardiovascular death or heart failure 
hospitalization
Secondary Objectives
Secondary Endpoints
Objective: To evaluate the efficacy of 
vericiguat compared with placebo on 
reducing the risk of cardiovascular death
Hypothesis (H2): Vericiguat is superior to 
placebo in reducing the risk of 
cardiovascular death.
Time from randomization to cardiovascular 
death
Objective: To evaluate the efficacy of 
vericiguat compared with placebo in 
reducing the risk of heart failure 
hospitalization
Hypothesis (H3): Vericiguat is superior to 
placebo in reducing the risk of the first 
event of heart failure hospitalization.
Hypothesis (H4): Vericiguat is superior to 
placebo in reducing the risk of all heart 
failure hospitalization events.
-Time from randomization to the first event 
of heart failure hospitalization
-Time from randomization to all heart 
failure hospitalization events
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Objective: To evaluate the efficacy of 
vericiguat compared with placebo in 
reducing the risk of all-cause mortality or 
heart failure hospitalization
Hypothesis (H5): Vericiguat is superior to 
placebo in reducing the risk of all-cause 
mortality or heart failure hospitalization.
Time from randomization to the first event 
of all-cause mortality or heart failure 
hospitalization
Objective: To evaluate the efficacy of 
vericiguat compared with placebo in 
reducing the risk of all-cause mortality
Hypothesis (H6): Vericiguat is superior to 
placebo in reducing the risk of all-cause 
mortality.
Time from randomization to all-cause 
mortality
Objective: To evaluate the safety and 
tolerability of vericiguat compared with 
placebo
-Selected nonserious adverse events
-Serious adverse events
-Events of clinical interest
Tertiary/Exploratory Objectives
Tertiary/Exploratory Endpoints
Objective: To evaluate the efficacy of 
vericiguat compared with placebo in 
reducing the risk of heart failure 
hospitalization or urgent heart failure visit, 
defined as a heart failure visit that does not 
meet the criteria for heart failure 
hospitalization
Time from randomization to the first event 
of heart failure hospitalization or urgent 
heart failure visit
Objective: To evaluate the efficacy of 
vericiguat compared with placebo in 
reducing the risk of cardiovascular 
hospitalization
Time from randomization to the first event 
of cardiovascular hospitalization
Objective: To evaluate the efficacy of 
vericiguat compared with placebo in 
reducing the total number of heart failure 
hospitalization events
Total number of heart failure hospitalization 
events
Objective: To evaluate the efficacy of 
vericiguat compared with placebo on the 
health-related quality of life measures
-Change from baseline in EuroQol 
Five-Dimension Questionnaire measures
-Change from baseline in Kansas City 
Cardiomyopathy Questionnaire measures
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Objective: To evaluate the treatment effect 
of vericiguat compared with placebo on 
kidney function
Slope of change in eGFR from baseline
Objective: To evaluate the plasma 
pharmacokinetics of vericiguat
Plasma vericiguat concentration
Objective: To explore the relationship 
between genetic variation and response to 
the treatment(s) administered, and 
mechanisms of disease. Variation across the 
human genome may be analyzed for 
association with clinical data collected in 
the study
Germline genetic variation and association 
to clinical data collected in this study
Objective: To evaluate the treatment effect 
of vericiguat compared with placebo on 
exploratory biomarkers
Change from baseline in exploratory 
biomarkers
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4
STUDY DESIGN
4.1
Overall Design
This is a randomized, placebo-controlled, parallel-group, multisite, double-blind, 
event-driven, Phase 3 clinical outcome study of the sGC stimulator, vericiguat, in adults with 
chronic HFrEF. In this study, chronic HFrEF is defined as no HFH within 6 months or 
outpatient IV diuretic use within 3 months before randomization.
Approximately 6000 participants will be randomly allocated in a 1:1 ratio to either vericiguat 
or matching placebo on a background of GDMT. Enrollment of participants on ARNI and 
SGLT2i therapy is encouraged, with the goals of approximately 30% of the randomized 
population prescribed ARNI and, independently, 15% prescribed SGLT2i at baseline. The 
desired proportion of participants on GDMT may be achieved by capping the number of 
participants not on ARNI or SGLT2i therapy at randomization in IRT to avoid under-
representation of these participant subgroups. Likewise, achieving the desired proportion of 
participants without previous HFH (approximately 30% to 40% of the study population) may 
require capping the number of participants with a history of HFH. Enrollment of participants 
with eGFR 15 to 30 mL/min/1.73 m2 range will be limited to approximately 15% of the total 
study population. An important goal of the study will be to ensure adequate enrollment of 
participants historically underrepresented in HF studies.
Titration to the target dose of 10 mg once daily will be based on tolerability (see Section 6.6). 
The primary endpoint will be time to first event of CV death or HFH in participants with 
chronic HFrEF on GDMT. Participants will be treated until the Final Visit, which will be 
scheduled after required numbers of CV deaths (approximately 590) are observed. Based on 
an assumed placebo incidence rate of 6.0 participants with a CV death event per 100 patient-
years of follow-up, the projected median follow-up will be 22.5 months. All participants will 
be followed until study completion to assess for the occurrence of endpoint events and for 
14 days after last treatment dose for selective AE monitoring. Clinical outcome events will 
be adjudicated by an independent CEC. An external DMC will monitor data for safety. There 
will be a formal IA with the potential to stop the study for overwhelming evidence of 
efficacy as described in Section 9.7.
Specific procedures to be performed during the study, including prescribed times and 
associated visit windows, are outlined in Section 1.3 of the SoA. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
Unlike VICTORIA, which enrolled a worsening chronic HFrEF population, the target 
population for this study is adults with chronic HFrEF. As such, only those participants who 
have not had a recent worsening event (including an HFH within 6 months or IV diuretic use 
without hospitalization within 3 months) will be included. Risks of recurrent HFH and of 
CV death decrease significantly within a few months of a worsening event and excluding 
those who have had an event in the preceding 6 months will ensure that the population
enrolled does not overlap with that of VICTORIA. Another difference is an inclusion 
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criterion limiting enrollment to those who have an EF of 40% or less, consistent with the 
current HF guideline definition of HFrEF.
The lower limits of the screening NT-proBNP entry criterion match those used in both the 
PARADIGM-HF and DAPA-HF studies. This enrichment criterion is well-accepted in the 
HF literature and will ensure that enrolled participants have chronic HFrEF with residual risk 
for events.
NT-proBNP can be both a marker of disease severity and of ongoing decompensation. The 
upper limit of the screening NT-proBNP entry criterion of 6000 pg/mL will help minimize 
enrollment of those participants who have subclinical worsening of their HF. In VICTORIA, 
participants with baseline NT-proBNP levels less than 4000 pg/mL derived the greatest 
benefit from vericiguat with the benefit attenuating as baseline NT-proBNP levels 
approached 8000 pg/mL [Ezekowitz, J. A., et al 2020].
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
Primary Efficacy Endpoint
The primary efficacy endpoint of the study is the time to first event of CV death or HFH. 
This integrated measure of HF morbidity and mortality is a frequently used primary endpoint 
in Phase 3 HFrEF studies, including VICTORIA.
Secondary and Exploratory Efficacy Endpoints
The secondary efficacy endpoints include time to an event of CV death, time to the first 
event of HFH, time to all HFH events, time to the first event of all-cause mortality or HFH, 
and time to all-cause mortality. The exploratory endpoints include time to the first event of 
UHF visit or HFH, time to the first event of CV hospitalization, total number of HFH events, 
eGFR slope, and change from baseline in KCCQ, and EQ-5D-5L. These endpoints are 
additional measures of HF morbidity and mortality frequently evaluated in Phase 3 HFrEF 
studies.
4.2.1.2
Safety Endpoints
A selective approach to AE data collection will be utilized since the safety profile for 
vericiguat has been well characterized throughout the clinical program and will be further 
monitored in the postmarketing setting. This approach includes limited AE collection with 
selected NSAEs being reported by sites (Section 8.4). Additional country-specific 
requirements for adverse event reporting are described in Appendix 7. All SAEs and other 
reportable events will be collected as described in Section 8.4.1.
Other safety assessments will include physical examination findings, and vital signs 
including pulse rate and BP assessment. Laboratory safety studies will include blood 
chemistry, hematology, and pregnancy testing (performed in WOCBP).
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Symptomatic hypotension, anemia, and laboratory values consistent with potential DILI 
events were selected as the prespecified ECIs for this study (Section 8.4.7). Symptomatic 
hypotension was selected based on vericiguat’s mechanism of action. Anemia was selected 
based on an increased incidence of anemia noted in the VICTORIA study. Potential DILI 
events are captured per standard requirement of Sponsor studies.
4.2.1.3
Pharmacokinetic Endpoints
PK assessments obtained from the data collected during this study are exploratory and will be 
investigated under a separate detailed PK evaluation and analysis plan.
4.2.1.4
Planned Exploratory Biomarker Research
The exploratory biomarker analyses will provide insights into the potential mechanisms of 
therapeutic effect in HF beyond what is currently understood about how vericiguat affects 
cellular function.
4.2.1.4.1 Planned Genetic Analysis
Genetic variation may impact a participant’s response to therapy, susceptibility to, severity, 
and progression of disease. Variable response to therapy may be due to genetic determinants 
that impact drug ADME, mechanism of action of the drug, disease etiology, and/or molecular 
subtype of the disease being treated. Therefore, where local regulations and IRB/IEC allow, a 
sample will be collected for DNA analysis from consenting participants.
DNA samples may be used for research related to the study intervention(s), the disease under 
study, or related diseases. They may also be used to develop tests/assays including diagnostic 
tests related to the disease under study, related diseases, and study intervention(s). Genetic 
research may consist of the analysis of 1 or more candidate genes, the analysis of genetic 
markers throughout the genome, or analysis of the entire genome. Analysis may be 
conducted if it is hypothesized that this may help further understand the clinical data.
The samples may be analyzed as part of a multistudy assessment of genetic factors involved 
in the response to understand study disease or related conditions.
Country-specific requirements are noted in Appendix 7.
4.2.1.5
Future Biomedical Research
The Sponsor will conduct FBR on specimens for which consent was provided during this 
study. This research may include genetic analyses (DNA), gene expression profiling (RNA), 
proteomics, metabolomics (serum, plasma), and/or the measurement of other analytes, 
depending on which specimens are consented for FBR.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol and will only be conducted on specimens from appropriately consented 
participants. The objective of collecting/retaining specimens for FBR is to explore and 
identify biomarkers that inform the scientific understanding of diseases and/or their 
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therapeutic treatments. The overarching goal is to use such information to develop safer, 
more effective drugs/vaccines, and/or to ensure that participants receive the correct dose of 
the correct drug/vaccine at the correct time. The details of FBR research are presented in
Appendix 6. Country-specific requirements are noted in Appendix 7.
4.2.2
Rationale for the Use of Comparator/Placebo
Vericiguat is being developed for use on a background of GDMT rather than as a 
replacement for any established therapy. To allow a blinded assessment, vericiguat will be 
compared with a matching placebo. While VICTORIA demonstrated a clinically meaningful 
benefit of vericiguat for the treatment of worsening chronic HFrEF on top of GDMT, chronic
HFrEF patients were excluded from the study. As such, the benefit of vericiguat in chronic 
HFrEF patients on top of GDMT is unknown. Utilizing placebo as a comparator for 
vericiguat allows for a representative population receiving GDMT.
Participants who experience an HF event during the study should be encouraged to complete 
the study on their assigned blinded study intervention. In the cases where a participant’s 
physician feels strongly that the participant should start open-label (commercially available) 
vericiguat, the blinded study intervention must be permanently discontinued for a minimum 
of 14 days to allow full safety monitoring of study intervention, followed by safe titration of 
open-label vericiguat as per the local prescribing guidelines (Section 7.1). Participants whose 
physicians initiate treatment with open-label vericiguat should continue in the study for 
follow-up, and vericiguat should be recorded as a concomitant medication (Section 6.5).
4.3
Justification for Dose
The starting dose for this study is 2.5 mg vericiguat or matching placebo, once daily. A 
titration regimen will be used to achieve the target dose of 10 mg vericiguat or matching 
placebo as described in Section 6.6.
4.3.1
Rationale for the Dose Selection/Regimen/Modification
The target dose and titration regimen for this study 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. In VICTORIA, this regimen was well tolerated with 
approximately 90% of participants receiving the target dose of 10 mg vericiguat once daily at 
1 year.
4.4
Beginning and End-of-Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (ie, the 
participant is unable to be contacted by the investigator). For purposes of analysis and 
reporting, the overall study ends when the Sponsor receives the last laboratory result or at the 
time of Final Contact with the last participant, whichever comes last.
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For studies conducted in the European Economic Area (EEA), the local start of the study is 
defined as First Site Ready (FSR) in any Member State.
4.4.1
Clinical Criteria for Early Study Termination
Early study termination will be the result of the following specified criteria:

A decision by the EOC to follow the unblinded external DMC’s recommendation to stop 
the study due to either overwhelming evidence of efficacy at the IA, or if the extent 
(incidence and/or severity) of emerging effects/clinical endpoints is such that the 
risk/benefit ratio to the study population as a whole is deemed unacceptable
(Sections 9.7, 10.1.4.2, and 10.1.4.3).
In addition, further recruitment in the study or at (a) particular study site(s) may be stopped 
due to insufficient compliance with the protocol, GCP, and/or other applicable regulatory 
requirements, procedure-related problems or the number of discontinuations for 
administrative reasons is too high.
4.4.2
Primary Completion Date
A blinded Sponsor clinical team will monitor the accrual of CEC-confirmed primary 
composite endpoint and CV death events throughout the study. The Primary Completion 
Date will be defined when the target number of CV death events are expected to have 
occurred. The Primary Completion Date will be used for operational and statistical 
procedures. For participants receiving study intervention, sites will be instructed to perform a 
Final Visit after the Primary Completion Date. For participants who have prematurely 
discontinued study intervention, sites will be instructed to conduct a Final Contact after the 
Primary Completion Date. Events and measurements occurring up to and including the 
Primary Completion Date will be the basis of the primary study results.
