The Effect of Vericiguat on Peripheral Vascular Function, Patient Health Status and Inflammation in Patients With Heart Failure With Reduced Ejection Fraction
Phase: PHASE4
Conditions: Heart Failure, Heart Failure With Reduced Ejection Fraction (HFrEF)
Sponsor: Josef Stehlik

 
 
The Effect of Vericiguat on Peripheral Vascular Function, Patient Health Status and 
Inﬂammation in Patients with Heart Failure with Reduced Ejection Fraction 
 
NCT05420012 
 
Document Type: Study Protocol and Statistical Analysis Plan 
 
Document Date: 5/29/2025 

Protocol Summary (ERICA) 
IRB_00152530 
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The Effect of Vericiguat on Peripheral Vascular Function, 
Patient Health Status and Inflammation in Patients with 
Heart Failure with Reduced Ejection Fraction. 
Protocol Summary 
IRB Approval 
Date of 
Current 
Version: 
5/29/2025 
University of 
Utah IRB #: 
IRB_00152530 
Sponsor: MERCK SHARP & DOHME LLC 
Principal 
Investigator: 
Josef Stehlik 
Internal Staff 
and  Sub-
Investigators: 
Site Name 
Staff Names 
University of Utah 
Josef Stehlik 
Haley McDougal 
John Kirk 
Tom Greene 
Stavros Drakos 
Emma Braun 
Arthur Chen 
Line Kemeyou 
Thomas Hanff 
Konstantinos Sideris 
Zachary Roylance 
Habeeb Mohammad 
Lina Brinker 
Veterans Affairs SLC Health Care 
System (VAMC) 
Josef Stehlik 
David Wray 
Haley McDougal 
Kanokwan Bunsawat 
Jarred Iacovelli 
Jia Zhao 
Jeremy Alpenglow 

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Thomas Hanff 
 
Konstantinos Sideris 
 
Zachary Roylance 
 
Lina Brinker 
 
This document was created using the ERICA Online System at the University of Utah. The document is created 
from study information approved by the IRB on the date listed above.  Any alteration to the original content of this 
document may not be considered to represent the study as approved by the IRB.  
 
 

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Background and Introduction 
 
 
The incidence of heart failure (HF) continues to increase, along with its associated morbidity, 
mortality, and cost. Novel therapeutic options have been proposed to address the needs of especially 
the patients who remain symptomatic despite optimal medical therapy. A number of factors lead to 
ongoing symptoms in patients with chronic heart failure (HF), including persistent abnormalities in 
myocardial function, neurohormonal dysregulation, and of the peripheral vascular system.  
 
The Phase 3 VICTORIA trial examined the efficacy of Vericiguat, a novel oral soluble guanylate 
cyclase (sGC) stimulator in patients with HF and reduced ejection fraction (HFrEF). Vericiguat 
enhances the cyclic guanosine monophosphate (GMP) pathway by directly stimulating soluble 
guanylate cyclase independent of nitric oxide (NO). The VICTORIA study showed that patients who 
received Vericiguat 2.5 mg once daily up-titrated to 10 mg daily had a lower incidence of the primary 
endpoint of cardiovascular death or first HF hospitalization compared to placebo.  
 
Determining the exact mechanism, or the respective contribution of different mechanisms, through 
which Vericiguat improves outcomes in HFrEF may allow for better tailoring of its use to individual 
patients. The preliminary results of an echocardiography sub-study indicate that there was no 
significant difference in the change of left ventricular ejection fraction (LVEF) between baseline and 
study end among patients assigned to the active drug vs placebo. We hypothesize that the beneficial 
effects of Vericiguat in HF may not be linked to improvement in myocardial contractility, but rather to 
the effects of cGC stimulation on the peripheral vasculature. This was not directly tested in 
VICTORIA. 
 
