Evaluation of Bosentan in the Management of Coronary Vasospasm: A Randomized Controlled Trial

The primary objective of this study is to evaluate whether **bosentan** therapy, when used adjunctively, can reduce the rate of epicardial vasospasm during follow-up spasm provocation testing in patients with previously confirmed epicardial vasospasm and ongoing angina-like symptoms. This is clinically relevant as it addresses the management of **coronary vasospasm**, a condition that can lead to significant morbidity due to its association with angina and potential myocardial ischemia.

Secondary objectives include:

• Assessing the efficacy of bosentan on anginal complaints using the SAQ summary score.
• Exploring the quality of life at 10 weeks using the EQ-5D scale.
• Evaluating differences in circulating endothelin levels at baseline.
• Assessing the safety and feasibility of bosentan treatment in this specific patient population.
• Exploring the efficacy of adjunctive bosentan treatment in reducing anginal complaints across different SAQ domains.
• Investigating whether bosentan more frequently changes epicardial to microvascular spasm compared to placebo and if this correlates with changes in anginal complaints.
• Assessing the effect of bosentan on coronary reactivity during repeat spasm provocation tests, specifically at what acetylcholine dose spasm occurs.

The clinical trial focuses on patients diagnosed with **coronary vasospasm**, specifically those with epicardial vasospasm confirmed through acetylcholine reactivity testing. The study population includes both male and female participants, aged 18 years and older, who are experiencing ongoing angina-like symptoms despite optimal regular care, which includes treatment with at least two daily antianginal medications such as nitrates and calcium channel blockers. Participants are required to have signed informed consent for participation. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity.

The clinical trial is designed to evaluate the efficacy of **bosentan** in the treatment of **coronary vasospasm**. This is a **randomized, controlled** trial with a double-blind design to ensure unbiased results. The trial will span approximately 20 months, with an estimated recruitment start date in September 2024 and an anticipated end date in May 2026. Participants will be randomly assigned to receive either bosentan or a placebo, with the primary objective being the reduction of epicardial vasospasm at follow-up spasm provocation testing.

Study visits are structured to include an initial screening visit, where eligibility is confirmed based on criteria such as a definitive diagnosis of epicardial vasospasm and ongoing angina-like complaints despite optimal care. Participants must be at least 18 years old and provide informed consent. Following the screening, participants will undergo baseline assessments before randomization. The treatment period will last up to 6 weeks, during which participants will have regular follow-up visits to monitor their response to the treatment and any adverse events. The primary endpoint is the absence of epicardial vasospasm during a repeat spasm provocation test at 10 weeks, assessed according to COVADIS criteria.

Secondary endpoints include angina relief, changes in quality of life, and safety assessments through laboratory analyses and monitoring of adverse cardiovascular events. The end-of-study visit will occur at the conclusion of the treatment period, where final assessments will be conducted. Participant involvement is expected to last approximately 10 weeks, with conditions for early termination including significant adverse events or withdrawal of consent. The trial aims to provide valuable insights into the potential benefits of bosentan as an adjunctive therapy for coronary vasospasm.

The clinical trial involves the administration of **Bosentan**, an endothelin receptor antagonist, in two different dosages. The first experimental medication is **Bosentan Aurobindo 62.5 mg film-coated tablets**. This pharmaceutical form is administered orally. The maximum daily dose is 125 mg, with a total maximum dose of 4375 mg over a treatment period of 4 weeks. The active substance, **Bosentan**, is of chemical origin and is classified under the ATC code C02KX01. The medication is manufactured by Aurobindo Pharma B.V. and is not a paediatric formulation.

The second experimental medication is **Bosentan Aurobindo 125 mg film-coated tablets**. This formulation is also administered orally. The maximum daily dose for this medication is 250 mg, with a total maximum dose of 10500 mg over a treatment period of 6 weeks. Like the 62.5 mg formulation, the active substance is **Bosentan**, and it is produced by Aurobindo Pharma B.V. This formulation is also not intended for paediatric use.

The trial includes a **placebo** as a non-experimental treatment to serve as a comparator. The placebo is formulated as an oral powder containing **microcrystalline cellulose**. The placebo is administered orally, with a maximum daily dose of 125 mg and a total maximum dose of 4375 mg over a 4-week treatment period. The placebo is used to assess the efficacy of the experimental medications by providing a baseline for comparison.

Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen. The trial aims to evaluate the efficacy of **Bosentan** in reducing the rate of epicardial vasospasm in patients with coronary artery spasm, as compared to the placebo.

Efficacy in this clinical trial will be assessed by evaluating the impact of adjunctive bosentan therapy compared to placebo on the rate of epicardial vasospasm in patients with previously proven epicardial vasospasm. The primary endpoint for efficacy is defined as the absence of epicardial vasospasm according to COVADIS criteria during a repeat spasm provocation test at 10 weeks. Secondary endpoints include the assessment of angina relief, measured by the mean within-subject change in the Seattle Angina Questionnaire Summary Score (SAQSS) from baseline to 10 weeks, and comparisons between the bosentan and placebo groups.

Additional exploratory endpoints will evaluate anginal complaints, quality of life, microvascular spasm, endothelin levels, and the overall improvement, deterioration, or no effect on spasm. Safety will also be monitored through repeat laboratory analyses, blood pressure measurements, and the occurrence of major adverse cardiovascular events (MACE) and other adverse events such as hospitalization for hypotension, angina, or myocardial infarction. The rate and reason for study drug discontinuation or study withdrawal will also be documented. Efficacy assessments will be conducted at specified timepoints, including baseline and at the 10-week follow-up.