A Randomized Parallel-Group, Placebo-Controlled, Double-Blind, Event-Driven, Multi-Center Pivotal Phase III Clinical Outcome Trial of Efficacy and Safety of the Oral sGC Stimulator Vericiguat in Subjects With Heart Failure With Reduced Ejection Fraction (HFrEF) - VerICiguaT GlObal Study in Subjects With Heart Failure With Reduced EjectIon FrAction (VICTORIA)
Phase: PHASE3
Conditions: Heart Failure, Chronic Heart Failure With Reduced Ejection Fraction
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT02861534 
Document Date: 
20-Dec-2017
A Randomized Parallel-Group, Placebo-Controlled, Double-Blind, Event-
Driven, MultiCenter Pivotal Phase III Clinical Outcome Trial of Efficacy 
and Safety of the Oral sGC Stimulator Vericiguat in Subjects With Heart 
Failure With Reduced Ejection Fraction (HFrEF) - VerICiguaT Global 
Study in Subjects With Heart Failure With Reduced Ejection Fraction 
(VICTORIA) 

Product:  MK-1242 (vericiguat)
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Confidential
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., NJ, U.S.A. 
(MSD)
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File 
Binder (or equivalent).
TITLE:
A Randomized Parallel-Group, Placebo-Controlled, Double-Blind, Event-Driven, Multi-
Center Pivotal Phase III Clinical Outcome Trial of Efficacy and Safety of the Oral sGC 
Stimulator Vericiguat in Subjects With Heart Failure With Reduced Ejection Fraction
(HFrEF) - VerICiguaT Global Study in Subjects With Heart Failure With Reduced Ejection
Fraction (VICTORIA)
IND NUMBER:  116,743
EudraCT NUMBER:  2016-000671-25
 
 
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TABLE OF CONTENTS
SUMMARY OF CHANGES................................................................................................ 10
1.0
TRIAL SUMMARY.................................................................................................. 19
2.0
TRIAL DESIGN........................................................................................................ 19
Trial Design ........................................................................................................... 19
2.1
Trial Diagram........................................................................................................ 21
2.2
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 21
Primary Objective(s) & Hypothesis(es) .............................................................. 21
3.1
Secondary Objective(s) & Hypothesis(es)........................................................... 21
3.2
Other Objectives (Exploratory)........................................................................... 22
3.3
4.0
BACKGROUND & RATIONALE.......................................................................... 23
Background ........................................................................................................... 23
4.1
Pharmaceutical and Therapeutic Background .................................................... 23
4.1.1
Pre-clinical and Clinical Trials ........................................................................... 25
4.1.2
Rationale................................................................................................................ 25
4.2
Rationale for the Trial and Selected Subject Population .................................... 25
4.2.1
Rationale for Dose Selection/Regimen/Modification ......................................... 26
4.2.2
Rationale for the Use of Comparator/Placebo ............................................. 27
4.2.2.1
Rationale for Endpoints ...................................................................................... 27
4.2.3
Efficacy Endpoints....................................................................................... 27
4.2.3.1
Safety Endpoints .......................................................................................... 27
4.2.3.2
Pharmacokinetic Endpoints ......................................................................... 27
4.2.3.3
Planned Exploratory Biomarker Research................................................... 27
4.2.3.4
Future Biomedical Research........................................................................ 28
4.2.3.5
Benefit/Risk ........................................................................................................... 28
4.3
5.0
METHODOLOGY ................................................................................................... 29
Entry Criteria........................................................................................................ 29
5.1
Diagnosis/Condition for Entry into the Trial ...................................................... 29
5.1.1
Subject Inclusion Criteria.................................................................................... 29
5.1.2
Subject Exclusion Criteria .................................................................................. 31
5.1.3
 
 
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Trial Treatment(s) ................................................................................................ 32
5.2
Dose Selection/Modification .............................................................................. 34
5.2.1
Dose Selection (Preparation) ....................................................................... 34
5.2.1.1
Dose Modification ....................................................................................... 34
5.2.1.2
5.2.1.2.1
Resumption of Study Treatment after Interruption............................... 35
Timing of Dose Administration .......................................................................... 37
5.2.2
Trial Blinding...................................................................................................... 37
5.2.3
Randomization ...................................................................................................... 37
5.3
Stratification.......................................................................................................... 37
5.4
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 37
5.5
Background Standard of Care............................................................................. 38
5.5.1
Prohibited Concomitant Medications.................................................................. 38
5.5.2
Rescue Medications & Supportive Care............................................................. 38
5.6
Diet/Activity/Other Considerations..................................................................... 38
5.7
Diet...................................................................................................................... 38
5.7.1
Contraception...................................................................................................... 38
5.7.2
Use in Pregnancy ................................................................................................ 39
5.7.3
Subject Withdrawal/Discontinuation Criteria................................................... 39
5.8
Subject Replacement Strategy............................................................................. 41
5.9
Beginning and End of the Trial ........................................................................... 41
5.10
Clinical Criteria for Early Trial Termination ................................................... 41
5.11
6.0
TRIAL FLOW CHART ........................................................................................... 42
7.0
TRIAL PROCEDURES ........................................................................................... 45
Trial Procedures ................................................................................................... 45
7.1
Administrative Procedures.................................................................................. 45
7.1.1
Informed Consent......................................................................................... 45
7.1.1.1
7.1.1.1.1
General Informed Consent.................................................................... 45
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 46
Inclusion/Exclusion Criteria ........................................................................ 46
7.1.1.2
Subject Identification Card .......................................................................... 46
7.1.1.3
Medical History ........................................................................................... 46
7.1.1.4
 
 
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Prior and Concomitant Medications Review ............................................... 46
7.1.1.5
7.1.1.5.1
Prior Medications.................................................................................. 46
7.1.1.5.2
Concomitant Medications..................................................................... 46
Assignment of Screening Number............................................................... 46
7.1.1.6
Assignment of Treatment/Randomization Number ..................................... 47
7.1.1.7
Trial Compliance ......................................................................................... 47
7.1.1.8
Clinical Procedures/Assessments........................................................................ 48
7.1.2
Height........................................................................................................... 48
7.1.2.1
Weight.......................................................................................................... 48
7.1.2.2
Physical Examinations................................................................................. 48
7.1.2.3
12-Lead Electrocardiogram ......................................................................... 48
7.1.2.4
Vital Signs.................................................................................................... 48
7.1.2.5
7.1.2.5.1
Blood Pressure Assessment .................................................................. 49
7.1.2.5.2
Pulse Rate ............................................................................................. 49
Quality of Life Measures ............................................................................. 49
7.1.2.6
7.1.2.6.1
Kansas City Cardiomyopathy Questionnaire........................................ 49
7.1.2.6.2
EuroQol Group 5-Dimensional, 5-level Questionnaire ........................ 50
Vital Status Assessment............................................................................... 50
7.1.2.7
Laboratory Procedures/Assessments .................................................................. 50
7.1.3
Laboratory Safety Evaluations..................................................................... 50
7.1.3.1
Pharmacokinetic/Pharmacodynamic Evaluations ........................................ 51
7.1.3.2
Biomarker Investigations............................................................................. 52
7.1.3.3
Planned Genetic Analysis Sample Collection.............................................. 52
7.1.3.4
Future Biomedical Research Sample Collection ......................................... 52
7.1.3.5
Other Procedures................................................................................................. 52
7.1.4
Withdrawal/Discontinuation........................................................................ 52
7.1.4.1
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 53
Blinding/Unblinding .................................................................................... 53
7.1.4.2
Calibration of Equipment............................................................................. 54
7.1.4.3
Visit Requirements.............................................................................................. 54
7.1.5
Screening...................................................................................................... 54
7.1.5.1
Treatment Period.......................................................................................... 55
7.1.5.2
 
 
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7.1.5.2.1
Randomization Visit ............................................................................. 55
7.1.5.2.2
Unscheduled Visits ............................................................................... 55
7.1.5.2.3
Final Visit ............................................................................................. 55
7.1.5.2.4
Final Phone Contact.............................................................................. 56
Premature Treatment Discontinuation......................................................... 56
7.1.5.3
7.1.5.3.1
Premature Treatment Discontinuation Visit ......................................... 56
7.1.5.3.2
Safety follow-up Visit........................................................................... 56
Other Ancillary Studies....................................................................................... 56
7.1.6
Echocardiography and Cardiac Magnetic Resonance Imaging ................... 56
7.1.6.1
Health Economics Outcomes Research ....................................................... 56
7.1.6.2
Assessing and Recording Adverse Events .......................................................... 57
7.2
Definition of an Overdose for This Protocol and Reporting of Overdose to 
7.2.1
the Sponsor.......................................................................................................... 57
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 58
7.2.2
Immediate Reporting of Adverse Events to the Sponsor.................................... 58
7.2.3
Serious Adverse Events ............................................................................... 58
7.2.3.1
Events of Clinical Interest............................................................................ 59
7.2.3.2
Protocol-Specific Exceptions to Serious Adverse Event Reporting ............ 60
7.2.3.3
Evaluating Adverse Events ................................................................................. 61
7.2.4
Sponsor Responsibility for Reporting Adverse Events ...................................... 64
7.2.5
TRIAL GOVERNANCE AND OVERSIGHT ................................................... 64
7.3
Executive Committee.......................................................................................... 64
7.3.1
National Leader Committee................................................................................ 64
7.3.2
Data Safety Monitoring Board............................................................................ 64
7.3.3
Clinical Events Committee ................................................................................. 65
7.3.4
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 65
Statistical Analysis Plan Summary ..................................................................... 66
8.1
RESPONSIBILITY FOR ANALYSES/IN-HOUSE BLINDING..................... 68
8.2
Hypotheses/Estimation ......................................................................................... 68
8.3
Analysis Endpoints ............................................................................................... 68
8.4
Efficacy Endpoints.............................................................................................. 68
8.4.1
Safety Endpoints ................................................................................................. 69
8.4.2
 
 
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Clinical Events Committee (CEC)...................................................................... 69
8.4.3
Analysis Population .............................................................................................. 69
8.5
Statistical Methods................................................................................................ 69
8.6
Statistical Methods for Efficacy Analyses .......................................................... 69
8.6.1
Statistical Methods for Safety Analyses ............................................................. 72
8.6.2
Summaries of Baseline Characteristics, Demographics, and Other Analyses .... 73
8.6.3
Interim Analysis.................................................................................................... 74
8.7
Futility Interim Analysis ..................................................................................... 74
8.7.1
Efficacy Interim Analysis ................................................................................... 74
8.7.2
Multiplicity Adjustment....................................................................................... 76
8.8
Determination of Sample Size.............................................................................. 77
8.9
Subgroup Analyses and Effect of Baseline Factors ........................................... 79
8.10
Compliance (Medication Adherence).................................................................. 80
8.11
Extent of Exposure................................................................................................ 80
8.12
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 80
Investigational Product ........................................................................................ 80
9.1
Packaging and Labeling Information ................................................................. 80
9.2
Clinical Supplies Disclosure................................................................................. 81
9.3
Storage and Handling Requirements.................................................................. 81
9.4
Discard/Destruction/Returns and Reconciliation .............................................. 81
9.5
Standard Policies................................................................................................... 81
9.6
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 82
Confidentiality....................................................................................................... 82
10.1
Confidentiality of Data ....................................................................................... 82
10.1.1
Confidentiality of Subject Records ..................................................................... 82
10.1.2
Confidentiality of Investigator Information........................................................ 82
10.1.3
Confidentiality of IRB/IEC Information............................................................. 83
10.1.4
Compliance with Financial Disclosure Requirements....................................... 83
10.2
Compliance with Law, Audit and Debarment ................................................... 83
10.3
Compliance with Trial Registration and Results Posting Requirements ........ 85
10.4
Quality Management System............................................................................... 86
10.5
 
 
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Data Management................................................................................................. 86
10.6
Publications ........................................................................................................... 86
10.7
11.0
LIST OF REFERENCES......................................................................................... 88
12.0
APPENDICES........................................................................................................... 90
Merck Code of Conduct for Clinical Trials........................................................ 90
12.1
Collection and Management of Specimens for Future Biomedical 
12.2
Research................................................................................................................. 92
Pharmacogenetics 
Informational 
Brochure 
for 
IRBs/IECs 
& 
12.3
Investigational Site Staff ...................................................................................... 96
Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and 
12.4
by Sample Types ................................................................................................. 105
Blood Pressure Measurement Guidance........................................................... 106
12.5
List of Abbreviations .......................................................................................... 107
12.6
13.0
SIGNATURES......................................................................................................... 109
Sponsor's Representative ................................................................................... 109
13.1
Investigator.......................................................................................................... 109
13.2
 
 
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LIST OF TABLES
    
Table 1
Trial Treatment .................................................................................................. 33
Table 2
Systolic Blood Pressure Criteria for Study Treatment Dose Modification........ 35
Table 3
Instructions for Resumption of Study Treatment after Interruption due to 
Intolerability....................................................................................................... 36
Table 4
Discontinuation Scenarios ................................................................................. 40
Table 5
Laboratory Tests ................................................................................................ 51
Table 6
Evaluating Adverse Events................................................................................ 62
Table 7
Primary Analysis Strategy for Efficacy Variables............................................. 72
Table 8
Analysis Strategy for Safety Parameters............................................................ 73
Table 9
Summaries of the Interim and Final Analyses................................................... 76
Table 10
Product Descriptions.......................................................................................... 80
 
 
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LIST OF FIGURES
          
Figure 1
Study Design...................................................................................................... 21
Figure 2
Testing of Primary and Secondary Endpoints ................................................... 77
 
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
4.2.1
5.11
8.1
Rationale for the Trial and 
Selected Patient Population
Clinical Criteria for Early Trial 
Termination 
Statistical 
Analysis 
Plan 
Summary
Section updated to indicate that 
futility analysis will be 
performed at 75% of CV death 
events. In addition, CV death 
assessment has been added to 
the futility criteria.
Due to a higher than projected 
number of primary composite 
events in the trial thus far, the 
futility analysis as originally 
proposed would be conducted 
earlier than planned and would 
occur at a time when 
insufficient study follow-up 
was achieved to enable an 
adequate futility assessment.
The futility analysis is now 
being revised to ensure that 
adequate study follow-up will 
be achieved at the time when 
the futility analysis is 
conducted. 
Also futility criteria on CV 
death have been added to the 
futility criteria, to be consistent 
with the efficacy interim 
analysis approach.
 
