Vericiguat in Patients With Metabolic Syndrome and Coronary Vascular Dysfunction

Study Overview
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Brief Summary
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Coronary vascular dysfunction is one of the final common pathways for the impact of multiple cardiovascular risk factors. The investigators will conduct a randomized, double-blind placebo-controlled study in individuals with the metabolic syndrome and baseline coronary vascular dysfunction to evaluate the impact of vericiguat, a stimulator of soluble guanylyl cyclase, on coronary vascular function using non-invasive cardiac magnetic resonance imaging.

Detailed Description
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Despite advances in medical therapy for the prevention of coronary artery disease, such as the treatments for high blood pressure and elevated cholesterol, several hundred thousand Americans continue to experience heart attacks every year. This may be related to risk factors which are not now identified and therefore treated. Endothelial dysfunction indexes the adverse impact of multiple risk factors and thus provides the opportunity to evaluate the benefit of an intervention which may improve function. Forty-five participants with metabolic syndrome and coronary vascular dysfunction will be randomized in a 2:1 ratio to receive vericiguat or placebo. 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. This titration protocol is the one stated in the FDA package insert for vericiguat. The vericiguat formulary will be an FDA approved version obtained by the Johns Hopkins Medical Institutions Pharmacy from Merck (manufacturer of vericiguat) and will be maintained by the Johns Hopkins Investigational Drug Service until it is administered. Cardiac MRI with isometric handgrip exercise, as well as echocardiography and blood studies will be used to assess coronary vascular and cardiac function and biomarkers indicative of nitric oxide pathways and factors impacting that pathway. The same procedures will be repeated at the end of the 6-10 week study drug administration period with an identical protocol, with special attention taken on the MRI to interrogate the same coronary segments as those studied at baseline.

Official Title
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Vericiguat in Patients With Metabolic Syndrome and Coronary Vascular Dysfunction

Conditions
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Metabolic Syndrome, Coronary Microvascular Dysfunction

Intervention / Treatment
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* Drug: Vericiguat
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age range 35-85 years Presence of the metabolic syndrome defined by the National Cholesterol Education Program, Adult Treatment Panel III (NCEP ATP III) definition, with at least three of the following five criteria: waist circumference > 40 inches (men) or >35 inches (women) blood pressure >130/80 mmHg fasting triglyceride (TG) level >150 mg/dL fasting high-density lipoprotein (HDL) cholesterol level <40mg/dL in men or <50mg/dL in women Fasting blood glucose >100 mg/dL Either one of the following: Men ≤ 40 or women ≤ 50 years of age with no history or symptoms of ischemic heart disease, or Men >40 or women >50 years of age with either one of the following a coronary angiography within the past 24 months showing no significant coronary artery disease, 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 24 months or if no prior calcium scan, one performed as a research study following consent with a score equal to 0 IHE-induced %-change in coronary flow ≤13% Exclusion Criteria: Systolic blood pressure <110 mm Hg Current or anticipated use of long-acting nitrates, soluble guanylate cyclase (sGC) stimulators, 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 with reproductive capacity not using an acceptable form of contraception History of claustrophobia Inability to lie flat and still for 45 minutes Presence of non-magnetic resonance (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