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5
STUDY POPULATION
Male or female participants with chronic HFrEF aged at least 18 years will be enrolled in this 
study.
As stated in the Code of Conduct for Clinical Trials (Appendix 1.1), our studies include 
people of varying age, race, ethnicity, and sex. The collection and use of these demographic 
data is to follow all local laws and guidelines in keeping with the needs for participant 
confidentiality while supporting the study of the disease, its related factors, and the IMP 
under investigation.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant meets all of the 
following criteria:
Type of Participant and Disease Characteristics
1. Has a history of chronic HF (NYHA Class II to IV) on GDMT with no events of HFH 
within 6 months or outpatient IV diuretic use within 3 months before randomization.
Demographics
2. Is male or female, from 18 years of age, at the time of providing documented informed 
consent.
Female Participants
3. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies: 
•
Is not a WOCBP
OR
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•
Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate 
of <1% per year), with low user dependency, or be abstinent from heterosexual 
intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent 
basis), as described in Appendix 5 during the 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 (ie, 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 24 hours before the first dose of study 
intervention.
-
If a urine test cannot be confirmed as negative (eg, 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 
in Section 8.3.6.
-
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.
-
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
Informed Consent
4. The participant (or legally acceptable representative) has provided documented informed 
consent/assent for the study. The participant may also provide consent/assent for FBR. 
However, the participant may participate in the study without participating in FBR.
Additional Categories
5. Has a screening NT-proBNP level within 30 days before randomization as shown in
Table 1. For participants with multiple NT-proBNP results during screening, the most 
recent value will be used to determine eligibility at the Randomization Visit.
Table 1
NT-proBNP Inclusion Criteria
NT-proBNP
(pg/mL)
Sinus rhythm 
600 to 6000
Atrial fibrillation
900 to 6000
NT-proBNP=N-terminal pro-brain natriuretic peptide.
The most appropriate natriuretic peptide level cutoff should be guided by the participant’s heart rhythm at the time of 
sample collection. Participants with paroxysmal atrial fibrillation with evidence of atrial fibrillation within 24 hours of 
sample collection will use the 900 pg/mL cutoff.
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6. Has an LVEF of ≤40% assessed within 12 months before randomization by any imaging 
method. 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 (ie, initiation of a GDMT) that might 
improve LVEF, must have a measurement of LVEF at least 3 months after the 
intervention to be eligible.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant meets any of the following 
criteria:
Medical Conditions
1. Has SBP <100 mm Hg or symptomatic hypotension.
2. Has a known allergy or sensitivity to vericiguat, any of its constituents, or any other sGC 
stimulator.
3. Is awaiting heart transplantation (United Network for Organ Sharing Class 1A / 1B or 
equivalent), is receiving continuous IV infusion of an inotrope, or has or anticipates 
receiving an implanted ventricular assist device.
4. Has amyloidosis or sarcoidosis.
Cardiac Comorbidity
5. Has primary valvular heart disease requiring surgical procedure or intervention or has 
undergone a valvular surgical procedure or intervention within 3 months before 
randomization.
6. Has hypertrophic cardiomyopathy.
7. Has acute myocarditis or Takotsubo cardiomyopathy.
8. Has received a heart transplant.
9. Has tachycardia-induced cardiomyopathy and/or uncontrolled tachyarrhythmia.
10. Has acute coronary syndrome (unstable angina, NSTEMI, or STEMI), undergone CABG 
or PCI within 3 months before randomization, or indication for coronary 
revascularization at the time of randomization.
11. Has symptomatic carotid stenosis, TIA, or stroke within 3 months before randomization.
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12. Has a history of repaired or unrepaired simple congenital heart disease (eg, atrial or 
ventricular septal defects, or patent ductus arteriosus) with ongoing hemodynamically 
significant residual lesions, or any history of complex congenital heart disease (eg, 
tetralogy of Fallot, transposition of the great arteries, single ventricle disease) regardless 
of repair status.
13. Has active endocarditis or constrictive pericarditis.
Noncardiac Comorbidity
14. Has an eGFR based on the CKD-EPI Creatinine Equation of <15 mL/min/1.73 m2 within 
30 days before randomization or is on chronic dialysis. For participants with multiple 
eGFR results during screening, the most recent value will be used to determine eligibility 
at the Randomization Visit.
15. Has 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). Screening albumin, ALT, AST, and total bilirubin results within 30 days 
before randomization 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 as defined in Appendix 8 [Fragaki, M., et al 2019].
16. Has malignancy or other noncardiac condition limiting life expectancy to <3 years.
17. Requires continuous home oxygen for severe pulmonary disease.
18. Has interstitial lung disease.
Prior/Concomitant Therapy
19. Had any discontinuation or dose modification of GDMT (including beta blockers, 
ACEI/ARBs, ARNI, MRAs, hydralazine-nitrate combinations, SGLT2is, or ivabradine) 
or vericiguat within 4 weeks before randomization.
20. Has concurrent or anticipated concomitant use of PDE5 inhibitors such as vardenafil, 
tadalafil, and sildenafil during the study.
21. Has concurrent use of an sGC stimulator such as riociguat or vericiguat.
Prior/Concurrent Clinical Study Experience
22. Has participated in another interventional clinical study or has been treated with another 
investigational product ≤30 days before randomization or plans to participate in any other 
study or study intervention during this study.
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Diagnostic Assessments
Not applicable.
Other Exclusions
23. Has a recent history (within the last year) of drug or alcohol abuse or dependence.
24. Is pregnant or breastfeeding or plans to become pregnant or to breastfeed during the 
study.
25. Has a 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.
26. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
Participants should maintain a diet consistent with recommendations in local guidelines, such 
as the ACCF/AHA and ESC Guidelines for the Management of Heart Failure during the 
study [Ponikowski, P., et al 2016] [Yancy, C. W., et al 2017].
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions
No restrictions are required.
5.3.3
Activity Restrictions
No restrictions are required.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently randomized in the study. 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, eligibility criteria, and any AEs or 
SAEs meeting reporting requirements as outlined in the data entry guidelines.
5.5
Participant Replacement Strategy
A participant who discontinues from study intervention or withdraws from the study will not 
be replaced.
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies (study intervention(s) provided by the Sponsor) will be packaged to support 
enrollment. Clinical supplies will be affixed with a clinical label in accordance with 
regulatory requirements.
6.1
Study Intervention(s) Administered
The study interventions to be used in this study are outlined in Table 2.
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Table 2
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP or 
NIMP/
AxMP
Sourcing
Vericiguat Experimental MK-1242 
(vericiguat)
Drug
Tablet
2.5 mg, 
5 mg, and 
10 mg
2.5 mg, 
5 mg, or 
10 mg 
QD
Oral
Titration:
2.5 mg 
titrated to 
5 mg titrated 
to 
10 mg / 
Day 1 until 
end of 
treatment
Test 
Product
IMP
Provided 
centrally 
by the 
Sponsor
Placebo
Placebo 
Comparator
Placebo for 
MK-1242 
(vericiguat)
Drug
Tablet
0 mg
matching 
placebo for 
2.5 mg, 
5 mg, and 
10 mg
0 mg QD Oral
Sham 
Titration:
0 mg / 
Day 1 until 
end of 
treatment
Placebo
IMP
Provided 
centrally 
by the 
Sponsor
EEA=European Economic Area; IMP=investigational medicinal product; NIMP/AxMP=noninvestigational/auxiliary medicinal product.
The classification of IMP and NIMP/AxMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country differences
with respect to the definition/classification of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
For detailed instruction for dose titration and modification see Section 6.6.
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All supplies indicated in Table 2 will be provided per the “Sourcing” column depending on 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (eg, not applicable in the 
case where multiple lots or batches may be required due to the length of the study, etc).
Refer to Section 8.1.9 for details regarding administration of the study intervention.
All placebos were created by the Sponsor to match the active product.
6.1.1
Medical Devices
Not applicable.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Specific evaluations required to select the proper dose for each participant are outlined in 
Section 6.6. The rationale for selection of doses to be used in this study is in Section 4.3.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions 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.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
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The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention randomization will occur centrally using an IRT system. There are 2 study 
intervention arms. Participants will be assigned randomly in a 1:1 ratio to vericiguat or 
matching placebo, respectively.
6.3.2
Stratification
Intervention randomization will be stratified according to baseline NYHA Class (II vs 
III/IV).
6.3.3
Blinding
A double-blinding technique with in-house blinding will be used. MK-1242 (vericiguat) and 
placebo will be packaged identically so that blind is maintained. The participant, the 
investigator, and Sponsor personnel or delegate(s) who are involved in the study intervention
administration or clinical evaluation of the participants are unaware of the intervention 
assignments.
6.4
Study Intervention Compliance
Interruptions from the protocol-specified treatment with compliance <80% require 
consultation between the investigator and the Sponsor and written documentation of the 
collaborative decision on participant management.
Sponsor consultation and written documentation on participant management is not required if 
the reason for <80% compliance is due to protocol-specified interruptions per the dose 
modification scheme (Section 6.6), investigator discretion, and/or an AE. Such instances of 
<80% compliance, as well as any instance of compliance between 80% and 100%, will not 
be considered a protocol deviation.
Administration of the first dose of study intervention will be witnessed by the investigator or
designee at the Randomization Visit only (Visit 2).
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date of each dose administered in 
the clinic will be recorded in the source documents and recorded in the eCRF.
•
Compliance with self-administered study intervention will be assessed at each scheduled 
visit. Assessments will be based on counting of returned tablets corroborated with 
participant reporting. To facilitate this, participants must be instructed to return all of the 
study intervention packaging including unused study intervention and empty packaging.
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•
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. Intervention start and stop dates, including dates for 
intervention delays and/or dose reductions will be recorded in the eCRF.
6.5
Concomitant Therapy
Per protocol, all participants should receive GDMT based on locally relevant guidelines such 
as ACCF/AHA and ESC Guidelines for the Management of Heart Failure applied 
individually at the discretion of the treating investigator and in line with individual 
tolerability [Ponikowski, P., et al 2016] [Yancy, C. W., et al 2017]. This includes 
medications such as beta blockers, ACEIs, ARBs, ARNI, MRAs, hydralazine-nitrate 
combinations, SGLT2is, ivabradine, and cardiac device therapies such as ICDs and 
biventricular pacemakers. Use of treatment expected to be reflected in future 
recommendations should be considered. 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. If there is a clinical indication for any medications specifically 
prohibited, discontinuation from study intervention may be required. The investigator should 
discuss any questions regarding this with the Sponsor Clinical Director. 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, the Sponsor, and the participant.
Participants whose physicians initiate treatment with open-label vericiguat should continue in 
the study for follow-up (Section 4.2.2, Section 7.1), and vericiguat should be recorded as a 
concomitant medication.
Any licensed COVID-19 vaccine (including for Emergency use) in a particular country is 
allowed in the study as long as they are mRNA vaccines, adenoviral vaccines, or inactivated 
vaccines.
As described in the DEGs, investigators should record the following: 

Medications taken within 30 days before and on the date of randomization.

Medications taken to treat HF (GDMT and any diuretics) during the period beginning 30 
days before enrollment (Visit 1) through 14 days after the last dose of study intervention 
(14-day Safety Contact).

Medications administered within 14 days before and during a clinical endpoint event, 
SAE, ECI, and other reportable events until recovery/stabilization of event.

All licensed COVID-19 vaccines received during the period beginning 30 days before 
enrollment (Visit 1) through 14 days after the last dose of study intervention (14 day 
Safety Contact).
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The Sponsor Clinical Director should be contacted if there are any questions regarding 
concomitant or prior therapy.
6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified for use in this study.
6.6
Dose Modification (Titration)
Participants will start with a 2.5 mg oral dose of blinded vericiguat or matching placebo once 
daily. The first titration to 5 mg vericiguat or matching placebo daily will occur at Visit 3 
(14±4 days after randomization). The second titration to the target dose of 10 mg vericiguat 
or matching placebo daily will occur at Visit 4 (28±4 days after randomization). These 
titration steps include sham titrations in the placebo arm. Dose titration will depend on mean 
sitting SBP and symptoms indicative of hypotension before administration of the dose as 
described in Table 3.
If the participant does not reach the 10-mg dose by 28±4 days after randomization, 
up-titration will be encouraged at any subsequent visit at the discretion of the investigator 
according to the SBP criteria in Table 3.
The intention of the protocol is to maintain participants on the 10-mg target dose of study 
intervention for as long as possible after randomization. However, if in the opinion of the 
investigator the participant does not tolerate the 10-mg target dose, in addition to considering 
reduction of the study intervention dose, the investigator should consider whether 
medications not shown to provide a HF benefit in clinical studies (eg, various classes and 
doses of calcium channel blockers or alpha-blockers) can be reduced before reducing the 
dose of the study intervention. For example, in the case of symptoms of orthostatic 
hypotension, the investigator should also consider the volume status and whether there is a 
necessity to change the dose of diuretics or alpha-blockers. If such adjustment or 
discontinuation of concomitant medications that are not associated with an outcome benefit is 
not possible or does not resolve signs and symptoms of intolerability, the investigator may at 
any time during the course of the study reduce the dose or interrupt study treatment in 
participants who no longer tolerate the current study intervention dose. The doses of disease 
modifying drugs shown to provide an outcome benefit, such as beta blockers, ACEI/ARBs,
ARNI, MRAs, hydralazine-nitrate combinations, SGLT2is, or future standard treatment 
recommended in the study population, should not be reduced for the sole purpose of 
facilitating the maintenance of study intervention dosing. In general, every attempt should be 
made to resume the study intervention upon temporary interruption and reach and maintain 
the 10-mg target dose of the study intervention when the investigator feels it is medically 
appropriate according to Table 3 and Table 4.