Studies from our group and others have collectively identified a marked reduction in vascular function, 
as determined by flow-mediated vasodilation (FMD) testing, in patients with HFrEF despite optimized 
pharmacotherapy, indicative of a pervasive, disease-related reduction in endothelial health. Endothelial 
dysfunction is characterized by NO dysregulation, inflammation, and oxidative stress. These factors 
impair the capacity of the vascular endothelium to perform its numerous functions including regulation 
of vascular tone and inflammatory processes. Importantly, endothelial dysfunction is also associated 
with reduced quality of life and  decreased physical capacity in patients with HFrEF. These 
studies suggest that the consequences of vascular dysfunction are far-reaching and support the concept 
that interventions targeting the peripheral vasculature to induce systemic effects could prove beneficial 
in cardiovascular disease. This is particularly relevant given the known relationship between 
endothelial dysfunction and mortality risk in patients with HFrEF. Improvement in peripheral vascular 
function in patients with HFrEF would in turn lead to improved physical capacity and health-related 
quality of life (hrQOL).  
 

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Preclinical studies provide evidence of cGC stimulation favorably affecting peripheral vascular 
function. In a rat model of HF, treatment with Ataciguat normalized endothelial function, improved 
sensitivity to NO, and reduced platelet activation. However, the impact of Vericiguat on vascular 
health has not been evaluated in human HF. A recent study also examined the effect of Vericiguat on 
inflammation and oxidative stress in HF. After 12 weeks of Vericiguat therapy, high sensitivity CRP 
(hsCRP) decreased significantly, and the probability of hsCRP value being ≤3.0 mg/L at the end of the 
study was higher in patients treated with Vericiguat compared to placebo. Although the impact of 
Vericiguat on upstream, pro-inflammatory cytokines such as IL-1β and IL-18 have not been 
determined, there is strong evidence supporting elevation of these biomarkers that reflect NRLP3 
inflammasome activation in patients with HFrEF. Given the recent success in clinical trials targeting 
the inflammasome in heart failure and recent evidence for the efficacy of sGC stimulation to mitigate 
NLRP3 inflammasome activity in other organ systems, there is strong rationale for the expectation that 
Vericiguat may favorably impact both upstream (IL-1β, IL-18, and IL-6) and downstream (hsCRP) 
proinflammatory biomarkers. Importantly, an inverse correlation between biomarkers of inflammation 
and endothelial function has been observed in other patient groups, supporting the concept that 
Vericiguat treatment may result in greater improvements in vascular function in those individuals who 
experience the largest reductions in vascular inflammation.  
 
Summary. 
This background provides clear rationale in support of the concept that direct stimulation of sGC could 
be a particularly effective approach to increase cGMP in conditions of increased 
inflammation/oxidative stress, endothelial dysfunction and reduced NO bioavailability. Thus, the aim 
of the proposed study is to examine the effect of Vericiguat on peripheral vascular function, 
inflammatory status, and patient health status. We also aim to identify patients who are particularly 
likely to benefit from Vericiguat treatment and predict that that these patients will be defined by 
baseline peripheral vascular dysfunction and high inflammatory state.  
 
 
 
Purpose and Objectives 
 
 
This is a randomized, placebo-controlled, parallel-group, single-center, double-blind trial of vericiguat 
in subjects with heart failure with reduced ejection fraction (HFrEF) to be conducted in conformance 
with Good Clinical Practice (GCP). 
Purpose 
The purpose of this study is to determine the effect of Vericiguat in patients with HFrEF. 
This study will: 
1) Evaluate the impact of Vericiguat on Peripheral Vascular Function; 

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2) Evaluate the impact of Vericiguat on Patients' Health Status; 
3) Evaluate the impact of Vericiguat on Inflammation; 
4) publish and disseminate results. 
Primary objective:  
 
1. To determine the impact of Vericiguat administration on vascular function in patients with 
HFrEF. 
  
Hypothesis: Endothelium-dependent vasodilation, as determined by flow-mediated 
vasodilation (FMD) testing, will be improved following 12-weeks of Vericiguat treatment 
compared to placebo.  
 
Secondary objectives: 
 
1. To determine the impact of Vericiguat administration on health-related quality of life and 
physical capacity in patients with HFrEF. 
  
Hypothesis 1a: Physical capacity, as determined by change in six minute walk test (6MWT) 
distance, will be better following 12-weeks of Vericiguat treatment compared to placebo. 
Hypothesis 1b: Quality of life, as determined by change of Kansas City Cardiomyopathy 
Questionnaire overall summary score, will be better following 12-weeks of Vericiguat 
treatment compared to placebo. 
  
