TIMELESS Trial Reveals Tenecteplase Safe in Late Window, With Efficacy in Subgroups of M1 Occlusion
New findings from the TIMELESS trial suggest that tenecteplase within 4.5 to 24 hours post-stroke might benefit certain subgroups, despite overall neutral outcomes.
Greg Albers, MD
New data from the TIMELESS trial (NCT03785678) showed that the use of tenecteplase between 4.5 to 24 hours after stroke in patients with occlusions of the middle cerebral artery or internal carotid artery did not result in better clinical outcomes than those with placebo; however, certain subgroups showed greater benefit. Notably, this was the first study to show that intravenous (IV) thrombolytics could be given up to 24 hours without an increase in brain hemorrhage.1,2
Greg Albers, MD, director of the Standard Stroke Center and founder of RapidAI, presented the findings in a late-breaker presentation at the 2024 International Stroke Conference (ISC), held February 7-9, in Phoenix, Arizona. At the same time of the presentation, the data were published in the New England Journal of Medicine.
Using the entire cohort, results showed an adjusted common odds ratio (OR) 1.13 (95% CI, 0.82-1.57; P = .45) for the distribution of scores on the modified Rankin scale (mRs) at 90 days for tenecteplase vs placebo. In a subgroup analysis of patients with occlusion of the M1 segment not powered for conclusions, 45.9% of those in the Tenecteplase achieved functional independence vs 31.4% of those on placebo (adjusted OR, 2.03; 95% CI, 1.14-3.66). In comparison with placebo, this subgroup of patients had an adjusted common OR of 1.59 (955 CI, 1.00-2.52) for mRs scores.
The study enrolled 458 patients with ischemic stroke who received tenecteplase (0.25 mg per kilogram of body weight, up to 25 mg; n = 228) or placebo (n = 230) 4.5 to 24 hours after the time of last known to be well. TIMELESS included only those who had a large-vessel occlusion of the internal carotid artery or the first (M1) or second (M2) segments of the middle cerebral artery and had evidence of salvageable ischemic brain tissue. Most of the cohort, 77.3% of patients, underwent thrombectomy immediately after receiving treatment.
READ MORE: Fibrinogenase Injection Improves Functional Outcome Following Ischemic Stroke
Because outcomes on the primary end point did not differ between treatment groups, formal hypothesis testing of the secondary outcomes was not performed. Functional independence, considered an mRS score of 2 or less, was observed in 46.0% (n = 104) of patients in the Tenecteplase group at 90 days vs 42.4% (n = 97) of those on control (adjusted OR, 1.18; 95% CI, 0.80-1.74).
In terms of safety, mortality at 90 days did not differ appreciably between the tenecteplase group (19.7%) and those on placebo (18.2%). In addition, the 2 treatment groups had a similar rate of symptomatic intracerebral hemorrhage (Tenecteplase: 3.2%; n = 7; placebo: 2.3%; n = 5) and incidence of parenchymal hematoma type 2 or any intracranial hemorrhage. Notably, investigators found no between-group differences in the incidence of adverse events (AEs), serious AEs, and withdrawal from the trial.
In a related editorial, Dana Leifer, MD, an associate professor of neurology at Weill Cornell Medicine, wrote, "Taken together, the trial results tentatively suggest that pretreatment with Tenecteplase before thrombectomy may be beneficial in patients with occlusions in the M1 segment when administered in the 4.5-to-24-hour window, but they also suggest that tenecteplase is probably unlikely to help patients who present with large-vessel occlusions and do not undergo thrombectomy. The trial excluded patients who did not have large- vessel occlusions, so it does not provide evidence about tenecteplase treatment in such patients."3
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