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Table 3
Systolic Blood Pressure Criteria for Study Intervention Dose Modification
Blood Pressure Assessment
Dose Modification
SBP ≥100 mm Hg and not on 10-mg target dose
Increase Dose
• SBP ≥100 mm Hg and on 10-mg target dose OR
• SBP ≥90 and <100 mm Hg
Maintain Dose
SBP <90 mm Hg, asymptomatic
•
If currently on 5 or 10 mg, decrease dose
•
If currently on 2.5 mg, interrupt dose
SBP <90 mm Hg, symptomatic 
Interrupt Dose 
A dose decrease from the 5- or 10-mg doses is possible at any time if the investigator feels 
this is justified for safety reasons. 
A dose assessment including reasons for dose modifications (maintenance, increase, 
decrease, interruption, or restart) will be collected at all visits in which a vital signs 
assessment is performed. Study intervention initiation, up-titration, or restart should only 
occur if mean SBP is ≥100 mmHg.
If the participant is not receiving the target dose of 10 mg, up-titration should be considered 
at any study visit at the discretion of the investigator according to the SBP criteria in Table 3.
Unscheduled visits may be used at the discretion of the investigator for up-titration and 
resumption of study intervention following interruptions (Section 8.11.2.2). Study 
intervention should be resumed as soon as medically justified at the discretion of the 
investigator.
There is no defined maximum time limit for temporary treatment interruption. In all cases, 
the reason for study intervention interruption or permanent study intervention discontinuation 
must be recorded in the eCRF.
6.6.1
Resumption of Study Intervention Following Interruption
Titration rules following restart of study intervention after temporary interruption due to 
intolerability are as follows:
•
Interruption during the titration phase (Days 0 to 28):
-
Restart study intervention at a scheduled visit and titrate with intervals as shown in 
Table 3 and Table 4.
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•
Interruption After Day 28
-
Restart as soon as possible (with an unscheduled visit if required) and titrate 
according to the instructions provided in Table 3 and Table 4.
-
Participant will then resume the planned visit schedule.
-
Unscheduled visits and/or contacts can be conducted at the discretion of the 
investigator (Section 8.11.2.2).
Table 4
Instructions for Resumption of Study Intervention After Interruption due to 
Intolerability
Dose at Time of 
Interruption
Length of 
Interruption
Restart Dose
Dose Level
1st Titration
(14 days ± 4)
Dose Level
2nd Titration
(28 days ± 4)
2.5 mg
Any time interval
2.5 mg
5 mg
10 mg
5 mg
Any time interval
2.5 mg
5 mg
10 mg
10 mg
>5 days
2.5 mg
5 mg 
10 mg 
10 mg
≤5 days
5 mg
10 mg
Not applicable
In cases when study intervention was interrupted for reasons other than intolerability, the 
investigator may use clinical judgment in restarting study intervention based on 
considerations including participant's prior history of tolerability to the intervention. Table 4
may be used at the discretion of the investigator as a guide for resumption of study 
intervention in such situations.
6.7
Intervention After the End of the Study
There is no study-specified intervention after the end of the study.
6.8
Clinical Supplies Disclosure
The emergency unblinding call center will use the intervention/randomization schedule for 
the study to unblind participants and to unmask study intervention identity. The emergency 
unblinding call center should only be used in cases of emergency (see Section 8.1.12). If the 
emergency unblinding call center is not available for a given site in this study, the central 
electronic intervention randomization system (IRT) should be used to unblind participants 
and to unmask study intervention identity. The Sponsor will not provide random 
code/disclosure envelopes or lists with the clinical supplies.
6.9
Standard Policies
Not applicable.
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
Since data on clinical events and vital status are essential to the primary analysis, they must 
be collected until the end of the study, even if the participant prematurely discontinues study 
intervention. Therefore, all efforts will be taken to obtain data on clinical events and vital 
status until the end of study. All participants who discontinue study intervention before 
completion of the protocol-specified treatment period will still continue to be monitored in 
the study and participate in the study visits/contacts and procedures as specified in
Section 1.3.2 and Section 8.11.3 unless the participant has withdrawn from the study 
(Section 7.2).
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention 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.
A participant must be discontinued from study intervention, but continue to be monitored in 
the study for any of the following reasons:
•
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.
•
If the participant begins treatment with open-label vericiguat (see Sec. 6.5).
•
Participant has an eGFR that is consistently <15/mL/min/1.73 m2 or requires chronic 
dialysis. 
Note: Vericiguat has not been studied in patients with eGFR <15 mL/min/1.73 m2 at 
treatment initiation or on dialysis and is therefore not recommended in these patients. If 
short-term dialysis is indicated, then interrupt study intervention prior to the start of 
dialysis and resume only after stopping dialysis and when the eGFR returns to 
≥15 mL/min/1.73 m2.
•
The participant has a confirmed positive serum pregnancy test.
Participants may be allowed to begin study intervention again if deemed medically 
appropriate, after consultation with the Sponsor.
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7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant or a participant’s legally acceptable representative requests to withdraw 
consent from the study, the investigator will clarify whether the participant wishes to 
withdraw completely from study (eg, no further site contact) or whether the participant is 
willing to be contacted for additional follow-up by phone. If the participant is willing to be 
contacted about their health status at a future timepoint, then the participant is not withdrawn 
from study follow-up. If a participant withdraws from the study, they will no longer receive 
study intervention or be followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from FBR, are outlined in 
Section 8.1.11. The procedures to be performed should a participant repeatedly fail to return 
for scheduled visits and/or if the study site is unable to contact the participant are outlined in
Section 7.3.
For participants who have withdrawn consent from further study follow-up, collection of 
clinical event and vital status data will be completed by review of medical or public records 
in accordance with participant informed consent and local regulations.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
•
At any time that a participant’s vital status is in question, the investigator should explore 
all possible options to locate the participant per local regulations (unless the participant 
has explicitly withdrawn his/her consent to any type of follow-up). The site must 
document all attempts to try to contact the participant in the medical records/source 
documents. The vital status will be collected for all randomized participants who have not 
withdrawn consent, irrespective of completion of study procedures.
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8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of 
study-site personnel responsibilities will be documented in the Investigator Trial File 
Binder (or equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
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 (eg, blood 
count) and obtained before providing documented informed consent may be used for 
screening or baseline purposes provided the procedures meet the protocol-specified 
criteria and were performed within the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
The estimated amount of blood collected from each participant over the duration of the study 
will be 116 mL (Laboratory Manual). This estimate is based on the median follow-up of 
22.5 months. The actual blood volume could be less or more depending on when the 
participant is enrolled relative to the Primary Completion Date. Repeat or unscheduled 
samples may be taken for safety reasons or for technical issues with the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study or FBR. If there are 
changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
documented informed consent is in place.
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8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
Specifics about the study and the study population are to be included in the study informed 
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the FBR consent to the 
participant, or the participant’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent before performing any procedure related 
to FBR. A copy of the informed consent will be given to the participant before performing 
any procedure related to FBR.
8.1.2
LVEF Assessment
A historical assessment of LVEF within 12 months before randomization may be used for 
screening. The most recent results must be used to determine eligibility. For participants 
without a historical LVEF assessment, an echocardiogram will be performed at screening 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 (ie, initiation of a GDMT) that might improve LVEF, 
must have a measurement of LVEF at least 3 months after the intervention to be 
eligible.
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8.1.3
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.4
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study-site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention
randomization, site personnel will add the treatment/randomization number to the participant 
identification card.
The participant ID card also contains contact information for the emergency unblinding call 
center so that a health care provider can obtain information about study intervention in 
emergency situations where the investigator is not available.
8.1.5
Medical History
A medical history will be obtained by the investigator or qualified designee at the Screening 
Visit; participant demographics will also be recorded. At the Randomization Visit, the 
medical history record will be updated with any new diagnoses that have occurred during the 
screening period.
8.1.6
Prior and Concomitant Medications Review
8.1.6.1
Prior Medications
The investigator or qualified designee will review prior medication use and record prior 
medication taken by the participant within 30 days before starting the study.
8.1.6.2
Concomitant Medications
The investigator or qualified designee will record all medications taken by the participant 
during the study as described in Section 6.5. The investigator or qualified designee will 
confirm that the participant is not receiving any medications prohibited during the study as 
described in Section 5.2.
8.1.7
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur before randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be reused for 
different participants.
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Each participant may only be rescreened once. Any participant who is rescreened will retain 
the original screening number assigned at the initial Screening Visit. Specific details on the 
Screening/Rescreening Visit requirements are in Section 8.11.1.2.
8.1.8
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be reassigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.9
Study Intervention Administration
Study intervention(s) will be administered by the investigator and/or study staff according to 
the specifications within the Operations Manual.
The first dose of study intervention will be administered at the study site at Visit 2 only. 
Subsequent dosing will be performed once daily by the participant (ie, unsupervised at 
his/her home) at approximately the same time each day.
The procedures for vital sign measurements required before and after the first dose of study 
intervention at Visit 2 are described in Section 8.3.2. At subsequent visits, perform vital sign 
measurements and dose assessment and modification (Sections 8.3.2 and 8.3.3) before 
dispensing study intervention.
8.1.9.1
Timing of Dose Administration
Study intervention should be taken with food at the same time each day. If a dose is missed, 
it should be taken as soon as the participant remembers on the same day of the missed dose. 
Participants should not take 2 doses of study intervention on the same day.
8.1.10 Study Intervention Compliance
Refer to Section 6.4 for instructions for recording study intervention compliance.
8.1.11 Discontinuation and Withdrawal
Participants who discontinue study intervention before completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits as outlined in 
the SoA (Section 1.3.2) and Section 8.11.3.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the Study Intervention Discontinuation Visit at the time of 
withdrawal. Any AEs that are present at the time of withdrawal should be followed in 
accordance with the safety requirements outlined in Sections 8.4 and 8.11.3.
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8.1.11.1 Withdrawal From Future Biomedical Research
Participants may withdraw their consent for FBR. Participants may withdraw consent at any 
time by contacting the study investigator. If medical records for the study are still available, 
the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant’s consent for 
FBR will be withdrawn. A letter will be sent from the Sponsor to the investigator confirming 
the withdrawal. It is the responsibility of the investigator to inform the participant of 
completion of withdrawal. Any analyses in progress at the time of request for withdrawal or 
already performed before the request being received by the Sponsor will continue to be used 
as part of the overall research study data and results. No new analyses would be generated 
after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no longer 
required by regulatory authorities to retain the study records) or the specimens have been 
completely anonymized, there will no longer be a link between the participant’s personal 
information and their specimens. In this situation, the request for specimen withdrawal 
cannot be processed.
8.1.12 Participant Blinding/Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and/or the 
dosage administered, he/she will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Before contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the 
investigator who is a qualified physician should make reasonable attempts to enter the 
intensity of the AEs observed, the relation to study intervention, the reason thereof, etc, in the 
medical record. If it is not possible to record this assessment in the medical record before the 
unblinding, the unblinding should not be delayed.
If unblinding has occurred, the circumstances around the unblinding (eg, date, reason, and 
person performing the unblinding) must be documented promptly, and the Sponsor Clinical 
Director notified as soon as possible.
Once an emergency unblinding has taken place, the investigator, site personnel, and Sponsor 
personnel may be unblinded so that the appropriate follow-up medical care can be provided 
to the participant.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or nonstudy treating physician should continue to be monitored in the 
study.
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Additionally, the investigator or medically qualified designee must go into the IRT system 
and perform the unblind in the IRT system to update drug disposition. If the emergency 
unblinding call center is not available for a given site in this study, the IRT system should be 
used for emergency unblinding if this is required for participant safety.
8.1.13 Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Efficacy Assessments
8.2.1
Clinical Events Assessment
Participants will be assessed for the occurrence of potential study endpoint events described 
in Section 9.4.1. Assessment for endpoint events will occur at each study visit as outlined in 
Section 1.3. The Sponsor may request this assessment at any time during the study in 
preparation for an IA. Investigators will also assess potential study endpoints they learn of 
between scheduled study visits.
8.2.2
New York Heart Association Functional Classification of Heart Failure
NYHA class will be assessed according to the classification in Table 5.
Table 5
New York Heart Association Functional Classification
Class
Symptoms
I
No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, 
palpitation, dyspnea, or anginal pain.
II
Slight limitation of physical activity in which ordinary physical activity leads to fatigue, 
palpitation, dyspnea, or anginal pain. The person is comfortable at rest.
III
Marked limitation of physical activity in which less-than-ordinary activity results in fatigue, 
palpitation, dyspnea, or anginal pain. The person is comfortable at rest.
IV
Inability to carry on any physical activity without discomfort but also symptoms of heart 
failure or the anginal syndrome even at rest, with increased discomfort if any physical activity 
is undertaken
8.2.3
EuroQol Group 5-Dimension, 5-level Questionnaire
The EQ-5D is a questionnaire used to assess current health status as reported by patients, 
consisting of 5 domain questions and 1 VAS response. The domain questions assess 
mobility, self-care, usual activities, pain/discomfort, anxiety/depression, with 5-level 
response options: no problems, slight problems, moderate problems, severe problems, and 
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extreme problems. Summary scores will be calculated from the 5 domain scores according to 
scoring instructions from the EuroQol group and the EQ-5D-5L value sets for the United 
States and for Europe.
The EQ-5D VAS records patient self-rated health on a 20 cm vertical VAS with endpoints 
labeled ‘the best health you can imagine’ and ‘the worst health you can imagine’ and is 
scored on a 0 to 100 scale.
The questionnaire is available in over 60 translations with established validity, reliability, and 
responsiveness. In cases when a validated translation is needed and not available for a 
specific language, participants who speak that language will be exempt from the requirement 
to complete the questionnaire.