 
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Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
8.7.1
8.7.2
Futility Interim Analysis 
Efficacy Interim Analysis
Futility analysis approach and 
futility bounds have been 
revised.
Language related to the number 
of primary endpoint events is
revised.
The analysis approach and 
futility bounds have been
updated to take into 
consideration that more 
endpoint and longer follow-up 
data will be available at the 
time of updated futility analysis
compared to the previous 
approach.
Additionally, since the study 
duration will be driven by the 
number of CV death events, the 
expected number of primary 
endpoint events may differ 
from the actual observed 
number of events.
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
4.3
Benefit/ Risk
Section updated to indicate that 
additional details regarding 
expected adverse reaction terms 
for subjects participating in this 
clinical trial are found in the 
Reference Safety Information
included in the IB
To make clear for investigators 
and sites participating in the 
trial where reference safety 
information can be found.
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
5.1.2
Subject Inclusion Criteria
Per inclusion criterion 5, 
elevated natriuretic peptides are 
required for study inclusion and 
minimal natriuretic peptide cut-
offs are listed for sinus rhythm 
and atrial fibrillation.  A note 
was added to this inclusion 
criterion 5 to indicate selection 
of the most appropriate 
natriuretic peptide level cut-off 
for a given patient should be 
guided by the investigator’s 
judgment of the impact of the 
heart rhythm at the time of 
blood draw on natriuretic 
peptide levels. 
In addition to the severity of 
heart failure, natriuretic peptide 
levels can be increased by the 
presence of atrial fibrillation. 
Patients with a medical history 
of atrial fibrillation may 
fluctuate between sinus rhythm 
and atrial fibrillation. In these 
cases, the investigator’s 
medical judgment is required to 
determine the relevance of the 
rhythm status near the last 
measurement on natriuretic 
peptides in determining the 
appropriate cut-off for study 
inclusion.
5.1.3
Subject Exclusion Criteria
Exclusion #5 which states “Has 
known allergy or sensitivity to 
any sGC stimulator” has been 
clarified to indicate that it also 
applies to subjects that have a 
prior history of hypersensitivity 
reaction to the active substance 
of the investigational product 
or any of its constituents.
A prior hypersensitivity 
reaction in exclusion #5 relates 
to either the active substance of 
the investigational product or to 
any of its constituents. 
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
5.1.3
Subject Exclusion Criteria
The inclusion/exclusion criteria 
related to pregnancy have been 
clarified by stating within 
Exclusion #26 that subjects 
who are pregnant or plan to 
become pregnant during the 
course of the trial are excluded 
from the trial.
This clarification has been 
added to explicitly state that 
subjects who are pregnant or 
planning pregnancy should be 
excluded from the trial.
5.2.1.2
6.0
Dose Modification
Trial Flow Chart
Text updated and footnote “y” 
added to clarify the instances in 
which the Table 2 dose 
modification guidance is to be 
followed.  
Table 2 dose modification 
guidance should be applied at 
all scheduled and unscheduled 
visits in which a SBP 
assessment is performed.
5.7.3
Use in Pregnancy
If a female subject of child-
bearing potential becomes 
pregnant during the study, 
study treatment will be 
discontinued; however, follow-
up in the trial will continue 
until study completion.  Such a 
subject would not be removed 
from the study.
VICTORIA is a double-blinded 
study; study treatment remains 
blinded throughout the trial 
period.  A subject discontinued 
from study treatment should 
still be followed until study 
completion.
6.0
Trial Flow Chart
The Study Flow Chart is being 
revised to indicate that in 
subjects who discontinue study 
treatment prematurely, follow-
up study visits should occur 
every 16 weeks from the 
previous study contact.
This revision provides a 
consistent approach to follow-
up for subjects who 
prematurely discontinue study 
therapy.
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
6.0
Trial Flow Chart
Per footnote “o” of the Trial
Flow Chart, the local laboratory 
tests of creatinine (for eGFR 
calculation) and NT-proBNP or 
BNP for study eligibility 
evaluation must be from 
assessments within 30 days 
before randomization. The 
assessments within 30 days 
before randomization can 
include recent historical local 
laboratory assessments 
available for the patient. 
This clarification is being 
provided to ensure research 
sites understand that a recent 
local laboratory assessment 
available for patients within 30 
days before randomization can 
be used to evaluate the eGFR 
and NT-proBNP / BNP 
requirements for the trial. 
6.0
Trial Flow Chart
Canadian Cardiovascular 
Society Functional 
Classification of Angina
(CCSA) added to Trial Flow 
Chart.
CCSA is to be performed at 
screening in all subjects with 
active stable angina. 
6.0
Trial Flow Chart
Footnotes “v” and “w” have 
been revised to indicate that the 
baseline echocardiogram and 
cardiac magnetic resonance 
imaging procedures should be 
performed prior to study drug 
administration and may be 
performed over the course of 
the screening period.
This update allows additional 
flexibility in scheduling the 
baseline imaging procedures 
for those subjects participating 
in the Echocardiography and/or 
Cardiac Magnetic Resonance 
Imaging substudies. 
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
6.0
Trial Flow Chart
Footnote “aa” was added to 
clarify that Clinical Events 
Assessment includes an 
assessment for the occurrence 
of study endpoints as described 
in Section 7.3.4. 
The purpose of this revision 
was to clarify the scope of the 
Clinical Events Assessment and 
to ensure consistency with 
Section 7.3.4. 
6.0
Trial Flow Chart
Submission of Hospitalization 
details added as a procedure to 
be completed for subjects in the 
United States (US) 
participating in the Health 
Economics Outcomes Research 
analysis. 
At US sites participating in the 
Health Economics Outcomes 
Research analysis, hospital 
billing information will be 
obtained from consenting 
subjects to inform a cost-
effectiveness analysis.
6.0
7.1.3.1
8.2
Trial Flow Chart 
Laboratory Safety Evaluations
Responsibility 
for 
In-house 
Blinding
NT-proBNP blinding will occur 
after Visit 2 which is the first 
day of study drug 
administration.
There is no risk to unblinding 
to study treatment arm by 
monitoring NT-proBNP levels 
on the baseline visit.
6.0
7.1.2.4
Trial Flow Chart 
12-Lead Electrocardiogram 
Added footnote “x” and 
updated text to provide 
additional instructions 
regarding ECG tracing to sites.
These instructions are being 
provided to ensure paper 
tracings are submitted 
appropriately. 
7.1.1.5.1
Prior Medications 
Additional guidance provided 
for the collection of prior 
medications for subjects 
entering the trial with an index 
event defined as IV diuretic use 
(without hospitalization).
Subjects who enter the trial 
with an index event defined as 
IV diuretic use (without 
hospitalization) are required to 
record the relevant IV diuretic.
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
7.1.1.5.2
Concomitant Medications
Reference to the Data Entry 
Guidelines provided. 
Additional instructions 
regarding recording 
concomitant medications are 
provided in the Data Entry 
Guidelines. 
7.1.1.8
Trial Compliance 
Additional instructions and 
clarification regarding sponsor 
consultation for low treatment 
compliance provided. 
There will be instances in this
trial where study drug
interruptions will be warranted
for subjects as investigators
adhere to protocol guidance in
Section 5.2.1. This clarification
makes clear for the study site,
that such study drug 
interruptions would not require 
a sponsor consultation and 
written documentation of 
collaborative decision on 
subject management.
Additionally, in cases where 
Sponsor notification is 
warranted, the updated 
instructions provided in this 
section ensure research sites 
understand the importance of 
timely notification of poor 
study drug compliance.
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
7.1.2.5.2
Pulse Rate
Additional instructions 
provided regarding the 
assessment of pulse rate at the 
randomization visit. This 
section also clarifies that the 
mean of three pulse rate 
assessments is to be obtained. 
This clarification is provided to 
ensure that pulse rate is 
assessed and recorded 
correctly. 
7.1.4.2
9.3
Blinding/Unblinding
Clinical Supplies Disclosure
Updated text to describe who 
may be unblinded following 
emergency unblinding and 
clarifies that the emergency 
unblinding call center should 
be used in cases of emergency 
only.
As management of the 
participant’s care following 
emergency unblinding requires 
documentation of the study 
treatment in the medical record, 
discovery of the treatment 
assignment following the 
unblinding is acceptable if it 
should occur. This revision will 
allow greater flexibility when 
describing who may become 
unblinded to a single 
participants treatment 
following an unblinding.
7.1.4.3
Calibration of Equipment 
Updated instructions for 
calibration of equipment used 
in the trial.
Textual revision was made to 
clarify investigator 
responsibility for calibration 
and maintenance of trial/study 
equipment.
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
7.1.5.1
Screening 
Updated text to include the 
correct abbreviation for left 
ventricular ejection fraction 
(LVEF).
Typographical error corrected. 
7.1.6.1
Echocardiography and Cardiac 
Magnetic Resonance Imaging 
Revised the description of 
Echocardiography and Cardiac 
Magnetic Resonance (CMR) 
Imaging substudies. 
This text clarifies that at 
participating sites, subjects may 
consent to echocardiography, 
CMR, or both if appropriate. 
8.1
Statistical 
Analysis 
Plan 
Summary
Clarifying language was added 
to reconfirm that the total 
number of subjects with a 
primary endpoint event may 
differ from the total number 
expected based on sample size.  
Since the study duration will be 
driven by the number of CV 
death events, the expected 
number of primary endpoint 
events may differ from the 
actual observed number of 
events.
8.4.3
Clinical Endpoints Committee
Title of section changed to 
Clinical Events Committee.
Title 
change 
made 
for 
consistency with Section 7.3.4.
8.9
Determination of Sample Size
Language related to the number 
of primary endpoint events is 
revised.
Since the study duration will be 
driven by the number of CV 
death events, the expected 
number of primary endpoint 
events may differ from the 
actual observed number of 
events.
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
VerICiguaT glObal study in subjects with heart failure with Reduced 
ejectIon frAction (VICTORIA)
Sponsor Product Identifiers
MK-1242
Vericiguat
Trial Phase
Phase III
Clinical Indication
Treatment of chronic heart failure with reduced ejection fraction 
(HFrEF)
Trial Type
Interventional
Type of control
Placebo, on a background of standard of care
Route of administration
Oral
Trial Blinding
Double-blind
Treatment Groups
Vericiguat 10 mg (titrated from 2.5 mg, to 5 mg, and to 10 mg), on a 
background of standard of care  
Placebo, on a background of standard of care  
Number of trial subjects
Approximately 4872 subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 
39 months from the time the first subject signs the informed consent 
until the last subject’s last study-related phone call or visit.
Duration of Participation
Each subject will participate in the trial from the time the subject signs 
the Informed Consent Form (ICF) through the final contact. This is an 
event-driven trial.  After a screening phase of up to 30 days, eligible 
subjects will be treated until the required number of cardiovascular 
(CV) death events is observed.  The estimated median follow-up 
duration is approximately 18 months, with a required minimum 
median follow-up duration of 10 months.  After last treatment dose, 
each subject will be followed for 14 days for adverse event 
monitoring. All subjects will be followed until study completion to 
assess for the occurrence of endpoint events.    
A list of abbreviations used in this document can be found in Section 12.6.
2.0 TRIAL DESIGN
Trial Design
2.1
This is a randomized, placebo-controlled, parallel-group, multi-center, double-blind, event-
driven trial of MK-1242 (vericiguat) in subjects with heart failure with reduced ejection 
fraction (HFrEF) to be conducted in conformance with Good Clinical Practice (GCP).
Approximately 4872 subjects will be randomized in this trial to evaluate the efficacy and 
safety of MK-1242 (vericiguat) compared with placebo, on a background of standard of care. 
After a screening phase of up to 30 days, eligible subjects will be treated until the required 
number of cardiovascular (CV) death events is observed (estimated median follow-up 
duration of approximately 18 months). All subjects will be followed until study completion 
to assess for the occurrence of endpoint events.  Clinical outcome events will be adjudicated 
by an independent clinical events committee (CEC). 
An independent Data Safety and 
Monitoring Board (DSMB) will monitor efficacy and safety data.
Randomization Ratio
1:1
 
 
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Subjects will be randomized within 30 days of the screening visit and within 6 months after 
hospitalization for heart failure or within a time period of up to 3 months if treatment with IV 
diuretic (without hospitalization) is used as an indicator for heart failure (HF)
decompensation.  No more than approximately 20% of subjects will be enrolled with an 
index HF decompensation occurring > 3 months prior to randomization.  Enrollment of 
subjects with estimated glomerular filtration rate (eGFR) calculated by the Modification of 
Diet in Renal Disease (MDRD) equation in the 15 mL/min/1.73 m2 to 30 mL/min/1.73 m2 
range will be limited to approximately 15% of the total study population. Randomization 
will be stratified according to region and race as described in Section 5.4.
A starting dose of MK-1242 (vericiguat) 2.5 mg or matching placebo will be initiated at the 
randomization visit.  Subjects will be up-titrated in a blinded fashion to 5 mg and then to the 
target dose of 10 mg of MK-1242 (vericiguat) or matching placebo using titration criteria 
based on mean systolic blood pressure (SBP) evaluation and clinical symptoms at 2 week 
intervals as further described in Section 5.2.1.2.  Following the 4-week titration phase, 
subjects will be evaluated in the clinic every 4 months until study completion.  Titration to 10 
mg in subjects who have not yet reached the target dose is intended at every visit throughout 
the study duration based on mean SBP measurement and safety considerations, at the 
discretion of the investigator (Section 5.2.1.2). After a 10-minute rest in seated position, 
SBP will be determined by averaging 3 replicate measurements obtained approximately 2 
minutes apart.  Accurate measurement of blood pressure is essential to dose titration and to 
detect potential safety issues during the trial.  Blood pressure will be monitored in 
accordance with the instructions provided in the Blood Pressure Measurement Guidance -
Section 12.5.
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures.
Formal futility and efficacy interim analyses are planned as described in Section 8.0-
Statistical Analysis Plan.
 
 
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Trial Diagram
2.2
Figure 1
Study Design
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
3.1
(1) Objective:  To evaluate the efficacy of the oral soluble guanylate cyclase (sGC)
stimulator MK-1242 (vericiguat) in comparison to placebo on a background of standard 
of care in increasing the time to first occurrence of the composite of CV death or HF 
hospitalization in subjects with HFrEF.
Hypothesis: MK-1242 is superior to placebo in increasing the time to first occurrence of 
the composite of CV death or HF hospitalization in subjects with HFrEF.
The study is considered to have met its primary objective if MK-1242 is superior to placebo 
in the primary hypothesis testing at the final analysis, or the study is stopped for 
overwhelming efficacy at the efficacy interim analysis.
Secondary Objective(s) & Hypothesis(es)
3.2
In subjects with HFrEF on a background of standard of care:
(1) Objective:  To evaluate the efficacy of MK-1242 (vericiguat) in increasing the time to 
CV death in comparison to placebo.
Hypothesis: MK-1242 (vericiguat) is superior to placebo in increasing the time to CV 
death.
 
 
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(2) Objective:  To evaluate the efficacy of MK-1242 (vericiguat) in increasing the time to 
first HF hospitalization in comparison to placebo.
Hypothesis: MK-1242 (vericiguat) is superior to placebo in increasing the time to first 
HF hospitalization.
(3) Objective:  To evaluate the efficacy of MK-1242 (vericiguat) in increasing the time to 
total HF hospitalizations (first and recurrent) in comparison to placebo.
Hypothesis: MK-1242 (vericiguat) is superior to placebo in increasing the time to total
HF hospitalizations.
(4) Objective: To evaluate the efficacy of MK-1242 (vericiguat) in increasing the time to the 
first occurrence of the composite of all-cause mortality or HF hospitalization in 
comparison to placebo.
Hypothesis:  MK-1242 is superior to placebo in increasing the time to the first 
occurrence of the composite of all-cause mortality or HF hospitalization. 
(5) Objective:  To evaluate the efficacy of MK-1242 (vericiguat) in increasing the time to 
all-cause mortality in comparison to placebo.
Hypothesis: MK-1242 is superior to placebo in increasing the time to all-cause mortality.
(6) Objective: To evaluate the safety and tolerability of MK-1242 (vericiguat).
Other Objectives (Exploratory)
3.3
In subjects with HFrEF on a background of standard of care:
(1) Objective: To evaluate the efficacy of MK-1242 (vericiguat) in comparison to placebo
in increasing the time to HF event, defined as composite of HF hospitalization or urgent 
HF visit (not meeting the criteria for a HF hospitalization).
(2) Objective: To evaluate the efficacy of MK-1242 (vericiguat) in comparison to placebo in 
increasing the time to first CV hospitalization.
(3) Objective: To evaluate the efficacy of MK-1242 (vericiguat) in comparison to placebo in 
reducing the total number of HF hospitalizations.
(4) Objective: To evaluate the efficacy of MK-1242 (vericiguat) in comparison to placebo
on the change in health-related quality of life summary measures (Kansas City 
Cardiomyopathy Questionnaire [KCCQ] and EuroQol Group 5-Dimensional [EQ-5D])
from baseline to each measured time point.
(5) Objective: To explore the relationship between genetic variation and response to the 
treatment administered.  Variations across the human genome may be analyzed for 
association with clinical data collected in this study.   
 
 
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(6) Objective: To explore relationship between baseline blood biomarker levels and response 
to treatment and the effect treatment has on established and emerging blood biomarkers.
4.0 BACKGROUND & RATIONALE
Background
4.1
Refer to the latest version of the Investigator’s Brochure (IB) for detailed background
information on MK-1242 (vericiguat). 
Pharmaceutical and Therapeutic Background
4.1.1
Vericiguat is a novel oral soluble guanylate cyclase (sGC) stimulator in development for 
chronic HF. Bayer and Merck Sharp & Dohme (MSD; Merck & Co. in North America) are 
developing vericiguat in collaboration and will engage in an academic-pharmaceutical 
industry partnership with the Canadian VIGOUR Centre (CVC) at the University of Alberta 
and the Duke Clinical Research Institute (DCRI) to conduct this study.
In patients with HF, endothelial dysfunction and oxidative stress may reduce nitric oxide 
(NO) bioavailability, resulting in insufficient sGC stimulation and reduced sGC-derived 
cyclic guanosine monophosphate (cGMP) synthesis. 
Insufficient sGC activity may be 
associated with coronary microvascular dysfunction and myocardial derangements in heart 
failure. This mechanism of cardiac and vascular dysfunction is not directly addressed by 
currently available therapies. In the presence of relative cGMP deficiency, sGC stimulators 
offer a novel approach to address the cGMP deficit in chronic HF through a dual mode of 
action with direct stimulation of sGC as well as enhancement of sGC sensitivity to 
endogenous NO.
High Mortality and Morbidity Upon Heart Failure Decompensation
Heart failure is a leading cause of cardiovascular (CV) morbidity and mortality and 
constitutes a major public health problem worldwide.  In 51 countries with a population of 
>900 million represented by the European Society of Cardiology (ESC), there are at least 15 
million patients with HF [1]. An estimated 5.1 million patients have HF in the United States 
(US); the incidence of HF approaches 10 per 1000 population after 65 years of age [2]. The
lifetime risk for developing HF is 1 in 5 for men and women [2]. In developed countries, 1–
2% of the adult population has HF, with the prevalence rising to ≥10% among persons 70 
years of age or older [3].
In patients with chronic HF, the requirement of hospitalization for HF indicates progression 
of the disease and is associated with substantially worsened prognosis compared to 
outpatients not hospitalized for HF [4].  Likewise, HF decompensation requiring intravenous 
(IV) decongestive treatment predicts unfavorable outcomes even in the absence of 
hospitalization [5].  While neurohumoral antagonists including angiotensin-converting 
enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), beta-blockers, and 
mineralocorticoid receptor antagonists (MRAs) have been shown to improve outcomes in
numerous large-scale HF clinical trials, the prognosis of patients who require hospitalization 
for HF remains unfavorable despite these treatments [6].  In the Aliskiren Trial on Acute 
Heart Failure Outcomes (ASTRONAUT), a placebo controlled study that randomized 
 
 
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hemodynamically stable patients recently hospitalized for HF, there was a 17% 1-year 
mortality rate and a 28% 1-year HF rehospitalization rate in the placebo group despite use of 
background standard of care therapies [7]. This increased mortality and morbidity in patients 
with worsening HF on top of standard of care represents a remaining unmet clinical need.
Standard HF treatment is well defined according to guideline recommendations such as 
American College of Cardiology Foundation (ACCF)/American Heart Association (AHA)
and European Society of Cardiology (ESC) Guidelines for the Management of Heart Failure 
[3] [8]. This includes treatment with ß-blockers, ACE inhibitors, ARBs, MRAs, diuretics, 
and will also include new recommendations for treatment according to future updates in 
guidelines. For instance, the recently approved drug sacubitril/valsartan (LCZ-696) has been 
shown to reduce the risk of CV death and HF hospitalization in patients with chronic HF
(New York Heart Association [NYHA] Class II-IV) with reduced ejection fraction when 
administered in conjunction with other HF therapies, in place of an ACE inhibitor or other 
ARB (hazard ratio [HR] 0.80; confidence interval [CI] 0.73 to 0.87, p<0.001) [9].
Other treatments with less-certain benefits in HFrEF or benefits observed in specific HFrEF 
subgroups are considered in various guidelines. For instance, in the ACCF/AHA guidelines 
the combination of hydralazine and isosorbide dinitrate can be used when there is a history of 
treatment intolerance to an ACE inhibitor or ARB (Class IIa) [8]. 
Furthermore, the 
ACCF/AHA guidelines recommend the combination of hydralazine and isosorbide dinitrate 
for African Americans with NYHA III-IV receiving optimal therapy with ACE inhibitors and 
beta blockers (Class I). It is important to note that patients taking long-acting nitrates are 
excluded from the VICTORIA trial.  The optimized application of standard therapy 
following the recommendations of locally relevant scientific guidelines will be expected by 
the protocol as applied individually at the discretion of the treating investigator in line with 
individual tolerability.
While disease-modifying treatments reduce the risk of sudden death, they do not abort it. 
Approximately half of the deaths in HF patients occur suddenly and unexpectedly, mainly
due to ventricular arrhythmias. Prevention of sudden cardiac death is an important goal of 
cardiac device treatment for HF and for this reason implantable cardioverter defibrillators
(ICD) have an important role in reducing the risk of death [3] [8].  In the ACCF/AHA 
guidelines ICD use is a Class I recommendation for primary and secondary prevention after a 
sufficient optimization of medical therapy in select patients with HFrEF [8]. 
Cardiac 
resynchronization therapy via a biventricular pacemaker is known to provide additional 
benefit when added to conventional therapy in reducing the risk of death from any cause and 
hospital admission for worsening HF [3] [8]. Cardiac device therapies such as ICDs and 
biventricular pacemakers should be utilized per local scientific guidelines. 
Insufficient Soluble Guanylate Cyclase Signaling is a Target in Heart Failure
The NO-sGC-cGMP pathway is a relevant mechanism in HF that is not targeted by 
neurohumoral antagonists. Deficiency in sGC-derived cGMP causes myocardial dysfunction 
and impaired endothelium-dependent vasotone regulation, including in the myocardial 
microcirculation [10].
Restoration of sufficient sGC–cGMP signaling appears to be an 
important target in HF. Previous attempts to increase cGMP remain limited. The long-term 
effects of nitrates and exogenous NO donors are limited by tolerance and they cause 
endothelial dysfunction, oxidative stress, and release of endothelin-1.
 
