Vericiguat in Patients With Metabolic Syndrome and Coronary Vascular Dysfunction
Phase: PHASE2
Conditions: Metabolic Syndrome, Coronary Microvascular Dysfunction
Sponsor: Johns Hopkins University

 
Date: June 3, 2025 
Principal Investigator: Thorsten Leucker, M.D., PhD.  
Application Number: IRB00310207 
 
 
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Study Title: Vericiguat in Patients with Metabolic Syndrome or Type 2 Diabetes Mellitus and 
Coronary Vascular Dysfunction 
 
NCT Number: 05711719 
 
Date: June 3, 2025

 
Date: June 3, 2025 
Principal Investigator: Thorsten Leucker, M.D., PhD.  
Application Number: IRB00310207 
 
 
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Version 4 Dated:   01/2021 
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JHM IRB - eForm A – Protocol 
 
 
• Use the section headings to write the JHM IRB eForm A, inserting the appropriate 
material in each. If a section is not applicable, leave heading in and insert N/A. 
• When submitting JHM IRB eForm A (new or revised), enter the date submitted to 
the field at the top of JHM IRB eForm A. 
 
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1. 
Abstract 
Provide no more than a one page research abstract briefly stating the problem, the research 
hypothesis, and the importance of the research. 
To this day, cardiovascular disease (CVD) continues to be the leading cause of death in the 
United States1. Although there has been a decrease in cardiovascular mortality, largely attributed 
to the identification and successful management of major risk factors such as hypertension and 
dyslipidemia, the rate of decline has recently slowed. The increasing prevalence of diabetes and 
of other, called “residual” risks that have not been adequately addressed,  are two of the main 
reasons why several hundred thousand Americans continue to experience myocardial infarctions 
and the consequences of the infarction each year1. Important risk factors for these adverse events 
are diabetes and the metabolic syndrome, an incompletely addressed risk factor (RR 2.35, [95% 
CI 2.02-2.73])1. The components of MetS (abdominal obesity, high blood pressure, impaired 
fasting glucose, dyslipidemia) are associated with inflammation, which is thought to have 
significant adverse effects on the vascular endothelium2,3. Endothelial dysfunction is a driver of 
the development and progression of coronary atherosclerosis, initiating and propagating  
processes which ultimately result in coronary clinical events4. Endothelial dysfunction, therefore, 
is one of the “final common pathways” for the impact of multiple atherosclerotic risk factors. 
Our team has developed and implemented non-invasive MRI methods to evaluate coronary 
vascular function in healthy individuals and in those with cardiovascular risk factors and 
coronary disease by assessing changes in coronary vascular dimension and flow accompanying 
isometric handgrip exercise, an endothelial-dependent stressor.  
 
Evaluating endothelial dysfunction by assessing coronary vascular function can thus not only 
index the adverse impact of multiple risk factors but also provide the opportunity to evaluate the 
benefit of an intervention which targets coronary vascular dysfunction. The synthesis and release 
of nitric oxide (NO) is an essential component of normal endothelial function. NO’s downstream 
effects include not only vasodilation and a resultant increase in coronary flow, but also anti-
proliferative, anti-coagulant, anti-adhesive, and anti-inflammatory effects5. Its beneficial vascular 
effects are mediated by stimulation of the soluble guanylyl cyclase (sGC) enzyme, which 
converts guanosine-5’-triphosphate (GTP) to the second messenger guanosine monophosphate 
(cGMP).  cGMP activates GMP-dependent protein kinases (PKG) which in turn phosphorylate 
several proteins that have vasorelaxant and anti-atherosclerotic effects6. Reduced bioavailability 
of NO associated with endothelial dysfunction, therefore, leads to   loss of its important 
downstream effects, and therefore may be one of the important  mechanisms responsible for 
progression of atherosclerosis and its associated adverse clinical outcomes7.  
 

 
Date: June 3, 2025 
Principal Investigator: Thorsten Leucker, M.D., PhD.  
Application Number: IRB00310207 
 
 
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Hypothesis: Vericiguat improves coronary vascular endothelial function in patients with 
metabolic syndrome or type 2 diabetes mellitus and impaired coronary vascular function. 
 
We will perform a placebo-controlled, randomized, double-blind study to test the hypothesis, 
that the administration of vericiguat, which increases soluble guanylate cyclase (sGC) activity 
despite low NO, improves coronary vascular function in patients with the metabolic syndrome or 
type 2 diabetes mellitus and coronary vascular dysfunction. We will be using MRI studies to 
evaluate coronary vascular function in response to study drug administration.   
 