8.2.4
Kansas City Cardiomyopathy Questionnaire
The KCCQ questionnaire used in this study consists of a 23-item, self-administered 
questionnaire intended for the quantification of HF patients’ perspectives of how their 
disease impacts their lives. The questionnaire requires, on average, 5 to 8 minutes for 
completion. The KCCQ measures the impact of patients’ HF, or its treatment, on 7 distinct 
domains using a 2-week recall period: symptom frequency, symptom burden, physical 
limitation, health perceptions, social function, self-efficacy, and symptom stability. The 
KCCQ domains of self-efficacy and symptom stability will be reported but are not 
considered in the efficacy assessment as they address patient knowledge and recent changes 
in symptoms respectively.
In addition, there are 3 summary scores; a total symptom scale that combines the symptom 
frequency and the symptom burden scores, a clinical summary scale that combines the total 
frequency and physical limitation scores to replicate the NYHA Classification, and an overall 
summary score that includes the Total Symptom, Physical Limitation, Social Limitation, and 
QoL scores.
The questionnaire is available in over 40 translations with established validity, reliability, and 
responsiveness. In cases when a validated translation is needed and not available for a 
specific language, participants who speak that language will be exempt from the requirement 
to complete the questionnaire.
8.2.5
Vital Status Assessment
The vital status assessment is included in the Final Contact and may be conducted at any time 
during the study. This assessment can be conducted by review of medical records or public 
records when vital status is in question in accordance with local regulations, unless the 
participant has specifically withdrawn consent for collection of vital status data.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood/tissue to be drawn/collected over the course of the study 
(from prestudy to poststudy visits), including approximate blood/tissue volumes 
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drawn/collected by visit and by sample type per participant, can be found in the Laboratory 
Manual.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A full physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) per institutional standard as outlined in the 
SoA. Height will also be measured once and recorded.
A brief directed physical examination will be conducted by an investigator or medically 
qualified designee (consistent with local requirements) per institutional standard as outlined 
in the SoA.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.2
Vital Signs
BP and pulse rate (each measured in triplicate) and weight will be assessed at the Screening 
Visit, Discontinuation Visit, Final Visit and at each study visit before study intervention is 
dispensed. At the Randomization Visit (Visit 2), BP and pulse assessments will also be 
completed 2 ± 0.5 hours after study intervention administration.
Accurate measurement of BP is essential to guide dose titration management 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.
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•
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.
•
Body weight will also be measured and recorded.
Dose assessment should be performed following BP assessment (Section 8.3.3).
8.3.3
Dose Assessment and Modification
After BP assessment, perform a dose assessment using Table 3. If indicated, see Section 6.6 
for instructions for dose modification.
8.3.4
Electrocardiograms
•
Single 12-lead ECG will be obtained and reviewed by an investigator or medically 
qualified designee (consistent with local requirements) as outlined in the SoA using an 
ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, 
and QTc intervals.
•
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.
Record ECG with a paper speed of 25 mm/sec. Ensure standard calibration is performed and 
provide record of a calibration mark indicating the equivalence of 1 mV signal to 10 mm 
vertical deflection on the ECG. 
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8.3.5
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant’s condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the Laboratory Manual and the SoA.
•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation In the study or within 14 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
8.3.6
Pregnancy Testing
• Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
Pregnancy testing (urine and/or serum as required by local regulations) should be 
conducted at monthly intervals during intervention. Sites will provide urine 
pregnancy testing kits to WOCBP for at-home testing every 4 weeks between visits. 
At scheduled study visits, site personnel will confirm with WOCBP that the 
required at-home pregnancy tests have been completed and will document such 
completion in site source records.
-
Pregnancy testing (urine and/or serum as required by local regulations) should be 
conducted at the end of relevant systemic exposure and correspond with the time 
frame for participant contraception in Section 5.1. The final pregnancy test is 
required 1 month after the last dose of study intervention and must be recorded in 
the site source records.
-
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 participant's participation in the study.
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NOTE:
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. Participants should be instructed to contact the site if the 
result of a home pregnancy test kit cannot be confirmed as negative.
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
Selective AE reporting by sites will be used in the study. The definitions of an AE or SAE, as 
well as the method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting AE, SAE, and other reportable safety event 
reports can be found in Appendix 3.
All events will be reported to the site by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorized representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of a selected NSAE, SAE, as well as other reportable safety 
events. Selected NSAEs are nonserious AEs that meet any of the following criteria: 
•
AE that leads to study intervention dose modification or discontinuation
•
AE that leads to withdrawal from the study
•
COVID-19 disease-related AE
Investigators need to document if an SAE was associated with a medication error, misuse, or 
abuse. 
Investigators remain responsible for following up selected NSAEs, SAEs, and other 
reportable safety events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of a 
selected NSAE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
Additional country-specific requirements for adverse event reporting are described in 
Appendix 7.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
Selected NSAEs, SAEs, and other reportable safety events that occur after the participant 
provides documented informed consent, but before intervention randomization, must be 
reported by the investigator if the event causes the participant to be excluded from the study, 
or is the result of a protocol-specified intervention, including, but not limited to washout or 
discontinuation of usual therapy, diet, or a procedure.
From the time of intervention randomization through 14 days after cessation of study 
intervention, selected NSAEs, SAEs, and other reportable safety events must be reported by 
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the investigator. All pregnancy and exposure during breastfeeding, from the time of 
intervention allocation/randomization through 1 month post cessation of study intervention 
must be reported by the investigator.
Additionally, any SAE brought to the attention of an investigator at any time outside the 
period specified in the previous paragraph must be reported immediately to the Sponsor if the 
event is considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. 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 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
Selected NSAEs, SAEs, and other reportable safety events will be recorded and reported to 
the Sponsor or designee within the time frames as indicated in Table 6.
Exception: A positive pregnancy test at the time of initial screening is not a reportable event 
unless the participant has received study intervention.
Additional country-specific requirements for adverse event reporting are described in 
Appendix 7.
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Table 6
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time
Period:
Target Consent to 
Main Consent
Main Consent to 
Randomization/
Allocation
Reporting Time 
Period:
Randomization/
Allocation 
Through 
Protocol-specified 
Follow-up Period
Reporting Time
Period:
After the 
Protocol-
specified 
Follow-up 
Period
Time Frame 
to Report 
Event and 
Follow-up 
Information to 
Sponsor
Selected NSAE
Additional country-
specific 
requirements for 
adverse event 
reporting are 
described in 
Appendix 7.
Report if:
– due to protocol-
specified intervention
– causes exclusion
Report if:
- leads to study 
intervention dose 
modification or 
discontinuation
- leads to 
withdrawal from 
the study
- COVID-19 
disease-related
Additional 
country-specific 
requirements for 
adverse event 
reporting are 
described in 
Appendix 7.
Not required
Per data entry 
guidelines
SAE
Report if:
– due to protocol-
specified intervention
– causes exclusion
Report all
Report if:
– drug/vaccine 
related.
(Follow ongoing 
to outcome)
Within 
24 hours of 
learning of 
eventa
Pregnancy/Lactation 
Exposure
Report if:
– participant has been 
exposed to any 
protocol-specified 
intervention (eg, 
procedure, washout,
or run-in treatment 
including placebo run-
in)
Exception: A positive 
pregnancy test at the 
time of initial 
screening is not a 
reportable event.
Report all
Previously 
reported –
Follow to 
completion/
termination; 
report outcome
Within 
24 hours of 
learning of 
event
ECI (require 
regulatory reporting)
Report if:
– due to intervention
– causes exclusion
Report
– potential DILI
– require 
regulatory 
reporting
Not required
Within 
24 hours of 
learning of 
event
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Type of Event
Reporting Time
Period:
Target Consent to 
Main Consent
Main Consent to 
Randomization/
Allocation
Reporting Time 
Period:
Randomization/
Allocation 
Through 
Protocol-specified 
Follow-up Period
Reporting Time
Period:
After the 
Protocol-
specified 
Follow-up 
Period
Time Frame 
to Report 
Event and 
Follow-up 
Information to 
Sponsor
ECI (do not require 
regulatory reporting)
Report if:
– due to intervention
– causes exclusion
Report
– symptomatic 
hypotension
- anemia
Not required
Within 
5 calendar days 
of learning of 
event
Cancer
Report if:
– due to intervention
– causes exclusion
Report all
Not required
Within 
5 calendar days 
of learning of 
event (unless 
serious)
Overdose
Not required
Report all
Not required
Within 
5 calendar days 
of learning of 
event (unless 
serious)
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious 
adverse event.
a
Event meeting serious criteria and determined not to meet endpoint criteria (as per Section 8.4.6) must be reported 
within 1 business day from the time of receipt of the Sponsor query.
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. Selected NSAEs, SAEs, and other reportable safety 
events, including pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose 
will be followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow selected nonserious AEs that occur in randomized participants 
for outcome. Further information on follow-up procedures is given in Appendix 3.
Additional country-specific requirements for adverse event reporting are described in 
Appendix 7.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities toward the safety of participants and the 
safety of a study intervention under clinical investigation are met.
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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 and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as AEs 
or SAEs
Potential prespecified efficacy endpoints will be submitted to an independent CEC (See 
Section 10.1.4.4) for adjudication. This will include all-cause mortality, including CV death 
and non-CV death.
The following events will not be subject to expedited reporting by the Sponsor to 
investigators, IECs/IRBs, and regulatory agencies, regardless of causality unless and until the 
event is reviewed by the CEC and found not to meet the specified criteria in the CEC charter 
for the following endpoint types:
•
CV death
•
CV hospitalizations
•
UHF visit
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Fatal events that are adjudicated to be non-CV deaths by the CEC will require an 
independent MSD company causality assessment and will be subject to expedited reporting, 
where required by local legislation, when there is sufficient evidence suggesting a causal 
relationship between study intervention and the event.
If any event submitted for adjudication is determined by the CEC not to meet the endpoint 
criteria in the CEC charter, the event will then be subject to expedited reporting (as 
appropriate, based upon both the investigator and independent MSD company causality 
assessment of drug relationship, as required by local legislation).
All of the endpoint events including confirmed adjudicated CV events will be reviewed and 
monitored by an external DMC, unblinded to study intervention, as part of the overall 
assessment of safety and efficacy of vericiguat. Based upon the regular DMC review of 
unblinded safety results, the DMC is empowered by the DMC charter to make 
recommendations with regard to study conduct to assure the continuing appropriate safety of 
the participants.
8.4.7
Events of Clinical Interest
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor.
Events of clinical interest for this study include:
1. Potential DILI events defined as: an elevated AST or ALT laboratory value that is greater 
than or equal to 3× the ULN and an elevated total bilirubin laboratory value that is greater 
than or equal to 2× the ULN and, at the same time, an alkaline phosphatase laboratory 
value that is less than 2× the ULN, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note: These criteria are based on available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an 
additional evaluation for an underlying etiology. The study-site guidance for assessment 
and follow-up of these criteria can be found in the Investigator Study File Binder (or 
equivalent).
2. Symptomatic hypotension
3. Anemia
ECIs of symptomatic hypotension and anemia that do not fit the SAE criteria do not require 
regulatory reporting Table 6.
8.5
Treatment of Overdose
In this study, an overdose is any dose higher than 10 mg vericiguat QD.
Limited data are available with regard to overdosage in human patients treated with 
vericiguat. In the event of an overdose, hypotension may result. Symptomatic treatment 
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should be provided. Vericiguat is unlikely to be removed by hemodialysis because of high 
protein binding.
Decisions regarding dose interruptions or modifications following a suspected overdose will 
be made by the investigator in consultation with the Sponsor’s Clinical Director based on the 
clinical evaluation of the participant.
8.6
Pharmacokinetics
The decision as to which plasma samples collected will be measured for evaluation of PK 
will be collaboratively determined by the Sponsor (eg, samples at lower doses may not be 
measured if samples at higher doses reveal undetectable drug concentrations). If indicated, 
these samples may also be measured and/or pooled for assay in an exploratory manner for 
metabolites and/or additional pharmacodynamic markers.
8.6.1
Blood Collection for Plasma MK-1242
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the Laboratory Manual. Blood samples will be collected for PK analysis as indicated in the 
SoA. At Visit 2, 1 sample will be collected predose. For all PK samples, date and time of the 
PK sample collection and date and time of last dose of study intervention intake must be 
documented.
Additional blood samples for PK should be collected at Visit 4, Visit 5, and approximately 
every 48 weeks at routine visits. PK samples obtained at additional time points based on the 
investigator’s discretion will not qualify as a protocol deviation and will be analyzed. 
Deviations from the specified time points will be documented and taken into account when 
calculating the PK parameters.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Biomarkers
Collection of samples for other biomarker research is also part of this study. The following 
samples for biomarker research are required and will be collected from all participants as 
specified in the SoA:
•
Blood for genetic analysis
•
Blood for exploratory biomarker analysis
Country-specific requirements are noted in Appendix 7.
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8.8.1
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample should be drawn for planned analysis of the association 
between genetic variants in DNA and drug response. This sample will not be collected at the 
site if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does 
not approve the collection of the sample for these purposes. If the sample is collected, 
leftover extracted DNA will be stored for FBR if the participant provides documented 
informed consent for FBR. If the planned genetic analysis is not approved, but FBR is 
approved and consent is given, this sample will be collected for the purpose of FBR.
Sample collection, storage, and shipment instructions for planned genetic analysis samples 
will be in the Operations/Laboratory Manual.
8.8.2
Exploratory Biomarker Sample Collection
In the event that the biomarker sample at the specified visit is not obtained, the sample can be 
taken at a subsequent visit within the next 12 months of treatment. Details on the collection, 
processing, storage, and shipment of biomarker samples will be provided in a separate 
Operations/Laboratory Manual and results of the biomarker analyses will be reported 
separately.
Investigators will not receive the results of analyses during the study, and no alerts will be 
sent.
8.9
Future Biomedical Research Sample Collection
If the participant provides documented informed consent for FBR, the following specimens 
will be obtained as part of FBR:
•
Leftover DNA for future research
•
Leftover exploratory biomarker samples for future research
Country-specific requirements are noted in Appendix 7.
8.10 Health Economics, Medical Resource Utilization and Health Economics
Not applicable.