2. To explore the relationship between inflammation and vascular function in response to 
vericiguat in patients with HFrEF. 
  
Hypothesis: A positive correlation between changes in FMD and biomarkers of inflammation 
will be observed following 12-weeks of Vericiguat treatment, such that the greatest 
improvements in FMD will be observed in those patients who experience the largest decreases 
in proinflammatory biomarkers (IL-1β, IL-6, IL-18, and hsCRP). 

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Study Population 
 
Age of Participants: 18+ 
 
Sample Size: 
At Utah: 
  
All Centers: 
30 
 
Inclusion Criteria: 
  
1. History of chronic HF with New York Heart Association (NYHA) Class II-III 
symptoms. Patients with NYHA 1 (asymptomatic) or NYHA 4 (severe limitations – 
symptoms even while at rest) symptoms, will not be enrolled. 
2. Left ventricular ejection fraction (LVEF) of ≤45% assessed within 12 months prior 
to randomization by any imaging method. 
3. Systemic blood pressure ≥90/60 mmHg. 
4. Standard guideline-directed HF therapy. 
5. If female of reproductive potential, agrees to avoid becoming pregnant while 
receiving study drug and for 14 days after the last dose of study drug by complying 
with abstinence from heterosexual activity or use (or have her partner use) 
contraception during heterosexual activity. 
 
 
Exclusion Criteria: 
  
1. Addition of a new disease-modifying HF pharmacotherapy or CRT-D in previous 4 
weeks.  

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2. Current or anticipated use of long-acting nitrates or nitric oxide (NO) donors 
including isosorbide dinitrate, isosorbide 5-mononitrate, pentaerythritol tetranitrate, 
nicorandil or transdermal nitroglycerin (NTG) patch, and molsidomine.  
3. Current or anticipated use of phosphodiesterase type 5 (PDE5) inhibitors such as 
vardenafil, tadalafil, and sildenafil. 
4. Current use or anticipated use of a soluble guanylate cyclase (sGC) stimulator such 
as riociguat. 
5. Known allergy or sensitivity to any sGC stimulator. 
6. Estimated glomerular filtration rate (eGFR) <15 mL/min/1.73 m2 or chronic dialysis. 
7. Patients who are pregnant or breastfeeding or plan to become pregnant or to 
breastfeed. 
 
 
Design  
 
Blinded Trial (Single or Double Blinded) 
Placebo Controlled Trial 
Randomized Trial 
 
 
A Randomized Parallel-Group, Placebo-Controlled, Double-Blind, Single - Center Trial of 
The Effect of Vericiguat on Peripheral Vascular Function, Patient Health Status and 
Inflammation in Patients with Heart Failure with Reduced Ejection Fraction. 
 
Study Procedures 
 
Recruitment/Participant Identification Process: 
Potential participants will be screened while admitted inpatients at the University and VA 
Hospitals or while attending routine clinic appointments in the Cardiovascular Medicine 
clinic. 
Clinicians will explain to eligible patients the purpose of the study, study interventions and 
evaluations, and the potential risks and benefits of participation, and will answer any 
questions. If a patient agrees to participate in the study, they will review and sign the IRB 
approved informed consent form before any study specific procedures are conducted. 
  
 
 
Informed Consent: 
Description of location(s) where consent will be obtained:  
University of Utah Health Sciences Center Veterans Affairs SLC Health Care System 
(VAMC) 
 
Description of the consent process(es), including the timing of consent:  
Potential participants will be screened while inpatients at the University and VA Hospitals or 
attending routine clinic visit in Cardiovascular medicine clinic. Clinicians will explain to 
eligible patients the purpose of the study, study interventions and evaluations, and the potential 

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risks and benefits of participation, and will answer any questions. If a patient agrees to 
participate in the study, they will review and sign the IRB approved informed consent form 
before any study specific procedures are conducted.  
 
Procedures: 
TRIAL PROCEDURES 
The Trial Flow Chart (Table 1) 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 timepoints if deemed clinically necessary by the investigator. 
 