 
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Direct Oral Soluble Guanylate Cyclase Stimulators
A novel class of sGC stimulators directly stimulates the NO receptor sGC with a dual mode 
of action. They sensitize sGC to endogenous NO by stabilizing the NO-sGC binding and also 
directly stimulate sGC via a different binding site, independently of NO. Their regional 
vasoactivity and potential direct myocardial effects are independent of biotransformation 
and, therefore, could provide an advanced tolerable option to restore cGMP signaling in HF. 
In the Phase IIb Left ventricular systolic dysfunction associated with Pulmonary 
Hypertension riociguat Trial (LEPHT, NCT01065454) in patients with systolic HF and 
secondary pulmonary hypertension, the 3 times daily administered oral sGC stimulator 
riociguat was well tolerated and improved cardiac index, pulmonary vascular resistance, 
systemic vascular resistance, and quality of life in addition to standard HF treatment over 16 
weeks while not significantly changing systemic BP or mean pulmonary arterial pressure 
(mPAP) which was the primary endpoint.
Vericiguat, a novel oral sGC stimulator with a similar mechanism of action to riociguat but 
with a longer half-life that allows for once daily dosing, is currently being developed for the 
treatment of heart failure.
Pre-clinical and Clinical Trials
4.1.2
Vericiguat has been evaluated in approximately 65 preclinical studies and has been 
administered to over 500 healthy subjects in 19 completed Phase I studies with single- and 
multiple-dose administration and approximately 740 heart failure subjects in two Phase IIb 
studies which studied vericiguat in worsening chronic heart failure subjects with reduced 
ejection fraction (HFrEF) and with preserved ejection fraction (HFpEF), respectively.  
Dose finding in subjects with HFrEF was studied in the Phase IIb SOCRATES-REDUCED 
study (NCT 0195162).
In this 12-week comparison of 4 different dosing strategies with 
placebo, vericiguat in doses up to 10 mg daily was well tolerated with a clinically significant 
reduction in N-terminal pro-Brain Natriuretic Peptide (NT-proBNP) levels in the 10 mg 
target dose arm [11] [12].
Rationale
4.2
Rationale for the Trial and Selected Subject Population
4.2.1
The worsening of chronic HF in patients despite the use of standard-of-care therapy as 
indicated by the need for hospitalization or the use of IV diuretics (without hospitalization) is 
associated with increased morbidity and mortality.
Vericiguat, a sGC stimulator, was studied in a Phase IIb dose-finding study (SOCRATES-
REDUCED in subjects with HFrEF [NCT0195162]).  In this trial, the highest target dose 
group demonstrated a reduction in NT-proBNP compared to placebo when added to standard 
of care.  These findings support the rationale for this Phase III clinical outcome trial in 
HFrEF: VICTORIA Trial.   
The VICTORIA trial will evaluate the clinical efficacy of vericiguat on a background of HF
standard therapy for subjects with HFrEF [3] [8] and will determine the clinical efficacy of 
 
 
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vericiguat in a pivotal Phase III trial in line with the available guidance on clinical 
investigation of medicinal products for the treatment of cardiac failure [13].
The primary endpoint of the study is the time-to first occurrence of the composite of CV 
death or HF hospitalization.
This endpoint integrates the cause-specific components CV 
death and HF hospitalization and is the most frequently used primary endpoint in recent 
Phase III HFrEF trials. Subjects without a HF hospitalization or CV death at the time of 
analysis will be censored at the time of a non-CV death or time of last information available 
for subjects still alive at time of analysis.
A futility interim analysis to assess lack of efficacy is planned at the time when 
approximately 75% of the planned number of CV death events is observed.  The futility 
analysis will be performed with both the primary endpoint and CV death, and early 
termination of the study will be considered for lack of efficacy on both the primary 
composite endpoint and CV death.  Additionally, a formal interim efficacy analysis for 
efficacy is also planned at the time when the futility analysis is performed.  Within the pre-
specified interim efficacy analysis, the primary purpose is to consider early termination of the 
study in the presence of substantial impact on both the primary composite endpoint and CV 
death.
A double-blind, randomized trial design comparing MK-1242 (vericiguat) versus placebo, on
a background standard of care, offers an unbiased evaluation of MK-1242 (vericiguat) as a 
treatment option for this patient population with worsening HF in an international trial.
Rationale for Dose Selection/Regimen/Modification
4.2.2
Dose selection for Phase III is based on results from the Phase IIb study SOCRATES-
REDUCED as well as the Phase I program in healthy volunteers.
Data from the Phase I studies show that in healthy volunteers doses up to 10 mg vericiguat 
are well tolerated.
Dose limiting pharmacodynamics effects in Phase I studies at higher 
doses were associated with orthostatic reactions and syncope (see current version of IB).
In the Phase IIb SOCRATES-REDUCED study, vericiguat doses from 1.25 mg up to a target 
dose of 10 mg were tested. Vericiguat 1.25 mg was confirmed as a ‘no effective dose’ with 
an overall profile comparable to placebo. Vericiguat 2.5 mg was associated with a first dose 
SBP lowering effect of approximately 3 mmHg (minimally effective dose) and defined as the 
‘minimally effective dose’. Vericiguat 2.5 mg will be used as the starting dose for all 
subjects in Phase III. In the highest target dose arm, vericiguat was titrated from a starting 
dose of 2.5 mg by 2 dose doublings in 2-week intervals up to 10 mg target dose. The blood 
pressure criterion for up-titration was SBP ≥100 mmHg.
The target dose was reached by 
72% of subjects receiving vericiguat compared to 75% of subjects sham up-titrated in the 
placebo group. The main reason for not up-titrating to target per protocol was maintaining 
dose without any increase when SBP was 90-100 mmHg.
Dose decreases were rarely 
required for SBP <90 mmHg. 10 mg was safe and well tolerated with a clinically meaningful 
reduction in NT-proBNP and favorable trends in the impact on clinical events.  
In conclusion, for vericiguat given on a background of standard of care, a titration regimen 
starting with 2.5 mg with blood pressure guided up-titration up to 10 mg once daily with 2 
dose doublings about every 14 days is expected to cover doses from a minimal 
 
 
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hemodynamically effective starting dose to the maximum clinically favorable dose of 10 mg 
and is deemed appropriate for the planned Phase III study.
Rationale for the Use of Comparator/Placebo
4.2.2.1
As a novel mechanism, MK-1242 (vericiguat) is being developed for use on a background of 
standard of care rather than as a replacement for any established mechanisms.  To allow a 
blinded assessment, vericiguat will be compared to a matching placebo.  Utilizing placebo as 
a comparator to the novel sGC stimulator MK-1242 (vericiguat) allows for a representative 
population receiving standard of care under "real life" conditions.  
Rationale for Endpoints
4.2.3
Efficacy Endpoints
4.2.3.1
The primary efficacy endpoint of the study is the time to first occurrence of the composite of 
CV death or HF hospitalization. As an integrated measure of HF morbidity and mortality,
this endpoint integrates the cause-specific components CV death and HF hospitalization and 
is the most frequently used primary endpoint in recent phase III HFrEF trials. As secondary 
efficacy variables, the study will further assess the impact of MK-1242 (vericiguat) on the 
total number of HF hospitalizations further describing the impact on the patient journey and 
all cause death as an additional measure of net benefit.
Safety Endpoints
4.2.3.2
Safety assessments will include adverse events (AEs), physical examination findings, and 
vital signs including pulse rate and blood pressure assessment.  Laboratory safety studies will 
include blood chemistry, hematology, and urine pregnancy testing (performed in women of 
childbearing potential).  Additionally, 12-lead electrocardiograms will be performed. 
AEs associated with symptomatic hypotension and syncope are pre-specified safety 
parameters and will be subject to inferential testing. 
Pharmacokinetic Endpoints
4.2.3.3
Pharmacokinetic investigations will be performed to determine systemic exposure to MK-
1242 (vericiguat) and its relationship with efficacy.  Plasma concentrations of MK-1242 
(vericiguat) will be collected at different time points using a sparse sampling approach in all 
participating subjects to facilitate this analysis.
Planned Exploratory Biomarker Research
4.2.3.4
Planned Genetic Analysis
Understanding genetic determinants of drug response is an important endeavor during 
medical research. This research will evaluate whether genetic variation within a clinical trial 
population correlates with response to the treatment(s) under evaluation. If genetic variation 
is found to predict efficacy or adverse events, the data might inform optimal use of therapies 
in the patient population. This research contributes to understanding genetic determinants of 
efficacy and safety associated with the treatments in this study.
 
 
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Future Biomedical Research
4.2.3.5
The Sponsor will conduct Future Biomedical Research on DNA specimens collected for 
future biomedical research during this clinical trial.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting specimens for Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
subjects receive the correct dose of the correct drug/vaccine at the correct time.  The details 
of this Future Biomedical Research sub-trial are presented in Section 12.2 - Collection and 
Management of Specimens for Future Biomedical Research.  Additional informational 
material for institutional review boards/ethics committees (IRBs/ERCs) and investigational 
site staff is provided in Section 12.3.
Benefit/Risk
4.3
Subjects in placebo-controlled clinical trials generally cannot necessarily expect to receive 
direct benefit from treatment during participation, as clinical trials 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 after hospitalization for 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 vasotone regulation and myocardial function, and is 
expected to fulfill this medical need. 
Based on its mechanism of action and available 
preclinical and clinical data, vericiguat has the potential to become a new effective treatment 
for the proposed patient population by reducing morbidity and mortality and improving 
quality of life. 
In the Phase IIb SOCRATES-REDUCED study, the 10 mg target dose of vericiguat reduced 
NT-proBNP and was well-tolerated compared to placebo.  This target dose was also 
associated with a numeric reduction in cardiac events.  This provides the basis to advance 
development to an event-driven, appropriately powered Phase III CV mortality and morbidity 
outcome study in subjects with HFrEF.  Anticipated side effects with the use of vericiguat are 
expected to be well manageable. Based on the existing results, the overall benefit/risk 
balance is expected to be positive.
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the IB and Informed Consent documents.  Additional details 
regarding expected adverse reaction terms for subjects participating in this clinical trial are 
found in the Reference Safety Information included in the IB.
 
 
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5.0 METHODOLOGY
Entry Criteria
5.1
Diagnosis/Condition for Entry into the Trial
5.1.1
Male and female subjects aged 18 years or older, with chronic HF (NYHA class II-IV), 
reduced ejection fraction (<45%), elevated natriuretic peptides, and previous HF 
decompensation (defined as HF hospitalization or use of IV diuretics for HF [without 
hospitalization]) will be enrolled in this trial.
Subject Inclusion Criteria
5.1.2
In order to be eligible for participation in this trial, the subject must:
1. Provide written informed consent for the trial.  The subject may also provide consent for 
Future Biomedical Research.  However, the subject may participate in the main trial 
without participating in Future Biomedical Research.
2. Be male or female, aged 18 years or older on the day of signing informed consent.
3. Have a history of chronic HF (NYHA class II-IV) on standard therapy before qualifying 
HF decompensation.
4. Have a previous HF hospitalization within 6 months prior to randomization or IV diuretic 
treatment for HF (without hospitalization) within 3 months prior to randomization.
Note: No more than approximately 20% of subjects will be randomized with a
qualifying HF hospitalization >3 months prior to randomization.
5. Have brain natriuretic peptide (BNP) or NT-proBNP levels within 30 days prior to 
randomization as follows: 
NT-proBNP
BNP
Sinus Rhythm
≥ 1000 pg/mL
≥ 300 pg/mL
Atrial Fibrillation 
≥ 1600 pg/mL
≥ 500 pg/mL
Note: BNP cannot be used to determine eligibility for inclusion in subjects on 
sacubitril/valsartan because sacubitril/valsartan led to ~15% increase in median BNP in 
the PARADIGM-HF trial [9].  NT-proBNP must be used to confirm eligibility for 
subjects taking sacubitril/valsartan.
Note: The most appropriate natriuretic peptide level cut-off should be guided by the 
investigator’s judgment of the impact of the heart rhythm at the time of blood draw on 
natriuretic peptide levels.
 
 
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6. Have a left ventricular ejection fraction (LVEF) of <45% assessed within 12 months prior 
to randomization by any method (most recent measurement must be used to determine 
eligibility).
7. Meet one of the following criteria:
a) The subject is a male.
b) The subject is a female who is not of reproductive potential, defined as a female 
who either: (1) is postmenopausal (defined as at least 12 months with no menses 
in women ≥45 years of age); (2) has had a hysterectomy and/or bilateral 
oophorectomy, bilateral salpingectomy, or bilateral tubal ligation/occlusion at 
least 6 weeks prior to screening; OR (3) has a congenital or acquired condition 
that prevents childbearing.
c) The subject is a female who is of reproductive potential and agrees to avoid 
becoming pregnant while receiving study drug and for 14 days after the last dose 
of study drug by complying with one of the following:  (1) practice abstinence†
from heterosexual activity OR (2) use (or have her partner use) acceptable 
contraception during heterosexual activity.  Acceptable methods of contraception 
are‡:
Single method (one of the following is acceptable):
•
Intrauterine device (IUD)
•
Vasectomy of a female subject’s male partner
•
Contraceptive rod implanted into the skin
Combination method (requires use of two of the following):
•
Diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide)
•
Cervical cap with spermicide (nulliparous women only)  
•
Contraceptive sponge (nulliparous women only) 
•
Male condom or female condom (cannot be used together) 
•
Hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or 
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or 
subcutaneous contraceptive injection.
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual 
lifestyle and if considered acceptable by local regulatory agencies and ERCs/IRBs.  
Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation 
methods, etc.) and withdrawal are not acceptable methods of contraception. 
‡If a contraceptive method listed above is restricted by local regulations/guidelines, 
then it does not qualify as an acceptable method of contraception for subjects 
participating at sites in this country/region.
 
 
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Subject Exclusion Criteria
5.1.3
The subject must be excluded from participating in the trial if the subject:
1. Is clinically unstable at the time of randomization as defined by:
a.
Administration of any intravenous treatment within 24
hours
prior to 
randomization, and/or
b.
Systolic blood pressure (SBP) <100 mmHg or symptomatic hypotension. 
2. Has concurrent or anticipated use of long-acting nitrates or NO donors including 
isosorbide dinitrate, isosorbide 5-mononitrate, pentaerythritol tetranitrate, nicorandil 
or transdermal nitroglycerin (NTG) patch, and molsidomine.
Note: Co-administration of short-acting nitrates, i.e., sublingual nitroglycerin spray 
as indicated for angina attacks, is allowed (See section 5.5.2).
3. Has concurrent use or anticipated use of phosphodiesterase type 5 (PDE5) inhibitors 
such as vardenafil, tadalafil, and sildenafil.
4. Has concurrent use or anticipated use of a sGC stimulator such as riociguat.
5. Has known allergy or sensitivity to any sGC stimulator. 
Note: Subjects with a known history of hypersensitivity to the active substance of the 
investigational product or to any of its constituents will be excluded from the trial.
6. Is awaiting heart transplantation (United Network for Organ Sharing Class 1A / 1B or 
equivalent), receiving continuous IV infusion of an inotrope, or has/anticipates 
receiving an implanted ventricular assist device.
Cardiac Comorbidity
7. Has primary valvular heart disease requiring surgery or intervention, or is within 
3 months after valvular surgery or intervention.
8. Has hypertrophic obstructive cardiomyopathy.
9. Has acute myocarditis, amyloidosis, sarcoidosis, Takotsubo cardiomyopathy.
10. Has post-heart transplant cardiomyopathy.
11. Has tachycardia-induced cardiomyopathy and/or uncontrolled tachyarrhythmia.
12. Has acute coronary syndrome (unstable angina, non-ST elevation myocardial 
infarction [NSTEMI], or ST elevation myocardial infarction [STEMI]) or coronary 
revascularization (coronary artery bypass grafting [CABG] or percutaneous coronary 
intervention [PCI]) within 60 days prior to randomization, or indication for coronary 
revascularization at time of randomization.
 
 
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13. Has symptomatic carotid stenosis, transient ischemic attack (TIA) or stroke within 60 
days prior to randomization.
14. Has complex congenital heart disease.
15. Has active endocarditis or constrictive pericarditis.
Non-cardiac comorbidity
16. Has an estimated glomerular filtration rate (eGFR) calculated based on the 
Modification of Diet in Renal Disease (MDRD) equation <15 mL/min/1.73 m2 or 
chronic dialysis.  
Note: No more than approximately 15% of subjects will enroll with an eGFR in the 
15 mL/min/1.73 m2 to 30 mL/min/1.73 m2 range.
17. Has severe hepatic insufficiency such as with hepatic encephalopathy.
18. Has malignancy or other non-cardiac condition limiting life expectancy to <3 years.
19. Requires continuous home oxygen for severe pulmonary disease.
20. Has current alcohol and/or drug abuse.
21. Has participated in another interventional clinical study and treatment with another 
investigational product ≤30 days prior to randomization or plans to participate in any 
other trial/investigation during the duration of this study.
22. Has a mental or legal incapacitation and is unable to provide informed consent.
23. Has a medical disorder, condition, or history thereof that in the opinion of the 
investigator would impair the subject’s ability to participate or complete the study.
24. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or 
child) who is investigational site or sponsor staff directly involved with this trial.
25. Has Interstitial Lung Disease.
26. Is pregnant or breastfeeding or plans to become pregnant or to breastfeed during the 
course of the trial.
Trial Treatment(s)
5.2
The treatment to be used in this trial is outlined below in Table 1.
 
 
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Table 1
Trial Treatment
Drug
Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen/Treatment Period
Use
MK-1242 
(Vericiguat)
2.5 mg
QD
Oral
Starting dose of 2.5 mg, up-
titrated to 5 mg and to 
10 mg; taken with food
(Visit 2 through Vn)
Experimental
MK-1242 
(Vericiguat)
5 mg
QD
Oral
Starting dose of 2.5 mg, up-
titrated to 5 mg and to 
10 mg; taken with food 
(Visit 3 through Vn)
Experimental
MK-1242 
(Vericiguat)
10 mg
QD
Oral
Starting dose of 2.5 mg, up-
titrated to 5 mg and to 
10 mg; taken with food 
(Visit 4 through Vn)
Experimental
MK-1242 
(Vericiguat) Placebo
Matching placebo for 2.5 mg 
QD
Oral
Starting dose of 2.5 mg, up-
titrated to 5 mg and to 10 
mg; taken with food (Visit 2 
through Vn)
Placebo-comparator
MK-1242 
(Vericiguat) Placebo
Matching placebo for 5 mg 
QD
Oral
Starting dose of 2.5 mg, up-
titrated to 5 mg and to 10 
mg; taken with food (Visit 3 
through Vn)
Placebo-comparator
MK-1242 
(Vericiguat) Placebo
Matching placebo for 10 mg 
QD
Oral
Starting dose of 2.5 mg, up-
titrated to 5 mg and to 10 
mg; taken with food (Visit 4
through Vn)
Placebo-comparator
 
 
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The first dose of trial treatment will be administered at the trial site at Visit 2
(randomization).  Subsequent dosing will be performed once daily by the subject (i.e., 
unsupervised at his/her home) at approximately the same time each day.
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 trial 
treatments in accordance with the protocol and any applicable laws and regulations.
Dose Selection/Modification
5.2.1
Dose Selection (Preparation)
5.2.1.1
This trial includes a dose titration regimen based on a subject’s sitting SBP as described in 
Section 5.2.1.2. 
Dose Modification 
5.2.1.2
Subjects will be randomized to a starting dose of MK-1242 vericiguat 2.5 mg or matching 
placebo.  In a blinded manner, the first titration to 5 mg will occur at Visit 3 (14±4 days after 
randomization) and the second titration to the target dose of 10 mg will occur at Visit 4 
(28±4 days after randomization).  These titration steps include sham titrations in the placebo 
arm.  Dose modification will depend on mean sitting SBP and the absence of symptoms 
indicative of hypotension (See Appendix 12.5 - Guidance for Blood Pressure Assessment) 
before intake of the dose as described in Table 2. Table 2 dose modification guidance should 
be applied at all scheduled and unscheduled visits in which a SBP assessment is performed.
If the subject does not reach the 10 mg dose step by 28±4 days after randomization, up-
titration should be considered at any subsequent visit at the discretion of the investigator 
according to the SBP criteria in Table 2.
The intention of the protocol is to maintain subjects on the target study drug dose for as long 
as possible after randomization.  However, if in the opinion of the investigator the subject
does not tolerate the target dose of study drug, in addition to considering the reduction of the 
study drug the investigator should consider whether medications not shown to provide an 
outcome benefit in clinical studies (e.g., various classes and doses of diuretics, calcium 
channel blockers, or alpha-blockers) can be reduced before reducing the dose of the study 
drug.  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. 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 trial reduce the dose 
or interrupt study treatment in subjects who no longer tolerate the current study drug dose.  
The doses of disease modifying drugs shown to provide an outcome benefit, such as β-
blockers, ACE inhibitors/ARBs, and MRAs, or future standard treatment recommended in 
the study population, should not be reduced for the sole purpose of facilitating the 
maintenance of study treatment dosing.  In general, every attempt should be made to resume 
the study treatment upon temporary interruption and reach and maintain the target dose of the 
study treatment when the investigator feels it is medically appropriate according to Table 2
and Table 3. 
 