8.11 Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
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8.11.1 Screening Period
8.11.1.1 Target Screening (Optional)
A single, optional Target Screening Visit may be performed to assess potential eligibility for 
participants who do not have a recent (within 30 days) historical assessment of any of the 
protocol-specified laboratory screening tests. After providing documented informed consent 
for this optional Target Screening, participants will be assigned a screening number and 
undergo a blood draw. If the decision to proceed to study screening is made, documented 
consent for the full study will be obtained and the Screening Visit will be conducted.
8.11.1.2 Screening Visit
Up to 30 days before intervention randomization, potential participants will be evaluated to 
determine that they fulfill the entry requirements as set forth in Section 5. For potential 
participants who are screen failures, 1 rescreening is allowed, which must include 
re-consenting potential participants.
The Screening Visit (Visit 1) and Randomization Visit (Visit 2) may occur on the same day if 
all required test results for the eligibility criteria are available. 
8.11.2 Treatment Period
Clinic visits must be conducted at the study site. If there are extenuating circumstances that
do not support an in-clinic visit (ie, incapacitating health conditions or local or national 
emergency situations), a telephone, video, or home visit using site staff or a nursing service 
may be used, if allowed by local regulations following consultation with the Sponsor.
8.11.2.1 Randomization Visit
The Randomization Visit (Visit 2) may occur on the same day as Screening Visit (Visit 1) if 
all required test results for the eligibility criteria are available. If Visits 1 and 2 occur on the 
same day, all procedures specified for both Visits 1 and 2 must only be conducted once after 
the participant has provided documented informed consent.
8.11.2.2 Unscheduled Visits
Unscheduled visits may be utilized at any time during the study at the discretion of the 
investigator. At unscheduled visits, the following assessments will be performed:
•
AE review and reporting (see Section 8.4 and Appendix 3)
•
BP and pulse rate (see Section 8.3.2) and dose assessment (see Section 8.3.3) before 
study intervention administration/dispensing
•
Clinical event assessment (see Section 8.2.1)
•
Concomitant medication review (see Sections 8.1.6.2 and 6.5)
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Upon interruption of the study intervention due to intolerability, intake should be resumed as 
soon as medically justified at the discretion of the investigator as described in Section 6.6. 
Investigators should make every attempt to resume study intervention in all participants after 
interruption as soon as medically justified.
8.11.3 Participants Who Prematurely Discontinue Study Intervention
Participants who prematurely discontinue study intervention will have a Study Intervention 
Discontinuation Visit at the time of permanent discontinuation of study intervention and will 
continue to be monitored until the end of the study (Section 1.3.2). After the last dose of 
Study Intervention, participants will have a safety follow-up contact (see Section 8.11.4). 
After the safety contact, additional follow-up contacts will occur every 24 weeks (±14 days) 
relative to Randomization (Day 1), for clinical event assessment to monitor for efficacy 
endpoint events and vital status through the end of the study (Final Contact). Follow-up 
contacts may be conducted via telehealth visits, phone calls, etc.
8.11.4 14-day Safety Contact
All participants will be required to complete a safety follow-up contact at least 14 days after 
the last dose of study intervention to determine if any AEs have occurred since the Final Visit
or Study Intervention Discontinuation Visit, as applicable.
8.11.5 Primary Completion Date Requirements
8.11.5.1 Final Visit
After the Primary Completion Date, a Final Visit will be conducted for participants who are 
receiving study intervention. Participants will continue study intervention until this visit and 
will be asked to stop taking study intervention at this visit.
8.11.5.2 Final Contact
After the Primary Completion Date, the Final Contact will be conducted for participants who 
prematurely discontinue study intervention. A Final Contact may be conducted via telehealth 
visit, phone call, etc.
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9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, but prior to any unblinding/final database lock, changes are made to 
primary and/or key secondary hypotheses, or the statistical methods related to those 
hypotheses, then the protocol will be amended (consistent with ICH Guideline E-9). Changes 
to exploratory or other non-confirmatory analyses made after the protocol has been finalized, 
but prior to unblinding/final database lock, will be documented in an sSAP and referenced in 
the CSR for the study. Post hoc exploratory analyses will be clearly identified in the CSR. 
Other planned analyses (ie, those specific to the analysis of PK data, exploratory biomarkers, 
PGA, FBR) are beyond the scope of this document or will be documented in separate 
analysis plans.
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2 to 9.12.
Study Design Overview
A Pivotal Phase 3 Randomized Placebo-controlled Clinical Study to 
Evaluate Efficacy and Safety of the sGC Stimulator Vericiguat/ 
MK-1242 in Adults With Chronic Heart Failure With Reduced 
Ejection Fraction
Treatment Assignment
Participants will be assigned randomly in a 1:1 ratio to vericiguat or 
matching placebo, respectively.
Stratification method: Treatment randomization will be stratified 
according to baseline NYHA Class (II vs III/IV).
Analysis Populations
Efficacy: ITT
Safety: APaT
Primary Endpoint(s)
Time from randomization to the first event of CV death or HFH
Secondary Endpoints
Time from randomization to CV death
Time from randomization to first event of HFH
Time from randomization to all HFH events (first and recurrent)
Time from randomization to the first event of all-cause mortality or 
HFH
Time from randomization to all-cause mortality
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Statistical Methods for 
Key Efficacy
The analysis of the primary endpoint will be performed with a 
one-sided stratified log-rank test to test whether the time to first 
event of CV death or HFH is prolonged in the vericiguat treatment 
group compared with placebo.
The same approach will be used for the endpoints of time to 
CV death, time to first event of HFH, time to all-cause mortality, 
and time to the first event of all-cause mortality or HFH.
The time to total HFH events will be tested with an Andersen-Gill 
model.
The type I error rate will be controlled at 0.025 (one-sided).
Statistical Methods for 
Key Safety Analyses
95% CIs will be provided for between-treatment differences in the 
percentage of participants with selected events; these analyses will 
be performed using the Miettinen and Nurminen method.
Interim Analyses
One IA for efficacy is planned at the time when approximately 70% 
(413) of the planned number of CV deaths (approximately 590) are 
observed. An external DMC will assess the unblinded results of the 
IA and may recommend early study termination for success if both 
the primary endpoint and the CV death endpoint are statistically 
significant based on the nominal significance level used for the IA.
Multiplicity
Hypotheses H2 and H3 (addressing CV death and HFH), will both 
be tested if the test of H1 is significant. Hypotheses H4, H5, and H6 
(addressing total HFH events, the composite of all-cause mortality 
or HFH, and all-cause mortality), will also be tested if the test of H1
is significant, and will follow a hierarchical testing approach. In 
addition, a multiplicity adjustment for the IA will be applied for the 
primary and secondary endpoints.
Sample Size and Power 
The sample size calculation is driven by the CV death endpoint. The 
relative reduction in the hazard with vericiguat is assumed to be 
20% for the CV death and primary endpoint, corresponding to a HR 
of 0.8. Using the log-rank test, approximately 590 CV deaths will be 
required to achieve 80% power conditional on a positive primary 
endpoint result with a one-sided alpha of 0.025. A sample size of 
6000 participants is expected to produce 590 CV death events in 
approximately 39.5 months assuming a placebo incidence rate of 6.0 
per 100 patient-years of follow up. It is expected that approximately 
1080 participants will have experienced a primary event at the time 
of 590 CV death events assuming a placebo incidence rate of 11.5 
participants with an event per 100 patient-years of follow up and a 
HR of 0.8. This number of participants with primary events (1080)
will provide approximately 95% power for primary hypothesis 
testing. However, since the study duration will be driven by the 
number of CV death events, the number of primary endpoint events 
(and thus, the power) may differ from the numbers provided above.
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9.2
Responsibility for Analyses/In-house Blinding
The statistical analyses of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
This study will be conducted as a double-blind study under in-house treatment blinding 
procedures. The laboratory values for NT-proBNP will also be blinded after randomization 
(Visit 2). The official, final database will not be unblinded until medical/scientific review has 
been performed, protocol violators have been identified, and data have been declared final 
and complete.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study treatment assignment. Randomization will be implemented in an IVRS.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3 Hypotheses, Objectives, and 
Endpoints.
9.3.1
Estimands
The following attributes define the primary estimand addressing the primary hypothesis:
•
The treatment condition of interest is vericiguat or placebo added to GDMT.
•
The population targeted by the clinical question are males or females at least 18 years of 
age with chronic HFrEF (as defined in Section 5).
•
The endpoint to address the clinical question is time to the composite endpoint of 
CV death or HFH, defined as the time from the date of randomization to the date of first 
occurrence of any endpoint event.
•
Intercurrent events of interest are discontinuation of study intervention and loss to 
follow-up (ie, withdrawal of consent, non-CV death). A treatment policy approach will 
be applied to discontinuation of study intervention, and a hypothetical strategy will be 
applied to lost to follow-up (ie, as though participants would have been followed for the 
primary endpoint events).
•
The population-level summary is the hazard ratio comparing vericiguat with placebo.
Analogous estimands will be used to evaluate the secondary objectives and hypotheses, 
except that the population-level summary for H4 (related to all occurrences of HFHs) will be 
the ratio of incidence rates rather than the hazard ratio.
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9.4
Analysis Endpoints
9.4.1
Efficacy Endpoints
Primary Endpoint
•
Time from randomization to the first event of CV death or HFH
Secondary Endpoints
•
Time from randomization to CV death
•
Time from randomization to first event of HFH
•
Time from randomization to total HFH events (first and recurrent)
•
Time from randomization to first event of all-cause mortality or HFH
•
Time from randomization to all-cause mortality
Exploratory Endpoints
•
Time from randomization to first event of HFH or UHF visit (not meeting the criteria for 
an HFH)
•
Time from randomization to first event of CV hospitalization
•
Total number of HFH events
•
Change from baseline in health-related quality of life measures (EQ-5D-5L and KCCQ)
•
Slope of change in eGFR from baseline
All of the above endpoints except change in eGFR and quality of life measures will be based 
on CEC-confirmed events.
9.4.2
Safety Endpoints
Safety measurements are described in Section 8 Study Assessments and Procedures.
9.5
Analysis Populations
The primary efficacy analysis population will be the ITT population, comprised of all 
randomized participants. Participants without any post-randomization information will be 
censored at Day 1.
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Except where noted otherwise, all efficacy analyses will classify participants according to 
their randomized intervention.
The population for all safety analyses will be the APaT population, comprised of all 
randomized participants, who have taken at least 1 dose of study intervention (vericiguat or 
placebo). All participants will be analyzed according to the actual intervention received. Any 
participants who inadvertently received both study interventions (placebo and blinded 
vericiguat) during the study will be analyzed according to the planned intervention.
9.6
Statistical Methods
9.6.1
Efficacy Analyses
Analysis of Primary Endpoint
The analysis of the primary endpoint will test whether the time to the first event of the 
composite endpoint is prolonged in the vericiguat intervention group compared with placebo. 
Randomized participants without any HFH or CV death events at the time of analysis will be 
censored at the earliest of: their last available information, the Primary Completion Date 
when the planned number of CV death events is achieved (Section 4.4.2), or the date of their 
non-CV death.
The analysis will be performed with a one-sided stratified log-rank test using the same 
stratification factor for randomization with a one-sided type I error rate of 0.025 (Table 7).
Kaplan-Meier estimates of the primary composite endpoint survival curves and the 
corresponding 95% CIs will be presented for each intervention group. The hazard ratio and 
corresponding 95% CI will be estimated based on a Cox proportional hazards model
stratified by the stratification factor for randomization.
In addition, as a sensitivity analysis the primary endpoint will be analyzed using the 5-STAR 
stratified testing approach by Mehrotra and West [Mehrotra, D. V. 2020].
The number and proportion of participants with a primary endpoint event, as well as 
incidence rates per 100 patient-years of follow-up, will be provided by intervention group.
Analysis of Secondary Endpoints
A one-sided stratified log-rank test similar to the one used for the primary efficacy endpoint 
will also be used to test whether the time to first HFH, time to CV death, time to all-cause 
mortality, and time to first event of all-cause mortality or HFH is prolonged in the vericiguat 
intervention group compared with placebo. Randomized participants without any endpoint
events at the time of analysis will be censored at the earliest of: their last available 
information, the study completion date when the planned number of primary endpoint events 
is achieved, or the date of their death when death is not included in the endpoint.
The time to total HFH events will be tested with an Andersen-Gill model (Table 7) 
[Andersen, P. K. 1982]. The Anderson-Gill model is an extension of the Cox proportional 
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hazards model, where the time increments between events will be included in the model to 
estimate the hazards. Intervention group and the stratification factors used for randomization 
will be included in the model as fixed effects. Robust standard errors will be used to account 
for correlations of event times within a participant.
On-treatment Analysis
On-treatment analyses for the primary and secondary efficacy endpoints will be performed as 
supportive analyses. These analyses will include all randomized participants who have taken 
at least 1 dose of study intervention (vericiguat or placebo) and will count only those events 
that occurred during the intervention period. Participants will be analyzed according to the 
actual intervention received for this analysis. Any participants who received both placebo 
and vericiguat during the study by mistake will be analyzed according to the planned 
intervention.
Missing Data
Participants who prematurely discontinue study intervention will be followed for further data 
collection. As long as the participant does not withdraw consent for any further data 
collection, every effort will be made to collect at least data on the components of the primary 
endpoint throughout the study. Therefore, it is expected that the amount of missing data will 
be minor, as most participants will be followed up until study termination.
For the primary analysis, participants without any HFH or CV death events at the time of 
analysis will be censored at their last available information or the date of their non-CV death 
(Table 7). The censoring mechanism is assumed to be noninformative.
Missing data sensitivity analyses will be performed to assess the robustness of the study 
results. Details will be described in the sSAP.
