Evaluation of Allopurinol on Cardiovascular Event Risk in Patients with High Cardiovascular Risk and Long-COVID Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this study is to evaluate the efficacy of **allopurinol** in reducing cardiovascular risk in patients with high and very high cardiovascular risk, including those over 60 years of age. This is clinically relevant as it addresses the potential of allopurinol to mitigate cardiovascular events in a population at significant risk, which may include conditions such as hyperuricemia, hypertension, ischemic stroke, intracerebral hemorrhage, transient ischemic attack (TIA), heart failure, peripheral arterial disease, atrial fibrillation, and diabetes mellitus. The study also considers the presence of long-COVID syndrome, which may further complicate cardiovascular health. No secondary objectives are specified in the provided data.

The clinical trial involves participants aged between **40 and 70 years** who are at very high and high cardiovascular risk. The study population includes both male and female subjects, with no vulnerable populations selected. Participants are required to have a serum uric acid level above 5 mg/dl within the last six months and must provide informed consent to participate. The trial targets individuals with conditions such as **hyperuricemia**, hypertension, ischemic stroke, intracerebral hemorrhage, transient ischemic attack (TIA), heart failure, peripheral arterial disease, atrial fibrillation, and diabetes mellitus. The sponsor has not provided the total number of participants. The selection criteria focus on individuals with a calculated 10-year risk of death from cardiovascular causes according to SCORE2, documented cardiovascular diseases, or diabetes or hypertension complicated by organ damage. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the effect of **allopurinol** on the risk of cardiovascular events in patients with high and very high cardiovascular risk, including those with long-COVID syndrome. The trial aims to determine whether allopurinol can reduce cardiovascular risk in the entire study population and specifically in individuals over 60 years of age. The study will involve participants aged between 40 and 70 years who have given informed consent and have serum uric acid levels above 5 mg/dL within the last six months. Participants must meet at least one criterion for very high or high cardiovascular risk, such as a calculated 10-year risk of death from cardiovascular causes according to SCORE2, documented cardiovascular diseases, or diabetes or hypertension complicated by organ damage.

The trial will span approximately five years, with an estimated recruitment start date of March 1, 2023, and an estimated end date of May 30, 2028. Participants will be randomly assigned to receive either allopurinol or a placebo, administered orally in tablet form. The maximum daily dose of allopurinol is 500 mg, with a maximum treatment period of 260 days. The primary endpoint is the occurrence of a major cardiovascular event (MACE), including all-cause death, cardiac death, stroke/TIA, acute coronary syndrome, and other related events. Secondary endpoints include individual MACE components, hospitalization for other reasons, assessment of organ complications, and the occurrence of long-COVID-19 symptoms.

Study visits will include an initial screening visit to confirm eligibility based on inclusion criteria, followed by regular follow-up visits to monitor treatment efficacy, safety, and the occurrence of any adverse events. The end-of-study visit will assess the overall outcomes and any long-term effects of the treatment. Participants are expected to be involved in the study for the entire duration unless they meet conditions for early termination, such as withdrawal of consent, non-compliance with study procedures, or the occurrence of significant adverse events. The trial is conducted in accordance with ethical guidelines and regulatory requirements to ensure the safety and well-being of all participants.

The clinical trial involves the administration of **Allopurinol**, marketed under the name Milurit, as the experimental medication. Milurit is formulated as a 200 mg **tablet** and is intended for **oral use**. The maximum daily dose of Allopurinol is 500 mg, with a total maximum dose of 500 mg over the course of the treatment period, which extends up to 260 days. The active substance, Allopurinol, is of chemical origin and is provided by EGIS PHARMACEUTICALS PLC. The trial aims to evaluate the effect of Allopurinol on reducing cardiovascular risk in patients with high and very high cardiovascular risk, including those with Long-COVID Syndrome.

The study also includes a **placebo** group, which consists of tablets containing **microcrystalline cellulose** and **magnesium stearate**. These substances are used as inactive ingredients to mimic the appearance and administration route of the active treatment, ensuring the double-blind nature of the trial. The placebo tablets are also administered orally, maintaining consistency with the experimental treatment. Compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the occurrence of a major cardiovascular event (MACE), which includes all-cause death, cardiac death, stroke/transient ischemic attack (TIA), acute coronary syndrome, coronary artery angioplasty or revascularization, peripheral arterial angioplasty, hospitalization for unstable angina, or worsening heart failure. Secondary endpoints will include the evaluation of individual MACE components, hospitalization for reasons other than the primary endpoint, and the assessment of the progression and/or development of organ complications and atherosclerosis. This will involve echocardiography, electrocardiographic examination for atrial fibrillation, ultrasound examination of the abdominal aorta, Doppler ultrasound of the carotid arteries, and the assessment of the ankle-brachial index.

Additional secondary endpoints include the occurrence of long-COVID-19 symptoms, the attainment of target serum uric acid levels of 5 mg/dL or 5.5 mg/dL depending on baseline values, and the assessment of other laboratory parameters such as estimated glomerular filtration rate (eGFR), albumin-to-creatinine ratio, urinary albuminuria, HbA1c, lipid profile, plasma C-reactive protein concentrations, and the activity of aspartate and alanine transaminases (AspAT, AlAT). The frequency of side effects and changes in participants' cardiovascular risk based on the Systematic Coronary Risk Evaluation (SCORE) 2 scale will also be evaluated. These assessments will be conducted using validated scales and laboratory tests at specified timepoints throughout the trial duration.