Inflammation is an important pathophysiological contributor to unstable atherosclerotic plaque, thrombo-embolic stroke, myocardial infarction, and vascular death. Internationally, clinical trials are targeting atherosclerotic inflammation in patients with coronary disease using methotrexate and colchicine. The CANTOS trial recently reported a significant reduction in risk of vascular events in patients with coronary disease treated with canukinumab, an interleukin-1B antagonist, with greatest efficacy in patients with lowest on-treatment CRP (HR 0.75, CI 0.66-0.85, p<0.001). CONVINCE is the only international trial targeting atherosclerotic inflammation for secondary prevention after non-cardioembolic stroke/TIA.
Aims:
The primary aim is to compare low-dose colchicine (0.5mg/day) plus usual care, to usual care alone, to prevent non-fatal recurrent ischaemic stroke/coronary events/vascular death after non-severe, non-cardioembolic TIA/stroke.
Secondary objectives will investigate safety, efficacy for secondary key outcomes (eg. fatal/non-fatal events), effect modification by pre-specified subgroups, and health-economic analysis.
Methods:
A Prospective, Randomised Open-label, Blinded-Endpoint assessment (PROBE) controlled Phase 3 clinical trial. Intervention is colchicine 0.5mg/day, and usual care defined as antiplatelet, lipid-lowering, antihypertensive treatment, and lifestyle advice.
Inclusion criteria:
1. Written consent
2. Age ≥40
3. Non-severe ischaemic stroke (modified Rankin score ≤3) or high-risk TIA (ABCD2>3, positive DWI, cranio-cervical artery stenosis)
4. Onset 72 hours-28 days pre-randomization
5. Qualifying stroke/TIA probably caused by large artery stenosis, lacunar disease, or cryptogenic embolism
6. GFR >50 ml/min.
Patients with stroke/TIA caused by cardio-embolism or other defined cause (eg. dissection), contra-indication to colchicine, or incapacity for participation in a clinical trial are excluded.
The anticipated median follow-up will be 36 months. The Primary analysis will be by intention-to-treat, comparing time to primary outcome in colchicine-treated and usual-care groups via a log-rank test with hazard ratios. Pre-specified secondary analyses will be performed.
CONVINCE is currently funded for 2,630 participants and is under way (recruiting or site roll-out in progress) in 9 European countries (128 patients randomised). However recent trials report reductions in post-stroke recurrence rates compared to earlier studies. Therefore, as a precaution to ensure adequate statistical power, the sample size will be increased to 3,592 patients. This application is to expand into 6 European countries and Canada, to recruit 500 of required additional patients.