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Table 7
Primary Analysis Strategy for Efficacy Variables
Endpoint
Statistical Method a
Analysis 
Population
Missing Data 
Approach
Primary Endpoint
Time from randomization to first event
of CV death or HFH
Stratified Log-Rank 
Test
ITT
Censored at the 
last available 
information
Secondary Endpoints
Time from randomization to CV death
Stratified Log-Rank 
Test
ITT
Censored at last 
known alive date
Time from randomization to the first 
event of HFH
Stratified Log-Rank 
Test
ITT
Censored at the 
last available 
information
Time from randomization to total HFH 
events (including the first and recurrent 
events)
Andersen-Gill model
ITT
Censored at the 
last available 
information
Time from randomization to first event 
of all-cause mortality or HFH
Stratified Log-Rank 
Test
ITT
Censored at last 
available 
information
Time from randomization to all-cause 
mortality
Stratified Log-Rank 
Test
ITT
Censored at last 
known alive date
CV=cardiovascular; HFH=heart failure hospitalization; ITT=intention to treat.
aStatistical models are described in further detail in the text. For stratified analyses, the stratification factors used for 
randomization will be used as stratification factors for analysis.
9.6.2
Safety Analyses
Safety and tolerability will be assessed by clinical review of AEs and other relevant 
parameters, including laboratory tests, and vital signs. 
The analysis of safety results will follow a two-part approach (Table 8): general safety 
assessment and assessment of safety topics of interest. 
General Safety Assessment
The following AEs will be collected for this study: any AE that leads to study intervention 
dose modification or discontinuation, any AE leading to withdrawal from the study, 
COVID-19 disease-related AEs, and any ECI or SAE (Section 8.4). The general safety 
assessment will include summarization of aforementioned AEs and broad AE categories. 
These safety endpoints will be summarized by frequency (percentage) of participants with 
specific events.
For continuous measures such as laboratory values and vital signs, summary statistics for
baseline, on-treatment, and change from baseline values will be provided.
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In addition, descriptive statistics in the above analyses will be supplemented with 95% CIs 
for between-treatment differences for specific AEs with incidence ≥5% of participants in at 
least 1 of the intervention groups and AEs by SOC. 95% CIs for between intervention group 
differences using the Miettinen and Nurminen (M&N) method (1985) [Miettinen, O. and 
Nurminen, M. 1985] will be provided.
CIs provided as part of the general safety assessment are neither associated with prespecified 
hypotheses nor adjusted for multiplicity. Therefore, CIs should be regarded as helpful 
descriptive measures for review of the safety profile, not a formal method for assessing 
statistical significance of between-group differences.
Assessment of Safety Topics of Interest
Safety topics of interest include AEs of symptomatic hypotension and anemia and laboratory 
values consistent with potential DILI events (Section 8.4.7). For these safety endpoints, 
descriptive statistics and CIs for between-group comparisons will be provided.
Table 8
Analysis Strategy for Safety Parameters
Analysis Part
Safety Endpoint
Descriptive 
Statistics
95% CIsa
General Safety 
Assessment
AE Summaryb
X
Specific AEsb, PDLCs, change from Baseline Results 
(Laboratory values, Vital Signs)
X
Specific AEsb (incidence ≥5% of participants in at least one 
of the intervention groups), AE b by SOCs
X
X
Safety Topics 
of Interest
Symptomatic hypotension
Anemia
Potential DILI
X
X
X
X
X
X
AE=adverse event; CI=confidence interval; DILI=drug-induced liver injury; ECI=events of clinical interest; PDLC=predefined limit of 
change; SAE=serious adverse event; SOC=System Organ Class; X=results will be provided.
a Difference in proportions between groups
b AEs include selected NSAEs (AEs that lead to study intervention dose modification or discontinuation, AEs that lead to 
discontinuation from the study, COVID-19 disease-related AEs), SAEs, and ECIs.
9.6.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses
The comparability of the intervention groups for each relevant characteristic will be assessed 
by the use of tables and/or graphs. No statistical hypothesis testing will be performed on 
these characteristics. The number and percentage of participants randomized and the primary 
reason for discontinuation will be displayed. Demographic variables (eg, age) and baseline 
characteristics will be summarized by treatment either by descriptive statistics or categorical 
tables.
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9.7
Interim Analyses
An efficacy IA is planned when approximately 70% (413) of the planned number of 
CV death events (590) are observed. Based on the assumptions from the sample size 
calculation, the IA will take place approximately 31.7 months after the start of the study, 
shortly after all participants have been accrued and approximately 8 months before the 
Primary Completion Date. To ensure that the study has accumulated adequate follow-up for 
safety assessment if stopped for positive efficacy results, the timing of the efficacy IA will 
also require that the median follow-up time be at least 10 months. Under the assumption of a 
placebo incidence rate of 6.0 participants with a CV death event per 100 patient-years of 
follow-up, the median follow-up time when 413 CV death events have been observed is 
expected to be approximately 15 months. The median treatment duration will be 
approximately 14 months.
If the study enrollment rate and/or observed incidence rate are substantially higher than 
anticipated and thus median follow-up time is less than 10 months when 413 CV death 
events have occurred, the efficacy IA will be delayed until 10 months of median follow-up is 
achieved. The efficacy IA may become unnecessary if the timing of the IA falls too close to 
the final analysis. The decision to adjust the timing of or to cancel the efficacy IA will be 
made by the blinded Sponsor team.
At the efficacy IA, the primary endpoint and the secondary endpoint of time to CV death will 
be tested. The study can be terminated early for success only if both the primary endpoint 
and the CV death endpoint are statistically significant based on the prespecified IA 
boundaries. Otherwise, the study will continue until the prespecified number of CV deaths 
(590) are accumulated.
The Hwang, Shih and De Cani (γ=-5.4) alpha-spending function [Hwang, I. K. and Shih, W. 
J. 1990] will be used for the efficacy IA to assess superiority of vericiguat. The spending 
function can be expressed as
with t denoting the percentage of information included at the respective IA.
With this alpha-spending approach and a percentage of information of 70%, the nominal 
significance level will be approximately 0.005 (one-sided) at the IA and 0.024 (one-sided) at 
the final analysis, respectively. This testing approach controls the one-sided alpha between 
the efficacy IA and final analysis at 0.025.
The actual alpha to be spent at the efficacy IA will be precisely determined using the number 
of observed CV death events and the alpha-spending function defined as above. This alpha 
level will be applied to both the primary endpoint and the CV death endpoint. At the final 
analysis, the actual alpha to be spent for each endpoint will be determined using the final 
number of primary endpoint and CV death events using the same spending function.
() = 	 
1 −−
1 −− ,
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Assuming hazard ratio for both the primary endpoint and CV death is 0.8, the probability to 
terminate the study for efficacy at the IA based on the aforementioned stopping rule is 
approximately 34%.
If the study can be stopped early for success, the nominal one-sided significance level of 
approximately 0.005 for the primary endpoint and CV death will be applied to other 
secondary endpoints as well.
If the primary endpoint test is significant at IA but CV death is not, the study will continue 
until the planned number of CV death events are accumulated. However, the hypothesis 
testing for the primary endpoint will be considered significant based on the IA. Analysis 
using the final database will be performed and included in the CSR.
An external DMC will assess the results of the IA and may recommend early study 
termination if the IA shows clear and consistent benefit of vericiguat as guided by the above 
described alpha-spending approach.
If the DMC recommendation leads to termination of the study at the IA due to efficacy, all 
participants will be scheduled for a Final Visit or Final Contact as appropriate. An additional 
analysis will be performed using the entire data collected up to the study completion, ie, it 
will also include data collected after the cutoff for the IA. This analysis will not be used to 
test any hypotheses.
9.8
Multiplicity
The study-wise one-sided alpha level will be controlled at 0.025 for the test of the primary 
endpoint. Multiplicity due to the IA at 70% of planned primary endpoint events and CV 
deaths will be controlled using a Hwang, Shih and De Cani (γ=-5.4) alpha-spending function.
Hypotheses H2 and H3 (addressing time to CV death and time to the first HFH), are 
considered to be supportive endpoints of the primary endpoint. They will be tested only if the 
test of H1 is successful but will not otherwise be controlled for multiplicity.
The other secondary endpoints, H4, H5, and H6, addressing time to total HFH events, time to 
all-cause mortality, and time to first event of composite of HFH or all-cause mortality, will 
be controlled for multiplicity using a hierarchical testing approach. These secondary 
endpoints will be tested only if the primary composite endpoint is significant at the IA or 
final analysis. Total HFH events will be tested first, and only if this is significant, the 
composite of all-cause mortality and HFH will be tested afterwards. All-cause mortality will 
be tested only if both of the above endpoints are tested significant.
At the IA, if the study is stopped early for efficacy, the secondary endpoints will be tested 
based on the same alpha as the primary composite endpoint using the aforementioned 
approach.
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9.9
Sample Size and Power Calculations
The sample size estimation is based on a 1:1 randomization and a study-wise one-sided 
significance level of 0.025. In accordance with the planned IA, the nominal one-sided 
significance level will be approximately 0.024 at the final analysis. A conservative approach 
of power calculation based only on the final analysis is used.
This study will be an event-driven study for CV deaths. The sample size calculation is driven 
by the power for the CV death endpoint and the ability to accumulate the target number of 
events within a reasonable time frame (39.5 months study duration from first participant 
randomized to the Primary Completion Date). The relative reduction in risk with vericiguat is 
assumed to be 20%, corresponding to a HR of 0.8 for CV death endpoint. Based on an 
expected incidence rate in the placebo group of 6 participants with an event per 
100 patient-years of follow-up for CV death (see Section 9.9.1), a sample size of 
approximately 6000 participants enrolled over approximately 27 months with approximately 
39.5 months study duration is expected to accumulate approximately 590 CV deaths. Those 
event counts will provide 80% power for CV death if a significant result is observed for the 
primary endpoint.
The incidence rate in the placebo group of the primary endpoint is expected to be 11.5 
participants with an event per 100 patient-years of follow up. The relative risk reduction with 
vericiguat is assumed to be 20%, relating to a HR of 0.8. With a sample size of 6000 
participants, it is expected that 1080 participants with a primary endpoint event will be 
observed and there will approximately be 95% power for primary hypothesis testing. The 
time point of final analysis will be based on the number of CV deaths events, and the total 
number of participants with primary endpoint event may vary depending on the actual event 
rate in the study.
If the study is not stopped early for success, the median follow-up time (including 
off-treatment time) is expected to be approximately 22.5 months.
9.9.1
Rationale for Incidence Rate Assumption
The estimated incidence rates for the primary endpoint and for CV death in the placebo arm
are based on incidence rates in PARADIGM-HF and DAPA-HF. In PARADIGM-HF, the 
incidence rate for the composite of CV death or HFH was ~10.5 participants with an event 
per 100 patient-years of follow-up in the sacubitril/valsartan and ~13.2 participants with an 
event per 100 patient-years of follow-up in the enalapril arms [Srivastava, P. K., et al 2018]. 
For CV death, the rates were approximately 6 and 7.5 participants with an event per 
100 patient-years of follow-up, respectively. In DAPA-HF, the incidence rates for the 
composite of CV death or HFH were 11.4 and 15.3 participants with an event per 
100 patient-years of follow-up in the dapagliflozin and placebo arms, respectively. For 
CV death, the incidence rates were 6.5 and 7.9 participants with an event per 
100 patient-years of follow-up in the dapagliflozin and placebo arms, respectively 
[McMurray, J. J. V., et al 2019]. Both studies included patients who had an HFH within 
6 months of randomization, so incidence rates for this study are expected to be lower. 
Detailed incidence rates for those without a HFH within 6 months are not available; however, 
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based on available data from those with and without a prior HFH at any point prior to 
enrollment in PARADIGM-HF and those with and without a HFH within 1 year prior to 
enrollment in DAPA-HF, the incidence rate for the primary endpoint in the placebo arm of 
this study is estimated to be 11.5 participants with an event per 100 patient-years of 
follow-up.
9.10 Subgroup Analyses
To determine whether the treatment effect is consistent across various subgroups, the 
estimate of the between-group treatment effect (with a nominal 95% CI) for the primary 
endpoints will be estimated and plotted within each category of the following classification 
variables in all participants:
•
Age (<65 years vs ≥65 years)
•
Sex (female vs male)
•
Geographic region (Eastern Europe / Western Europe / North America / Latin and South 
America / Asia Pacific)
•
eGFR at randomization (15 to 30 mL/min/1.73 m2 vs >30 to 60 mL/min/1.73 m2 vs 
>60 mL/min/1.73 m2)
•
NYHA class at baseline (II vs III/IV)
•
Ischemic heart disease at baseline, defined as history of 1 or more of the following 
conditions: CAD, MI, PCI, and/or CABG
•
Use of an ARNI at baseline 
•
Use of SGLT2i at baseline
•
Presence of ICD therapy at baseline
•
Baseline NT-proBNP (by Quartiles)
•
Baseline LVEF (< median, ≥median) 
•
Race (White / Black / Asian / Other) 
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9.11 Compliance (Medication Adherence)
Percent compliance will be calculated according to the following formula and summarized 
using descriptive statistics.
Compliance (%) = 
Number of Days on Therapy
x 100.
Number of Days in the Intervention Period
Deviations from protocol-directed administration will be summarized at the end of the study. 
9.12 Extent of Exposure
The extent of exposure will be summarized as the duration of study treatment. Furthermore, 
an exposure summary based on dosage and dose titration will also be provided.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1 Code of Conduct for Interventional Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
I.
Introduction
A. Purpose
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD), through its subsidiaries, 
conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, planning, conducting, analyzing, 
and reporting these trials in compliance with the highest ethical and scientific 
standards. Protection of participants in clinical trials is the overriding concern in the 
design and conduct of clinical trials. In all cases, MSD clinical trials will be 
conducted in compliance with MSD’s global standards, local and/or national 
regulations (including all applicable data protection laws and regulations), and 
International Council for Harmonisation Good Clinical Practice (ICH GCP) E6 and 
ICH General Considerations for Clinical Studies E8, and in accordance with the 
ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical 
interventional investigations sponsored by MSD irrespective of the party (parties) 
employed for their execution (eg, contract research organizations, collaborative 
research efforts). This Code is not intended to apply to trials that are observational in 
nature, or which are retrospective. Further, this Code does not apply to investigator-
initiated trials, which are not under the full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-
driven to assess safety, efficacy, and/or pharmacokinetic or pharmacodynamic 
indices of MSD or comparator products. Alternatively, MSD may conduct 
outcomes research trials, trials to assess or validate various endpoint measures, or 
trials to determine patient preferences, etc.
