Aernoud Fiolet

140 Chapter 5 Supplemental statistical section The primary hypothesis of the trial was that the colchicine 0.5mg once-daily would be superior to placebo with respect to the time from randomization to the first occurrence of any component of the primary composite end point of cardiovascular death, myocardial infarction, ischemic stroke or ischemia-driven coronary revascularization. LoDoCo2 was an event-driven trial powered to detect a hazard ratio of 0.7 in the primary end point. This effect size was chosen as it was beyond the upper limit of the confidence interval of the hazard ratio of the initial LoDoCo trial (hazard ratio, 0.33; 95% confidence interval, 0.18 - 0.59) but still clinically meaningful. Based upon these assumptions it was estimated that a minimum of 331 primary events would be required in order to detect such an effect with >90% power (two-sided alpha level of 0.05). With an expected annual primary event rate of 2.6% in the placebo group and the assumption that up to 10% of participants would report early intolerance to therapy, the trial aimed to enrol 6,053 screened patients, expecting 5,447 to be randomized (divided over both continents). Furthermore, the protocol required a minimum follow-up of one year for every participant. The sample size determination of the original protocol was based on a fixed sample size and a duration of follow-up of 3 years, 80% power to detect a relative risk reduction of 30% with an expected cumulative event rate of 8.4% for colchicine versus 12% for placebo for the composite of cardiovascular death, acute coronary syndrome, non-cardioembolic ischemic stroke, or out-of-hospital cardiac arrest. When The Netherlands joined the trial, the primary end point was changed and two major changes were made to the sample size determination: the power was increased from 80% to 90% and the trial became event-driven (331 events). The list of end points, including the primary end point, was revised several times during the trial; the latest and final revision took place in January 2020 (before the data were unblinded). In late 2018, the Steering Committee decided to terminate recruitment by 3 rd November 2018, because it was expected that the minimum required number of participants with a primary end point, with the prerequisite of the minimum follow-up of at least one year after randomization, could be accrued by then. Global end of trial date was set as 4th December 2019 (midnight 3 rd to 4 th December), after which a close-out visit was planned for all participants alive.