BACKGROUND: Anti-inflammatory therapy with long-term colchicine prevented vascular recurrence in coronary disease. Unlike coronary disease, which is typically caused by atherosclerosis, ischaemic stroke is caused by diverse mechanisms including atherosclerosis and small vessel disease or is frequently due to an unknown cause. We aimed to investigate the hypothesis that long-term colchicine would reduce recurrent events after ischaemic stroke. METHODS: We did a randomised, parallel-group, open-label, blinded endpoint assessed trial comparing long-term colchicine (0·5 mg orally per day) plus guideline-based usual care with usual care only. Hospital-based patients with non-severe, non-cardioembolic ischaemic stroke or high-risk transient ischaemic attack were eligible. The primary endpoint was a composite of first fatal or non-fatal recurrent ischaemic stroke, myocardial infarction, cardiac arrest, or hospitalisation (defined as an admission to an inpatient unit or a visit to an emergency department that resulted in at least a 24 h stay [or a change in calendar date if the hospital admission or discharge times were not available]) for unstable angina. The p value for significance was 0·048 to adjust for two prespecified interim analyses conducted by the data monitoring committee, for which the steering committee and trial investigators remained blinded. The trial was registered at ClinicalTrials.gov (NCT02898610) and is completed. FINDINGS: 3154 patients were randomly assigned between Dec 19, 2016, and Nov 21, 2022, with the last follow-up on Jan 31, 2024. The trial finished before the anticipated number of outcomes was accrued (367 outcomes planned) due to budget constraints attributable to the COVID-19 pandemic. Ten patients withdrew consent for analysis of their data, leaving 3144 patients in the intention-to-treat analysis: 1569 (colchicine and usual care) and 1575 (usual care alone). A primary endpoint occurred in 338 patients, 153 (9·8%) of 1569 patients allocated to colchicine and usual care and 185 (11·7%) of 1575 patients allocated to usual care alone (incidence rates 3·32 vs 3·92 per 100 person-years, hazard ratio 0·84; 95% CI 0·68-1·05, p=0·12). Although no between-group difference in C-reactive protein (CRP) was observed at baseline, patients treated with colchicine had lower CRP at 28 days and at 1, 2, and 3 years (p<0·05 for all timepoints). The rates of serious adverse events were similar in both groups. INTERPRETATION: Although no statistically significant benefit was observed on the primary intention-to-treat analysis, the findings provide new evidence supporting the rationale for anti-inflammatory therapy in further randomised trials. FUNDING: Health Research Board Ireland, Deutsche Forschungsgemeinschaft (German Research Foundation), and Fonds Wetenschappelijk Onderzoek Vlaanderen (Research Foundation Flanders), Belgium.

AZ Oostende Ostend Belgium

Biomedical Research Institute of Lleida Universitat de Lleida Lleida Spain

Center for Clinical Trials Essen University Hospital Essen Essen Germany

Centre for Clinical Brain Sciences University of Edinburgh Edinburgh UK

Centre of Neurology Institute of Clinical Medicine Faculty of Medicine Vilnius University Vilnius Lithuania

Cork University Hospital Cork Ireland

Department of Clinical Neurosciences and Hotchkiss Brain Institute Cumming School of Medicine University of Calgary and Foothills Medical Centre Calgary AB Canada

Department of Clinical Neurosciences University of Cambridge Cambridge UK

Department of Neurology Amsterdam University Medical Centers Amsterdam Netherlands

Department of Neurology and Department of Geriatric and Stroke Medicine Tallaght University Hospital The Adelaide and Meath Hospital Dublin Ireland incorporating the National Children's Hospital and Academic Unit of Neurology School of Medicine Trinity College Dublin Dublin Ireland

Department of Neurology and Neurosurgery University of Tartu Tartu Estonia

Department of Neurology Herlev and Gentofte Hospital and Department of Brain and Spinal Cord Injury Rigshospitalet Hospital Copenhagen University Hospital Copenhagen Denmark

Department of Neurology University Hospital Bern and University of Bern Bern Switzerland

Department of Neurology University Hospitals Leuven Leuven Belgium

Department of Neurosciences and Mental Health Hospital Santa Maria CHLN Centro de Estudos Egas Moniz Faculdade de Medicina Universidade de Lisboa Lisbon Portugal

Department of Neurosciences Department of Experimental Neurology and Leuven Research Institute for Neuroscience and Disease KU Leuven University of Leuven Leuven Belgium

Health Research Board Stroke Clinical Trials Network Ireland Dublin Ireland

HRB Clinical Research Facility University of Galway Galway Ireland

Institute for Medical Informatics Biometry and Epidemiology University Hospital University Duisburg Essen Essen Germany

Institute of Psychiatry and Neurology Warsaw Poland

International Clinical Research Center and Department of Neurology St Anne's University Hospital and Masaryk University Brno Brno Czech Republic

Klinikum Main Spessart Lohr Germany

Mater Misericordiae University Hospital Dublin Ireland

Population Health Sciences Institute Newcastle University Newcastle UK

RCSI University of Medicine and Health Sciences and Beaumont Hospital Dublin Ireland

School of Medicine University College Cork Cork Ireland

School of Medicine University College Dublin Dublin Ireland

School of Medicine University of Limerick Limerick Ireland

Stroke Unit Department of Neurology CHC Groupe Santé Liège Belgium

Stroke Unit Department of Neurology Hospitalt Universitari Arnau de Vilanova de Lleida Lleida Spain

TCD Biostatistics Unit Discipline of Public Health and Primary Care School of Medicine Trinity College Dublin Dublin Ireland

University Hospital Monklands Airdrie UK

University Hospital of North Durham Durham UK

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