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

Peter Kelly; Christian Weimar; Robin Lemmens; Sean Murphy; Francisco Purroy; Anita Arsovska; Natan M Bornstein; Anna Czlonkowska; Urs Fischer; Ana Catarina Fonseca; John Forbes; Michael D Hill; Dalius Jatuzis; Janika Kõrv; Christina Kruuse; Robert Mikulik; Paul J Nederkoorn; Martin O'Donnell; Peter Sandercock; David Tanne; Georgios Tsivgoulis; Cathal Walsh; David Williams; Marialuisa Zedde; Christopher I Price

doi:10.1177/2396987320972566

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

Eur Stroke J. 2021 Jun;6(2):222-228. doi: 10.1177/2396987320972566. Epub 2021 Jun 18.

Authors

Peter Kelly^{1

2}, Christian Weimar³, Robin Lemmens^{4

4

5}, Sean Murphy^{1

2}, Francisco Purroy^{6

7}, Anita Arsovska⁸, Natan M Bornstein⁹, Anna Czlonkowska¹⁰, Urs Fischer¹¹, Ana Catarina Fonseca¹², John Forbes¹³, Michael D Hill¹⁴, Dalius Jatuzis¹⁵, Janika Kõrv¹⁶, Christina Kruuse¹⁷, Robert Mikulik¹⁸, Paul J Nederkoorn¹⁹, Martin O'Donnell²⁰, Peter Sandercock²¹, David Tanne²², Georgios Tsivgoulis²³, Cathal Walsh²⁴, David Williams^{25

25}, Marialuisa Zedde²⁶, Christopher I Price²⁷

Affiliations

¹ Mater University Hospital and University College Dublin, Ireland.
² Health Research Board Stroke Clinical Trials Network, Ireland.
³ Institut für Medizinische Informatik, Biometrie und Epidemiologie, Universitätsklinikum Essen, University Duisburg-Essen, Essen, Germany.
⁴ VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, Leuven, Belgium.
⁵ University Hospitals Leuven, Department of Neurology, Leuven, Belgium.
⁶ Stroke Unit, Department of Neurology, Hospitalt Universitari Arnau de Vilanova de Lleida, Spain.
⁷ Universitat de Lleida, Biomedical Research Institute of Lleida (IRBLleida) , Universitat de Lleida (UdL), Spain.
⁸ University Clinic of Neurology, Medical Faculty, University "Ss Cyril and Methodius", Skopje, North Macedonia.
⁹ Shaare-Zedek Medical Center, Jerusalem, Israel.
¹⁰ Second Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland.
¹¹ Stroke Centre and Clinical Trial Unit, University of Bern, Bern, Switzerland.
¹² Department of Neurology, University Hospital Bern, Inselspital, University of Bern, Bern, Switzerland.
¹³ School of Medicine, University of Limerick, Limerick, Ireland.
¹⁴ University of Calgary & Foothills Medical Centre, Calgary, Alberta, Canada.
¹⁵ Centre of Neurology, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Lithuania.
¹⁶ Department of Neurology and Neurosurgery, University of Tartu, Tartu, Estonia.
¹⁷ Herlev Gentofte Hospital and University of Copenhagen, Denmark.
¹⁸ International Clinical Research Center and Neurology Department, St. Anne's University Hospital and Masaryk University Brno, Czech Republic.
¹⁹ Amsterdam University Medical Centers (AUMC), Department of Neurology | Location AMC, Amsterdam, The Netherlands.
²⁰ HRB Clinical Research Facility Galway and National University of Ireland Galway, Ireland.
²¹ Centre for Clinical Brain Sciences, Edinburgh, UK.
²² Centre for Clinical Brain Sciences, University of Edinburgh UK.
²³ Second Department of Neurology, "Attikon" Hospital, National and Kapodistrian, University of Athens, School of Medicine, Athens, Greece.
²⁴ Mathematics Applications Consortium for Science and Industry and Health Research Institute, University of Limerick, Ireland.
²⁵ RCSI University of Medicine and Health Sciences and Beaumont Hospital, Dublin, Ireland.
²⁶ Neurology Unit, Stroke Unit, Azienda Unità Sanitaria locale-IRCCS di Reggio Emilia, Italy.
²⁷ Institute of Neuroscience, Newcastle University, Newcastle, UK.

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.

Keywords: Ischaemic stroke; colchicine; inflammation; randomised controlled trial.