Evaluation of Colchicine and Thiamine Hydrochloride in Patients with Heart Failure Secondary to Ischemic Heart Disease: A Randomized Controlled Trial

The primary objective of the study titled "COLchicine and Thiamine in Heart Failure due to Ischemic Heart Disease (COLT-HF)" is to evaluate the impact of **colchicine** and **thiamine** in individuals with heart failure secondary to ischemic heart disease. Specifically, the study aims to assess:

• The effect of colchicine compared to placebo on the composite outcome of cardiovascular death, a heart failure event (defined as heart failure hospitalization or urgent heart failure visit), or ischemic cardiovascular events, including myocardial infarction, ischemic stroke, or arterial revascularization.
• The effect of thiamine on the composite outcome of cardiovascular death or heart failure hospitalization.

These objectives are clinically relevant as they address the potential of colchicine and thiamine to reduce significant adverse cardiovascular outcomes in patients with heart failure due to ischemic heart disease, which could lead to improved patient management and outcomes.

The secondary objectives include determining whether colchicine and thiamine reduce the risk of death from any cause and hospitalization from any cause. These objectives further explore the broader impact of these treatments on overall mortality and morbidity, providing additional insights into their potential benefits in this patient population.

The clinical trial involves a total of **2200 participants** diagnosed with **heart failure** secondary to ischemic heart disease. The study population includes both male and female subjects, aged 45 years and older, who exhibit symptoms classified as NYHA class II-IV. Participants have a documented left ventricular ejection fraction of 45% or less within one year prior to enrollment and are receiving optimal medical treatment for heart failure according to local clinical practice. The trial population was selected based on the presence of ischemic heart disease as the etiology of heart failure, with a history of coronary artery disease and a determination of the cause of heart failure due to ischemic heart disease. Participants can be enrolled in either an ambulatory or hospitalized setting. The study does not include a vulnerable population, and no specific lifestyle considerations such as diet or physical activity are highlighted in the selection criteria.

The clinical trial is designed to evaluate the effects of **colchicine** and **thiamine** in patients with **heart failure** secondary to ischemic heart disease. This study employs a phase III, 2x2 factorial, randomized, open-label, blinded-endpoint (PROBE) design. Participants will be randomly assigned to receive either colchicine or a placebo, and thiamine or no thiamine, to assess the independent effects of these interventions. The primary endpoints include the composite of cardiovascular death, heart failure events, or ischemic cardiovascular events for the colchicine arm, and cardiovascular death or heart failure events for the thiamine arm. Secondary endpoints encompass all-cause death, hospitalization, serious adverse events, and side effects leading to study drug discontinuation.

The trial is expected to commence recruitment on September 1, 2024, and conclude by April 30, 2028. Participants will be involved in the study for a maximum treatment period of 48 weeks. The study will include several key visits: an initial screening visit to confirm eligibility based on criteria such as age, documented ischemic heart disease, and left ventricular ejection fraction, followed by regular follow-up visits to monitor health status, adherence to the treatment regimen, and any adverse events. The end-of-study visit will assess the final outcomes and gather data on the primary and secondary endpoints.

Participants may be withdrawn from the study early if they experience serious adverse events, fail to adhere to the study protocol, or if the investigator deems it necessary for their safety. The trial aims to provide valuable insights into the potential benefits of colchicine and thiamine in managing heart failure due to ischemic heart disease, contributing to the optimization of treatment strategies for this condition.

The clinical trial involves the administration of **Benerva 300 mg gastro-resistant tablets**, which contain the active substance **thiamine hydrochloride**. This medication is provided in the form of a gastro-resistant tablet, designed to prevent the release of the active ingredient until it reaches the intestines. The dosage for this trial is set at 300 mg per day, administered orally. The maximum treatment period is 48 weeks. The medication is manufactured by TEOFARMA S.R.L. and is classified under the ATC code A11DA01, which corresponds to thiamine (vitamin B1). Participant compliance with the dosing schedule will be monitored throughout the study.

Another experimental treatment in the trial is **COLCHICINA LIRCA 0.5 mg tablets**, containing the active substance **colchicine**. This medication is provided in tablet form and is administered orally at a dosage of 0.5 mg per day. The treatment duration is also set for a maximum of 48 weeks. The manufacturer of this product is ACARPIA FARMACEUTICI S.R.L., and it is classified under the ATC code M04AC01, which pertains to colchicine. Compliance with the prescribed dosing regimen will be closely monitored to ensure adherence.

The study also includes a **placebo tablet** that matches the appearance of the COLCHICINA LIRCA tablets. This placebo is used as a comparator treatment to evaluate the efficacy of colchicine in the trial. The placebo does not contain any active pharmaceutical ingredients and is administered in the same manner as the colchicine tablets, ensuring blinding of the study participants and investigators. The placebo administration will follow the same schedule as the active treatment, and participant adherence will be monitored to maintain the integrity of the trial results.

Efficacy in the clinical trial titled "COLchicine and Thiamine in Heart Failure due to Ischemic Heart Disease (COLT-HF)" will be assessed through a series of primary and secondary endpoints. The primary endpoints for the trial are defined separately for the two treatment arms. In the **colchicine** arm, efficacy will be evaluated based on a composite outcome of cardiovascular (CV) death, heart failure (HF) event, or ischemic cardiovascular event, which includes myocardial infarction, ischemic stroke, or arterial revascularization. For the **thiamine** arm, the primary endpoint is a composite of CV death or HF event.

Secondary endpoints include all-cause death, hospitalization, serious adverse events, and side effects or adverse events that result in the discontinuation of the study drug. The trial employs a prospective, randomized, open-label, blinded-endpoint (PROBE) design to ensure objective assessment of these outcomes. The trial is structured as a phase III, 2x2 factorial randomized controlled trial (RCT) to independently test the effects of colchicine versus placebo and thiamine versus no thiamine (control) in participants with heart failure secondary to ischemic heart disease (IHD).