 
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Table 2
Systolic Blood Pressure Criteria for Study Treatment 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 
Dose decrease from 5 or 10 mg doses is possible at any time if the investigator feels this is 
justified for safety reasons.  
Reasons for dose modifications (maintenance, increase, decrease, interruption, or restart) will 
be collected at all scheduled and unscheduled visits in which a vital signs assessment is 
performed.
If the subject 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 2.
5.2.1.2.1 Resumption of Study Treatment after Interruption 
Upon interruption of the study drug due to intolerability, intake should be resumed as soon as 
medically justified at the discretion of the investigator. There is no defined maximum time 
limit for temporary treatment interruption.  In all cases, the reason for study drug interruption 
or permanent study drug discontinuation must be recorded.
Titration rules following restart of study drug after temporary interruption of study drug are 
as follows:
•
Interruption During the Titration phase (Day 0 - Day 28)
o
Restart study drug at a scheduled visit and titrate with intervals as shown in
Table 3. 
•
Interruption After Day 28
o
Restart as soon as possible (with an unscheduled visit if required) and titrate 
according to the instructions provided in Table 2 and Table 3. 
o
Subject will then resume the planned visit schedule.
o
Unscheduled clinic and/or phone contacts can be conducted at the discretion 
of the investigator.
 
 
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Table 3
Instructions for Resumption of Study Treatment 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
10 mg
 
 
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Timing of Dose Administration
5.2.2
Administration is once daily. The study drug should be taken with food.  Subjects will be 
instructed to take study medication at the same time each day.
Trial Blinding 
5.2.3
A double-blinding technique with in-house blinding will be used.  MK-1242 (vericiguat) and 
matching placebo will be packaged identically. The subject, the investigator and Sponsor 
personnel or delegate(s) who are involved in the treatment or clinical evaluation of the 
subjects are unaware of the group assignments.
See Section 7.1.4.2, Blinding/Unblinding, for a description of the method of unblinding a 
subject during the trial, should such action be warranted.
Randomization
5.3
Treatment allocation/randomization will occur centrally using an interactive voice response 
system / integrated web response system (IVRS/IWRS).
There are 2 treatment arms.  
Subjects will be assigned randomly in a 1:1 ratio to MK-1242 or matching placebo, 
respectively.
Stratification
5.4
Treatment allocation/randomization will be stratified within the following strata:

Eastern Europe (plus Israel and South Africa) 

Western Europe

North America (Black)

North America (Non-black)

Latin and South America

Asia Pacific (including Australia) 
The stratification variable race is nested within the region North America. Resulting from the 
combination of these 2 stratification factors, subjects will be randomized into 6 different 
strata.
Concomitant Medications/Vaccinations (Allowed & Prohibited)
5.5
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may 
be required.  The investigator should discuss any questions regarding this with the Sponsor 
Clinical Director.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the subject's primary physician.  However, the decision to continue the 
subject on trial therapy or vaccination schedule requires the mutual agreement of the 
investigator, the Sponsor and the subject.
 
 
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Background Standard of Care
5.5.1
Per protocol, all subjects should receive standard HF treatment following locally relevant 
guidelines such as ACCF/AHA and ESC Guidelines for the Management of Heart Failure 
recommendations applied individually at the discretion of the treating investigator and in 
line with individual tolerability [3] [8]. This includes medications such as ß-blockers, ACE 
inhibitors, ARBs, and MRAs and cardiac device therapies such as ICDs and biventricular 
pacemakers.  Use of treatment expected to be reflected in future recommendations (such as 
the recently approved combination of sacubitril/valsartan) should be considered.
Any dose adaptation, addition, changed or added route of administration, omission, or 
cessation of concomitant standard therapy is possible whenever deemed necessary by the 
investigator in line with guideline-recommended dosing irrespective of blinded dosing of the 
study drug.   
Prohibited Concomitant Medications
5.5.2
Listed below are specific restrictions for concomitant therapy during the course of the trial:
1. Long-acting nitrates or NO donors: co-administration of nitrate preparations with a 
longer-lasting effect than sublingual nitroglycerin (NTG) such as isosorbide dinitrate and 
isosorbide 5-mononitrate, pentaerythritol tetranitrate, nicorandil or transdermal NTG 
patch, or molsidomine is not allowed. In contrast, co-administration of short-acting 
nitrates, i.e., sublingual NTG spray as indicated for angina attacks, is allowed.
2. PDE5 inhibitors: co-administration of vardenafil, tadalafil, or sildenafil is not allowed.
3. sGC stimulators other than the study drug (such as riociguat) are not allowed during 
study drug treatment.
Immediate medical attention should be sought in case of hypotension symptoms after the use 
of short-acting nitrates (allowed) or after the accidental use of long-acting nitrates, PDE5 
inhibitors, or non-study treatment sGC stimulators (not allowed).
Rescue Medications & Supportive Care
5.6
No rescue or supportive medications are specified to be used in this trial.
Diet/Activity/Other Considerations
5.7
Diet
5.7.1
Subjects should maintain a diet consistent with recommendations in local guidelines, such as
the ACCF/AHA and ESC Guidelines for the Management of Heart Failure [3] [8] during the 
course of the study. 
Contraception
5.7.2
Female subjects must agree to avoid becoming pregnant while receiving study drug and for 
14 days after the last dose of study drug by complying with one of the following:  (1) practice 
 
 
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abstinence† from heterosexual activity OR (2) use (or have her partner use) acceptable 
contraception during heterosexual activity.  Acceptable methods of contraception are ‡:
Single method (one of the following is acceptable):

Intrauterine device (IUD)

Vasectomy of a female subject’s male partner

Contraceptive rod implanted into the skin
Combination method (requires use of two of the following):

Diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide)

Cervical cap with spermicide (nulliparous women only)  

Contraceptive sponge (nulliparous women only) 

Male condom or female condom (cannot be used together) 

Hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or 
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or 
subcutaneous contraceptive injection.
†
Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual lifestyle 
and if considered acceptable by local regulatory agencies and ERCs/IRBs.  Periodic 
abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and 
withdrawal are not acceptable methods of contraception. 
‡
If a contraceptive method listed above is restricted by local regulations/guidelines, then it 
does not qualify as an acceptable method of contraception for subjects participating at 
sites in this country/region.
Use in Pregnancy
5.7.3
If a subject inadvertently becomes pregnant while on treatment with MK-1242 (vericiguat), 
study treatment will immediately be discontinued.  The subject will continue to be followed 
for clinical events and vital status until study completion.  The pregnancy event will be 
reported and followed as described in Section 7.2.2-Reporting of Pregnancy and Lactation.
Subject Withdrawal/Discontinuation Criteria
5.8
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal procedures; including specific details regarding 
withdrawal from Future Biomedical Research, are provided in Section 7.1.4 – Other 
Procedures.
 
 
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Table 4 provides reasons why a subject must be discontinued from treatment but may 
continue to be monitored in the trial, as well as reasons why a subject must be discontinued 
from treatment and the trial.
Table 4
Discontinuation Scenarios
Reason for Discontinuation Scenario
Action
The subject or legal representative (such as 
a parent or legal guardian) withdraws 
consent.
Discontinuation from Treatment 
Investigator to clarify whether subject 
wishes to withdraw completely from trial 
(no further contact) or whether subject is 
willing to be contacted for additional 
follow-up.
The subject’s treatment assignment has 
been unblinded by the investigator, Merck 
subsidiary or through the emergency 
unblinding call center.
Discontinuation from Treatment (should 
continue to monitor in the trial)
The subject has a medical condition or 
personal circumstance which, in the 
opinion of the investigator and/or Sponsor, 
places the subject at unnecessary risk 
through continued participation in the trial 
while on study treatment or does not allow 
the subject to adhere to the requirements of 
the protocol.
Discontinue from Treatment 
(should continue to monitor in the trial)
The subject has a confirmed positive serum 
pregnancy test.
Discontinue from Treatment 
(should continue to monitor in the trial)
Study drug treatment is intended to continue in all randomized subjects until the final visit, 
with the goal that subjects are on the target dose of study drug for as long as possible. The 
study drug will also be continued after any non-fatal potential clinical outcome event, 
including after HF hospitalizations.
Study drug discontinuation for any reason 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 subject discontinued study drug treatment. 
Therefore, all efforts will be taken to obtain data on clinical events and vital status until the
end of study. 
Thus, subjects who permanently discontinue study drug will still be followed for clinical 
events and vital status until study completion. They should attend all scheduled protocol-
defined visits and study procedures as provided in the visit schedule (Section 6.0) just as 
those who remain on study drug.  If the subject does not attend scheduled study visits, 
follow-up of clinical events specified as endpoints may continue by phone, unless the subject 
 
 
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explicitly withdraws his/her consent to any type of follow-up. In such cases, the phone 
contact will not be considered a protocol deviation.
At any time a subject’s vital status is in question, the investigator should explore all possible 
options to contact the subjects per local regulations (unless the subject has explicitly 
withdrawn his/her consent to any type of follow-up). The site must document all attempts to 
try to contact the subjects in the medical records/source documents. The vital status will be 
collected for all randomized subjects who have not withdrawn consent, irrespective of 
completion of study procedures.
In all cases, the reason for temporary interruption or permanent study drug discontinuation 
must be recorded in the electronic case report form (eCRF) and in the subject's medical 
records.
Subjects may be allowed to begin treatment/vaccination again if deemed medically 
appropriate, unless he/she has been unblinded.
Subject Replacement Strategy
5.9
A subject who discontinues from the trial will not be replaced.
Beginning and End of the Trial
5.10
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last study-related phone-call or visit,
discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by 
the investigator).
Clinical Criteria for Early Trial Termination
5.11
The clinical trial may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the trial population as 
a whole is unacceptable.  In addition, further recruitment in the trial or at (a) particular trial 
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.
At 75% of the CV death events, a futility interim analysis is planned and the DSMB may 
recommend early termination of the trial due to the lack of efficacy of vericiguat.  Also at 
75% of the CV death events, an efficacy interim analysis is planned and the DSMB may 
recommend early termination of the trial if clear and consistent efficacy is observed for 
vericiguat.
 
 
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6.0 TRIAL FLOW CHART
Trial Period 
Screening
Treatment
Premature Treatment Discontinuationf
Visit Number/Title:
1
Screena
2
Randb
3
4
5
6
7
Visitn
c
Final 
Visit d
Final 
Phone 
Contacte
Discon 
Visitg
Safety 
Follow-up 
Visit h
Cont. 
through 
end of triali
Scheduled Days/Week/Month:
Day
-30 to -1 
Day
1
Day 
14
Day
28 
Week 16
(Month 4)
Week 
32 
(Month 8)
Week 48
(Month 12)
and 
Yearlyj
Every 16 
weeks  
At time of 
Efficacy 
Cut-off
14 days  
after Final 
Visit 
At time of 
permanent 
treatment 
discon
14 days  
from last 
dose 
Every 16 
weeks 
Scheduling Window 
Days/Weeks/Months:
±4 days
±4 days
±2 weeks
±2 weeks
±2 weeks
±2 weeks
+1 week
+1 week
±2 weeks
Administrative Procedures
Informed Consent
X
Informed Consent for Future 
Biomedical Research
X
Informed Consent for Imaging 
Substudiesv,w
X
Demographics & Medical History
X
Inclusion/Exclusion Criteria
X
X
Subject Identification Card
X
X
Prior and Concomitant Medication 
Review
X
X
X
X
X
X
X
X
X
X
X
X
Treatment Randomization 
X
MK-1242 or Placebo 
Administration/Dispensingk
X
X
X
X
X
X
X
Clinical Procedures/Assessments
Height 
X
Weight 
X
X
X
X
X
X
X
X
X
X
X
Physical Examl
X
X
X
X
Electrocardiogram (12 Lead)x
X
X
X
X
Vital Signs (Pulse, BP)m
X
X
X
X
X
X
X
X
X
X
X
X
Dose Assessmenty
X
X
X
X
X
X
NYHA Classification
X
X
X
X
X
X
X
X
X
X
X
X
CCSAz
X
QOL Questionnaires (KCCQ & 
EQ-5D)
X
X
X
X
X
X
X
X
Trial Medication Compliance
X
X
X
X
X
X
X
X
Clinical Events Assessmentaa
X
X
X
X
X
X
X
X
X
X
X
Adverse Events Monitoring
X
X
X
X
X
X
X
X
X
X
X
X
Vital Statusn
Xn
Echocardiogramv 
X
X
Cardiac Magnetic Resonance 
Imagingw
X
X
Submission 
of 
Hospitalization 
Details (US subjects only) bb
X
X
X
X
X
X
X
X
X
X
X
X
 
 
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Trial Period 
Screening
Treatment
Premature Treatment Discontinuationf
Visit Number/Title:
1
Screena
2
Randb
3
4
5
6
7
Visitn
c
Final 
Visit d
Final 
Phone 
Contacte
Discon 
Visitg
Safety 
Follow-up 
Visit h
Cont. 
through 
end of triali
Scheduled Days/Week/Month:
Day
-30 to -1 
Day
1
Day 
14
Day
28 
Week 16
(Month 4)
Week 
32 
(Month 8)
Week 48
(Month 12)
and 
Yearlyj
Every 16 
weeks  
At time of 
Efficacy 
Cut-off
14 days  
after Final 
Visit 
At time of 
permanent 
treatment 
discon
14 days  
from last 
dose 
Every 16 
weeks 
Scheduling Window 
Days/Weeks/Months:
±4 days
±4 days
±2 weeks
±2 weeks
±2 weeks
±2 weeks
+1 week
+1 week
±2 weeks
Local Laboratory Assessments
Creatinine (calculation of eGFRo) 
X
BNP/NT-proBNPo
X
Central Laboratory Assessments
NT-proBNPp
X
X
X
X
Xu
X
Hematology
X
X
X
X
Xu
X
X
Chemistry 
X
X
X
X
Xu
X
X
Liver Function Tests
X
X
X
X
Xu
X
X
Hemoglobin A1c
q
X
X
X
X
Xu
X
Urine Pregnancy Testr
X
X
X
X
X
Xu
X
Blood for Genetic Analysiss
X
Blood for PK evaluationt
X
X
X
Xu
X
Blood for Biomarkers
X
X
X
Xu
X
a.
Screening can start as early as at time of hospitalization or upon intravenous diuretic treatment for heart failure.
b.
Screening visit and Randomization (Visit 2) can occur on the same day if the subject is clinically stable as defined as having not received IV treatment for > 24 hours and having SBP ≥ 100 mmHg.  
In this case, all procedures specified for Visit 2 must be done after informed consent is given and will replace screening visit procedures.
c.
Vn: Starting from Visit 7 (Week 48) all subsequent visits will be scheduled at 16 ±2 week intervals until study completion is reached.  
d.
The Final visit will be conducted for all subjects (including those who prematurely discontinued study treatment) when the planned number of CV death events is reached and the efficacy cut-off is 
announced by the Sponsor.  
e.
All subjects will be contacted by phone within 14 days (+ 1 week) of the Final visit to assess for clinical events, adverse events, and vital status (if applicable).
f.
Premature treatment discontinuation visits are relevant to subjects who permanently discontinue study treatment.  These visits do not apply to subjects who temporarily interrupt study treatment. 
g.
Discontinuation visits will be conducted at the time of permanent treatment discontinuation for the collection of clinical events, adverse events, and other procedures listed.  
h.
In-clinic safety follow-up visit required for all subjects who permanently discontinue study treatment prematurely.  Visit to be conducted within 14 days (+ 1 week) after last dose study treatment.
i.
Subjects who permanently discontinue treatment prematurely will continue in-clinic visits every 16 weeks, including the Final Visit and Final Phone Contact.  
j.
Procedures completed at Week 48 and at each yearly visit until study completion.
k.
Dose assessment based on criteria described in Section 5.2.1.2.
l.
Complete physical exam completed at Visit 2.  Directed physical exams to be completed at Week 48 (Visit 7), subsequent Yearly visits, and the Premature Discontinuation Visit and/or Final Visit. 
m.
Three measurements, each approximately 2 min apart. Visit 2: Prior to and at 2 ±0.5h post study-drug dosing; Visitn until Final visit: vital sign measurement is only needed prior to study drug dosing.  
Blood Pressure and pulse rate measurements should be performed as described in Appendix 12.5
n.
This assessment can be performed at any point in the trial when vital status is in question. 
o.
Local laboratory creatinine and NT-proBNP or BNP within 30 days before randomization will be entered in eCRF to confirm eligibility.  The creatinine assessed at this time will be used to calculate 
eGFR by MDRD equation. Recent historical local laboratory assessments may be used provided these assessments were obtained within 30 days before randomization.
p.
NT-proBNP measurements assessed by the central lab will be blinded after Visit 2.
q.
Hemoglobin A1c to be evaluated in diabetic subjects only. 
r.
In case of positive urine pregnancy test, a confirmatory serum test will be done. A negative result is required for randomization.
s.
Refer to section 7.1.3.4 for sample collection information.
t.
In case the PK sample at the specified visits cannot be obtained at a specified time point, the sample can be taken at the subsequent visits within the year of treatment.  Exact collection date/time of the 
 
 
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Trial Period 
Screening
Treatment
Premature Treatment Discontinuationf
Visit Number/Title:
1
Screena
2
Randb
3
4
5
6
7
Visitn
c
Final 
Visit d
Final 
Phone 
Contacte
Discon 
Visitg
Safety 
Follow-up 
Visit h
Cont. 
through 
end of triali
Scheduled Days/Week/Month:
Day
-30 to -1 
Day
1
Day 
14
Day
28 
Week 16
(Month 4)
Week 
32 
(Month 8)
Week 48
(Month 12)
and 
Yearlyj
Every 16 
weeks  
At time of 
Efficacy 
Cut-off
14 days  
after Final 
Visit 
At time of 
permanent 
treatment 
discon
14 days  
from last 
dose 
Every 16 
weeks 
Scheduling Window 
Days/Weeks/Months:
±4 days
±4 days
±2 weeks
±2 weeks
±2 weeks
±2 weeks
+1 week
+1 week
±2 weeks
PK samples and date/time of last study drug intake (either at home on the day before the sample or at site) must be documented.
u.
Not applicable for subjects who prematurely discontinue from study treatment. 
v.
At sites participating in the imaging substudies, subjects may elect to participate in an echocardiography substudy as described in Section 7.1.6.1. The baseline echocardiogram should be performed 
prior to study drug administration and may be performed over the course of the screening period. 
w.
At sites participating in the imaging substudies, subjects may elect to participate in a cardiac magnetic resonance imaging substudy as described in Section 7.1.6.1. The baseline cardiac magnetic 
resonance imaging should be performed prior to study drug administration and may be performed over the course of the screening period.
x.
At each scheduled ECG assessment, sites should print 2 original paper tracings.  One original paper tracing should be maintained in subject files and second original paper tracing should be mailed to 
the core ECG vendor (batched once monthly).
y.
Dose assessment to be performed at all scheduled and unscheduled visits when BP is assessed. 
z.
Performed only in subjects with a medical history of active stable angina.
aa.
Clinical Events Assessment includes an assessment for the occurrence of study endpoint events as described in Sec. 7.3.4.
bb.
At US sites participating in the Health Economics Outcomes Research analysis, hospital billing information will be obtained to inform a cost-effectiveness analysis.
Abbreviations: CCSA = Canadian Cardiovascular Society Functional Classification of Angina EQ-5D = EuroQol Group 5-dimension, 5-level questionnaire; KCCQ= Kansas City Cardiomyopathy 
Questionnaire; NYHA = New York Heart Association; ECG = electrocardiogram; BP = blood pressure; NT-proBNP = N-terminal brain natriuretic peptide; PK=pharmacokinetics; QoL=quality of Life; 
eGFR=estimated Glomerular Filtration Rate; US = United States
 
 
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7.0 TRIAL PROCEDURES
Trial Procedures
7.1
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
7.1.1
Informed Consent
7.1.1.1
The investigator or qualified designee must obtain documented consent from each potential 
subject or each subject’s legally acceptable representative prior to participating in a clinical 
trial or Future Biomedical Research. If there are changes to the subject’s status during the 
trial (e.g., health or age of majority requirements), the investigator or qualified designee must 
ensure the appropriate consent is in place. 
7.1.1.1.1 General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  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 subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
 
 
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7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, answer all of his/her questions, and obtain written informed consent before 
performing any procedure related to the Future Biomedical Research sub-trial.  A copy of the 
informed consent will be given to the subject.
Inclusion/Exclusion Criteria
7.1.1.2
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
Subject Identification Card
7.1.1.3
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial. The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency. The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the subject 
provides written informed consent. At the time of treatment allocation/randomization, site 
personnel will add the treatment/randomization number to the Subject Identification Card.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
Medical History
7.1.1.4
A medical history will be obtained by the investigator or qualified designee.  
Prior and Concomitant Medications Review
7.1.1.5
7.1.1.5.1 Prior Medications
The investigator or qualified designee will review prior medication use, and record prior 
medication taken by the subject 30 days before starting the trial. For subjects entering the 
trial with an index event defined as IV diuretic use (without hospitalization) per inclusion 
criterion 4, sites should report the diuretic administered within the required 3 month 
timeframe with the route of administration reported as intravenous.
7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial as instructed in the Data Entry Guidelines.
Assignment of Screening Number
7.1.1.6
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or treatment allocation.  Each 
subject will be assigned only one screening number.  Screening numbers must not be re-used 
for different subjects.
 
