Colchicine for prevention of vascular inflammation in Non-CardioEmbolic stroke (CONVINCE) – study protocol for a randomised controlled trial

Abstract

Background Inflammation contributes to unstable atherosclerotic plaque and stroke. In randomised trials in patients with coronary disease, canukinumab (an interleukin-1B antagonist) and colchicine (a tubulin inhibitor with pleiotropic anti-inflammatory effects) reduced recurrent vascular events. Hypothesis: Anti-inflammatory therapy with low-dose colchicine plus usual care will reduce recurrent vascular events in patients with non-severe, non-cardioembolic stroke and TIA compared with usual care alone. Design CONVINCE is a multi-centre international (in 17 countries) Prospective, Randomised Open-label, Blinded-Endpoint assessment (PROBE) controlled Phase 3 clinical trial in 3154 participants. The intervention is colchicine 0.5 mg/day and usual care versus usual care alone (antiplatelet, lipid-lowering, antihypertensive treatment, lifestyle advice). Included patients are at least 40 years, with non-severe ischaemic stroke (modified Rankin score ≤3) or high-risk TIA (ABCD2 > 3, or positive DWI, or cranio-cervical artery stenosis) within 72 hours-28 days of randomisation, with qualifying stroke/TIA most likely caused by large artery stenosis, lacunar disease, or cryptogenic embolism. Exclusions are stroke/TIA caused by cardio-embolism or other defined cause (e.g. dissection), contra-indication to colchicine (including potential drug interactions), or incapacity for participation in a clinical trial. The anticipated median follow-up will be 36 months. The primary analysis will be by intention-to-treat. Outcome The primary outcome is time to first recurrent ischaemic stroke, myocardial infarction, cardiac arrest, or hospitalisation with unstable angina (non-fatal or fatal). Summary CONVINCE will provide high-quality randomised data on the efficacy and safety of anti-inflammatory therapy with colchicine for secondary prevention after stroke. Schedule First-patient first-visit was December 2016. Recruitment to complete in 2021, follow-up to complete in 2023.

Immune Pathways in Etiology, Acute Phase, and Chronic Sequelae of Ischemic Stroke

“…The ongoing CONVINCE trial (Colchicine for Prevention of Vascular Inflammation in Non-CardioEmbolic Stroke) seeks to fill this gap by including patients 3 to 28 days after noncardioembolic strokes or high-risk transient ischemic attack randomized to treatment with 0.5 mg colchicine or placebo and follow-up for 36 months. 58 Other anti-inflammatory agents or targets being tested in vascular high-risk cohorts include P-selectin, p38 mitogen-activated protein (MAP) kinase, phospholipases, salicylates, or n-3 fatty acids. 6,59,60 However, global anti-inflammatory therapies may ultimately remain a blunt instrument because of the important role of both context-dependent and time-dependent changes in innate and adaptive immunity.…”

The Potential Impact of Neuroimaging and Translational Research on the Clinical Management of Lacunar Stroke

“…Anti-inflammatory drugs: colchicine in non-cardioembolic strokes (CONVINCE) [40], uric acid (URICO-ICTUS) [41], and canakinumab [42]. BBB: blood-brain barrier; CONVINCE: colchicine for prevention of vascular inflammation in non-cardioembolic stroke; LACI-2: lacunar intervention trial-2; RSSI: recent small subcortical infarcts; SVD: small vessel disease; SPARCL: stroke prevention by aggressive reduction in cholesterol levels; SPS3: secondary prevention of small subcortical stroke trial; URICO-ICTUS: uric acid in patients with acute stroke trial; WMH: white matter hyperintensities.…”

“…Colchicine is an anti-inflammatory drug with different mechanisms of action, including microtubule disruption, neutrophile targeting, and inhibition of inflammasome-mediated IL-1β maturation [196]. The CONVINCE is a phase III PROBE design trial that will assess the efficacy of colchicine in patients with non-severe, non-cardioembolic stroke or high-risk TIA [40]. Canakinumab is a therapeutic monoclonal antibody targeting interleukin-1β innate immunity that reduced cardiovascular events in patients with myocardial infarction and high CRP levels.…”

Colchicine for Coronary Artery Disease: A Review

“…Unfortunately, clinical trials of colchicine for peripheral artery disease are few. The Ongoing CONVINCE study with high-quality randomized data will prove colchicine for secondary prevention after stroke is effective and safety ( 62 ). An ongoing LEADER-PAD study will provide some information on PAD.…”