2. 
Objectives  
(include all primary and secondary objectives) 
Primary Objective: 
1. To characterize the impact of vericiguat on global (micro- and macro- vascular function) 
coronary vascular function by comparing the responses prior to, and following, vericiguat 
administration, to isometric handgrip exercise, an endothelial-specific stressor in patients 
with the metabolic syndrome or type 2 diabetes mellitus and baseline coronary vascular 
dysfunction. 
Secondary Objective: 
1. To compare changes in resting, pre-isometric hand exercise (IHE), coronary blood flow 
before and following study drug administration within and between the vericiguat and 
placebo groups. 
2. To compare coronary flow and cross-sectional area prior to the isometric handgrip 
exercise before, and following study drug administration within and between the 
vericiguat and placebo groups.  
3. To obtain serum,  plasma, and urine laboratory studies to characterize markers/mediators 
of inflammation and of the nitric oxide signaling pathway prior to and following up-
titration of the study drug.  
3. 
Background  
(briefly describe pre-clinical and clinical data, current experience with procedures, drug or 
device, and any other relevant information to justify the research) 
Coronary vascular function can be assessed by examining changes in coronary blood flow and 
dimension following initiation of a coronary endothelial-dependent stimulus.  If function is 
normal, the stimulus results in a significant increase in coronary blood flow and dimension, but if 
abnormal, the result is only a small, or no, increase, or even a decrease.  These changes  were 
previously assessed via placement of a catheter within the studied artery8. Because that 
procedure is invasive, the associated risks did not justify most studies in individuals without 
known or suspected significant stenoses or in the serial studies required to assess the benefit of 
an intervention designed to improve coronary vascular function. The Hopkins investigator team 
for this proposed study, however, has extensive experience in using MRI methodology to non-
invasively and safely study coronary vascular function in healthy individuals9 and in those with 
pro-inflammatory states10 and coronary disease11 and to perform serial studies to assess the 
impact of interventions12. 

 
Date: June 3, 2025 
Principal Investigator: Thorsten Leucker, M.D., PhD.  
Application Number: IRB00310207 
 
 
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Regulation of coronary blood flow occurs at the site of resistance vessels and allows for optimal 
matching between oxygen supply and demand. Normal vascular responses to endothelial-
dependent stimuli are primarily mediated by nitric oxide (NO)9. Downstream effects of NO 
include vascular smooth muscle vasodilatation with a resultant increase in coronary dimension 
and flow. There are, as well, anti-proliferative, anti-coagulant, anti-adhesive, and anti-
inflammatory effects of NO5. Reduced bioavailability of NO with resultant impaired downstream 
signaling is thought to be one of the central consequences of many established and residual risk 
factors and one responsible mechanism for the impact of these risk factors on progression of 
atherosclerosis and its associated adverse clinical outcomes7. NO is formed by a reaction 
catalyzed by endothelial nitric oxide synthase (eNOS), present in both endothelial and red blood 
cells13, which uses L-arginine, NADPH, H+, and O2 substrates to form NO as well as citrulline, 
H2O, and NADP. Its beneficial vascular effects are mediated by stimulation of soluble guanylyl 
cyclase (sGC), which converts guanosine-5’-triphosphate (GTP) to the second messenger 
guanosine monophosphate (cGMP).  cGMP activates GMP-dependent protein kinases (PKG) 
which in turn phosphorylate several proteins that have vasorelaxant and anti-atherosclerotic 
effects6. 
Decreased eNOS activity or “uncoupling” of the eNOS reaction in the setting of established and 
residual risk factors associated with pro-inflammatory and oxidative stresses decreases NO 
bioavailability which not only results in loss of NO’s beneficial effects but also may result in the 
formation of peroxynitrite, which generates free radicals14. 
 
Vericiguat stimulates sGC both independently of, and synergistically with, NO15. Vericiguat 
enhances the cGMP pathways by directly stimulating sGC through a binding site independent of 
NO, and it sensitizes sGC to any bioavailable NO by stabilizing NO binding to the sGC binding 
site15. Thus, the beneficial attributes of NO bioavailability may accrue despite the decreased 
bioavailability associated with the metabolic syndrome.  Our study will test whether the coronary 
vascular response to isometric handgrip exercise (IHE), an endothelial-dependent stressor, 
improves from the study performed prior to and that performed following the administration of 
vericiguat.  We will also test whether the response differs from the response in those randomized 
to placebo and whether the results on the follow-up exams differ between those randomized to 
vericiguat and those randomized to placebo.   
 