Table 1. Trial Flow Chart 
Administrative Procedures 
Informed Consent 
The investigator or qualified designee must obtain documented consent from each potential 
subject prior to participating in the clinical trial. 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. 
General Informed Consent 
Consent must be documented by the subject’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’s approval/favorable 
opinion in advance of use. The subject 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. 
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 requirements, applicable laws and regulations and 
Sponsor requirements. 
Inclusion/Exclusion Criteria 

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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 
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 
A medical history will be obtained by the investigator or qualified designee. 
Prior and Concomitant Medications Review 
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.  
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 
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. 
Any subject who is screened multiple times will retain the original screening number assigned 
at the initial screening visit.  
Assignment of Treatment/Randomization Number 
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.  

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A single subject cannot be assigned more than one treatment/randomization number. 
Trial Compliance  
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 starting at Randomization Visit and at Visit 1. 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. 
Consultation should occur in a timely manner upon site learning of poor study drug 
compliance.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. 
Clinical Procedures/Assessments 
Height 
Height will be measured without shoes, using a stadiometer or other appropriate device. 
Weight 
Body weight will be measured using a standardized scale at each of the pre-defined time 
points outlined in the Trial Flow Chart. 
Physical Examinations 
Physical examination will be done at a clinical visit (inpatient or outpatients) preceding 
screening or randomization. The documentation will be reviewed by the investigator or 
qualified designee. 
Vital Signs 
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.  

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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. 
Pulse Rate 
Pulse rate is to be assessed after the subject has been seated for a 10 minute rest. Three 
measurements of the pulse rate must will be taken 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. 
Quality of Life Measures 
Kansas City Cardiomyopathy Questionnaire 
The KCCQ-12 is a 12-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-12 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-12 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, PhysicalLimitation, 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. 
Visual Analogue Scale 
The 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. 
Vital Status Assessment 

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Vital status is collected at Week 2, Week 8 and 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 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below.  
Laboratory tests are specified in Table 2. 
  
NT-proBNP, TNF-α, hsCRP, IL-1β, IL-6, IL-18 measurements assessed by the central lab will 
be blinded after Visit 2. 
Table 2. Laboratory Tests 
Hematology                                                                     Chemistry                                             
                Other 
Hematocrit 
(Hct)                                                               Bicarbonate                                            Natriuretic 
Peptide (NTproBNP) 
Hemoglobin (Hb)                                                              Blood 
glucose                                         Serum β-human chorionicgonadotropin†          
Mean corpuscular volume(MCV)                                     Blood urea nitrogen 
(BUN)                      TNF-α 
Mean corpuscular hemoglobin 
(MCH)                             Calcium                                                    hsCRP 
Mean corpuscularhemoglobin 
concentration(MCHC)      Creatinine                                                 IL-1β 
Platelet 
count                                                                   Chloride                                                    IL-6 
Red blood cells (RBC)                                                     Potassium 
(K)                                           IL-18 
Red cell distribution width(RDW)                                     Sodium (Na)  
Reticulocytes 
White blood cells (WBC) 

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Flow Mediated Dilation (FMD) 
A blood pressure cuff will be placed on the arm, distal to the ultrasound Doppler probe on the 
brachial artery. Simultaneous measurements of brachial artery blood velocity and vessel 
diameter will be performed using a linear array transducer operating in duplex mode, with an 
imaging frequency of 14 MHz and Doppler frequency of 5 MHz (Logic 7, GE Medical 
Systems, Milwaukee, WI). All measurements will be obtained with the probe appropriately 
positioned to maintain an insonation angle of 60° or less. The sample volume will be 
maximized according to vessel size and centered within the vessel on the basis of real-time 
ultrasound visualization. The brachial artery will be insonated approximately midway between 
the antecubital and axillary regions, and measurements of diameter and blood velocity 
(Vmean) will be obtained continuously at rest and for 2 minutes after cuff deflation. End-
diastolic, ECG R-wave-gated images will be collected via video output from the Logic 7 for 
off-line analysis of brachial artery vasodilation using automated edge-detection software 
(Medical Imaging Applications, Coralville, IA). During FMD, non-invasive arterial blood 
pressure may be assessed. Systemic arterial blood pressure (ABP) will be measured non-
invasively on a continuous basis using finger photoplethysmography (Finometer,Ohmeda, 
Madison, WI, USA). The finometer cuff will be placed on a finger and supported at heart 
level. 
6 MWT (Six-minute walk test) 
Six-minute walk test distance will be performed according to published guidelines for this 
patient group by trained research staff. The 6MWT will be performed indoors, along a flat, 
straight corridor with a hard surface. The subjects will wear comfortable clothing and shoes. 
The subjects will be instructed on the objectives of the test and be provided instructions on 
how the test will be carried out.   
Cardiac and Inflammation Marker Investigations 
Cardiac and inflammation marker investigations will examine the impact of vericiguat on HF 
and peripheral vascular disease progression and identify candidate markers that may predict 
drug response to the treatment. 
Marker blood samples will be collected at the time points indicated in Study Flow Chart. 
Investigators will not receive the results of analyses during the study, and no alerts will be 
sent.  
Other Procedures 
Withdrawal/Discontinuation 
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. 
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 