 
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Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 7.1.5.1.  
Assignment of Treatment/Randomization Number
7.1.1.7
All eligible subjects will be randomly allocated and will receive a treatment/randomization 
number.  The treatment/randomization number identifies the subject for all procedures 
occurring after treatment allocation/randomization.  Once a treatment/randomization number 
is assigned to a subject, it can never be re-assigned to another subject.
A single subject cannot be assigned more than 1 treatment/randomization number.
Trial Compliance
7.1.1.8
Subjects will be directed to bring any used and unused bottles to each visit.  The investigator 
must maintain a complete and current accountability record for the blinded investigational 
product. 
Study drug will be dispensed at each visit starting at Visit 2.  Compliance with blinded trial 
medication will be assessed by tablet counts of returned medication.  To facilitate this, 
subjects must be instructed to return all of the study drug packaging including unused study 
drug and empty packaging.
Any discrepancies between actual and expected amount of returned study medication must be 
discussed with the subject at the time of the visit, and any explanation must be documented 
in the source records.
Interruptions from the protocol specified treatment compliance <80% require consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on subject management.
Sponsor consultation and written documentation of collaborative decision on subject 
management is not required if reason for <80% compliance is due to protocol specified 
(Section 5.2.1) interruptions per dose modification scheme, investigator discretion, and/or 
adverse event. Such instances of <80% compliance will not be considered a protocol 
deviation.
Consultation should occur in a timely manner upon site learning of poor study drug 
compliance. While awaiting Sponsor feedback, the research site should conduct patient 
counseling regarding importance of study drug adherence, and the investigator can dispense 
study drug after such counseling, if in their medical judgment, the patient is able to comply 
moving forward with study treatment instructions
Administration of trial medication will be witnessed by the investigator and/or trial staff at 
the randomization visit only.
 
 
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Clinical Procedures/Assessments
7.1.2
Height
7.1.2.1
Height will be measured without shoes, using a stadiometer or other appropriate device. 
Weight
7.1.2.2
Body weight will be measured using a standardized scale at each of the pre-defined time 
points outlined in the Trial Flow Chart – Section 6.0.
Physical Examinations 
7.1.2.3
The investigator or qualified designee will perform a full physical exam at the time of 
randomization.  Clinically significant abnormal findings should be recorded as medical 
history.
Directed physical exams with a focus on cardiovascular assessment will be performed at the 
yearly visits and at the Premature Discontinuation Visit and/or Final Visit.
12-Lead Electrocardiogram
7.1.2.4
Electrocardiograms (ECG) will be obtained as described in the Trial Flow Chart-Section 6.0.

Subjects 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 subject 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 1mV signal to 10 mm
vertical deflection on the ECG. The same ECG machine should be used at all time points for 
an individual subject. 
At each scheduled ECG assessment, sites should print 2 original paper tracings.  One original 
paper tracing should be maintained in subject files and the second original paper tracing 
should be mailed to the core ECG vendor (batched once monthly).
These ECGs will be used to assess the impact of study drug on electrocardiographic changes 
such as heart rate and repolarization. 
Vital Signs
7.1.2.5
Vital sign measurements include a triplicate measurement of sitting blood pressure and pulse 
rate.  Site personnel should use the same blood pressure measuring device throughout the 
study for each subject.  Other procedures should not be performed during the time of the 
blood pressure and pulse rate measurements.  Detailed information regarding BP monitoring 
is located in Appendix 12.5.
 
 
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7.1.2.5.1 Blood Pressure Assessment 
Blood pressure assessment is to be completed after the subject has been seated for a 10-
minute rest.  Whenever possible, BP measurements should be obtained using the same arm,
same BP monitoring device, and same examiner at each visit.  Systolic and diastolic blood 
pressures will be determined by averaging 3 replicate measurements obtained approximately 
2 minutes apart.  At the randomization visit, blood pressure assessment will also be 
completed 2 ± 0.5 hour after dose is administered. 
7.1.2.5.2 Pulse Rate
Pulse rate is to be assessed after the subject has been seated for a 10 minute rest. The pulse 
rate will be determined by averaging 3 replicate measurements obtained approximately 2
minutes apart.
Assessment of pulse rate can be manual (rather than using an automated device); however, 
when done manually, pulse rate must be measured in the brachial/radial artery for at least 30 
seconds.
At the randomization visit, pulse rate will also be completed 2 ± 0.5 hour after dose is 
administered.  
Quality of Life Measures
7.1.2.6
7.1.2.6.1 Kansas City Cardiomyopathy Questionnaire
The KCCQ is 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’ heart 
failure, or its treatment, on 7 distinct domains using a 2-week recall period: symptom 
frequency, symptom burden, physical limitation, health perceptions, social limitations, 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 
Quality of Life scores. The clinical summary score and its components address the most 
relevant concepts for the heart failure patients, showing good correlation with improvement 
following HF hospitalization.    
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, subjects who speak that language will be exempt from the requirement to 
complete the questionnaire. 
 
 
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7.1.2.6.2 EuroQol Group 5-Dimensional, 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 one visual analogue scale (VAS) response. The domain 
questions assess, mobility, self-care, usual activities, pain/discomfort, anxiety/depression, 
with 5-level Likert response options; no problems, slight problems, moderate problems, 
severe problems, and 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 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, subjects who speak that language will be exempt from the requirement to 
complete the questionnaire. 
Vital Status Assessment
7.1.2.7
Vital status is collected at the Final Phone Contact.  This assessment can also be performed at 
any point in the trial when vital status is in question, unless subject has specifically 
withdrawn consent for further follow-up. 
Laboratory Procedures/Assessments
7.1.3
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. The total amount of blood to be drawn/collected over the course of the trial 
(from pre-trial to post-trial visits), including approximate blood volumes drawn/collected by 
visit and by sample type per subject can be found in Section 12.4.
Laboratory Safety Evaluations 
7.1.3.1
Laboratory tests are specified in Table 5.
NT-proBNP measurements assessed by the central lab will be blinded after Visit 2.
 
 
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Table 5
Laboratory Tests
Hematology
Chemistry
Other 
Hematocrit (Hct)
Alanine aminotransferase 
(ALT)
Hemoglobin A1c (HbA1c) in 
Diabetic subjects
Hemoglobin (Hb)
Albumin (serum)
N-terminal pro-Brain 
Natriuretic Peptide (NT-
proBNP) 
Mean corpuscular volume 
(MCV)
Alkaline phosphatase
Serum β-human chorionic 
gonadotropin†
Mean corpuscular 
hemoglobin (MCH)
Aspartate aminotransferase 
(AST)
Mean corpuscular 
hemoglobin concentration 
(MCHC)
Bicarbonate 
Platelet count 
Bilirubin (Total)
Red blood cells (RBC)
Blood glucose
Red cell distribution width 
(RDW)
Blood urea nitrogen (BUN)
Reticulocytes
Calcium 
White blood cells (WBC)
Chloride
Creatinine
Gamma glutamyl transferase 
(GGT)
Potassium (K)
.
Sodium (Na)
Uric acid
† Serum β-human chorionic gonadotropin only to be conducted in the event urine pregnancy test is positive
Pharmacokinetic/Pharmacodynamic Evaluations
7.1.3.2
For the investigation of systemic exposure to vericiguat and its relationship with efficacy, the 
plasma concentrations of vericiguat will be determined at different time points using a sparse 
sampling approach in all participating subjects.
Blood samples will be collected at the time points indicated in Section 6.0-Study Flow Chart.
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. Date 
and time of the PK sample collection and date and time of last study drug intake (either at 
home on the day before the sample or at site) must be documented.  
Details about the collection, processing, storage and shipment of samples will be provided 
separately.
 
 
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Pharmacokinetics and, if applicable, pharmacokinetics/pharmacodynamics (PK/PD) 
modeling using population approaches to describe vericiguat PK including potential 
influence of relevant subject covariables (e.g., age, gender, body weight, etc.) or potentially 
to relate parameters of clinical safety and efficacy response with vericiguat plasma 
concentrations will be investigated under a separate detailed PK/PD evaluation and analysis 
plan.
Biomarker Investigations 
7.1.3.3
Biomarker investigations will examine the impact of vericiguat on HF disease progression 
and identify candidate biomarkers that may predict drug response to the treatment.
Biomarker blood samples will be collected at the time points indicated in Section 6.0-Study 
Flow Chart. 
In the event the biomarker sample at the specified visit is not obtained, the sample can be 
taken at a subsequent visit within the year of treatment.
Details on the collection, processing, storage and shipment of biomarker samples will be 
provided in a separate 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.
Planned Genetic Analysis Sample Collection
7.1.3.4
This genetic analysis sample should be drawn for planned analysis of the association between 
genetic variants in DNA and drug response. If there is either a documented law or regulation 
prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for 
these purposes, then this sample will not be collected at that site. If the sample is collected, 
leftover extracted DNA will be stored for future biomedical research if the subject signs the 
FBR consent. 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 provided in the operations/laboratory manual.
Future Biomedical Research Sample Collection
7.1.3.5
The following specimens are to be obtained as part of Future Biomedical Research:
DNA For future research.
Refer to Section 7.1.3.4 for further description of the Future Biomedical Research sample.
Other Procedures
7.1.4
Withdrawal/Discontinuation
7.1.4.1
Subjects who discontinue/withdraw from treatment prior to completion of the treatment 
regimen should be encouraged to continue to be followed for all remaining study visits.
 
 
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When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the Premature Treatment Discontinuation visit should be performed at the time 
of discontinuation.  Any adverse events which are present at the time of 
discontinuation/withdrawal should be followed in accordance with the safety requirements 
outlined in Section 7.2 - Assessing and Recording Adverse Events.
7.1.4.1.1 Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main trial 
are still available, the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@merck.com), and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed.  A letter will 
be sent from the Sponsor to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
trial data and results.   No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen destruction cannot be processed.
Blinding/Unblinding
7.1.4.2
STUDY TREATMENT IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE SUBJECT. EVERY EFFORT 
SHOULD BE MADE NOT TO UNBLIND THE SUBJECT UNLESS NECESSARY.
For emergency situations where the investigator or sub-investigator needs to identify the drug 
used by a subject 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 sub-investigator the emergency unblinding call center will 
provide the information to him/her promptly and report unblinding to the sponsor.  The 
emergency unblinding call center will make a record promptly however, the investigator or 
sub-investigator must enter the intensity of the adverse experiences observed,   their relation 
to study drug, the reason thereof, etc., in the medical chart etc., before unblinding is 
performed. Subjects whose treatment assignment has been unblinded must be discontinued 
from study drug.
Section 5.8 outlines the criteria for allowing subjects who are discontinued from treatment to 
continue to be monitored in the trial.
 
 
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Additionally, the investigator must go into the IVRS system and perform the unblind in the 
IVRS system to update drug disposition.  In the event that the emergency unblinding call 
center is not available for a given site in this trial, IVRS/IWRS should be used for emergency 
unblinding in the event that this is required for subject safety.
In the event that unblinding has occurred, the circumstances around the unblinding (e.g., 
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 principal investigator, site personnel, and Sponsor personnel may be 
unblinded so that the appropriate follow-up medical care can be provided to the participant.
Subjects whose treatment assignment has been unblinded (by the investigator, Merck 
subsidiary, or through the emergency unblinding call center) must be discontinued from 
study drug.
Calibration of Equipment
7.1.4.3
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical trial 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 is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
trial site.
Visit Requirements
7.1.5
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
Screening
7.1.5.1
Up to 30 days prior to treatment allocation/randomization, potential subjects will be 
evaluated to determine whether they fulfill the entry requirements as set forth in Section 5.1.  
If subject is outside of the 30-day screening period and would like to be rescreened, then 
screening procedures may be repeated after consultation with the Sponsor and re-signing the 
ICF. At screening, a signed written informed consent must be available. All subsequent 
procedures will be done after the informed consent is signed.
Procedures for the Screening visit can be performed over several days. Alternatively, the 
screening visit and randomization visit can take place on the same day and subjects can be 
randomized during this visit if all required tests for eligibility criteria are available.
The screening visit can start from hospitalization (or upon IV diuretic treatment for HF
without hospitalization) and no more than 30 days before randomization (Visit 2). 
Additionally, evidence of a LVEF <45% within 12 months prior to randomization by any 
method (most recent measurement must be used) must be provided.  The investigator is 
asked to ensure that the assessment of the LVEF represents the status at the time of study 
enrollment, so if clinically warranted, the investigator is encouraged to repeat the EF 
assessment. 
 
 
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Subjects who sign the ICF and, who for any reason (e.g., failure to satisfy the selection 
criteria), do not continue on to randomization will be considered a screen failure. 
Treatment Period
7.1.5.2
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.  Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
7.1.5.2.1 Randomization Visit
At the randomization visit (within 30 days after the screening visit started, and up to 6 
months after hospitalization or 3 months after IV therapy for HF without hospitalization), 
subjects who fulfill all inclusion/exclusion criteria will be randomized to either MK-1242 
(vericiguat) or placebo on a background of standard of care HF treatment.
As noted above, the Screening visit and the Randomization visit can occur on the same day, 
if all required tests for eligibility criteria are available at screening visit.
All procedures and assessments specified for this visit will be done after screening visit 
procedures are performed. 
7.1.5.2.2 Unscheduled Visits
In the event a subject requires an unscheduled visit for dose modification, the following 
assessments will be performed:
•
Adverse events
•
Dose assessment
•
Clinical events
•
Concomitant medication: record any new or ongoing medication or changes in dosage
•
Blood pressure and pulse rate (3 measurements, each approximately 2 minutes apart) 
prior to study drug dosing  
Upon interruption of the study drug due to intolerability, intake should be resumed as soon as 
medically justified to the discretion of the investigator as described in Section 5.2.1.2. 
Investigators should make every attempt to resume study drug treatment in all subjects after 
interruption of study drug as soon as medically justified.
7.1.5.2.3 Final Visit
The Final visit will be conducted for all subjects when the planned number of CV death 
events is reached and the efficacy cut-off is announced by the Sponsor.  
If applicable, subjects will continue study treatment until this visit, and will be asked to stop 
taking study drug medication at this visit. Those subjects who prematurely discontinued 
study drug treatment are still required to attend the Final visit for collection of clinical events 
and all other procedures listed in the study flow chart. 
 
 
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7.1.5.2.4 Final Phone Contact 
All subjects will be contacted by phone within 14 days (+ 1 week) of the Final visit to assess 
for clinical events, adverse events and vital status (if applicable). 
Premature Treatment Discontinuation 
7.1.5.3
7.1.5.3.1 Premature Treatment Discontinuation Visit 
A premature treatment discontinuation visit will be conducted at the time of treatment 
discontinuation for the collection of clinical events, adverse events, and other procedures 
listed in Section 6.0
7.1.5.3.2 Safety follow-up Visit
An in-clinic safety follow-up visit will be conducted for all subjects who discontinue study 
drug prematurely.  This visit will be conducted within 14 days + 1 week after last dose of 
study treatment.  Subjects who discontinue treatment prematurely will continue to attend all 
protocol specified visits and perform all procedures stipulated in that visit, including the 
Final visit, except in case the subject specifically withdrew consent for further follow-up and 
no additional information is permitted to be collected.   If the subject does not attend the 
study visit, a telephone contact for collection of protocol defined endpoint events should 
occur.  In such cases, the phone contact will not be considered a protocol deviation.
Other Ancillary Studies
7.1.6
Echocardiography and Cardiac Magnetic Resonance Imaging 
7.1.6.1
At sites participating in the Echocardiography Imaging substudy, approximately 938 subjects 
may consent to undergo echocardiography at randomization and Month 8.
At sites participating in the Cardiac Magnetic Resonance (CMR) Imaging substudy, 
approximately 180 subjects without contraindications for magnetic resonance imaging
assessment may consent to CMR imaging at randomization and Month 8. 
Subjects are not required to participate in the echocardiography or CMR imaging substudy in 
order to participate in the main trial. In addition, subjects must provide separate informed 
consent in order to participate in these substudies. 
Additional details will be specified in separate Site Imaging Procedure Manuals and Imaging 
Substudy Analysis Plans. 
Health Economics Outcomes Research 
7.1.6.2
The Health Economics Outcomes Research (HEOR) analysis has a pre-specified analytical 
plan focusing on healthcare resource use parameters as well as patient-reported outcome 
assessments.  For the United States population, hospital billing information will be obtained 
to inform a United States cost-effectiveness analysis.
Additional details regarding the HEOR analysis will be provided in a separate manual.
 
 
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Assessing and Recording Adverse Events
7.2
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events. 
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. From the time of treatment allocation/randomization through 14 days following 
cessation of treatment, all adverse events must be reported by the investigator. Such events 
will be recorded at each examination on the Adverse Event case report forms/worksheets.  
The reporting timeframe for adverse events meeting any serious criteria is described in 
section 7.2.3.1. The investigator will make every attempt to follow all subjects with non-
serious adverse events for outcome.
Electronic reporting procedures can be found in the Electronic Data Capture (EDC) data 
entry guidelines. Paper reporting procedures can be found in the Investigator Trial File 
Binder (or equivalent).
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
7.2.1
Sponsor
In this trial, an overdose is defined as any occasion when the subject has taken (accidentally 
or intentionally) any dose higher than the maximal target dose prescribed in the protocol.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a non-serious adverse event, unless other serious 
criteria are met.
 