If successful, a sGC mediated prevention strategy could be tested to learn whether improved 
coronary vascular function would improve outcomes in those with, and at risk for, the 
development and progression of coronary vascular disease (Figure 1). 
 

 
Date: June 3, 2025 
Principal Investigator: Thorsten Leucker, M.D., PhD.  
Application Number: IRB00310207 
 
 
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We have extensive experience using magnetic resonance imaging (MRI) to assess coronary 
endothelial-dependent vascular function non-invasively in healthy individuals  and in those with 
coronary disease11 and pro-inflammatory states10 using isometric handgrip exercise, an 
endothelial NO pathway-specific stressor9  
 
Our MRI technique can detect meaningful changes in coronary vascular function in people with 
impaired baseline coronary vascular function following an intervention and we will use this 
methodology in the proposed study to assess the impact of stimulating sGC with vericiguat on 
coronary vascular function in patients with impaired baseline function. 
 
4. 
Study Procedures 
a. Study design, including the sequence and timing of study procedures   
(distinguish research procedures from those that are part of routine care). 
Participants who meet enrollment criteria will be asked to provide consent. Women of 
reproductive capacity will undergo a urine pregnancy test and those who are pregnant 
will be excluded from further participation. Men over 40 years of age and women 
over 50 years of age with no clinical coronary angiographic study within the prior 36 
months demonstrating no significant coronary disease in at least one major coronary 
artery will undergo a research CT scan to measure coronary calcium score. If the 
score is ≤10 in at least one major coronary artery, they, and those who meet the other 
eligibility criteria will undergo assessment of coronary vascular function using MRI 
methodology. Those with normal function will not undergo any additional study 
Figure 1: Hypothesis: Vericiguat improves coronary vascular endothelial function in patients with the metabolic 
syndrome or type 2 diabetes mellitus and impaired coronary vascular function. L-Arg= L-arginine, NO= nitric 
oxide, eNOS= endothelial nitric oxide synthase, sGC= soluble guanylyl cyclase, cGMP= cyclic guanosine 
monophosphate, PKG= cyclic GMP–dependent protein kinases 

 
Date: June 3, 2025 
Principal Investigator: Thorsten Leucker, M.D., PhD.  
Application Number: IRB00310207 
 
 
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procedures. Those with abnormal global (micro- and macro- vascular function) 
coronary vascular function will undergo an echocardiographic study to assess systolic 
and diastolic function and baseline laboratory studies. They will then be randomized 
to vericiguat or placebo in a 2:1 ratio. Following randomization, the participants will 
undergo a study drug titration phase as follows: Initial 2.5 mg/day for two weeks, 
then 5 mg/day for two weeks, and then 10 mg/day for two weeks.  Blood pressure and 
clinical symptoms will be assessed following each two-week period to determine 
whether the up titration should be performed, as guided by evaluation of blood 
pressure and clinical symptoms21. Identical appearing placebo tablets will also be 
titrated so as to maintain double-blinding of the investigators and participants.  Next, 
study participants will continue the maximally tolerated maintenance dose for an 
additional 6 weeks. The study concludes with a final assessment of global (micro- and 
macro- vascular function) coronary vascular function with the same MRI protocol 
and follow-up laboratory studies and an echocardiogram.  (Figure 2)  
 
 
Figure 2: Study overview: Vericiguat in Patients with Metabolic Syndrome or type 2 diabetes mellitus 
and Coronary Vascular Dysfunction.  
Study type: Interventional-treatment 
Trial design: Randomized 
Number of Enrolled Participants: 45 total participants, 30 in the vericiguat and 15 in 
the placebo group. 
 
 
Coronary Artery Calcium (CAC) Score 

 
Date: June 3, 2025 
Principal Investigator: Thorsten Leucker, M.D., PhD.  
Application Number: IRB00310207 
 
 
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For men >40 and women >50 years of age who have not had coronary angiography 
(including CT angiography) within the prior 36 months, a CAC score will be 
determined. A computed tomography (CT) scan will be performed without contrast 
agents with 10 to 15 minutes of total room time at about 1 to 2.5 mSv of radiation22.  
 