The design (ie, participant population, duration, statistical power) must be 
adequate to address the specific purpose of the trial and shall respect the data 
protection rights of all participants, trial site staff and, where applicable, third 
parties. Input may be considered from a broad range of stakeholders, including 
patient advocacy groups/patients representing the trial population, caregivers, and 
healthcare providers to ensure operational feasibility. Trial design also includes 
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proactive identification of critical to quality factors using a risk-based approach. 
Plans are then developed to assess and mitigate risks to those factors as 
appropriate during the trial. All trial protocols are and will be assessed for the 
need and capability to enroll underrepresented groups. Participants must meet 
protocol entry criteria to be enrolled in the trial.
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in 
diverse populations, including people of varying age, race, ethnicity, gender, and 
accounting for other potential disease related factors. MSD selects investigative 
sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary 
considerations. Prior to trial initiation, sites are evaluated by MSD personnel (or 
individuals acting on behalf of MSD) to assess the ability to successfully conduct 
the trial. Individuals involved in trial conduct receive training commensurate with 
their role prior to their becoming involved in the trial.
Where appropriate, and in accordance with regulatory authority guidance, MSD 
will make concerted efforts to raise awareness of clinical trial opportunities in 
various communities. MSD will seek to engage underrepresented groups and 
those disproportionately impacted by the disease under study. MSD will support 
clinical trial investigators to enroll underrepresented groups and expand access to 
those who will ultimately use the products under investigation.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol 
and Good Clinical Practice (GCP). MSD reviews clinical data for accuracy, 
completeness, and consistency. Data are verified versus source documentation 
according to standard operating procedures. Per MSD policies and procedures, if 
potential fraud, scientific/research misconduct, privacy incidents/breaches or 
Clinical Trial-related Significant Quality Issues are reported, such matters are 
investigated. When necessary, appropriate corrective and/or preventative actions 
are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary 
results of its registered trials of marketed products in which treatment is assigned, 
according to the prespecified plans for data analysis. To the extent scientifically 
appropriate, MSD seeks to publish the results of other analyses it conducts that are 
important to patients, physicians, and payers. Some early phase or pilot trials are 
intended to be hypothesis generating rather than hypothesis testing; in such cases, 
publication of results may not be appropriate since the trial may be underpowered and 
the analyses complicated by statistical issues such as multiplicity.
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MSD’s policy on authorship is consistent with the recommendations published by the 
International Committee of Medical Journal Editors (ICMJE). In summary, 
authorship should reflect significant contribution to the design and conduct of the 
trial, performance or interpretation of the analysis, and/or writing of the manuscript. 
All named authors must be able to defend the trial results and conclusions. MSD 
funding of a trial will be acknowledged in publications.
III.Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board 
[IRB]/Independent Ethics Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory 
authority acceptance/authorization prior to implementation of the trial or amendment, 
in compliance with local and/or national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s 
brochure, and other relevant trial documents must be reviewed and approved by an 
IRB/IEC before being implemented at each site, in compliance with local and/or 
national regulations and ICH Guidelines. Changes to the protocol that are required 
urgently to eliminate an immediate hazard and to protect participant safety may be 
enacted in anticipation of ethics committee approval. MSD will inform regulatory 
authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is 
of primary importance. Potential participants will be informed of the risks and 
benefits of, as well as alternatives to, trial participation. At a minimum, trial designs 
will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only 
after informed consent is obtained. Trial designs include procedures and systems for 
the identification, monitoring, and reporting of safety concerns. Participants may 
withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
During trial planning, the need for an independent Data Monitoring Committee 
(DMC) is assessed. DMC review of data accumulated during the conduct of the trial 
is integral to the well-being of trial participants.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent 
possible, as well as all applicable data protection rights. Unless required by law, only 
the investigator, Sponsor (or individuals acting on behalf of MSD), ethics committee, 
and/or regulatory authorities will have access to confidential medical records that 
might identify the participant by name.
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D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed 
consent authorized by an ethics committee.
E. Trial Results
At the time of providing informed consent and in accordance with local laws and 
regulations, participants should be informed about the plans for availability of trial 
results.
IV.Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate 
investigators (or the sponsoring institution) in a fair manner for the work performed 
in support of MSD trials. MSD does not pay incentives to enroll participants in its 
trials. However, when enrollment is particularly challenging, additional payments 
may be made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate 
referring physicians for time spent on medical record review and medical evaluation 
to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the 
investigator or sponsoring institution is being paid or provided a grant for performing 
the trial. However, the local ethics committee may wish to alter the wording of the 
disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source 
of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (eg, to scientific meetings, 
investigator meetings, etc) will be consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the 
trial protocol, and in signing the protocol, agree to support these ethical and scientific 
standards.
10.1.2 Financial Disclosure
Financial disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor’s responsibility to determine, based on these regulations, whether a request for 
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financial disclosure information is required. It is the investigator’s/subinvestigator’s 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, frequently known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3 Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant 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.
The participant 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.
Pursuant to Union law (Clinical Trials Directive 2001/20/EC and Clinical Trials Regulation 
536/2014), the Investigator is responsible for pseudonymizing and assigning a key-
code/patient ID to each study subject.  In addition, the Investigator is required by Union law 
to store the Key (linking the Patient ID to the full name of the study subject) at the site in the 
EU/EEA throughout the course of the study and for a designated period of time thereafter.  
Finally, the study site is only permitted to share pseudonymized study subject personal data 
with the Sponsor.  
The European Data Protection Board, in its Recommendations 01/2020 on measures that 
supplement transfer tools to ensure compliance with the EU level of protection of personal 
data (“Recommendations”), states in Paragraph 85 that pseudonymization (of study subject) 
personal data under the conditions described above constitutes an effective supplemental 
measure.  
Organizational measures are contractually imposed on third party vendors wherever possible, 
to ensure that Personal Data are protected by industry-best practices against accidental 
destruction or loss (physical/logical) which include regular backup procedures, Firewalls, and 
disaster recovery plans.
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In support of Corporate Policy 1 Information Risk Management, on a Sponsor-wide basis all 
supplier relationships, both IT and non-IT related, are strongly encouraged to meet the 
Sponsor’s Supplier Information Risk Management Standard.  To protect the confidentiality, 
availability and integrity of Sponsor information, conformity to information risk 
requirements by supplier personnel, hardware and software may be measured, analyzed and 
appropriate corrective/preventive actions taken as necessary. Based on the supplier criticality, 
additional activities (e.g., on-site reviews, integrated business continuity exercises) may be 
required to ensure the cyber-resiliency of the supplier on an on-going basis.
The Sponsor has implemented (Corporate Policy 13.1 Information Security Standards 
Handbook) an organization-wide process to assign user access rights based on the whether 
the employee/contractor has a legitimate need to utilize a database in order to carry out 
his/her job; manager approval is required when granting user access rights (beyond those 
sites or databases intended for all employees/contractors); and a process is in place for an 
annual review by each manager of the user access rights currently in place.  Organizational 
measures, also contractually imposed on third party vendors, to prevent data processing 
systems from being used by unauthorized persons include i) user identification and 
authentication procedures (e.g., special characters, minimum length, regular change of 
password), and ii) automatic blocking (e.g., password or timeout).
The Sponsor utilizes a database called “InForm”, operated by Oracle, for the storage of its 
study subject clinical trial data. InForm is a role-based system and only authorized users can 
see the data. Sites may only see the data they have entered.  Access by Sponsor users is 
restricted to only those associated with a specific clinical trial. 
Study sites are provided with a password to access the database.  Access to InForm requires 
https (Secure Socket Layer) with a FIPS 140-2 compliant algorithm to connect to the 
application via the study site’s web browser.  Once logged into the system, the connection 
between the database, located in Ashburn, Virginia, USA, and the site, is encrypted.  The 
Sponsor also stores the name and access credentials of the Investigators and other site staff 
(Study Coordinators) who record patient data into InForm.  Such study staff personal data is 
not pseudonymized.  Note, such encryption during transmission may not meet all conditions 
imposed by the EDPB in its Recommendations for this encryption, on its own, to constitute 
an effective supplemental measure.
Data, whether concerning a study subject or site staff, stored in the InForm database is 
encrypted.  Note, such encryption may not meet all conditions imposed by the EDPB in its 
Recommendations for this encryption, on its own, to constitute an effective supplemental 
measure.  
Whenever possible, organization wide measures are imposed on third party vendors to 
prevent unauthorized persons from gaining access to the data processing systems available on 
premises and in facilities (including databases, application servers and related hardware), 
where Personal Data are processed, include i) Access control system (ID reader, chip), ii) key 
management, card-keys procedures, and iii) on-site security personnel and alarm system.
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InForm is a HIPAA Part 11 capable system.  Any data entered/changed or deleted will be 
associated with a viewable audit trail.
The Sponsor has EU-approved Binding Corporate Rules since 2017, covering all aspects of 
its Global Privacy Program (Corporate Policy 20).  Pursuant to organization-wide 
requirements, the Sponsor periodically conducts audits of the vendors providing IT services, 
including Oracle, the vendor supporting the InForm database.  The most recent audit of 
Oracle and its operations of InForm occurred in May 2020.  Finally, Oracle has obtained ISO 
27001 certification for the various databases it offers to third parties as a service, including 
the InForm database.
10.1.3.1 Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee, affiliated institution, and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution, and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2 Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked before transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules,
and regulations.
10.1.3.3 Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
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10.1.4 Committees Structure
10.1.4.1 Steering Committee
This study will be conducted in consultation with a Steering Committee. The Steering 
Committee is comprised of:
Sponsor personnel,
Investigators participating in the study, and
Consulting therapeutic-area experts and clinical trialists.
The Steering Committee will provide guidance on the operational aspects of the study and 
make recommendations to the EOC.
Specific details regarding responsibilities and governance of the Steering Committee will be 
described in a separate charter.
10.1.4.2 Executive Oversight Committee
The EOC is comprised of members of Sponsor Senior Management and an external 
cardiologist. The EOC will receive and decide on any recommendations made by the DMC 
and Steering Committee regarding the study.
10.1.4.3 External Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an external DMC will 
monitor the interim data from this study. The voting members of the committee are external 
to the Sponsor. The members of the DMC must not be involved with the study in any other 
way (eg, they cannot be study investigators) and must have no competing interests that could 
affect their roles with respect to the study.
The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the study. Also, the DMC will review interim 
study results, consider the overall risk and benefit to study participants (Section 9.7 Interim 
Analysis) and recommend to the EOC whether the study should continue in accordance with 
the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the external collaborating organization 
protocol team; meeting facilitation; the study governance structure; and requirements for and 
proper documentation of DMC reports, minutes, and recommendations will be described in 
the DMC charter that is reviewed and approved by all the DMC members.
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10.1.4.4 Clinical Events Committee (CEC)
A CEC will evaluate the following events for the purposes of confirming them according to 
the criteria in Section 9, as well as evaluating the presence of confounding factors.
1.
Death
2.
CV hospitalizations
3.
UHF visits
The CEC will be comprised of qualified members, who are not investigators in the study and 
are not otherwise associated with the Sponsor. The adjudication guidance and clinical 
endpoint definitions are described in detail in the CEC charter.
All personnel involved in the adjudication process will remain blinded to study intervention 
allocation throughout the study.
10.1.4.5 National Leader Committee
The primary role of the National Leader Committee is to serve as the interface between the 
Steering Committee and the study sites to facilitate the progress of the study at the regional 
level. The National Leader Committee is composed of Country Leads selected by the 
Sponsor from the investigators in each country with appropriate clinical study experience. 
National Leader Committee members should participate with their local study site to ensure 
adequate direct experience with the study.
10.1.5 Publication Policy
The results of this study may be published or presented at scientific meetings. 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 site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, 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.
Authorship will be determined by mutual agreement and in line with ICMJE authorship 
requirements.
10.1.6 Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trials Regulation 536/2014, the 
Sponsor of the study is solely responsible for determining whether the study and its results 
are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu, https://euclinicaltrials.eu, or other local registries. MSD, as 
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Sponsor of this study, will review this protocol and submit the information necessary to 
fulfill these requirements. MSD entries are not limited to FDAAA or the EMA clinical trials 
Regulation 536/2014 mandated trials. Information posted will allow participants to identify 
potentially appropriate studies for their disease conditions and pursue participation by calling 
a central contact number for further information on appropriate study locations and study-site 
contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials Regulation 536/2014, or other locally mandated registries 
are that of the Sponsor and agrees not to submit any information about this study or its results 
to those registries.
10.1.7 Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol, generally accepted standards of GCP 
(eg, ICH GCP: Consolidated Guideline and other generally accepted standards of GCP), and 
all applicable federal, state, and local laws, rules, and regulations relating to the conduct of 
the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority.
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.8 Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
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Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source 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.
Records and documents, including participants’ documented informed consent, 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. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). 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/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
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10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study-site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2 Appendix 2: Clinical Laboratory Tests

Visit 1/Screening laboratory tests (Section 1.3.1) may be performed at a local laboratory, 
central laboratory, or by Point of Care device. Historical results collected within 30 days 
before randomization are also acceptable.

After screening, the tests detailed in Table 9 will be performed by the central laboratory.
If extenuating circumstances prevent submission of samples to the central laboratory, a 
local laboratory may be used for protocol-required laboratory assessments, with the 
exception of NT-proBNP. The local laboratory results must be entered into the eCRF.