 
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If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious adverse event using the terminology “accidental or intentional 
overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation to the Sponsor
7.2.2
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.  Pregnancies and lactations that occur from the time of treatment 
allocation/randomization through 14 days following cessation of Sponsor’s product must be 
reported by the investigator.  All reported pregnancies  must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of 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.
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Immediate Reporting of Adverse Events to the Sponsor
7.2.3
Serious Adverse Events
7.2.3.1
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event.
 
 
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Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. 
●
Is a cancer;
●
Is associated with an overdose.
Refer to Table 6 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause, that occurs to any subject must be reported within 24 hours 
to the Sponsor if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 14 days 
following cessation of treatment, any serious adverse event, or follow up to a serious adverse 
event, including death due to any cause, whether or not related to the Sponsor's product, must 
be reported within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time outside of the time period specified in the previous paragraph also 
must be reported immediately to the Sponsor.
All subjects with serious adverse events must be followed up for outcome.
Events of Clinical Interest
7.2.3.2
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 14 days 
following cessation of treatment, any ECI, or follow up to an ECI, whether or not related to 
the Sponsor’s product, must be reported within 24 hours to the Sponsor, either by electronic 
media or paper.  Electronic reporting procedures can be found in the EDC data entry 
guidelines.  Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
 
 
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Events of clinical interest for this trial include:
1. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon 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 trial site guidance for assessment 
and follow up of these criteria can be found in the Investigator Trial File Binder (or 
equivalent).
2. symptomatic hypotension. Subjects will be monitored for symptomatic hypotension.
The DSMB will monitor with special attention to the relationship to baseline BP. While 
all hypotension AEs will be captured, only symptomatic hypotension is considered an 
event of clinical interest. 
3. syncope.
Protocol-Specific Exceptions to Serious Adverse Event Reporting
7.2.3.3
Potential pre-specified efficacy endpoints will be submitted for adjudication to an 
independent CEC (see Section 7.3.4).  This will include all-cause mortality, including 
cardiovascular and non-cardiovascular death.
The following events will not be subject to expedited reporting/unblinding by the Sponsor to 
investigators, Ethics Committees/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:

Cardiovascular Death

Cardiovascular hospitalizations 

Urgent Heart Failure Visit
Fatal events that are adjudicated to be non-cardiovascular deaths by the CEC will require an 
independent Merck company causality assessment and will be subject to expedited reporting, 
where required by local legislation, when there is evidence suggesting a causal relationship 
between vericiguat and the event. 
If an 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 investigator and Merck company causality assessment of drug 
relationship, as required by local legislation).  
 
 
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Note that all of these events, including confirmed adjudicated cardiovascular events, will be 
reviewed and monitored by an external DSMB unblinded to treatment as part of the overall 
assessment of safety and efficacy for vericiguat.  Based upon their regular review of 
unblinded safety results, the DSMB is empowered by the DSMB charter to make 
recommendations with regard to trial conduct to assure the continuing appropriate safety of 
the subjects participating in the study.  
Evaluating Adverse Events
7.2.4
An investigator who is a qualified physician will evaluate all adverse events with respect to 
the elements outlined in Table 6. The investigator’s assessment of causality is required for 
each adverse event.  Refer to Table 6 for instructions in evaluating adverse events.
 
 
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Table 6
Evaluating Adverse Events
Maximum
Mild
awareness of sign or symptom, but easily tolerated  (for pediatric trials, awareness of symptom, but easily tolerated)
Intensity
Moderate
discomfort enough to cause interference with usual activity (for pediatric trials, definitely acting like something is wrong)
Severe
incapacitating with inability to work or do usual activity (for pediatric trials, extremely distressed or unable to do usual activities)
Seriousness
A serious adverse event (AE) is any adverse event occurring at any dose or during any use of Sponsor's product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred [Note: This does not include an 
adverse event  that, had it occurred in a more severe form, might have caused death.]; or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient 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 pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in the 
patient’s medical history.); or
†Is a congenital anomaly/birth defect  (in offspring of subject taking the product regardless of time to diagnosis); or
Is a cancer (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local requirements); or
Overdose, although not serious per ICH definition, whether accidental or intentional, with or without an accompanying adverse event/serious adverse event, is 
reportable to the Sponsor within 24 hours to meet certain local requirements.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor's product to be discontinued?
Relationship to 
Sponsor's 
Product
Did the Sponsor's product cause the adverse event?   The determination of the likelihood that the Sponsor's product caused the adverse event 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 drug and the adverse event 
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 adverse event:
Exposure
Is there evidence that the subject 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 trials 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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Relationship
The following components are to be used to assess the relationship between the Sponsor's product and the AE:  (continued)
to Sponsor's 
Product
(continued) 
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 trial is a single-dose drug trial); or (4) Sponsor's product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor's product in this trial?
      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 trial is a single-dose drug trial); 
or (3) Sponsor's product(s) is/are used only one time.)
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH 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 SUBJECT THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR
CLINICAL DIRECTOR AND THE INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE.
Consistency 
with Trial 
Treatment 
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 case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following:
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
Subject 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 subject with overdose without 
an associated AE.)
 
 
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Sponsor Responsibility for Reporting Adverse Events
7.2.5
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
TRIAL GOVERNANCE AND OVERSIGHT
7.3
Executive Committee
7.3.1
The executive committee (EC) provides scientific leadership of the VICTORIA study.  As 
described in the EC charter, the EC consists of the following individuals:
•
Executive Committee Chair
•
Co-principal investigators 
•
Independent academic scientific leaders
•
Clinical leaders from the Canadian VIGOUR Centre 
•
Clinical leaders from the Duke Clinical Research Institute 
•
Sponsor Senior Management 
The EC will be responsible for all scientific aspects of the study, maintaining effective and 
independent scientific oversight, and will ensure that study execution and management are of 
the highest quality.  The EC will convene regularly to discuss and report on ongoing 
supervision of the study.  The EC serves as the publications committee and is responsible for 
oversight of all public and scientific communications and publications.  On decisions 
regarding early termination of the trial, the EC will receive recommendations from the 
DSMB and then the EC will provide recommendations to the Sponsor, who has final decision 
making rights.
National Leader Committee
7.3.2
The primary role of the National Leader Committee is to serve as the interface between the 
Executive Committee and the study sites for the VICTORIA trial and to facilitate the 
progress of the study at the regional level.  The National Leader Committee is composed of 
Country Leads selected by the Executive Committee from investigators in each country with 
appropriate clinical trial experience.  National Leader Committee members should participate 
with their local site in VICTORIA to ensure adequate direct experience with the trial.
Data Safety Monitoring Board
7.3.3
To supplement the routine trial monitoring outlined in this protocol, an external Data Safety 
Monitoring Board (DSMB) will monitor the interim data from this trial.  The voting 
members of the committee are external to the Sponsor.  The members of the DSMB must not 
be involved with the trial in any other way (e.g., they cannot be trial investigators) and must 
have no competing interests that could affect their roles with respect to the trial. 
 
 
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The DSMB will make recommendations to the EC regarding steps to ensure both subject 
safety and the continued ethical integrity of the trial.  Also, the DSMB will review interim 
trial results, consider the overall risk and benefit to trial participants (see Section 8.7 -
Interim Analyses) and recommend to the EC if the trial 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 Sponsor; meeting facilitation; the trial 
governance structure; and requirements for and proper documentation of DSMB reports, 
minutes, and recommendations will be described in a separate charter that is reviewed and 
approved by the DSMB.  The DSMB will monitor the trial at an appropriate frequency, as 
described in the detailed DSMB charter.  The DSMB will also make recommendations to the 
Sponsor regarding steps to ensure both subject safety and the continued ethical integrity of 
the trial.
A DSMB recommendation will be communicated to the Sponsor as agreed to in the 
Collaboration agreement.
Clinical Events Committee
7.3.4
A Clinical Events Committee (CEC) will evaluate the following events for the purposes of 
confirming them according to the criteria in Section 8.0 – Statistical Analysis Plan, as well as 
evaluating the presence of confounding factors.
1) Death
2) Cardiovascular Hospitalizations
3) Urgent Heart Failure Visit
All personnel involved in the adjudication process will remain blinded to treatment allocation 
throughout the trial. Specific details regarding endpoint definitions can be found in the CEC 
Charter.
8.0 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, changes are made to primary and/or 
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, will be documented in a supplemental SAP (sSAP) and referenced in the Clinical 
Study Report (CSR) for the study.  Post hoc exploratory analyses will be clearly identified in 
the CSR.  PK/PD endpoints and analysis approaches will be described in a separate detailed 
PK/PD evaluation and analysis plan. 
 
 
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Statistical Analysis Plan Summary
8.1
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 8.2 to 8.10.
Study Design Overview
A randomized parallel-group, placebo-controlled, double-blind, 
event-driven, multi-center phase III clinical outcome trial of 
efficacy and safety of the oral sGC stimulator Vericiguat in subjects 
with heart failure with reduced ejection fraction (HFrEF)
Treatment Assignment
Randomization method: Treatment allocation/randomization will 
occur centrally using an interactive voice response system / 
integrated web response system (IVRS/IWRS). There are 2 
treatment arms. Subjects will be assigned randomly in a 1:1 ratio to 
MK-1242 (vericiguat) or matching placebo, respectively.
Stratification method: Treatment allocation/randomization will be 
stratified in the following strata:
a. Eastern Europe plus Israel and South Africa  
b. Western Europe
c. North America (Black)
d. North America (Non-black)
e. Latin and South America
f. Asia Pacific (including Australia) 
Analysis Populations
Primary Efficacy Analysis: ITT population.  
Secondary Efficacy Analysis: ITT population
Safety: All subjects as treated (ASaT)
Primary Endpoint(s)
Time to the first occurrence of the composite endpoint of CV death or 
HF hospitalization.
Secondary Endpoints
Time to CV death
Time to first HF hospitalization
Time to total HF hospitalizations (first and recurrent)
Time to the composite of all-cause mortality or HF hospitalization
Time to all-cause mortality
Statistical Methods for 
Key Efficacy
The analysis of the primary endpoint will be performed with a one-
sided log-rank test, stratified by the same strata that are considered for 
randomization, to test if the time to first composite of CV death or HF 
hospitalization is prolonged in the vericiguat treatment group 
compared to placebo.
The same one-sided stratified log-rank test will be used to test if the 
time-to first HF hospitalization, time-to CV death, time-to all-cause 
mortality, and time to the composite of all-cause mortality and HF 
hospitalization is prolonged in the vericiguat treatment group 
compared to placebo.
The time-to total HF hospitalization will be tested with an Andersen-
Gill model to compare the vericiguat treatment group to placebo.
The overall study-wise type I error rate will be controlled at 0.025
(one-sided).
 
 
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Statistical Methods for 
Key Safety Analyses
95% confidence intervals (Tier 1 and Tier 2) will be provided for 
between-treatment differences in the percentage of subjects with 
events; these analyses will be performed using the unstratified 
Miettinen and Nurminen method.  In addition, p-values will be 
provided for Tier 1 safety endpoints. 
Interim Analyses
One interim analysis for efficacy is planned at the time when 
approximately 75% (587) of the planned number of CV death 
events are observed and the median follow up time is at least 10 
months.  At the interim analysis, both the primary composite 
endpoint of time to CV death or HF hospitalization and its 
component time to CV death will be tested. The study can only be 
terminated early for success if both the primary endpoint and the 
CV death component are statistically significant based on the 
nominal significance level used for the interim analysis.
At the same time as the interim analysis for efficacy, a futility 
analysis will be performed with the option to terminate the study 
early if it is determined at the time of analysis that the study is 
unlikely to demonstrate the efficacy of vericiguat on the primary 
endpoint and CV death. 
An unblinded Data Safety Monitoring Board (DSMB) will assess 
the unblinded results of the interim analysis and may recommend 
early study termination for overwhelming efficacy or futility.
Multiplicity
The secondary endpoints will be separated into two families. The 
first family consists of the components of the primary endpoint, CV 
death and HF hospitalization, and the second family consists of total 
HF hospitalization, composite of all-cause mortality or
HF 
hospitalization, and all-cause mortality.
CV death and HF 
hospitalization will be tested only if the primary composite endpoint 
is significant and will be tested in parallel with multiplicity adjusted 
for the interim analysis only.  Other secondary endpoints will be 
tested using a hierarchical testing approach.
Sample Size and Power 
The sample size calculation is driven by the CV death component of 
the composite primary endpoint. For the CV death component, the 
expected event rate in the comparator group after 12 months is 11%. 
The relative risk reduction with vericiguat is assumed to be 20% for 
both CV death and primary endpoint, relating to a HR of 0.8. Using 
the log-rank test, a sample size of 4872 subjects and a total of 782
CV deaths will be required to achieve 80% power. With this sample 
size, it is expected that 1561 subjects with a primary endpoint event 
will be observed and there will approximately be 98% power for 
primary hypothesis testing. However, since the study duration will 
be driven by the number of CV death events, the expected number 
of primary endpoint events may differ from the actual observed 
number of primary endpoint events.
 
 
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RESPONSIBILITY FOR ANALYSES/IN-HOUSE BLINDING 
8.2
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 central laboratory values for NT-pro BNP will also be blinded after 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 interactive voice 
response system (IVRS).
Hypotheses/Estimation
8.3
Objectives and hypotheses of the study are stated in Section 3.0 – Objectives & Hypotheses
Analysis Endpoints
8.4
Efficacy and safety endpoints that will be evaluated are listed below.
Efficacy Endpoints
8.4.1
Primary Endpoint
The primary endpoint of the study is the time to the first occurrence of the composite 
endpoint of CV death or HF hospitalizations. Subjects without a HF hospitalization or CV 
death at the time of analysis will be censored at time of non-CV death or time of last 
information available during the pre-specified follow-up period for subjects still alive at time 
of analysis.
Only clinical events confirmed by CEC will be used to define the primary 
endpoint. 
Secondary Endpoints
The secondary study endpoints are:
•
Components of the primary composite endpoint:

Time to CV death

Time to first HF hospitalization
•
Time to total HF hospitalizations (first and recurrent)
•
Time to first occurrence of the composite of all-cause mortality or HF hospitalization
•
Time to all-cause mortality 
 
 
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Exploratory Endpoints
The following endpoints will be considered outside of the testing procedure and considered 
as exploratory endpoints:
•
Time to first HF event, defined as composite of HF hospitalization or urgent HF visit (not 
meeting the criteria for a HF hospitalization).
•
Time to first CV hospitalization
•
Total number of HF hospitalizations
•
Change from baseline in health-related quality of life measures (KCCQ and EQ-5D)
Safety Endpoints
8.4.2
Safety measurements are described in Section 7.0 – Trial Procedures
Clinical Events Committee (CEC)
8.4.3
A clinical events committee (CEC) will be created to review and adjudicate each suspected 
clinical endpoint event without unblinding treatment. The CEC will comprise qualified 
members, who are not investigators in the study and not otherwise directly associated with 
the sponsor. The CEC members will remain blinded to treatment throughout the adjudication 
process and the study. The adjudication guidance and clinical endpoint event definitions will 
be described in detail in the CEC charter. Only clinical endpoint events adjudicated by the 
CEC will be used in the final efficacy and safety analyses.
Analysis of CEC adjudicated clinical events not already pre-specified as the primary, 
secondary or exploratory endpoints will be described in the supplemental Statistical Analysis 
Plan (sSAP).
Analysis Population
8.5
The primary endpoint analysis will use the Intention-to-Treat (ITT) population.  The ITT 
population includes all randomized subjects.  The subjects will be analyzed according to the 
planned treatment.  Subjects without any post-randomization information will be censored at 
Day 1.  
The ITT population will also be used for the secondary and exploratory efficacy endpoints 
analyses.  The subjects will be analyzed according to the planned treatment. Subjects without 
any post-randomization information will be censored at Day 1 for time to event endpoints.
The All-Subjects-as-Treated (ASaT) population will be used for safety analyses. The ASaT 
population includes all subjects who have taken at least one dose of study drug (vericiguat or 
placebo).  All subjects will be analyzed according to the actual treatment received.  Any 
subjects in ASaT who received both placebo and vericiguat during the study by mistake will 
be analyzed according to the planned treatment. 
Statistical Methods
8.6
Statistical Methods for Efficacy Analyses
8.6.1
Efficacy results will be deemed to be statistically significant after consideration of the Type I 
error control strategy as described in Sections 8.7 and 8.8.
A brief summary of analysis 
 
 
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approaches for the primary and secondary efficacy endpoints are described in Table 7.
Nominal p-values will be computed for other efficacy analyses, but should be interpreted 
with caution due to potential issues of multiplicity.
Analysis of Primary Endpoint
The analysis of the primary efficacy endpoint will follow the intention-to treat principle and 
will be performed in the ITT population, comprised of subjects randomized. Subjects will be 
analyzed as randomized.  The analysis of the primary endpoint will be based on results from 
adjudication and will test if the time to the first occurrence of the composite endpoint is 
prolonged in the MK-1242 (vericiguat) treatment group. Randomized subjects without any 
HF hospitalization or CV death event at the time of analysis will be censored at their last 
available information or the date of their non-CV death. 
The analysis will be performed with a one-sided log-rank test, stratified by the same six strata
by region and race that are considered for randomization, testing the following null 
hypothesis:
H0: 
SVericiguat(t) = SPlacebo(t) 
for all time points t ≥ 0.
The alternative hypothesis will be:
      H1: 
SVericiguat(t) > SPlacebo(t) 
for at least one time point t ≥ 0 and
            SVericiguat(t) ≥ SPlacebo(t)
for all time points t ≥ 0.
SVericiguat denotes the (event-free) survival function of the vericiguat treatment group and 
SPlacebo denotes the (event free) survival function of the placebo treatment group. 
The overall study-wise one-sided type I error rate will be controlled at 0.025. The following 
decision rule to test the null hypothesis will be applied:
If the z-value from the one-sided stratified log-rank test (for the difference SVericiguat - SPlacebo)
is larger than the critical quantile from the standard normal distribution (z1-α , with α being 
the nominal significance level at the respective interim or final analysis), the null hypothesis 
will be rejected in favor of the alternative hypothesis.
Kaplan-Meier estimates of the primary composite endpoint (95% confidence interval) 
survival curves will be presented for each treatment group. Hazard ratio, relative risk 
reduction and corresponding 95% confidence intervals will be estimated based on a Cox 
proportional hazards model stratified by the same factors as used for the primary efficacy 
analysis.
The number and proportion of subjects with a CV death or HF hospitalization event will be 
provided by treatment group. In addition, rates per 100 patient-years will be provided.
Analysis of Secondary Endpoints  
Analogous to the analysis of the primary endpoint, the analysis of the secondary efficacy 
endpoints will be performed under the intention to treat principle. All subjects randomized 
will be included in the analysis. Subjects will be analyzed as randomized.
 