MRI methods for Coronary Vasoreactivity:  
MR will be performed on a 3 T CMR scanner (Achieva, Philips Healthcare, Best, 
NL) in the morning after an overnight fast.  For endothelial function imaging, 
alternating anatomical and velocity-encoded images will be collected at baseline and 
during approximately 6 min of continuous isometric handgrip exercise (IHE). The 
exercise is performed using a handgrip dynamometer at 30% of each participant’s 
maximum force, which is determined prior to the MRI study, as previously 
reported9,23. Images will be taken perpendicular to a proximal or mid-straight segment 
of the coronary artery and/or coronary sinus best identified on survey scans11. Cross-
sectional anatomical (bright blood sequence) and phase contrast velocity encoded 
spiral CMR will be obtained using single breath-hold cine sequences with 
reproducibility of the techniques published previously9,23. The MRI will be used to 
measure cross-sectional area (CSA), coronary flow velocity (CFV), and to calculate 
coronary blood flow (CBF) changes in response to the IHE.  If technical problems 
prevent adequate interrogation of the coronary response, the participant will be asked 
to undergo a second screening MRI study. Coronary MRI will be repeated following 
the study drug administration period with an identical protocol with special attention 
taken to interrogate the same coronary segments as those studied at baseline, using 
anatomic landmarks of coronary ostia and branch vessels- as we have done in the 
past9 and to replicate the identical MRI IHE protocol. 
 
MRI analysis:  
Images will be analyzed blinded to study-drug assignment and clinical information 
for CEF (e.g., change in cross-sectional area (CSA), coronary flow velocity (CFV), 
and calculated coronary blood flow (CBF), as previously validated and described9,23. 
Coronary CSA will be quantified using a semi-automated software tool (Cine version 
3.15.17, General Electric, Milwaukee, WI, USA) as previously reported11. For CBV 
and CBF measurements, phase-contrast images will be analyzed using semi-
automated commercial software (FLOW Version 3.0, Medis, NL); the coronary 
blood-flow (CBF, in ml/minute) is derived from diastolic coronary flow velocity 
(CFV, in cm/sec) as previously described9,11. Only native coronary segments will be 
analyzed. Our prior studies using this methodology demonstrated low intra- and inter-
observer variability with good reproducibility over eight weeks9. 
 
Echocardiography  
Participants may also be asked to undergo echocardiographic studies to evaluate 
cardiac function. Systolic function will be assessed by measuring the ejection fraction 
(EF), calculated as stroke volume divided by the end-diastolic volume. Diastolic 
function will be assessed by looking at the annular e’ velocity, the septal and lateral e’ 
velocities, the average E/e’ ratio, the LA volume index and the peak TR velocity24. 
We will obtain images before and after a 90 second passive leg raise as well to assess 
hemodynamic variations 25. Strain and strain rate measurements will be obtained 

 
Date: June 3, 2025 
Principal Investigator: Thorsten Leucker, M.D., PhD.  
Application Number: IRB00310207 
 
 
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using myocardial speckle tracking to evaluate regional myocardial contractile 
function26.  
b. If your study involves data/biospecimens from participants enrolled under other 
research studies with a written consent or under a waiver of consent, please list the 
IRB application numbers for those studies.  Please note:  Certificate of 
Confidentiality (CoC) protections applied to the data in source studies funded by NIH 
or CDC will extend to this new study if the funding was active in 2016.  If this 
situation applies, Section 36, question 6 in the application will need to be answered 
“Yes” and “Hopkins Faculty” should be selected in question 7. No other documents 
are required.  
 
Not applicable 
 
c. Study duration and number of study visits required of research participants. 
Study Duration: 24 months 
Number of study visits per participant: 4 to 8, depending on whether the MRI and 
echo will be performed on the same day and how many titration steps are performed.    
 
d. Blinding, including justification for blinding or not blinding the trial, if applicable. 
This study will be double-blinded to minimize bias and maximize the validity of the 
results. All study personnel and the participants will be blinded to study drug 
assignment to avoid bias in data collection and analysis. The Hopkins Investigational 
Pharmacy will have access to study drug assignment if there is a clinical need for the 
subjects’ treating physicians to be aware of assignment. 
 
e. Justification of why participants will not receive routine care or will have current 
therapy stopped. 
Participants will continue to receive routine care and will not have any current 
therapy stopped.  
 
f. Justification for inclusion of a placebo or non-treatment group. 
This study is intended to develop an intervention and does not require participants to 
forgo treatment they would otherwise receive. Vericiguat is not considered a 
treatment for this patient population so the placebo group is not considered a “non-
treatment” group.  
 
g. Definition of treatment failure or participant removal criteria. 
There is no defined treatment failure.  
Participation in this study is on a volunteer basis. As such, individuals may decline 
continued participation. If new data appear indicating risks not presently foreseen 
associated with administration of the study drug or any of the study procedures, the 
study may be terminated and participants removed.  
 
h. Description of what happens to participants receiving therapy when study ends or if a 
participant’s participation in the study ends prematurely. 
The study drug is not considered a treatment and thus will no longer receive the drug 
when the study ends or if participation ends prematurely. 

