Glucagon-like Peptide-1 Receptor Agonists for Endovascular Stroke Thrombectomy

Background/Importance: Endovascular thrombectomy (EVT) has substantially improved functional outcomes and decreased mortality in acute ischemic stroke patients with large vessel occlusions (LVOs). However, more than half of the patients die or have significant disability at 90 days after EVT. Studies suggest considerable infarct growth despite successful EVT and infarct volume predicts survival and functional outcome after EVT. There is an unmet need for interventions to reduce infarct growth and improve the functional outcomes of patients with an acute LVO who undergo EVT. Glucagon-Like Peptide-1 receptor agonists (GLP-1 RAs) have been suggested to decrease infarct growth and improve motor and sensory impairments in both diabetic and non-diabetic animal models of stroke. GLP-1 RAs also consistently decreased the risk of major adverse cardiovascular events (MACE), with the most profound effect in stroke prevention, in large-scale randomized clinical trials (RCTs) of patients with and without history of diabetes. Research Aims: The overall goal of this study is to test whether semaglutide can improve the functional outcomes of adults with acute ischemic stroke attributed to an intracranial LVO who are planned for treatment with EVT. We are performing a vanguard phase to obtain factual feasibility and will then move into the full phase trial. Methods: Glucagon-like peptide-1 receptor agonists for Endovascular Stroke Thrombectomy (LEAST) is a multicentre, prospective, randomized, open label, blinded endpoint (PROBE) clinical trial. For the vanguard phase, LEAST will recruit a total of 100 adult patients scheduled to receive EVT at approximately 10 high-volume stroke research centres in Canada over 1.5 to 2 years. For the full trial, LEAST will recruit an additional 726 patients from approximately 52 global stroke research centres, for a total of 826 participants. Participants fulfilling the inclusion and exclusion criteria will be randomly assigned up to 6 hours from the end of the EVT procedure, defined as the time of the last angiographic run, to either receive semaglutide (0.25 mg subcutaneous \[SC\] weekly for 4 weeks followed by 0.5 mg SC weekly for another 8 weeks) or to no semaglutide treatment. Outcomes: For the vanguard phase the primary endpoint is recruitment rate (target \>6 participants per centre per year). For the full trial, the primary endpoint is the proportion of participants with functional independence (mRS 0-2) at 90 (±14) days. For the vanguard phase the secondary endpoints are retention rate (target \>90% of study participants remaining in the trial) and medication adherence (target \>75%). For the full trial, the secondary endpoints are the difference between groups in the proportion of participants with functional independence (mRS 0-2) at 7 (±2) and 30 (±7) days; the difference between groups in mRS scores at 7 (±2), 30 (±7) and 90 (±14) days; the difference between groups in NIHSS scores at 36 (±12) hours; the difference between groups in EQ-5D-5L scores at 90 (±14) days; and the difference between groups in incident cerebrovascular and cardiovascular events at 90 (±14) days.