Evaluation of Colchicine in Patients with Ischemia and Coronary Microvascular Dysfunction: A Randomized, Placebo-Controlled Trial

The primary objective of this study is to evaluate the efficacy of **colchicine** in improving coronary flow and coronary flow reserve in patients presenting with angina symptoms and coronary microvascular disease (CMD). This is clinically relevant as CMD is a condition that can lead to significant cardiac symptoms and morbidity despite the absence of obstructive coronary artery disease, and improving coronary flow could potentially alleviate symptoms and improve patient outcomes.

Secondary objectives include:

• Assessing the improvement of symptom burden with colchicine.
• Determining the effect of colchicine on arterial reactivity and proteomic profiles.
• Investigating the mechanism underlying CMD through small artery analysis.

The clinical trial involves participants diagnosed with **coronary microvascular disease** (CMD), specifically those exhibiting angina symptoms. The study population includes both male and female subjects, with an age range spanning from 18 to 64 years. Participants were selected based on specific criteria, including a myocardial blood flow reserve (MBFR) of less than 2.5 or a hyperemic myocardial blood flow (hMBF) of less than 2.3 ml/g/min, and the absence of obstructive coronary artery disease as determined by clinical assessment using [15O]H2O-PET. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Lifestyle factors such as diet, physical activity, and habits were not specified in the available data.

The clinical trial is designed to evaluate the efficacy of **colchicine** in patients with coronary microvascular disease (CMD) and ischemia without obstructive coronary artery disease. This is a randomized, double-blind, placebo-controlled trial, conducted over a period of six months. Participants will be randomly assigned to receive either colchicine 500 microgram tablets or a placebo, administered orally. The primary objective is to assess changes in myocardial blood flow reserve using [15O]H2O-PET scans from baseline to the end of the study. Secondary endpoints include changes in symptom burden, vascular function, and protein pathway analyses.

The trial will commence with a screening visit to confirm eligibility based on inclusion criteria, such as having CMD with specific myocardial blood flow parameters and no obstructive coronary artery disease. Following successful screening, participants will be enrolled and randomized. Study visits will occur at baseline, mid-study, and at the end of the six-month period. Each visit will involve assessments including PET scans, symptom questionnaires, and blood tests for protein pathway analysis. The end-of-study visit will include a final evaluation of all primary and secondary endpoints.

Participant involvement is expected to last approximately six months, with the possibility of early termination if significant adverse events occur or if the participant withdraws consent. The trial is anticipated to start recruitment in February 2024 and conclude by May 2026. The study is not classified as low intervention and is categorized as a Phase 4 trial, focusing on a well-known drug in a new patient population. The trial will adhere to rigorous ethical standards and regulatory requirements to ensure participant safety and data integrity.

The clinical trial involves the administration of **Colchicine 500 microgram Tablets** as the primary experimental medication. Colchicine is provided in tablet form and is administered orally. The dosage is set at 0.5 mg per day, with a maximum total dose of 100 mg over a treatment period of up to 6 months. The tablets are packed into trial-drug-containers as specified in the study protocol. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen.

In addition to colchicine, the trial includes the use of **ADENOSINE** as an auxiliary treatment. Adenosine is administered as an injectable solution, with a maximum daily dose of 100 units. The administration is limited to a single day, serving as a heart stressor in the study. The precise dosing and administration schedule are determined by the study protocol, and participant response is closely monitored.

Another auxiliary treatment used in the trial is **REGADENOSON**, which is administered via intravenous injection/infusion or intramuscular injection. The maximum daily dose is 10 ml, with a total maximum dose of 20 ml, administered over a single day. Regadenoson acts as a heart stressor, and its administration is carefully controlled and monitored according to the study protocol.

A **PLACEBO** is also utilized in the trial as a comparator treatment. The placebo is provided in tablet form and administered orally, mirroring the administration schedule of colchicine. The dosage is set at 0.5 mg per day, with a maximum total dose of 100 mg over a treatment period of up to 6 months. The use of a placebo allows for the assessment of colchicine's efficacy and safety in comparison to a non-active treatment.

Additionally, **local anesthetics** are employed as auxiliary treatments in the trial. These are administered subdermally, with a maximum daily dose of 50 ml and a total maximum dose of 100 ml, limited to a single day of administration. The use of local anesthetics is intended to support the primary and auxiliary treatments, ensuring participant comfort and compliance with the study protocol.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the change in **myocardial bloodflow reserve** (MBFR) as assessed by [15O]H2O-PET scan from baseline to six months. This measurement will provide insight into the improvement of coronary flow and coronary flow reserve in patients with angina symptoms and coronary microvascular disease.

Secondary endpoints include changes in symptom burden, which will be evaluated using the Seattle Angina Questionnaire at baseline and after six months. Additionally, the trial will investigate changes in myocardial blood flow (MBF) and hyperemic myocardial blood flow (hMBF) using [15O]H2O-PET scans at the same timepoints. The study will also explore protein pathways and functional mechanisms in arteries associated with colchicine treatment, as well as changes in vascular function and protein pathway analyses in subsamples.

The efficacy parameters will be collected and analyzed at baseline and after six months of treatment. The use of validated tools such as the Seattle Angina Questionnaire and [15O]H2O-PET scans ensures the reliability and accuracy of the data collected. These assessments will provide comprehensive insights into the therapeutic effects of colchicine in patients with coronary microvascular disease.