Aernoud Fiolet

120 Chapter 5 In contrast to selective inhibition of interleukin-1 β by canakinumab, colchicine has broad cellular effects that include inhibition of tubulin polymerization and alteration of leukocyte responsiveness. 8-10 In the Colchicine Cardiovascular Outcomes Trial (COLCOT) involving patients who had a myocardial infarction within 30 days before enrollment, the percentage of those who had the composite endpoint of cardiovasculardeath, resuscitated cardiac arrest,myocardial infarction, stroke, or urgent hospitalization for angina leading to coronary revascularization was lower among those who received 0.5 mg of colchicine once daily than among those who received placebo. 11 In an earlier trial of low-dose colchicine (LoDoCo) involving patients with chronic coronary disease, we found that the risk of acute cardiovascular events was lower among those who received 0.5 mg of colchicine once daily than among those who did not receive colchicine. 12 This was an open-label trial involving only 532 patients, and the results required confirmation. Accordingly, we conducted an investigator-initiated, randomized, controlled, double-blind, event-driven trial of low-dose colchicine (LoDoCo2) to determine whether 0.5 mg of colchicine once daily, as compared with placebo, prevents cardiovascular events in patients with chronic coronary disease. METHODS Trial design and oversight Patient recruitment in the LoDoCo2 trial commenced on August 4, 2014, at 13 centers affiliatedwithGenesisCare and theHeart andVascular Research Institute of Sir Charles Gairdner Hospital in Western Australia. On October 27, 2016, patient recruitment was expanded with the inclusion of 30 centers of the Dutch Network for Cardiovascular Research in the Netherlands. Enrollment was completed by December 3, 2018. The design of the trial has been published previously. 13 The trial protocol, available with the full text of this article at NEJM.org , was approved by a centralized institutional review board in each participating country. An independent data and safety monitoring board reviewed cumulative safety data to safeguard the well-being of the patients. Full details of the trial organization and a list of the trial sites and investigators are provided in the Supplementary Appendix, also available at NEJM.org . The academic and clinical investigators designed the study, collected and managed thedata, performed the statistical analyses, anddrafted themanuscript.The funders