Vericiguat in Patients With Metabolic Syndrome and Coronary Vascular Dysfunction

Johns Hopkins University

Status and phase: Completed; Phase 2

Conditions: Coronary Microvascular Dysfunction; Metabolic Syndrome

Treatments: Drug: Placebo; Drug: Vericiguat

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT05711719

IRB00310207

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 45 patients

Sex: All

Ages: 35 to 85 years old

Volunteers: No Healthy Volunteers

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, or hemoglobin A1c greater or equal to 5.7%

• 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 in a t least one major vessel, 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 Agatston score <10 in at least one major coronary vessel.

• 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

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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45 participants in 2 patient groups, including a placebo group

Vericiguat

Experimental group

Description:

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.

Treatment:

Drug: Vericiguat

Placebo

Placebo Comparator group

Description:

A placebo tablet will be administered orally once daily.

Treatment:

Drug: Placebo