Evaluation of Vericiguat on Microvascular Function in Patients with Documented Epicardial and Microvascular Vasospastic Angina: A Randomized Controlled Trial

The primary objective of the study is to determine the impact of **vericiguat** on microvascular function in patients with documented vasospastic angina pectoris using laser speckle contrast analysis (LASCA). This is clinically relevant as it may provide insights into the therapeutic potential of vericiguat in improving microvascular function, which is crucial for patients suffering from vasospastic angina, a condition characterized by spasms in the coronary arteries that can lead to chest pain and other cardiovascular complications.

Secondary objectives include:

• To determine the impact of vericiguat on microvascular function in patients with documented vasospastic angina pectoris using EndoPAT.
• To assess the impact of vericiguat on quality of life using the Seattle Angina Questionnaire, Rose Dyspnea Score, EQ-5D-5L, iPCQ, iMCQ, and the ORBITA-2 symptom smartphone app.
• To evaluate the impact of vericiguat on angina burden using the Seattle Angina Questionnaire and the ORBITA-2 symptom smartphone app.
• To assess the impact of vericiguat treatment on the occurrence of major adverse cardiovascular events.
• To characterize the pharmacokinetics of vericiguat in patients with vasospastic angina.
• To determine the safety profile of vericiguat treatment in patients with documented vasospastic angina pectoris.

The clinical trial involves participants diagnosed with **vasospastic angina pectoris**, specifically those with unequivocal epicardial and/or microvascular vasospastic angina. The study population includes both male and female subjects over the age of 18, with no specific upper age limit indicated. Participants are required to have recurrent angina symptoms provoked by exercise or repeated attacks of angina at rest at least once weekly, despite current medical treatment. The trial excludes individuals with flow-limiting coronary artery stenosis, defined by any coronary artery diameter reduction greater than 50% or specific fractional flow reserve measurements. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Participants were selected based on documented unambiguous epicardial and/or microvascular coronary vasospasm according to the COVADIS criteria, confirmed by invasive acetylcholine provocation testing. Female participants must meet specific reproductive health criteria, including post-menopausal status or the use of highly effective birth control methods. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the impact of **vericiguat** on microvascular function in patients with documented vasospastic angina pectoris. This is a Phase IV, randomized, double-blind, placebo-controlled study. The trial will span approximately two years, with an estimated recruitment start date in November 2024 and an anticipated end date in September 2026. Participants will be randomly assigned to receive either vericiguat or a placebo, with the primary endpoint being the difference in the area under the curve for cutaneous microvascular conductance during acetylcholine iontophoresis after 10-week treatment periods.

Study visits will follow a structured sequence, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, recurrent angina symptoms, and documented coronary vasospasm. Participants will then undergo baseline assessments before randomization. Follow-up visits will occur at regular intervals to monitor safety, adherence, and efficacy outcomes. The end-of-study visit will include final assessments and data collection. The expected length of participant involvement is approximately 20 weeks, including a 10-week treatment period and follow-up. Conditions that may lead to early termination from the study include adverse events, withdrawal of consent, or non-compliance with study procedures.

Throughout the trial, secondary endpoints will be evaluated, including differences in peak cutaneous microvascular conductance, vasodilator function, and quality of life measures. The study will also assess the occurrence of major adverse cardiac events. The trial aims to provide comprehensive data on the efficacy and safety of vericiguat in improving microvascular function in this patient population.

The clinical trial involves the administration of several experimental medications, including **Miovisin**, which contains the active substance **acetylcholine chloride**. Miovisin is provided as a powder and solvent for solution for injection, specifically for intraocular use. The concentration used for iontophoresis is 1%, with a maximum daily dose of 0.4 ml and a total treatment period of up to 3 days. The route of administration is iontophoresis, and the product is manufactured by Farmigea SPA.

Another experimental medication is **NIPRUSS**, containing **sodium nitroprusside dihydrate**. It is formulated as a powder for solution for infusion. The concentration for iontophoresis is 0.1%, with a maximum daily dose of 0.4 ml, administered over a maximum treatment period of 3 days. The route of administration is iontophoresis, and the product is manufactured by Altamedics GmbH.

**NovoRapid**, containing **insulin aspart**, is also included in the trial. It is provided as a solution for injection in a vial, with a maximum daily dose of 0.4 ml and a treatment period of up to 3 days. The administration route is iontophoresis, and the product is manufactured by Novo Nordisk A/S.

**MIOCHOL-E** is another experimental treatment, containing **acetylcholine chloride**. It is available as a powder and solvent for instillation solution for intraocular use. The concentration for iontophoresis is 1%, with a maximum daily dose of 0.4 ml and a treatment period of up to 3 days. The administration route is iontophoresis, and the product is manufactured by Dr. Gerhard Mann Chem.-Pharm. Fabrik GmbH.

The trial also includes **Verquvo**, containing **vericiguat**, available in film-coated tablets of 2.5 mg, 5 mg, and 10 mg. The maximum daily doses are 2.5 mg, 5 mg, and 10 mg, respectively, with treatment periods of up to 2 days for the 2.5 mg and 5 mg doses, and up to 6 days for the 10 mg dose. The route of administration is oral, and the product is manufactured by Bayer AG.

Non-experimental treatments in the study include placebo tablets, available in 2.5 mg, 5 mg, and 10 mg dosages. These are used as comparator treatments to evaluate the efficacy of the experimental medications. The placebo tablets are administered orally, with dosing schedules matching those of the corresponding Verquvo dosages.

The efficacy of the clinical trial titled "Vericiguat in Vasospastic Angina (ViVA)" will be assessed using both primary and secondary endpoints. The primary endpoint focuses on the difference in the area under the curve for cutaneous microvascular conductance in APU/s during acetylcholine iontophoresis after 10-week placebo versus 10-week vericiguat treatment periods. This will provide a quantitative measure of microvascular function improvement.

Secondary endpoints include a variety of measures to comprehensively evaluate the impact of vericiguat. These include:

• Difference in peak cutaneous microvascular conductance in APU/mmHg during acetylcholine iontophoresis.
• Difference in the absolute and relative change in cutaneous microvascular conductance from baseline to peak conductance.
• Assessment of vasodilator function using the Reactive Hyperemia Index (RHI) with EndoPAT.
• Microvascular function assessed with LASCA using SNP and insulin iontophoresis.
• Quality of life changes measured by the ORBITA-2 application, Seattle Angina Questionnaire, Rose Dyspnea Score, EQ-5D-5L, EQ-VAS, iPCQ, and iMCQ index scores.
• Angina burden calculated by the frequency of angina attacks using the ORBITA-2 application.
• Occurrence of major adverse cardiac events during the study period.

These endpoints will be measured and analyzed at specified timepoints, including baseline and after the 10-week treatment periods with placebo and vericiguat. The trial will utilize tools such as laser speckle contrast analysis (LASCA) and EndoPAT to assess microvascular function and vasodilator response. The study aims to provide a comprehensive evaluation of vericiguat's efficacy in improving microvascular function and quality of life in patients with vasospastic angina.