 
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A one-sided stratified log-rank test similar to the one used for the primary efficacy endpoint 
will be used to test if the time to first HF hospitalization, time to CV death, time to all-cause 
mortality, and time to first occurrence of the composite of all-cause mortality or HF 
hospitalization is prolonged in the vericiguat treatment group compared to placebo.
The time-to total HF hospitalization will be tested with an Andersen-Gill model [14] to 
compare the vericiguat treatment group to placebo. The Anderson-Gill model is an extension 
of the Cox proportional hazards model, where the hazard for the kth event, i.e. including both 
first and recurrent, for a subject i at time t, is given by
hik(t) = h0(t) exp(βTx), 
with h0(t) being the baseline hazard and x the vector of covariates for subject i.
Treatment 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 subject [15] [16].
The following null hypothesis will be compared with the alternative hypothesis:
H0:
HRVericiguat/Placebo = 1
H1:
HRVericiguat/Placebo < 1
Superiority of MK-1242 (vericiguat) over placebo in prolonging the time to total HF 
hospitalization will be concluded, if the upper limit of the confidence interval of the hazard 
ratio is below 1 with the confidence level matching the nominal alpha level used for testing at 
the interim or final analysis. Estimates of treatment comparisons and effect size including 
95% confidence intervals will be provided based on the fitted model. 
In addition, time to total HF hospitalizations and CV death will be analyzed using the Wei, 
Lin, Weissfeld (WLW) method [17], and details will appear in the supplemental SAP.
Missing Data
Subjects who prematurely withdraw from study treatment will be followed for further data 
collection. As long as the subject 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
up to the last safety phone call which occurs two weeks after the final study visit. Subjects 
are requested to attend the protocol specified study visits. If a subject does not attend the 
regular study visits, the investigator will contact the subject via telephone to collect at least 
data for the primary endpoint.
Due to this follow up approach, it is expected that the amount of missing data will be only 
minor, as most subjects will be followed up until trial termination.
For the primary analysis, subjects without any HF hospitalization or CV death event at the 
time of analysis will be censored at their last available information or the date of their non-
CV death. The censoring mechanism is assumed to be non-informative.
 
 
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Supportive analyses will be performed to assess the impact of a potential informative 
censoring and missing data, and details will be described in the supplemental statistical 
analysis plan.
Table 7
Primary Analysis Strategy for Efficacy Variables
Endpoint/Variable
Statistical Method†
Analysis 
Population
Missing Data 
Approach
Primary Hypothesis:
Time to first occurrence of the composite 
endpoint of CV death or HF 
hospitalization
Stratified Log-Rank 
Test
ITT
Censored at the 
last available 
information
Secondary Endpoints:
Time to the first occurrence of CV death 
Stratified Log-Rank 
Test
ITT
  
Censored at last 
known alive date
Time to the first occurrence of HF 
hospitalization 
Stratified Log-Rank 
Test
ITT
Censored at the 
last available 
information
Time to total HF hospitalizations 
(including the first and recurrent events)
Andersen-Gill model ‡
ITT
Censored at the 
last available 
information  
Time to first occurrence of the composite 
of all-cause mortality or HF 
hospitalization
Stratified Log-Rank 
Test
ITT
Censored at last 
available
information
Time to all-cause mortality
Stratified Log-Rank 
Test
ITT
Censored at last 
known alive date   
† Statistical 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.
‡ Treatment group and the stratification factors used for randomization will be included in the model as fixed 
effects.  
Statistical Methods for Safety Analyses
8.6.2
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse events (AEs), laboratory tests, and vital signs.
The analysis of safety results will follow a tiered approach (Table 8). The tiers differ with 
respect to the analyses that will be performed. Safety parameters or adverse events of special 
interest that are identified a priori constitute “Tier 1” safety endpoints that will be subject to 
inferential testing for statistical significance with p-values and 95% confidence intervals 
provided for between-group comparisons. Other safety parameters will be considered Tier 2 
or Tier 3. Tier 2 parameters will be assessed via point estimates with 95% confidence 
intervals provided for between-group comparisons; only point estimates by treatment group 
are provided for Tier 3 safety parameters. P-values (Tier 1 only) and 95% confidence 
intervals (Tier 1 and Tier 2) will be provided for between-treatment differences in the 
percentage of subjects with events; these analyses will be performed using the unstratified
Miettinen and Nurminen method.
Adverse events (specific terms as well as system organ class terms) and predefined limits of 
change in laboratory and vital signs that are not pre-specified as Tier-1 endpoints will be 
classified as belonging to "Tier 2" or "Tier 3", based on the number of events observed.  
 
 
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Membership in Tier 2 requires that at least 4 subjects in at least one treatment group exhibit 
the event; all other adverse events and predefined limits of change will belong to Tier 3.
The threshold of at least 4 events was chosen because the 95% confidence interval for the 
between-group difference in percent incidence will always include zero when treatment 
groups of equal size each have less than 4 events and thus would add little to the 
interpretation of potentially meaningful differences.  Because many 95% confidence intervals 
may be provided without adjustment for multiplicity, the confidence intervals should be 
regarded as a helpful descriptive measure to be used in review, not a formal method for 
assessing the statistical significance of the between-group differences in adverse events and 
predefined limits of change.
Continuous measures such as changes from baseline in laboratory and vital signs that are not 
pre-specified as Tier-1 endpoints will be considered Tier 3 safety parameters. Summary 
statistics for baseline, on-treatment, and change from baseline values will be provided by 
treatment group in table format. In addition, summary statistics for the difference between 
treatment groups will also be provided, along with nominal p-values for between-group 
differences. Mean change from baseline over time will be plotted with the corresponding 
standard errors.
Table 8
Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoint†
p-Value
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 1
• Syncope
• Symptomatic hypotension
X
X
X
Tier 2
Any AE
X
X
Any Serious AE
X
X
Any AE leading to death
X
X
Any Drug-Related AE
X
X
Any Serious and Drug-Related AE
X
X
Discontinuation due to AE
X
X
Specific AEs, SOCs, or PDLCs‡ (incidence ≥4 of 
subjects in one of the treatment groups)
X
X
Tier 3
Specific AEs, SOCs or PDLCs‡ (incidence <4 of 
subjects in all of the treatment groups)
X
Change from Baseline Results (Labs, Vital Signs)
X
†
Adverse Event references refer to both Clinical and Laboratory AEs.
‡
Includes only those endpoints not pre-specified as Tier 1 or not already pre-specified as Tier-2 endpoints.
Note: SOC=System Organ Class; PDLC=Pre-Defined Limit of Change; X = results will be provided.
Summaries of Baseline Characteristics, Demographics, and Other Analyses
8.6.3
The comparability of the treatment 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 subjects randomized and the primary reason 
 
 
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for discontinuation will be displayed.  Demographic variables (e.g., age) and baseline 
characteristics will be summarized by treatment either by descriptive statistics or categorical 
tables.
Interim Analysis
8.7
Futility Interim Analysis
8.7.1
A futility interim analysis to assess lack of efficacy is planned at the time when 
approximately 75% (587) of the planned number of CV death events are observed, and is 
projected to take place approximately 33 months after the start of the study.  The futility 
analysis, to be performed at the same time as the interim efficacy analysis (see Section 8.7.2, 
Efficacy Interim Analysis), will be performed with both the primary composite endpoint and 
CV death. 
The futility boundary will be based on the point estimate of hazard ratio 
(vericiguat/placebo). A point estimate of hazard ratio above 0.95 for the primary endpoint 
and a point estimate of hazard ratio above 1.0 for CV death, simultaneously, will be 
considered meeting the futility criteria.  Based on simulation analysis, the impact of this 
futility analysis approach on the overall study power is negligible.  Under the null hypothesis 
with true hazard ratio equal to 1 (no treatment effect) for CV death and for the primary 
endpoint, the probability of stopping the study for futility is approximately 47%.  If the true 
effect size is 20% (hazard ratio of 0.80) as projected for CV death and for the primary 
endpoint, the probability of stopping for futility is less than 0.1%.  An unblinded DSMB will 
assess the results of the futility interim analysis and may recommend early study termination 
for futility.
Efficacy Interim Analysis
8.7.2
An efficacy interim analysis is also planned at the same time of futility analysis when 
approximately 75% of the planned number of CV death events are observed.  Based on the 
assumptions from the sample size calculation, the interim analysis will take place 
approximately 33 months after start of the study, shortly after all subjects have been accrued.  
To ensure that the study has accumulated adequate follow up for safety assessment when 
stopped for positive efficacy results, the timing of the efficacy interim analysis should also 
ensure that the median follow up time is at least 10 months.  Under the assumption of an 11% 
12-month placebo event rate for CV death, the median follow-up time when 75% of CV 
death events have been observed is expected to be approximately 375 days.  Approximately 
51% of the subjects will have follow-up time of at least 12 months, 38% of at least 15 
months, and 26% of at least 18 months. The median treatment duration will be 340 days.  
If the observed CV death event rate is substantially higher than anticipated and thus median 
follow-up time is less than 10 month when 75% of the planned number of CV events has
occurred, the efficacy interim analysis will be delayed until 10 months of median follow up is 
achieved.  In this case, the futility analysis will also be delayed and will be performed at the 
same time as the interim efficacy analysis.  Under an extreme scenario of a much higher than 
anticipated event rate, the efficacy interim analysis may become unnecessary if the timing for 
the efficacy IA falls too close to the final analysis.  The decision to adjust the timing of the 
efficacy interim analysis or to cancel the efficacy interim analysis under a higher than 
expected event rate will be made by the blinded Sponsor team.
 
 
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At the efficacy interim analysis, the primary endpoint and the secondary endpoint of time to
CV death will be tested. The study can only be terminated early for success if both the 
primary endpoint and the CV death endpoint are statistically significant based on the pre-
specified interim analysis boundaries. The testing approach controls the overall alpha-level 
between the primary endpoint and CV death.
The Hwang, Shih and DeCani (γ=-6.5) alpha spending function will be used for the efficacy
interim analysis to assess superiority of MK-1242 (vericiguat). The spending function can be 
expressed as 
with t denoting the percentage of information included at the respective interim analysis. 
With this alpha spending approach, the nominal significance level will be approximately 
0.0049 (one-sided) at the interim analysis and 0.0242 at the final analysis, respectively.  This 
testing approach controls the one-sided alpha between the efficacy interim analysis and final 
analysis at 0.025.  The corresponding observed hazard ratio for the stopping boundary is 
approximately 0.81 for CV death at the efficacy interim analysis.  
The actual α to be spent at the efficacy interim analysis and final analysis will be precisely 
determined using the number of actually observed primary outcome events and the alpha 
spending function defined as above.
At the time of the interim analysis, approximately 587 CV death events and approximately 
1171 (may vary depending on the actual event rate) primary endpoint events are expected. A 
one-sided stratified log-rank test will be used to assess if vericiguat prolongs the time to 
primary composite endpoint event compared with placebo. The same nominal significance 
level as used for the primary composite endpoint will also be used for the analysis of the CV 
death component.
If the study can be stopped early for success, the nominal one-sided significance level of 
approximately 0.0049 for the primary endpoint and CV death will be applied to other
secondary endpoints as well.
If the study cannot be stopped early for success, the CV death component will be analyzed at 
the final analysis time point as one of the secondary endpoints. 
An unblinded DSMB will assess the results of the interim analysis and may recommend early 
study termination if the interim analysis shows clear and consistent benefit of vericiguat as 
guided by the above described alpha-spending approach.
If the DSMB recommendation leads to termination of the study at the interim analysis due to 
efficacy, all subjects will be called in to their final visit. The complete analysis will be based 
on the entire data collected until the study completion, i.e. it will also include data collected 
after the cut-off for the interim analysis.
 
 
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Table 9 summarizes the timing, number of events, endpoint, and the efficacy and futility 
bounds at each of the interim analysis and at the final analysis.
Table 9
Summaries of the Interim and Final Analyses
Analysis
Key Endpoint(s)
Target Number of Events
Anticipated 
Time From 
Study Start
Statistical Testing Criteria
Futility Interim 
Analysis
Primary Endpoint
Time to CV Death
587 CV Death† (75% of 
planned number of events)
Month 33†
A point estimate of HR>0.95 for 
the primary endpoint and a point 
estimate of HR>1.0 for CV 
death for futility
Efficacy Interim 
Analysis
Primary Endpoint, 
Time to CV Death
587 CV Deaths† (75% of 
planned number of events)
Month 33†
P<0.0049 (one-sided) on both 
endpoints for efficacy, 
corresponding to an observed 
HR<0.81 for Time to CV Death
Final Analysis
Primary Endpoint, 
Secondary Endpoints
782 CV deaths†
Month 39†
P<0.0242 (one-sided) for 
statistical significance, using the 
pre-specified multiplicity 
adjustment approach (Section 
8.8)
†Median follow up time of 10 months are also required.
Multiplicity Adjustment
8.8
The study-wise one-sided alpha level will be controlled at 0.025 for the test of the primary 
endpoint.  Multiplicity due to the interim analysis at 75% of planned CV death events will be 
controlled using a Hwang, Shih and DeCani (γ=-6.5) alpha spending function as described in 
section 8.7.
The secondary endpoints will be separated into two families. The first family consists of the 
components of the primary endpoint, time to CV death and time to first HF hospitalization.
The second family will consist of the endpoints of time to total HF hospitalization, time to 
all-cause mortality, and time to first occurrence of composite of HF hospitalization or all-
cause mortality. The endpoints from the second family will be tested hierarchically and at 
the same time be adjusted for the interim analysis, thereby maintaining the study-wise alpha 
level.  These secondary endpoints will only be tested if both the primary composite endpoint 
and CV death are significant at the interim analysis, or if the primary composite endpoint 
alone is significant at the final analysis. Total HF hospitalization will be tested first, and only 
if this is significant, the composite of all-cause mortality and HF hospitalization will be 
tested afterwards.  All-cause mortality will be tested only if both of the above endpoints are 
tested significant (see Figure 2 for the procedure at the final analysis).
At the interim analysis, if the study is stopped early for efficacy due to success on the 
primary composite endpoint and separately the CV death component, then the HF 
hospitalization component will be tested at the same alpha level as the CV death component.  
In addition, the family of secondary endpoints will be tested in a sequential manner using the 
same alpha as the primary composite endpoint.
 
 
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Figure 2
Testing of Primary and Secondary Endpoints
Determination of Sample Size
8.9
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 interim analysis, the nominal 
one-sided significance level will be 0.0242 at the final analysis.  A conservative approach of 
power calculation based only on the final analysis is used.  
The study will be an event-driven study. It is planned to accrue subjects during 30 months 
and have a follow-up of 9 months after the last subject is included in the study. This leads to 
total study duration of 39 months. It is assumed that setting up of all sites will take 
approximately 12 months, assuming a quadratic ramp-up function for subject accrual.
The primary analysis will be performed in the ITT population. Every effort will be made to 
follow-up subjects that prematurely stop study medication to collect at least information for 
the primary endpoint (i.e. information on hospitalizations and death). 
It is assumed that 2% of subjects per year will prematurely stop study medication and either 
object to further follow-up or be lost to follow-up, despite efforts to contact them. In 
addition, it is assumed that approximately 10% per year of subjects will stop study treatment 
and can be followed up off treatment for the primary endpoint. When a subject in the 
placebo group stops treatment prematurely, it is assumed that the hazard for CV death and 
HF hospitalization does not change, as the subject is expected to continue with standard heart 
failure therapy. For vericiguat subjects stopping treatment prematurely, it is assumed that 
they switch to the hazard of the placebo group, as they henceforth will switch back to 
 
 
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standard heart failure therapy. These effects will dilute the observed treatment effect when 
the ITT analysis approach is used. The sample size calculations are adjusted for this dilution.
The sample size calculation is driven by the CV death component of the composite primary 
endpoint. For the CV death component, the expected event rate in the comparator group 
after 12 months is 11%.  The relative risk reduction with vericiguat is assumed to be 20%, 
relating to a HR of 0.8. Using the log-rank test, a sample size of 4872 subjects and a total of 
782 CEC confirmed CV deaths will be required to achieve 80% power. 
For the comparator arm, the event rate of the composite endpoint, i.e. first HF hospitalization 
or CV death, is expected to be 23% after 12 months. The relative risk reduction with 
vericiguat is assumed to be 20%, relating to a HR of 0.8. With a sample size of 4872
subjects, it is expected to observe 1561 subjects with a composite endpoint event and 
expected power of approximately 98%. The time point of final analysis will be based on the 
number of CV deaths, and the total number of subjects 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 times) is expected to be approximately 532 days. Approximately 74% of the 
subjects will have follow up time of at least 12 months, 60% of at least 15 months, and 47% 
of at least 18 months. The median treatment duration will be approximately 480 days.
If the CV death event rate is much higher than anticipated such that the median follow up 
time is less than 10 months when 782 CV death events have been observed, the study will 
continue until a median follow up time of 10 months has been achieved. 
Expected event rate and relative risk reduction 
The assumed comparator event rates refer to the placebo arm of the ASTRONAUT study 
population with stabilized worsening chronic HFrEF on standard therapy for HFrEF.  The 
event rate of these patients with worsening chronic HFrEF requiring hospitalization is 
extrapolated to those receiving IV diuretic treatment for worsening HF because outpatient 
management of worsening HF was reported to portend a similarly high risk of death 
compared to inpatient HF events, and may be equally sensitive to the effects of therapy [5].
The estimated annual event rate for the primary endpoint and for CV mortality in the control 
(standard of care) arm was based on the ASTRONAUT study in patients with stabilized 
worsening chronic HFrEF on standard HF therapy that was conducted between 2009 and 
2012 [7]. Both trials recruit from similar geographic regions (North America, Latin America, 
Eastern Europe, Western Europe, and Asia/Pacific).  In the ASTRONAUT trial, Asia/Pacific 
had the greatest representation with 32% of the trial population. Otherwise there was a fairly 
equal distribution across the regions, and the intent in VICTORIA is also to have equal 
distribution across regions. Other key differences in the ASTRONAUT patient population 
include a lower LVEF cutpoint (≤40%), the lack of atrial fibrillation-specific natriuretic 
peptide cutpoints, the lack of inclusion of IV diuretic use without hospitalization as an 
enrichment criteria, and the lack of sacubitril/valsartan as a background standard of care
therapy.  The rate of a first event of either CV death or HF hospitalization was 37% at 12 
months, and 17% for CV mortality as single endpoint [7].
 
