<jats:sec><jats:title>Rationale:</jats:title><jats:p> While thrombolysis is standard of care for patients with acute ischemic stroke (AIS) within 4.5 h of symptom onset, the benefit of tenecteplase beyond this time window is less certain. </jats:p></jats:sec><jats:sec><jats:title>Aim:</jats:title><jats:p> The TIMELESS trial (NCT03785678) aims to determine if treatment with tenecteplase increases the proportion of good clinical outcomes among patients with stroke due to a large vessel occlusion who present beyond 4.5 h after symptom onset. </jats:p></jats:sec><jats:sec><jats:title>Sample size estimates:</jats:title><jats:p> A total of 456 patients will provide ⩾90% power to detect differences in the distribution of modified Rankin Scale scores at Day 90 at the two-sided 0.049 significance level. </jats:p></jats:sec><jats:sec><jats:title>Methods and design:</jats:title><jats:p> TIMELESS is a Phase III, double-blind, randomized, placebo-controlled trial of tenecteplase with or without endovascular thrombectomy in patients with AIS and evidence of salvageable tissue via imaging who present within the 4.5- to 24-h time window with an internal carotid artery (ICA) or middle cerebral artery (MCA) (M1/M2) occlusion. </jats:p></jats:sec><jats:sec><jats:title>Study outcomes:</jats:title><jats:p> The primary efficacy objective of tenecteplase compared with placebo will be evaluated with ordinal modified Rankin Scale scores at Day 90. Safety will be evaluated via incidence of symptomatic intracranial hemorrhage, incidence and severity of adverse events, and mortality rate. </jats:p></jats:sec><jats:sec><jats:title>Discussion:</jats:title><jats:p> Results from TIMELESS will contribute to understanding of the safety and efficacy of tenecteplase administered 4.5–24 h following symptom onset for patients with an ICA or MCA occlusion. </jats:p></jats:sec>