NOTE: As NT-proBNP results are expected to remain blinded during the treatment 
period (after first dose of study intervention), protocol-specified NT-proBNP 
tests must not be performed at local laboratories.

Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5. Screening laboratory assessments may be performed at the local laboratory.
NOTE: Central laboratory testing may be used once during screening.

Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
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Table 9
Protocol-required Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
MCV
MCH
MCHC
RDW
WBC count with 
Differential 
(%, absolute counts):
Neutrophils (Total)
Immature granulocytes
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
MPV
Reticulocytes
Nucleated RBCs
Chemistry 
Sodium
Chloride
Bicarbonate
Potassium
BUN
Creatinine (eGFR)
Uric Acid 
Calcium
Glucose (fasting is not required)
Liver Function 
Tests
Alkaline 
phosphatase
ALT/SGPT
AST/SGOT
GGT
Total bilirubin (and direct bilirubin, if total 
bilirubin is above the ULN)
Albumin
Other
NT-proBNP
Pregnancy 
Testing
Highly sensitive serum or urine hCG pregnancy test (as needed for WOCBP)
Other Screening 
Tests
FSH (as needed in WONCBP only)
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; CKD-EPI=Chronic Kidney 
Disease Epidemiology Collaboration; eGFR=estimated glomerular filtration rate; FSH=follicle-stimulating hormone;
GGT=gamma-glutamyl transferase; hCG=human chorionic gonadotropin; MCH=mean corpuscular hemoglobin; 
MCHC=mean corpuscular hemoglobin concentration; MCV=mean corpuscular volume; MPV=mean platelet volume; 
NT-proBNP=N-terminal pro-brain natriuretic peptide; RBC=red blood cell; RDW=red cell distribution width; 
SGOT=serum glutamic-oxaloacetic transaminase; SGPT=serum glutamic-pyruvic transaminase; ULN=upper limit of 
normal; WBC=white blood cell; WOCBP=women of childbearing potential; WONCBP=women of nonchildbearing 
potential.
Notes:
Urea is acceptable if BUN is not available per institutional standard.
Liver Function tests include ALT/SGPT, AST/SGOT, alkaline phosphatase, albumin, GGT, and total bilirubin.
eGFR will be calculated using the CKD-EPI formula.
Urine pregnancy testing and other screening tests may be performed by the local laboratory.
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
NT-proBNP results that could unblind the study will not be reported to investigative sites or 
other blinded personnel after Visit 2 until the study has been unblinded.
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10.3 Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Selected nonserious AEs, SAEs, and other reportable safety events will be reported by the 
sites.
Additional country-specific requirements for adverse event reporting are described in 
Appendix 7.
10.3.1 Definitions of Medication Error, Misuse, and Abuse
Medication Error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic intentional, excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired nontherapeutic 
effect.
10.3.2 Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
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) temporally 
associated with the use of a study intervention.
•
Note: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, medical device, combination product, or protocol-specified procedure whether 
investigational or marketed (including placebo, active comparator product, or run-in 
intervention), manufactured by, licensed by, provided by, or distributed by the Sponsor 
for human use in this study.
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Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent preexisting 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.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
Any new cancer or progression of existing cancer.
Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, 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 preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgical procedure(s) planned prior to informed consent to treat a preexisting condition 
that has not worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
Selected NSAEs are nonserious AEs that meet any of the following criteria:
•
AEs that lead to study intervention dose modification or discontinuation
•
AEs that lead to withdrawal from the study
•
COVID-19 disease-related AEs
Additional country-specific requirements for adverse event reporting are described in 
Appendix 7.
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10.3.3 Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
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
-
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a preexisting condition that has not 
worsened is not an SAE.) A preexisting condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
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 (eg, 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
-
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
-
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events 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 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
-
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
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10.3.4 Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a cancer.
•
Is associated with an overdose.
10.3.5 Recording AE and SAE
Selected nonserious AEs, SAEs, and other reportable safety events will be reported by the 
sites.
Additional country-specific requirements for adverse event reporting are described in 
Appendix 7.
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
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 AE CRF page.
•
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 blinded 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. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/toxicity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
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•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) reported during the study and assign it to 1 of the following
categories:
-
Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort, and not interfering with everyday activities (for pediatric studies, 
awareness of symptoms, but easily tolerated).
-
Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies, definitely acting like something is wrong).
-
Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with an SAE. Severe is a category used for rating 
the intensity of an event; and both AE and SAE can be assessed as severe (for 
pediatric studies, extremely distressed or unable to do usual activities).
Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (pill
count, diary, etc), expected pharmacologic effect, or measurement of 
drug/metabolite in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal 
product)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
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-
Dechallenge: Was the Sponsor’s product discontinued or dose/exposure/frequency 
reduced?
◦
If yes, did the AE resolve or improve?
◦
If yes, this is a positive dechallenge.
◦
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the Sponsor’s 
product; (3) the study is a single-dose drug study; or (4) Sponsor’s product(s) is/are 
only used 1 time.)
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in this 
study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose drug study; or (3) Sponsor’s 
product(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the CRFs/worksheets by an 
investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
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•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
◦
There is evidence of exposure to the Sponsor’s product. The temporal sequence 
of the AE onset relative to the administration of the Sponsor’s product is 
reasonable. The AE is more likely explained by the Sponsor’s product than by 
another cause.
-
No, there is not a reasonable possibility of Sponsor’s product relationship:
◦
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable 
OR the AE is more likely explained by another cause than the Sponsor’s 
product. (Also entered for a participant with overdose without an associated 
AE.)
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
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 1 of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by 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.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
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10.3.6 Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
Selected nonserious AEs, SAEs, and other reportable safety events will be reported by the 
sites. 
Additional country-specific requirements for adverse event reporting are described in 
Appendix 7.
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
-
Reference Section 8.4.1 for reporting time requirements.
•
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 EDC 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 EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure email of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, 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 CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4 Appendix 4: Medical Device and Drug–Device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
Not applicable.
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10.5 Appendix 5: Contraceptive Guidance
10.5.1 Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), 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.
•
Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two 
FSH measurements in the postmenopausal range is required.
-
Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-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.
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10.5.2 Contraceptive Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
•
Progestogen-only subdermal contraceptive implantb
•
IUSc
•
Non-hormonal IUD
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner of 
the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method 
of contraception should be used. A 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 participants of clinical studies.
b    If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to 
those which inhibit ovulation.
c    IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
-  Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and LAM.
-  Male condom with cap, diaphragm, or sponge with spermicide.
-  Male and female condom should not be used together (due to risk of failure with friction).
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10.6 Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is 
a sign of a normal or abnormal process or of a condition or disease. A biomarker may 
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
2. Scope of Future Biomedical Research3, 4
The specimens consented and/or collected in this study as outlined in Section 8.9 will be 
used in various experiments to understand:
-
The biology of how drugs/vaccines work
-
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
-
Other pathways with which drugs/vaccines may interact
-
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease, and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research3, 4
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research.
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b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study 
visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research3, 4
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participants’ clinical information with future test results. In 
fact, little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history, and intervention outcomes is
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number that does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
5. Biorepository Specimen Usage3, 4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses using the future biomedical research specimens may be performed by 
the Sponsor, or an additional third party (eg, a university investigator) designated by the 
Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy and 
confidentiality requirements. Any contracted third-party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
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Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research3, 4
Participants may withdraw their consent for FBR and ask that their biospecimens not be 
used for FBR. Participants may withdraw consent at any time by contacting the study 
investigator. If medical records for the study are still available, the investigator will 
contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant's specimens 
will be flagged in the biorepository and restricted to study use only. If specimens were 
collected from study participants specifically for FBR, these specimens will be removed 
from the biorepository and destroyed. Documentation will be sent to the investigator 
confirming withdrawal and/or destruction, if applicable. It is the responsibility of the 
investigator to inform the participant of completion of the withdrawal and/or destruction, 
if applicable. Any analyses in progress at the time of request for withdrawal/destruction 
or already performed before the request being received by the Sponsor will continue to be 
used as part of the overall research study data and results. No new analyses would be 
generated after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no 
longer required by regulatory authorities to retain the study records) or the specimens 
have been completely anonymized, there will no longer be a link between the 
participant’s personal information and their specimens. In this situation, the request for 
withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens3, 4
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the study. Specimens may be stored for longer 
if a regulatory or governmental authority has active questions that are being answered. In 
this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not used in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility, which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security3, 4
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
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9. Reporting of Future Biomedical Research Data to Participants3, 4
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population3, 4
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research3, 4
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@MSD.com.
13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
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10.7 Appendix 7: Country-specific Requirements
10.7.1 Country-specific Requirements for Germany
For sites participating in Germany all NSAEs must be reported to the Sponsor.
This revision applies to the following sections:
•
Section 4.2.1.2 – Safety Endpoints
•
Section 8.4 – Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events
•
Section 8.4.1 – Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information 
•
Section 8.4.3 – Follow-up of AE, SAE, and Other Reportable Safety Event Information 
•
Section 10.3 – Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
•
Section 10.3.2 – Definition of AE
•
Section 10.3.5 – Recording AE and SAE
•
Section 10.3.6 – Reporting of AEs, SAEs, and Other Reportable Events to the Sponsor
10.7.2 Country-specific Requirements for China
Sites participating in China will not collect specimens for planned genetic analysis, 
exploratory biomarker research, and future biomedical research. 
This applies to the following sections: 
•
Section 4.2.1.4.1 – Planned Genetic Analysis
•
Section 4.2.1.5 – Future Biomedical Research
•
Section 8.8 – Biomarkers
•
Section 8.9 – Future Biomarker Sample Collection
10.7.3 Country-specific Requirements for South Korea
An additional clinic visit will be performed for all participants in South Korea between study 
visits V4 (Day 28 ± 4 days) and V5 (Week 24 ± 14 days). This additional clinic visit will be 
conducted as an unscheduled visit and should occur anytime 2 to 8 weeks after V4.
This applies to Section 1.3.1 – Schedule of Activities-All Participants. 
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10.8 Appendix 8: Determination of ALBI Grade
The ALBI Grade is based on a linear score calculated using the values for blood albumin and 
bilirubin in the following formula:
ALBISCORE = (log10[bilirubin] × 0.66) + (albumin × -0.085) where albumin is in g/L and 
bilirubin in µmol/L [Johnson, P. J., et al 2015].
ALBI Grade
ALBISCORE
1
≤-2.60
2
-2.59 to -1.39
3
> -1.39
Calculation of the ALBI Grade maybe facilitated by use of online medical calculators 
(https://www.mdcalc.com/albi-albumin-bilirubin-grade-hepatocellular-carcinoma-hcc).
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10.9 Appendix 9: Abbreviations
Abbreviation
Expanded Term
ACCF
American College of Cardiology Foundation
ACEI
angiotensin-converting enzyme inhibitor
ADME
absorption, distribution, metabolism, and excretion
AE
adverse event
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
CEC
Clinical Events Committee
cGMP
cyclic guanosine monophosphate
CI
confidence interval
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
Coronavirus disease caused by severe acute respiratory syndrome 
coronavirus 2
CRF
Case Report Form 
CRT
Cardiac resynchronization therapy
CSR
Clinical Study Report
CTFG
Clinical Trial Facilitation Group 
CV
cardiovascular
DAPA-HF
Dapagliflozin in Patients With Heart Failure and Reduced Ejection 
Fraction
DEGs
Data Entry Guidelines
DILI
drug-induced liver injury
DMC
Data Monitoring Committee 
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Abbreviation
Expanded Term
DNA
deoxyribonucleic acid 
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic Case Report Form
EDC
electronic data collection 
EEA
European Economic Area
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
EQ-5D
EuroQol Group 5-Dimensional questionnaire
EQ-5D-5L
EuroQol Group 5-Dimensional, 5-level questionnaire
EQ VAS
EuroQol Group Visual Analog Scale
ESC
European Society of Cardiology
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FSH
follicle-stimulating hormone 
FSR
First site ready
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
HIV
human immunodeficiency virus
HR
hazard ratio
HRT
hormone replacement therapy
IA
interim analysis(ses)
IB
Investigator’s Brochure 
ICD
implantable cardioverter-defibrillator
ICF
Informed Consent Form
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Abbreviation
Expanded Term
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ICMJE
International Committee of Medical Journal Editors
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRT
interactive response technology
ITT
Intention to treat
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
IVRS
interactive voice response system
KCCQ
Kansas City Cardiomyopathy Questionnaire
LAM
lactational amenorrhea method
LVEF
left ventricular ejection fraction
M&N
Miettinen and Nurminen method
MRA
mineralocorticoid receptor antagonist
MRI
magnetic resonance imaging
mRNA
messenger ribonucleic acid 
NO
nitric oxide
NSAEs
nonserious adverse event 
NSTEMI
non-ST elevation myocardial infarction
NT-proBNP
N-terminal pro-brain natriuretic peptide
NYHA
New York Heart Association
PARADIGM-
HF
Prospective Comparison of ARNI with ACEI to Determine Impact on 
Global Mortality and Morbidity in Heart Failure
PCI
percutaneous coronary intervention
PDE5
phosphodiesterase type 5
PK
pharmacokinetic
QD
Once daily
QoL
quality of life
RNA
ribonucleic acid
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Abbreviation
Expanded Term
SAE
serious adverse event 
SAP
Statistical Analysis Plan
SBP
systolic blood pressure
SD
standard deviation
sGC
soluble guanylate cyclase
SGLT2i
sodium-glucose cotransporter 2 inhibitor 
SLAB
supplemental laboratory test(s)
SoA
schedule of activities
SOC
System Organ Class
sSAP
supplemental Statistical Analysis Plan
STEMI
ST elevation myocardial infarction
SUSAR
suspected unexpected serious adverse reaction
TIA
transient ischemic attack
UHF
urgent heart failure
ULN
upper limit of normal
VAS
Visual Analog Scale
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
08XPKP

PRODUCT: MK-1242
118
PROTOCOL/AMENDMENT NO.: 035-03
MK-1242-035-03 FINAL PROTOCOL
25-JAN-2024
11
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