 
Date: June 3, 2025 
Principal Investigator: Thorsten Leucker, M.D., PhD.  
Application Number: IRB00310207 
 
 
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i. If biological materials are involved, please describe all the experimental procedures 
and analyses in which they will be used. 
The experimental procedure is venipuncture.  Analyses for routine chemistry and 
hematology studies as well as markers/mediators of inflammation and the nitric oxide 
signaling pathway will be performed.  
 
5. 
Inclusion/Exclusion Criteria 
 
Inclusion Criteria: 
• Age range 35-85 years 
• Presence of type 2 diabetes mellitus or of the metabolic syndrome defined by the 
NCEP ATP III definition, with at least three of the following five criteria:   
o waist circumference > 40 inches (men) or > 35 inches (women) 
o blood pressure > 130/85 mmHg 
o fasting triglyceride (TG) level > 150 mg/dL 
o fasting high-density lipoprotein (HDL) cholesterol level < 40 mg/dL in 
men or < 50 mg/dL in women 
o fasting blood glucose > 100 mg/dL or HbA1c ≥5.7% 
• Either one of the following: 
o Men ≤ 40 or women ≤ 50 years of age with no history or symptoms of 
ischemic heart disease, or 
o Men >40 or women >50 years of age with either one of the following: 
§ a coronary angiography (including CT angiography) within the 
past 36 months showing no significant coronary artery disease in at 
least one major coronary artery, defined as >50% stenosis of the 
left main coronary artery and/or >70% stenosis of another major 
coronary vessel, or  
§ a coronary artery calcium score obtained within the prior 36 
months or if no prior calcium scan, one performed as a research 
study following consent with a score ≤10 in at least one major 
coronary artery. 
• IHE-induced %-change in coronary flow < or equal to 13% 
 
Exclusion Criteria: 
• Systolic blood pressure <110 mm Hg 
• Current or anticipated use of long-acting nitrates, a sGC stimulator, or 
phosphodiesterase type 5 (PDE5) inhibitors  
• Hematocrit <30% 
• Unable to understand the risks, benefits, and alternatives of participation so as to 
provide informed consent 
• Women who are pregnant. 
• Women who are breastfeeding 
• Women with reproductive capacity not using an acceptable form of contraception 
• History of claustrophobia 
• Inability to lie flat and still for 45 minutes 

 
Date: June 3, 2025 
Principal Investigator: Thorsten Leucker, M.D., PhD.  
Application Number: IRB00310207 
 
 
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• Presence of non-MR-compatible objects or devices, such as intra-orbital debris, 
intra-auricular implants, intra-cranial clips, an implanted defibrillator or a 
pacemaker  
•  History as a machinist, welder, metal worker or a similar activity that poses the 
risk of metal exposure to the eyes 
 
6. 
Drugs/ Substances/ Devices 
a. The rationale for choosing the drug and dose or for choosing the device to be used. 
As detailed above, we propose using vericiguat to “bypass” the requirement for nitric 
oxide synthesis in an attempt to improve endothelial function and hence coronary 
vascular function in individuals with preexisting dysfunction27.  If successful, a sGC-
directed prevention strategy may improve coronary vascular function and decrease 
cardiovascular risk. The dose and titration described to reach the dose is that used for 
patients with heart failure and approved by the FDA to treat those patients28.   
b. Justification and safety information if FDA approved drugs will be administered for 
non-FDA approved indications or if doses or routes of administration or participant 
populations are changed. 
Vericiguat is approved for reducing the risk of cardiovascular death and heart failure 
hospitalization following hospitalization or need for outpatient intravenous diuretics 
in adults with symptomatic chronic heart failure and ejection fraction less than 45%. 
The dose and route of administration are the same as that administered for this FDA 
approved indication. The dose is not changed from that used for the marketed drug.    
 