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of discontinuation. Any adverse events which are present at the time of 
discontinuation/withdrawal should be followed in accordance with the safety requirements. 
Blinding/Unblinding 
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 investigational 
pharmacy and make a request for emergency unblinding. The investigator or sub-investigator 
will enter the intensity of the adverse experiences observed, their relation to study drug, the 
reason thereof, etc., in the medical chart. 
Visit Requirements 
Visit requirements are outlined in Trial Flow Chart.  
Screening 
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. 
Additionally, evidence of a LVEF <45% within 12 months prior to randomization by any 
method (most recent measurement must be used) must be provided.  
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 
Visit requirements are outlined in Trial Flow Chart. Total treatment period will be 12 weeks. 
Randomization Visit 
At the randomization visit, subjects who fulfill all inclusion/exclusion criteria will be 
randomized to either 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. 

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Eligible subjects will be provided a blood pressure machine and cuff to perform at-home blood 
pressure assessment required at FU phone call A ( performed at week 2 ) and FU phone call B 
( performed at week 8 ). 
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. 
Investigators should make every attempt to resume study drug treatment in all subjects after 
interruption of study drug as soon as medically justified. 
Follow-Up Phone Calls 
Patients will be contacted at specific timepoints mentioned in study Flow Chart to assess for 
clinical events,adverse events, blood pressure measurements and vital status (if applicable) and 
titrate the investigational drug doses accordingly.  
Final Visit 
Final Visit's study procedures are outlined in Study Flow Chart. 
Final Phone Contact 
All subjects will be contacted by phone after 14 days of the Final visit to assess for clinical 
events, adverse events and vital status (if applicable).  
 
 
Procedures performed for research purposes only:  
 
 
Statistical Methods, Data Analysis and Interpretation 
 

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Statistical Methods 
 
General 
Standard descriptive statistics (proportions and frequencies for categorical factors; means, standard 
deviations, and designated percentiles for numeric factors) will display baseline characteristics by 
randomized treatment group. If a substantial imbalance is identified in a particular baseline factor, the 
ITT analyses described below will be accompanied by sensitivity analyses to investigate the impact of 
inclusion of this factor as a covariate.  Outcomes with substantial skewness may be transformed prior 
to subsequent analyses to better approximate normality. Analyses evaluating the effect of the treatment 
on study outcomes will be performed in accordance with the intention-to-treat principle, with subjects 
analyzed according to their randomly assigned treatment irrespective of the achieved dose of 
Vericiguat. Unless specified otherwise, hypothesis tests will be performed with 2-sided α=0.05, 
without adjustment for multiple comparisons.  
 
Primary Analysis 
The effect of administration of Vericiguat on the primary FMD outcome will be estimated by applying 
an analysis of covariance to compare the mean FMD levels at 12 weeks between the Vericiguat and 
placebo groups, with the baseline FMD levels included in the model as a covariate.  
 
Secondary Analyses 
The effect of administration of Vericiguat on the secondary 6-minute walk test and KCCQ outcomes 
will be estimated by applying separate analyses of covariance to compare the mean levels of these 
outcomes at 12 weeks between the Vericiguat and placebo groups, with the baseline level of the 
outcome included as a covariate. Separate analysis of covariance models will also be used to estimate 
the effects of the intervention on C-Reactive Protein and Interleukinς 1β, 6, 18. If these markers 
exhibit heavy positive skewness, as we expect, they will be log transformed prior to analysis.  
 
