Clinical trial NCT05711719: Vericiguat in Patients With Metabolic Syndrome and Coronary Vascular Dysfunction
Official title: Vericiguat in Patients With Metabolic Syndrome and Coronary Vascular Dysfunction
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Metabolic Syndrome
Coronary Microvascular Dysfunction
Keywords: Cardiac Magnetic Resonance Imaging
Lead sponsor: Johns Hopkins University
Sponsor class: OTHER
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2023-02-03
Enrollment: 45
Sex: ALL
Minimum age (years): 35
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Double-blind, placebo controlled trial
Primary purpose: PREVENTION

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Absolute change in coronary cross-sectional area (in mm²) within the vericiguat group as assessed by Magnetic Resonance Imaging (MRI)
timeFrame: Baseline and 6 weeks following initiation of up-titrated dose
measure: Relative change in coronary cross-sectional area (as percentage) within the vericiguat group as assessed by Magnetic Resonance Imaging (MRI)
timeFrame: Baseline and 6 weeks following initiation of up-titrated dose
measure: Absolute change in coronary cross-sectional area (in mm²) between the vericiguat group and the placebo group as assessed by Magnetic Resonance Imaging (MRI)
timeFrame: Baseline and 6 weeks following initiation of up-titrated dose
measure: Relative change in coronary cross-sectional area (as percentage) between the vericiguat group and the placebo group as assessed by Magnetic Resonance Imaging (MRI)
timeFrame: Baseline and 6 weeks following initiation of up-titrated dose
Secondary outcomes:
measure: Changes in interleukin 1 (IL-1) measured using blood samples (in pg/mL)
timeFrame: Baseline and 6 weeks following initiation of up-titrated dose
measure: Changes in interleukin 6 (IL-6) measured using blood samples (in pg/mL)
timeFrame: Baseline and 6 weeks following initiation of up-titrated dose
measure: Changes in interleukin 10 (IL-10) measured using blood samples (in pg/mL)
timeFrame: Baseline and 6 weeks following initiation of up-titrated dose
measure: Changes in tumor necrosis factor (TNF)-alpha measured using blood samples (in pg/mL)
timeFrame: Baseline and 6 weeks following initiation of up-titrated dose
measure: Changes in high sensitivity C-Reactive Protein (hsCRP) measured using blood samples (in mg/L)
timeFrame: Baseline and 6 weeks following initiation of up-titrated dose
measure: Changes in cyclic guanosine monophosphate (cGMP) measured using blood samples (in pmol/mL)
timeFrame: Baseline and 6 weeks following initiation of up-titrated dose
measure: Changes in left ventricular ejection fraction (as percentage) as assessed by echocardiography
timeFrame: Baseline and 6 weeks following initiation of up-titrated dose
measure: Changes in e' velocities (in cm/s) as assessed by echocardiography
timeFrame: Baseline and 6 weeks following initiation of up-titrated dose
measure: Changes in E/e' ratio as assessed by echocardiography
timeFrame: Baseline and 6 weeks following initiation of up-titrated dose
measure: Changes in left atrium volume index (in mL/BSA) as assessed by echocardiography
timeFrame: Baseline and 6 weeks following initiation of up-titrated dose
measure: Changes in peak tricuspid regurgitation (TR) velocity (in m/s) as assessed by echocardiography
timeFrame: Baseline and 6 weeks following initiation of up-titrated dose
measure: Changes in strain (as percentage) as assessed by echocardiography
timeFrame: Baseline and 6 weeks following initiation of up-titrated dose
measure: Absolute change in coronary flow (in mL/min) within the vericiguat group as assessed by Magnetic Resonance Imaging (MRI)
timeFrame: Baseline and 6 weeks following initiation of up-titrated dose
measure: Relative change in coronary flow (as percentage) within the vericiguat group as assessed by Magnetic Resonance Imaging (MRI)
timeFrame: Baseline and 6 weeks following initiation of up-titrated dose
measure: Absolute change in coronary flow (in mL/min) between the vericiguat group and the placebo group as assessed by Magnetic Resonance Imaging (MRI)
timeFrame: Baseline and 6 weeks following initiation of up-titrated dose
measure: Relative change in coronary flow (as percentage) between the vericiguat group and the placebo group as assessed by Magnetic Resonance Imaging (MRI)
timeFrame: Baseline and 6 weeks following initiation of up-titrated dose
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: Johns Hopkins Hospital
state: Maryland
Study officials:
affiliation: Johns Hopkins University
name: Thorsten M Leucker, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
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