c. Justification and safety information if non-FDA approved drugs without an IND will 
be administered. 
We will be using an FDA approved drug. 
7. 
Study Statistics 
a. Primary outcome variable. 
In a paired analysis, we hypothesize that there is a significant change in coronary 
flow and dimension with isometric handgrip exercise (IHE) in the group randomized 
to vericiguat from that measured at baseline, prior to the initiation of vericiguat, to 
that measured following vericiguat administration and up-titration. We will be using 
either a paired student t-test or a Wilcoxon test to examine this hypothesis. 
In unpaired analyses, we hypothesize that the change in the vericiguat group from 
baseline to post-up titration with be greater than the change in the placebo group. We 
will be using either an unpaired student t-test or a Mann-Whitney test to examine this 
hypothesis 
  
b. Secondary outcome variables. 
We will conduct bivariate analyses to compare markers/mediators of inflammation 
and that of the nitric oxide pathway.  
Other exploratory outcome variable that we are interested in include age, sex, and 
race. We will be using parametric and non-parametric tests for continuous variables 
and chi-square or Fisher’s exact tests for categorical variables.  
 
c. Statistical plan including sample size justification and interim data analysis. 

 
Date: June 3, 2025 
Principal Investigator: Thorsten Leucker, M.D., PhD.  
Application Number: IRB00310207 
 
 
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All sample size calculations are based on 80% power and 5% alpha error for two-
sided tests. We have prior studies with small sample sizes to inform our baseline 
expectations12. For our primary analysis, our minimum expected difference in change 
in coronary flow with IHE in the vericiguat group with our planned sample size of 
n=30 in the vericiguat group, allowing for 10% loss to follow-up at 8 weeks (n=27 
remaining), with 80% power and an alpha of 0.05 is 7.8% ± 13.6%. The detectable 
effect size at 90% power is 9.1% ± 13.6%. (Figure 3). 
 
 
 
 
 
The study investigators will be responsible for analyzing the study data to assess the 
completeness of data collection, to assess any adverse events, and to identify any 
findings which may have clinical relevance.  This will be performed while 
maintaining the blind. A Data Safety and Monitoring Committee will review and, if 
necessary unblind, the data when the outcomes of the first third (n=15) of the 
anticipated enrolled participants are available and at the end of the study. This 
committee may request to review/audit the data at any time. 
  
The data will be maintained in a REDCap database.  
 
The data will be unblinded following the completion of the protocol, and 
medical/scientific review has been completed, protocol violators have been identified 
and data has been declared complete, although the Hopkins Institutional Review 
Board and Data Safety and Monitoring Committee may request prior unblinding.    
 
Figure 3: Power and sample size calculated for estimated difference in change in 
coronary flow with IHE from baseline to 8 weeks in the vericiguat group 

 
Date: June 3, 2025 
Principal Investigator: Thorsten Leucker, M.D., PhD.  
Application Number: IRB00310207 
 
 
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The routine safety laboratory studies will be analyzed within 48 hours of collection.  
The MRI data will be analyzed within two months of each study 
 
d. Early stopping rules. 
The study will be stopped early on the recommendation of the Data Safety and 
Monitoring Committee or if there is any new published information regarding the 
safety of the study drug or the study procedures.   
 
 
8. 
Risks 
a. Medical risks, listing all procedures, their major and minor risks and expected 
frequency. 
Study Drug: 
Vericiguat is available in an oral tablet formulation. These tablets may be crushed and 
mixed with water immediately before administration for patients with swallowing 
difficulties. There is a risk of developing hypotension as a result of receiving this 
medication. In the clinical trial for heart failure with reduced ejection fraction 28, 
patients who had concurrent or anticipated use of long-acting nitrates (e.g, isosorbide 
mononitrate, isosorbide dinitrate, transdermal nitroglycerin) were excluded. In the 
same trial, anemia developed in more patients in the vericiguat group than placebo 
(7.6% vs 5.6%), however, anemia was common at randomization and although 
vericiguat modestly lowered hemoglobin by 16 weeks, this effect did not further 
progress29. 
 
Serum Samples: 
Obtaining samples may cause slight discomfort when the needle is inserted into the 
arm vein. The potential side effects of taking blood samples may include dizziness, 
soreness and/or bruising of the skin for several days. In very rare circumstances, 
bleeding or infection can develop at the needle puncture site. However, the procedure 
is performed by trained personnel using sterile and standard medical practices. 
 
Cardiac MRI: 
The risks of this study are the same as the risks of a patient receiving a clinical 
cardiac MRI exam.    
 