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Double-blind, placebo controlled trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vericiguat<br>Initial 2.5 mg/day for two weeks, then 5 mg/day for two weeks, and then 10 mg/day for two weeks. Systolic blood pressure will be measured before and following each titration The participant will receive the final titration dose for a total of six weeks.. The drug is administered as an oral tablet once daily. | Drug: Vericiguat<br>* Up-titration will be performed as guided by the evaluation of blood pressure and clinical symptoms<br>* Other names: Verquvo;|
| Placebo Comparator: Placebo<br>A placebo tablet will be administered orally once daily. | Drug: Placebo<br>* Administered the same way<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute change in coronary flow (in mL/min) within the vericiguat group as assessed by Magnetic Resonance Imaging (MRI) | The absolute changes in coronary flow (in mL/min) 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 at the end of the study drug administration period as assessed by MRI. | Baseline and 6 weeks following initiation of up-titrated dose | 
| Relative change in coronary flow (as percentage) within the vericiguat group as assessed by Magnetic Resonance Imaging (MRI) | The relative changes in coronary flow (as percentage) 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 at the end of the study drug administration period as assessed by MRI. | Baseline and 6 weeks following initiation of up-titrated dose | 
| Absolute change in coronary cross-sectional area (in mm²) within the vericiguat group as assessed by Magnetic Resonance Imaging (MRI) | The absolute changes in coronary cross-sectional area (in mm²) 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 at the end of the study drug administration period as assessed by MRI. | Baseline and 6 weeks following initiation of up-titrated dose | 
| Relative change in coronary cross-sectional area (as percentage) within the vericiguat group as assessed by Magnetic Resonance Imaging (MRI) | The relative changes in coronary cross-sectional area (as percentage) 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 at the end of the study drug administration period as assessed by MRI. | Baseline and 6 weeks following initiation of up-titrated dose | 
| Absolute change in coronary flow (in mL/min) between the vericiguat group and the placebo group as assessed by Magnetic Resonance Imaging (MRI) | The absolute changes in coronary flow (in mL/min) with isometric handgrip exercise (IHE) in the vericiguat group as compared to the placebo group as assessed by MRI. | Baseline and 6 weeks following initiation of up-titrated dose | 
| Relative change in coronary flow (as percentage) between the vericiguat group and the placebo group as assessed by Magnetic Resonance Imaging (MRI) | The relative changes in in coronary flow (as percentage) with isometric handgrip exercise (IHE) in the vericiguat group as compared to the placebo group as assessed by MRI. | Baseline and 6 weeks following initiation of up-titrated dose | 
| Absolute change in coronary cross-sectional area (in mm²) between the vericiguat group and the placebo group as assessed by Magnetic Resonance Imaging (MRI) | The absolute changes in coronary cross-sectional area (in mm²) with isometric handgrip exercise (IHE) in the vericiguat group as compared to the placebo group as assessed by MRI. | Baseline and 6 weeks following initiation of up-titrated dose | 
| Relative change in coronary cross-sectional area (as percentage) between the vericiguat group and the placebo group as assessed by Magnetic Resonance Imaging (MRI) | The relative changes in coronary cross-sectional area (as percentage) with isometric handgrip exercise (IHE) in the vericiguat group as compared to the placebo group as assessed by MRI. | Baseline and 6 weeks following initiation of up-titrated dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in interleukin 1 (IL-1) measured using blood samples (in pg/mL) | IL-1 (in pg/mL), an inflammatory marker, will be measured in blood samples to assess changes from baseline. | Baseline and 6 weeks following initiation of up-titrated dose | 
| Changes in interleukin 6 (IL-6) measured using blood samples (in pg/mL) | IL-6 (in pg/mL), an inflammatory marker, will be measured in blood samples to assess changes from baseline. | Baseline and 6 weeks following initiation of up-titrated dose | 
| Changes in interleukin 10 (IL-10) measured using blood samples (in pg/mL) | IL-10 (in pg/mL), an inflammatory marker, will be measured in blood samples to assess changes from baseline. | Baseline and 6 weeks following initiation of up-titrated dose | 
| Changes in tumor necrosis factor (TNF)-alpha measured using blood samples (in pg/mL) | TNF-alpha (in pg/mL), an inflammatory marker, will be measured in blood samples to assess changes from baseline. | Baseline and 6 weeks following initiation of up-titrated dose | 
| Changes in high sensitivity C-Reactive Protein (hsCRP) measured using blood samples (in mg/L) | hsCRP (in mg/L), an inflammatory marker, will be measured in blood samples to assess changes from baseline. | Baseline and 6 weeks following initiation of up-titrated dose | 
| Changes in cyclic guanosine monophosphate (cGMP) measured using blood samples (in pmol/mL) | cGMP (in pmol/mL), a mediator in the nitric oxide pathway, will be measured in blood samples to assess changes from baseline. | Baseline and 6 weeks following initiation of up-titrated dose | 
| Changes in left ventricular ejection fraction (as percentage) as assessed by echocardiography | An ultrasound evaluation of the heart will be performed to assess the impact of vericiguat on left ventricular ejection fraction (%). | Baseline and 6 weeks following initiation of up-titrated dose | 
| Changes in e' velocities (in cm/s) as assessed by echocardiography | An ultrasound evaluation of the heart will be performed to assess the impact of vericiguat on e' velocities (in cm/s). | Baseline and 6 weeks following initiation of up-titrated dose | 
| Changes in E/e' ratio as assessed by echocardiography | An ultrasound evaluation of the heart will be performed to assess the impact of vericiguat on the E/e' ratio. | Baseline and 6 weeks following initiation of up-titrated dose | 
| Changes in left atrium volume index (in mL/BSA) as assessed by echocardiography | An ultrasound evaluation of the heart will be performed to assess the impact of vericiguat on the left atrium volume index (in mL/BSA). | Baseline and 6 weeks following initiation of up-titrated dose | 
| Changes in peak tricuspid regurgitation (TR) velocity (in m/s) as assessed by echocardiography | An ultrasound evaluation of the heart will be performed to assess the impact of vericiguat on peak TR velocity (in m/s). | Baseline and 6 weeks following initiation of up-titrated dose | 
| Changes in strain (as percentage) as assessed by echocardiography | An ultrasound evaluation of the heart will be performed to assess the impact of vericiguat on strain (as percentage). | Baseline and 6 weeks following initiation of up-titrated dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cardiac Magnetic Resonance Imaging