CLEAR Trial: A 2×2 factorial placebo-controlled trial of colchicine and spironolactone in patients with acute myocardial infarction (MI).

PI: Sanjit Jolly, Professor of Medicine, McMaster University, member of Canadian Association of Interventional trials network

Rationale: Colchicine: Inflammation is likely a key mechanism in atherosclerosis. Available randomized trials suggests that colchicine may reduce cardiovascular events but there are concerns regarding non CV mortality that need to be resolved from the largest trial. The finding of increased non-CV mortality may be spurious similar to the statin story or real and we are poised to resolve this in the CLEAR trial. Spironolactone: Similar to angiotensin receptor blockers, routine use of spironolactone in patients with acute MI (without heart failure), may be beneficial in preventing ventricular remodelling, heart failure and death.

Primary outcomes: The primary outcome for colchicine is CV death, MI or stroke and for spironolactone is CV death or new or worsening heart failure.

Power: The trial will have 80% power to detect a 25% relative risk reduction for a control event rate of 9%.

Blinding and Concealed Allocation: Patients, physicians and study staff are blinded as matching placebo is used. The Population Health Research Institute is the co-ordination site and uses computer randomization with variable block size ensuring concealed allocation.

Progress: We have recruited 7063 patients from 14 countries and completed recruitment on November 8, 2022. We expect to complete follow up in May 2024 with a median of 3 years of follow up and present in fall 2024. . There is 1.2 visits per patient left (approximately 8800 for 7062 patients) that are are due to happen before study close out.

Experience of Team and Co-ordination Centre: The group has successfully completed a number of large scale randomized trials including TOTAL, COMPLETE, OASIS 5, 6, 7 and 8 trials. Dr. Sanjit Jolly (PI), Jessica Tyrwhitt (Study manager) and Elizabeth Skuriat (Study Coordinator) are managing day to day operations of the trial. Senior clinical trialists Drs. Salim Yusuf, John Cairns, Shamir Mehta, John Eikelboom, PJ Devereaux are providing senior leadership on the steering committee of the trial. Senior statisticians Lehana Thabane and Shirikant Bangdiwala are providing biostatistical leadership for the trial. Dr. Lavi chairs the adjudication committee. Drs. Welsh, Sheth, Natarajan, Bertrand, Conen, Graham, Madan and Cantor are key recruiters. Dr. Schwalm is a KT expert and will develop strategies post trial implementation into practice.

Importance: Based on randomized trials, colchicine has a class IIB recommendation in patients with coronary artery disease. CLEAR will be the largest trial of colchicine and determine whether colchicine in acute myocardial infarction should be a class I indication. Both colchicine and spironolactone are widely available, inexpensive medications that can rapidly deployed to help the health of Canadians with acute myocardial infarction.

Trial funding: The trial was funded by 2 CIHR grants (total $5,204,224) and a grant from Boston Scientific ($7,284,00) and received in kind donation of study drugs from Tiofarma. However, due to 20% across the board cut from CIHR and delays due to COVID, we have a deficit and so this funding will be important to help us to complete the trial and allow us to complete median 3 year follow up. We confirm that we can complete the trial with this additional funding.

Will the trial be publicly reported by January 15, 2025: With recruitment complete and final visit expected in May 2024 for a median of 3 years of follow, the target would be a simultaneous publication and presentation in the fall of 2024 at major international meeting and a top tier journal (NEJM, JAMA or Lancet).

Co-ordination centre: The trial will be coordinated at the Population Health Research Institute (PHRI), McMaster University. The PHRI has coordinated large practice-changing trials in cardiology. Examples include HOPE[1] (N=9000), CURE[2] (N=12500), OASIS 5[3]and 6[4] (N=25000 & 12000, respectively), and RELY (N=18113), TOTAL[5] (N=10732) and COMPLETE[6] (N=4041). The study operations team will be supervised by Jessica Tyrhitt who has >10yrs of experience in managing large multicenter trials in ACS. All the data points required for this trial, from baseline to the follow-up visit, are being collected centrally by PHRI in electronic Case Report Forms (eCRFs), using the iDataFax database and randomization by the ROME electronic system.