1/2 Low dose colchicine in pAtients with peripheral artery DiseasE to assess residual vascular risk (LEADER-PAD)

This submission comprises two applications (Clinical and Statistical Data Coordinating Centers). We propose to enroll all 1000 US participants of a planned 6150 multinational participants in a randomized, double blind, placebo-controlled international trial - LEADER-PAD – comparing low dose colchicine 0.5 mg/daily with placebo

in patients with peripheral artery disease (PAD). This is the first trial designed to establish whether targeting inflammation with a widely available anti-inflammatory drug could reduce the risk of both cardiovascular and limb-related outcomes. The US trial leadership is comprised of an experienced group of investigators in a Clinical

Coordination Center (CCC; Duke Clinical Research Institute, Durham, NC), a Statistical and Data Coordination Center (SDCC; Duke Clinical Research Institute, Durham, NC and Population Health Research Institute, Hamilton, ON) and a diverse Executive and Steering Committee of experts in the field representing clinicians,

trialists, and patient advocates. Lower extremity PAD impacts over 200 million patients worldwide and is associated with high morbidity and mortality. Patients with PAD have a 6-fold increased risk of dying of a cardiovascular event compared with patients without PAD. In a recent systematic review by investigators at PHRI

comprising five trials and 11,816 patients with coronary disease, colchicine significantly reduced the risk of myocardial infarction, stroke, or cardiovascular death by 25%. A pilot vanguard trial is underway in Canada comparing low dose colchicine with placebo in patients with lower extremity PAD and has successfully

randomized 118 patients with 92% adherence to colchicine. Herein we propose the U.S. portion of the randomized LEADER-PAD trial with enrollment occurring at 44 centers in the US and an innovative, yet proven centralized telephone follow-up to 1) ease participant travel burden and 2) avoid pandemic and staffing related

disruptions. The trial duration is 48 months plus 6-month start-up and 6-month closeout. Average follow-up is 2.3-years with a minimum of 14 months and maximum of 4-years for individuals enrolled early. LEADER-PAD will have 90% power to detect a 23% reduction in the composite primary efficacy endpoint (major adverse

cardiovascular and limb events). There will be prespecified subgroup analyses by race / ethnicity and sex as well as by baseline high sensitivity c-reactive protein, a marker of inflammation. Secondary endpoints include cardiovascular death, myocardial infarction, stroke, and severe limb ischemia requiring an intervention including

major vascular amputation, total vascular amputation, overall mortality, venous or arterial thromboembolism, as well as health-related quality of life and functional status outcomes. The multinational statistical coordinating center is PHRI and the proposed CCC leverages DCRI’s prior relationship with US sites enrolling into PAD

studies; while the proposed SDCC for U.S. enrollment into LEADER-PAD leverages PHRI’s statistical expertise and role as the multinational statistical coordinating center and DCRI’s unique expertise in centralized follow-up. LEADER-PAD has received GCRFF approval as a multinational clinical trial application.