All MRI equipment used in this study is the same as the equipment that is used for 
standard clinical care. There are no studies showing any health hazard associated with 
magnetic field exposure (Yamaguchi 2011 and Schenck 2000) itself.   
 
Ferromagnetic objects may experience forces near the MRI scanner and elongated 
metallic implants may lead to unintended heating around the implant during MRI 
scanning.  The potential for injury related to such objects is well described (Schenck 
2000) and patients with such risks are excluded from participating in this  study.   
 
Echocardiography 
A transthoracic echocardiogram uses ultrasound technology that is based on 
transducing harmless sound waves. It is noninvasive and does not use radiation.  

 
Date: June 3, 2025 
Principal Investigator: Thorsten Leucker, M.D., PhD.  
Application Number: IRB00310207 
 
 
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Coronary artery calcium score: 
CAC scoring is obtained using 1-2.5 mSv (depending on participant size) of ionizing 
radiation. By comparison, the average American is exposed to about 3 mSv of 
radiation from natural sources per year30. 
 
b. Steps taken to minimize the risks. 
To protect against and minimize the potential risks of vericiguat, study participants 
will undergo a careful history as well as physical examinations at baseline and during 
the titration and follow-up visits  to identify any potential or new health conditions 
which might increase the risk of taking the study drug. . Concurrent or anticipated use 
of long-acting nitrates, sGC stimulators or PDE5 inhibitors, which might potentiate 
any hypotensive effects is an exclusion criterion for participation in the study. Those 
with a hematocrit of <30% will also be excluded. The study drug will be titrated 
every two weeks to a maximum dose of 10 mg with close monitoring of the systolic 
blood pressure. In the clinical trial for HFrEF28, the main reason for not up-titrating to 
target per protocol was a SBP in the  90-100 mmHg range. Dose decreases were 
rarely required for SBP <90 mmHg, and the 10 mg dose was considered safe and well 
tolerated. The study drug will not be further up-titrated if the systolic blood pressure 
is< 110 mmHg. If the systolic pressure is <100 mmHg, the dose will be decreased.  
Trained personnel will perform the blood collection procedure and will make every 
effort to minimize any associated risks or discomfort. 
 
The MRI scanning will be performed using the same MRI Device Safety Protocol 
used for the device MRI study (Protocol NA_00051707). 
 
c. Plan for reporting unanticipated problems or study deviations. 
All clinically significant unanticipated problems and study deviations will be reported 
to the DSMC and the IRB according to The Johns Hopkins Medicine Institutional 
Review Board published guidelines. The anticipated three-member DSMC will 
include at least one cardiologist familiar with the management of patients with 
coronary disease, and a statistician. The DSMC will have access to study drug 
assignment if requested and will make recommendations to Dr. Leucker regarding 
any safety concerns and recommendations regarding continuation of the study 
 
d. Legal risks such as the risks that would be associated with breach of confidentiality. 
Once the data are acquired, they will be assigned a code for each subject with 
identification secured and accessible only to the principal and other investigators, and 
the research coordinators.  Patient clinical information such as copies of clinical 
studies and imaging reports will be filed in a locked filing cabinet with access under 
control of Dr. Leucker, the other investigators, and study coordinators. Patient 
information summarized and/or converted into electronic form (tables, images, etc.) 
will be identified by the assigned code. We will abide by the Johns Hopkins 
Institutional policy that all identifiers in images and data acquired under IRB-
approved research protocols must be removed if they leave the institution, for 
example in presentations.   
e. Financial risks to the participants. 

 
Date: June 3, 2025 
Principal Investigator: Thorsten Leucker, M.D., PhD.  
Application Number: IRB00310207 
 
 
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All study related costs will be paid from research sources, as stated in the consent 
form 
 
9. 
Benefits 
a. 
Description of the probable benefits for the participant and for society. 
There will be no direct benefit to individuals who participate in this study. 
Participants in clinical trials may benefit from receiving closer follow-up and 
improved access to physicians when compared to those not participating in such 
studies.  If the results regarding the safety and efficacy outcomes demonstrate a 
favorable effect of vericiguat, then their participation in this study would expect 
to benefit future patients with the metabolic syndrome or type 2 diabetes mellitus 
and endothelial dysfunction.  
 
10. 
Payment and Remuneration 
a. 
Detail compensation for participants including possible total compensation, 
proposed bonus, and any proposed reductions or penalties for not completing the 
protocol. 
Each study participant will receive $100 for each visit during which an MRI will 
be performed and $60 for other visits. In addition, participants will be reimbursed 
for transportation and parking expenses and given a $10 meal voucher following 
procedures requiring prior fasting.  
 