 
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Because the timeframe for inclusion will be 6 months in the planned study, opposed to 
inclusion within a median of 5 days after stabilization after hospitalization for an acute HF 
decompensation in ASTRONAUT [7], a more conservative expected annual event rate of 
11% CV mortality and 23% annual event rate for the composite of CV death and HF 
hospitalization is chosen for sample size calculation.  Since elevated levels of NT-proBNP 
are mandated by the protocol as a second enrichment factor in addition to the initial 
decompensation, and since event rates in patients enrolled after the median time after CV 
hospitalization in EMPHASIS-HF (83.4 % patients had been previously hospitalized for CV 
reasons within 6 months of the study, with ≈50 % of them hospitalized because of HF [18] 
[19] were only slightly lower than those in patients enrolled before the median, no greater 
reduction in assumed event rates is estimated. 
We consider a 20% relative risk ratio (RRR), corresponding to a hazard ratio of 0.8, in the 
primary composite of CV death and HF hospitalization as a clinically relevant treatment 
effect in the planned high-risk population.  With an assumed annual event rate of 23%, the 
absolute reduction by 4.6 percentage points results in a number needed to treat (NNT) of 22 
to prevent 1 event per year. A 20% RRR in in CV mortality is considered as clinically 
relevant treatment effect.  With an assumed annual event rate of 11%, the absolute reduction 
of 2.2 percentage points results in a NNT of 45 to prevent one CV death per year.
Subgroup Analyses and Effect of Baseline Factors
8.10
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 subjects: 

Age (<65 years vs. ≥65 years)

Sex (Female vs. Male)

Geographic region (Eastern Europe / Western Europe / North America / Latin and 
South America / Asia Pacific) 

Index event (IV diuretic within 3 months of randomization / Hospitalization within 3 
months of randomization / Hospitalization 3 to 6 months prior to randomization)

eGFR at randomization (between 15 and 30 mL/min/1.73 m 2 vs. above 30 
mL/min/1.73 m2)

NYHA class at baseline (II/III/IV)

Use of sacubitril/valsartan at baseline 

Baseline NT-pro BNP (by Quartiles)

Baseline ejection fraction (<35% vs. ≥35%)

Race (Caucasian / Black / Asian / Other) 

Race in North America only (Black vs. Non-black) 
In addition to the above subgroup analyses by baseline factors, if it is observed or anticipated 
that the background standard care treatment evolves over time during the course of the study, 
 
 
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analysis to assess the consistency of the treatment effect of MK-1242 under different
background therapies will be performed.  Details of the analysis approach will be pre-
specified in the supplemental Statistical Analysis Plan (sSAP). 
Compliance (Medication Adherence)
8.11
Compliance for study treatment will be collected during the study as described in 7.1.1.8. 
Deviation from protocol-directed administration will be summarized at the end of the study. 
Extent of Exposure
8.12
The extent of exposure will be summarized as the duration of study treatment. Furthermore, 
exposure summary based on dosage and dose titration will also be provided.
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
9.1
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 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 10.
Clinical supplies will be packaged to support enrollment and replacement subjects as 
required.  When a replacement subject is required, the Sponsor or designee needs to be 
contacted prior to dosing the replacement supplies.
Table 10
Product Descriptions
Product Name & Potency
Dosage Form
MK-1242 2.5 mg
Tablet
MK-1242 5 mg
Tablet
MK-1242 10 mg
Tablet
MK-1242 2.5 mg Placebo
Tablet
MK-1242 5 mg Placebo
Tablet
MK-1242 10 mg Placebo
Tablet
All placebos were created by the Sponsor to match the active product.
Packaging and Labeling Information
9.2
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
 
 
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Subjects will receive blinded bottles. No kitting is required.
Clinical Supplies Disclosure
9.3
The emergency unblinding call center will use the treatment/randomization schedule for the 
study to unblind subjects and to unmask study treatment identity. The emergency unblinding 
call center should only be used in cases of emergency (see Section 7.1.4.2). In the event that 
the emergency unblinding call center is not available for a given site in this study, the central 
electronic treatment allocation/randomization system (IVRS/IWRS) should be used in order 
to unblind subjects and to unmask study treatment identity. The Sponsor will not provide 
random code/disclosure envelopes or lists with the clinical supplies.
Treatment identification information is to be unmasked ONLY if necessary for the welfare of 
the subject.  Every effort should be made not to unblind the subject unless necessary. 
In the event that unblinding has occurred, the circumstances around the unblinding (e.g., 
date, reason and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible.  Only the principal investigator or 
delegate and the respective subject’s code should be unblinded.  Trial site personnel and 
Sponsor personnel directly associated with the conduct of the trial should not be unblinded to 
treatment assignment. Subjects whose treatment assignment has been unblinded (by the 
investigator, Merck subsidiary, or through the emergency unblinding call center) must be 
discontinued from study drug.
Section 5.8 outlines the criteria for allowing subjects who are discontinued from treatment to 
continue to be monitored in the trial.
Storage and Handling Requirements
9.4
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
Discard/Destruction/Returns and Reconciliation
9.5
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. For all trial 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.
Standard Policies
9.6
Trial 
site 
personnel 
will 
have 
access 
to 
a 
central 
electronic 
treatment 
allocation/randomization system (IVRS/IWRS system) to allocate subjects, to assign 
 
 
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treatment to subjects and to manage the distribution of clinical supplies. Each person 
accessing the IVRS system must be assigned an individual unique PIN.  They must use only 
their assigned PIN to access the system, and they must not share their assigned PIN with 
anyone.
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
10.1
Confidentiality of Data
10.1.1
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 institutional review board, ethics review committee (IRB/ERC) 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 trial 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.
Confidentiality of Subject Records
10.1.2
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.
Confidentiality of Investigator Information
10.1.3
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
 
 
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Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
10.1.4
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this trial.  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.
Compliance with Financial Disclosure Requirements
10.2
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 
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, commonly 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.
Compliance with Law, Audit and Debarment
10.3
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
 
 
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The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial 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 as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
 
 
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ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the CI during the 
anticipated review process, thorough understanding of clinical trial methods, appropriate 
enrollment of subject cohort, timely achievement of trial milestones).  The Protocol CI must 
be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
10.4
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007, 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the 
Sponsor of the trial is solely responsible for determining whether the trial and its results are 
subject 
to 
the 
requirements 
for 
submission 
to 
http://www.clinicaltrials.gov, 
www.clinicaltrialregister.eu or other local registries. Merck, as Sponsor of this trial, will 
review 
this 
protocol 
and 
submit 
the 
information 
necessary 
to 
fulfill 
these 
requirements. Merck entries are not limited to FDAAA or the EMA clinical trials directive 
mandated trials. Information posted will allow subjects to identify potentially appropriate 
trials for their disease conditions and pursue participation by calling a central contact number 
for further information on appropriate trial locations and trial site contact information.   
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
 
 
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Sponsor and agrees not to submit any information about this trial or its results to those 
registries.
Quality Management System
10.5
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
Data Management
10.6
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
Publications
10.7
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
 
 
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are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
 
 
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11.0 LIST OF REFERENCES
[1]
Ambrosy AP, Fonarow GC, Butler J, Chioncel O, Greene SJ, Vaduganathan M, 
et al. The global health and economic burden of hospitalizations for heart 
failure: lessons learned from hospitalized heart failure registries. J Am Coll 
Cardiol. 2014 Apr 1;63(12):1123-33.
[2]
Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, et al. 
Heart disease and stroke statistics-2014 update: a report from the American 
Heart Association. Circulation. 2014 Jan 21;129(3):e28-e292.
[3]
McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Bohm M, Dickstein K, 
et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart 
failure 2012: The Task Force for the Diagnosis and Treatment of Acute and 
Chronic Heart Failure 2012 of the European Society of Cardiology. Developed 
in collaboration with the Heart Failure Association (HFA) of the ESC. Eur 
Heart J. 2012 Jul;33(14):1787-847.
[4]
Sharma K, Kass DA. Heart failure with preserved ejection fraction: 
mechanisms, clinical features, and therapies. Circ Res. 2014 Jun 20;115(1):79-
96.
[5]
Skali H, Dwyer EM, Goldstein R, Haigney M, Krone R, Kukin M, et al. 
Prognosis and response to therapy of first inpatient and outpatient heart failure 
event in a heart failure clinical trial: MADIT-CRT. Eur J Heart Fail. 2014 
May;16(5):560-5.
[6]
Butler J, Braunwald E, Gheorghiade M. Recognizing worsening chronic heart 
failure as an entity and an end point in clinical trials. JAMA. 2014 Aug 
27;312(8):789-90.
[7]
Gheorghiade M, Bohm M, Greene SJ, Fonarow GC, Lewis EF, Zannad F, et al. 
Effect of aliskiren on postdischarge mortality and heart failure readmissions 
among patients hospitalized for heart failure: the ASTRONAUT randomized 
trial. JAMA. 2013 Mar 20;309(11):1125-35.
[8]
WRITING COMMITTEE MEMBERS, Yancy CW, Jessup M, Bozkurt B, 
Butler J, Casey DE Jr, et al. 2013 ACCF/AHA guideline for the management of 
heart 
failure: 
a 
report 
of 
the 
American 
College 
of 
Cardiology 
Foundation/American Heart Association Task Force on practice guidelines. 
Circulation. 2013 Oct 15;128(16):e240-327.
[9]
McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, et al. 
Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J 
Med. 2014 Sep 11;371(11):993-1004.
[10]
Gheorghiade M, Marti CN, Sabbah HN, Roessig L, Greene SJ, Bohm M, et al. 
Soluble guanylate cyclase: a potential therapeutic target for heart failure. Heart 
Fail Rev. 2013 Mar;18(2):123-34.
 
 
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[11]
Pieske B, Butler J, Filippatos G, Lam C, Maggioni AP, Ponikowski P, et al. 
Rationale and design of the SOluble guanylate Cyclase stimulatoR in heArT 
failurE Studies (SOCRATES). Eur J Heart Fail. 2014 Sep;16(9):1026-38.
[12]
Gheorghiade M, Greene SJ, Butler J, Filippatos G, Lam CS, Maggioni AP, et 
al. Effect of Vericiguat, a Soluble Guanylate Cyclase Stimulator, on Natriuretic 
Peptide Levels in Patients With Worsening Chronic Heart Failure and Reduced 
Ejection Fraction: The SOCRATES-REDUCED Randomized Trial. JAMA. 
2015 Dec 1;314(21):2251-62.
[13]
European Medicines Agency. Concept paper on the need for revision of note for 
guidance on clinical investigation of medicinal products for the treatment of cardiac 
failure [Internet]. London: European Medicines Agency; 2013. Available from: 
www.ema.europa.eu/ema/pages/includes/document/open_document.jsp?webContent
Id=WC500139480/.
[14]
Andersen PK, Gill RD. Cox's regression model for counting processes: a large 
sample study. Ann Stat. 1982;10:1100–1120.
[15]
Joffe SW, Dewolf M, Shih J, McManus DD, Spencer FA, Lessard D, et al. 
Trends in the medical management of patients with heart failure. J Clin Med 
Res. 2013 Jun;5(3):194-204.
[16]
Greene SJ, Gheorghiade M, Borlaug BA, Pieske B, Vaduganathan M, Burnett 
JC Jr, et al. The cGMP signaling pathway as a therapeutic target in heart failure 
with preserved ejection fraction. J Am Heart Assoc. 2013 Dec 11;2(6):e000536.
[17]
Wei LJ, Lin DY, Weissfeld L. Regression analysis of multivariate incomplete 
failure time data by modeling marginal distributions. J Am Stat Assoc 
1989;84(408):1065-73.
[18]
Dhillon S. Eplerenone: a review of its use in patients with chronic systolic heart 
failure and mild symptoms. Drugs. 2013 Sep;73(13):1451-62.
[19]
Heart Failure Society of America, Lindenfeld J, Albert NM, Boehmer JP, 
Collins SP, et al. HFSA 2010 comprehensive heart failure practice guideline. J 
Card Fail. 2010 Jun;16(6):e1-2.
 
 
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12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
12.1
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of subject safety is the overriding concern in 
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the 
party (parties) employed for their execution (e.g., contract research organizations, collaborative research efforts). This 
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
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 Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  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 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. 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.  Merck funding of a trial will be acknowledged in publications. 
 
 
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III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC 
approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects 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.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a Merck trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible. Unless required by law, 
only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.   Merck does not pay incentives to 
enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may be made
to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
 
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Collection and Management of Specimens for Future Biomedical Research
12.2
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 Research
The specimens collected in this trial as outlined in Section 7.1.3.5 – Future Biomedical 
Research Sample Collection will be used to study various causes for how subjects may 
respond to a drug/vaccine.  Future biomedical research specimen(s) will be stored to 
provide a resource for future trials conducted by the Sponsor focused on the study of 
biomarkers responsible for how a drug/vaccine enters and is removed by the body, how a 
drug/vaccine works, other pathways a drug/vaccine may interact with, or other aspects 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 Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in the 
Future Biomedical Research sub-trial.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all subjects or legal guardians, at a trial 
visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the subjects on Visit 1.  If delayed, 
present consent at next possible Subject Visit. Informed consent must be obtained 
prior to collection of all Future Biomedical Research specimens.  Consent forms 
signed by the subject will be kept at the clinical trial site under secure storage for 
regulatory reasons.  
 
 
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A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository. Each consent will be assessed for appropriate 
specimen permissions.  
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of subject consent for Future Biomedical Research will be captured in 
the electronic Case Report Forms (eCRFs). Any specimens for which such an 
informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen Collections
Collection of specimens for Future Biomedical Research will be performed as 
outlined in the trial flow chart. In general, if additional blood specimens are being 
collected for Future Biomedical Research, these will usually be obtained at a time 
when the subject is having blood drawn for other trial purposes.
4. Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are 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 trial site, unique codes will be placed on the Future Biomedical Research 
specimens for transfer to the storage facility.  This first code is a random number which 
does not contain any personally identifying information embedded within it. The link (or 
key) between subject identifiers and this first unique code will be held at the trial site.  No 
personal identifiers will appear on the specimen tube.  
5. Biorepository Specimen Usage
Specimens obtained for the Merck Biorepository will be used for analyses using good 
scientific practices.  Analyses utilizing the Future Biomedical Research specimens may 
be performed by the Sponsor, or an additional third party (e.g., 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 this sub-trial. 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 Research 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial. If medical records for the main 
trial are still available, the investigator will contact the Sponsor using the designated 
 
 
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mailbox (clinical.specimen.management@merck.com) and a form will be provided to 
obtain appropriate information to complete specimen withdrawal. Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. 
Documentation will be sent to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for specimen destruction can not be processed. 
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main 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 trial site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
trial, the trial 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 Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated trial 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 (e.g., ISO17799) to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Subjects
No information obtained from exploratory laboratory studies will be reported to the 
subject, family, or physicians. Principle reasons not to inform or return results to the 
subject include: Lack of relevance to subject health, limitations of predictive capability, 
and concerns regarding misinterpretation.
If any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information. 
After the clinical trial has completed, if any exploratory results are definitively associated 
with clinical significance, the Sponsor will endeavor to make such results available 
 
 
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through appropriate mechanisms (e.g., scientific publications and/or presentations). 
Subjects 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 Population
Every effort will be made to recruit all subjects diagnosed and treated on Sponsor clinical 
trials for Future Biomedical Research.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized. No additional 
risks to the subject have been identified as no additional specimens are being collected 
for Future Biomedical Research (i.e., only leftover samples are being retained).
The Sponsor has developed strict security, policies and procedures to address subject 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 e-mailed directly to 
clinical.specimen.management@merck.com.
13. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
-
E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
 
 
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Pharmacogenetics Informational Brochure for IRBs/IECs & Investigational Site Staff
12.3
 
 
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Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and by 
12.4
Sample Types
Trial Visit/
Cycle/etc:
Screen-
ing Visit 
Rand 
Visits 2
Treatment 
Visit 5
Week 16
Treatment
Visit 6
Week 32
Treatment 
Visits 7 Week 
48 and Yearly 
Visits
Every 16 
week 
visits
Discon
Visit 
Safety 
Follow-up 
Visit
Final 
Visit 
Blood 
Parameter 
Approximate Blood Volume (mL)
Hematology
2
2
2
2
2
2
2c
Serum/Plasma 
Chemistry 
(including liver 
function tests)
6
6
6
6
6
6
6c
Serum β-Human 
Chorionic 
Gonadotropin 
(β-hCG)a
Included 
with the 
Chemistry 
Sample
Included with 
the Chemistry 
Sample
Included with 
the 
Chemistry 
Sample
Included with 
the Chemistry 
Sample
2
NT-proBNP
2
2
2
2
2
2c
Local 
NT-
proBNP/BNP
2
Local Creatinine
2
Hemoglobin 
A1cb
2
2
2
2
2
2c
Blood for 
Planned Genetic 
Analysis 
8.5
Pharmacokinetic 
Sample
6
6
6
6
6c
Blood for  
Biomarkers
12
12
12
12
12c
Expected Total 
(mL)
4
38.5
30
24
18
2
30
8
30
a.
For female subjects of child bearing potential only.  
b.
Sample obtained in subjects with diabetes mellitus only.
c.
Not applicable for subjects who prematurely discontinue.
 
 
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Blood Pressure Measurement Guidance 
12.5
Accurate measurement of blood pressure is essential to guide dose titration management and 
to detect potential safety signals during the trial. 
A number of factors related to the subject can cause significant deviations in measured blood 
pressure. These include room temperature, exercise, alcohol or nicotine consumption, 
positioning of the arm, muscle tension, bladder distension, talking, and background noise.
Blood Pressure and Pulse Rate should be measured under the following conditions: 
o
Measurement of Pulse Rate and Blood Pressure must be conducted after 10 
minute resting period with subject comfortably seated in a chair with the legs 
uncrossed and the back and arm supported.  Measurements should not be made 
while the subject is on an examining table.  The subject should be instructed to 
relax as much as possible and to not talk during the measurement procedure
o
The examiner should ensure that the middle of the cuff on the upper arm is at the 
level of the right atrium (the mid-point of the sternum).
o
The subject should be asked to remove all clothing that covers the location of cuff 
placement.
o
The same examiner should assess the subject at all subsequent visits and use the
same device under same external conditions.
o
The protocol requires 3 measurements – approximately 2 min apart. Please 
record the time, positioning and arm used for each measurement
 
 
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List of Abbreviations 
12.6
Abbreviation
Meaning
ACCF
American College of Cardiology Foundation
ACE
Angiotensin Converting Enzyme
AE
Adverse Event
AHA
American Heart Association
ALT 
Alanine aminotransferase
AST
Aspartate aminotransferase
ARB
Angiotensin Receptor Blocker
ARO 
Academic Research Organization
BNP
Brain Natriuretic Peptide
BUN
Blood Urea Nitrogen
CABG
Coronary Artery Bypass Grafting
CCSA
Canadian 
Cardiovascular 
Society 
Functional 
Classification of Angina
CEC
Clinical Events Committee
cGMP 
cyclic Guanosine Monophosphate
CI
Confidence Interval
CMR
Cardiac Magnetic Resonance 
CRT
Cardiac Resynchronization Therapy
CVC 
Canadian VIGOUR Centre
CV
Cardiovascular
DCRI
Duke Clinical Research Institute
DSMB 
Data Safety Monitoring Board
ECI
Events of Clinical Interest
eCRF 
electronic Case Report Form
eGFR
estimated Glomerular Filtration Rate
EQ-5D
EuroQol Group 5-Dimensional
ESC
European Society of Cardiology
GCP
Good Clinical Practice
HEOR
Health Economics Outcomes Research
HFpEF 
Heart Failure with preserved Ejection Fraction
HF
Heart failure
HFrEF 
Heart Failure with reduced Ejection Fraction
HR
Hazard Ratio
IB
Investigator’s Brochure
ICD 
Implantable Cardioverter-Defibrillators
ICF
Informed Consent Form
KCCQ
Kansas City Cardiomyopathy Questionnaire
LVEF 
Left Ventricular Ejection Fraction
MDRD
Modification of Diet in Renal Disease
MRA
Mineralocorticoid Receptor Antagonist
NNT
Number Needed to Treat
NO 
Nitric Oxide
NTG
Nitroglycerin
NT-proBNP 
N-terminal pro-Brain Natriuretic Peptide
NYHA 
New York Heart Association
PDE5 
Phosphodiesterase type 5
RRR
Relative Risk Ratio
SAE 
Serious Adverse Event
SBP
Systolic Blood Pressure
 
 
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05DNY5

Product:  MK-1242 (vericiguat)
108
Protocol/Amendment No.: 001-04 
MK-1242-001-04 Final Protocol
20-Dec-2017
Confidential
Abbreviation
Meaning
sGC 
soluble Guanylate Cyclase
SoC
Standard of Care
TIA
Transient Ischemic Attack
 
 
04TC79
 
 
05DNY5

Product:  MK-1242 (vericiguat)
109
Protocol/Amendment No.: 001-04 
MK-1242-001-04 Final Protocol
20-Dec-2017
Confidential
13.0 SIGNATURES
Sponsor's Representative
13.1
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
13.2
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0 – TRIAL PROCEDURES (Assessing and Recording Adverse 
Events).  I also agree to handle all clinical supplies provided by the Sponsor and collect and 
handle all clinical specimens in accordance with the protocol.  I understand that information 
that identifies me will be used and disclosed as described in the protocol, and that such 
information may be transferred to countries that do not have laws protecting such 
information.  Since the information in this protocol and the referenced Investigator’s 
Brochure is confidential, I understand that its disclosure to any third parties, other than those 
involved in approval, supervision, or conduct of the trial is prohibited.  I will ensure that the 
necessary precautions are taken to protect such information from loss, inadvertent disclosure 
or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
 
 
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05DNY5