We will also provide scatter plots with Pearson and Spearman partial correlations with adjustment for 
randomized treatment group to describe the association of the change in FMD from baseline to 12 
weeks with changes in individual inflammatory markers during the same time interval. We will also 
provide Pearson and Spearman correlations relating changes in FMD to changes in inflammatory 
markers separately within the two randomized groups. Positively skewed inflammatory markers will 
be log transformed prior to this analysis.  
 

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Power analyses 
We expect to enroll and randomize 24 study subjects. With an anticipated drop-out rate of 15%, data 
from 20 subjects will be available for analysis.  
 
Primary Outcome. 
Flow-Mediated Dilation (FMD): Output from FMD testing is maximal change in brachial artery 
diameter across a 2-min period following 5 min of supra-systolic arterial occlusion, expressed as % 
change from pre-occlusion baseline. We hypothesize that the treatment will lead to a 5.1% increase in 
FMD relative to the control group. We anticipate a standard deviation (SD) in %FMD 2.4% in patients 
with HFrEF. With this SD, 10 evaluable patients per treatment group will provide at least 80% power 
with 2-sided α=0.05 to detect an increase in mean %FMD of 3.18% relative to the control group. The 
minimum detectable effect of 3.18% is well under the hypothesized effect size of 5.1%, indicating that 
the design has excellent statistical power to evaluate the hypothesized treatment effect on the primary 
outcome. This power calculation conservatively assumes a 0 correlation between the baseline and 12-
week FMD values; if the serial correlation is at least 0.5, the study will have at least 80% power to 
detect an 2.76% increase in %FMD.  
 
Secondary Outcomes 
6MWT: We anticipate SD of 100 m in the  6MWT. With this assumed SD, 10 evaluable patients per 
treatment group will provide at least 80% power with 2-sided α=0.05 to detect an increase in 6MWT 
distance of 115 m so long as the serial correlation between the baseline and 12 week 6MWT values is 
at least 0.5. 
 
Kansas City Cardiomyopathy Questionnaire (KCCQ): We anticipate an SD for the change in the 
KCCQ of 19.9 points.  Based on this assumed SD, 10 evaluable patients per treatment group will 
provide at least 80% power with 2-sided α=0.05 to detect an improvement in mean KCCQ of 24.4 
points. It is anticipated that KCCQ score changes will be smaller. The absolute differences may be 
hypothesis generating and provide pilot data for future targeted investigations.   
 
hsCRP: We project a median and interquartile range from the baseline hsCRP values of 3.68 mg/L and 
(1.14-8.41 mg/L), respectively. Under the assumption that hsCRP is lognormally distributed, we 
estimate an SD of 1.323 for log transformed hsCRP. Based on this assumed SD, 10 evaluable patients 
per treatment group will provide at least 80% power with 2-sided α=0.05 to detect an 83% reduction in 
the geometric mean hsCRP for the treatment group compared to the control group.  
 

Protocol Summary (ERICA) 
 
IRB_00152530 
Page 18 of 18 
 
IRB Approval 5/29/2025 
 
Interleukins 1β, 6, 18 and TNF-α: We also assume an SD of 1.323 for log transformed IL-1β, IL-6, IL-
18, TNF-α. Hence, we also expect that 10 evaluable patients per treatment group will provide at least 
80% power with 2-sided α=0.05 to detect an 83% reduction in the geometric mean of these biomarkers 
for the treatment group compared to the control group. 
 
We note that with 10 patients per group, our proposed design provides excellent statistical power to 
detect the hypothesized treatment effect on the primary outcome of FMD. Our statistical power will 
allow to detect large effects on the secondary outcomes. Hence, analyses of the secondary outcomes 
will be exploratory. 
 
Correlational analyses 
A sample size of 20 evaluable subjects is sufficient to detect a partial correlation of 0.59 with 80% 
power and 2-sided type-1 error of 5%. 
Multiplicity. In this preliminary study, all hypothesis tests will be performed on a comparisonwise 
basis, without adjustment for multiple comparisons.