11. 
Costs 
a. 
Detail costs of study procedure(s) or drug (s) or substance(s) to participants and 
identify who will pay for them. 
There is no cost to the participants related to the study procedures or drug.  
 
12. 
Transfer of Materials 
Transfer of biospecimens from Johns Hopkins to another organization for research 
purposes and receipt of biospecimens from an outside organization for your research 
must adhere to JHU policies for material transfer (https://ventures.jhu.edu/faculty-
inventors/forms-policies/ ) and biospecimen transfer 
(https://hpo.johnshopkins.edu/enterprise/policies/176/39187/policy_39187.pdf?_=0.622
324232879).  
 
Please complete this section if your research involves transfer or receipt of biospecimens. 
 
a. Will you receive biospecimens from an external entity for this research? [Yes/No].  
 
If “Yes”, please confirm you will secure an MTA/research agreement from the 
appropriate office  (JHTV/ORA) prior to transfer.  
 
See: https://ventures.jhu.edu/technology-transfer/material-transfer-agreements/ . 
 
No 
 
b. Will you transfer biospecimens to an external entity as part of this research? [Yes/No] 
 
If “Yes”, please address each of the following: 
 

 
Date: June 3, 2025 
Principal Investigator: Thorsten Leucker, M.D., PhD.  
Application Number: IRB00310207 
 
 
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No 
 
1) Describe the nature of the research collaboration with the external entity and the 
rationale for the transfer. (Include an explanation of your intellectual contribution to 
the design of the research study, resulting data and sharing, and participation in the 
planned publications.) 
2) Please confirm you will secure an MTA through the appropriate office (JHTV or 
ORA) prior to transfer. 
(See: https://ventures.jhu.edu/technology-transfer/material-transfer-agreements/.) 
  
3) If the biospecimens you intend to transfer were obtained through clinical or research 
procedures at Johns Hopkins and “Other” is selected in Item 4, Section 23, please 
submit the following items in that Section: 
 
a. A pdf version of a completed JHTV Online “Material Transfer Agreement 
Request Form for Outbound Material” https://ventures.jhu.edu/technology-
transfer/material-transfer-agreements/ OR a copy of the COEUS PD 
(Proposal Development Summary). 
b. A completed Biospecimen Transfer Information Sheet 
https://www.hopkinsmedicine.org/institutional_review_board/forms/.   
c. A signed and dated “De-identified Human Subject Certification” 
https://www.hopkinsmedicine.org/institutional_review_board/forms/  
d. Approval documents from recipient site, if applicable. 
e. Copies of the consent forms associated with the IRB protocols under which 
the biospecimens were collected, with language appropriate to this transfer 
highlighted.  
f. The name of the specialist you are working with in ORA to complete a 
contract/MTA. 
Please see the following website for more information about transferring human 
biospecimens to outside entities: 
https://www.hopkinsmedicine.org/institutional_review_board/news/announcement_transf
er_human_biospecimens_outside_entities.html/ .   
 
 
References: 
 
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Association. https://www.ahajournals.org/doi/epub/10.1161/CIR.0000000000001052 
doi:10.1161/CIR.0000000000001052. 

 
Date: June 3, 2025 
Principal Investigator: Thorsten Leucker, M.D., PhD.  
Application Number: IRB00310207 
 
 
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2. Tziomalos, K., Athyros, V. G., Karagiannis, A. & Mikhailidis, D. P. Endothelial dysfunction 
in metabolic syndrome: Prevalence, pathogenesis and management. Nutr. Metab. Cardiovasc. 
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Serum PCSK9 Levels in People With HIV Independent of Low‐Density Lipoprotein 
Cholesterol. J. Am. Heart Assoc. 7, e009996 (2018). 

 
Date: June 3, 2025 
Principal Investigator: Thorsten Leucker, M.D., PhD.  
Application Number: IRB00310207 
 
 
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Date: June 3, 2025 
Principal Investigator: Thorsten Leucker, M.D., PhD.  
Application Number: IRB00310207 
 
 
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Leopold, J. A. & Loscalzo, J. The Emerging Role of Precision Medicine in 
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Date: June 3, 2025 
Principal Investigator: Thorsten Leucker, M.D., PhD.  
Application Number: IRB00310207 
 
 
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