Tenecteplase versus alteplase in acute ischaemic cerebrovascular events (TRACE-2): a phase 3, multicentre, open-label, randomised controlled, non-inferiority trial

Abstract

Background: There is increasing interest in replacing alteplase with tenecteplase as the preferred thrombolytic treatment for patients with acute ischaemic stroke. We aimed to establish the non-inferiority of tenecteplase to alteplase for these patients.

Methods: In this multicentre, prospective, open-label, blinded-endpoint, randomised controlled, non-inferiority trial, adults with an acute ischaemic stroke who were eligible for standard intravenous thrombolysis but ineligible for endovascular thrombectomy were enrolled from 53 centres in China and randomly assigned (1:1) to receive intravenous tenecteplase (0·25 mg/kg, maximum dose of 25 mg) or intravenous alteplase (0·9 mg/kg, maximum dose of 90 mg). Participants had to be able to receive treatment within 4·5 h of stroke, have a modified Rankin Scale (mRS) score of no more than 1 before enrolment, and have a National Institutes of Health Stroke Scale score of 5-25. Patients and treating clinicians were not masked to group assignment; clinicians evaluating outcomes were masked to treatment type. The primary efficacy outcome was the proportion of participants who had a mRS score of 0-1 at 90 days, assessed in the modified intention-to-treat population (all randomly assigned participants who received the allocated thrombolytic), with a non-inferiority margin of 0·937 for the risk ratio (RR). The primary safety outcome was symptomatic intracranial haemorrhage within 36 h, assessed in all participants who received study drug and had a safety assessment available. The trial is registered with ClinicalTrials.gov, NCT04797013, and has been completed.

Findings: Between June 12, 2021, and May 29, 2022, 1430 participants were enrolled and randomly assigned to tenecteplase (n=716) or alteplase (n=714). Six patients assigned to tenecteplase and seven to alteplase did not receive study product, and five participants in the tenecteplase group and 11 in the alteplase group were lost to follow-up at 90 days. The primary outcome in the modified intention-to-treat population occurred in 439 (62%) of 705 in the tenecteplase group versus 405 (58%) of 696 in the alteplase group (RR 1·07, 95% CI 0·98-1·16). The lower limit of the RR's 95% CI was greater than the non-inferiority margin. Symptomatic intracranial haemorrhage within 36 h was observed in 15 (2%) of 711 in the tenecteplase group and 13 (2%) of 706 in the alteplase group (RR 1·18, 95% CI 0·56-2·50). Mortality within 90 days occurred in 46 (7%) individuals in the tenecteplase group versus 35 (5%) in the alteplase group (RR 1·31, 95% CI 0·86-2·01).

Interpretation: Tenecteplase was non-inferior to alteplase in people with ischaemic stroke who were eligible for standard intravenous thrombolytic but ineligible for or refused endovascular thrombectomy.

Funding: National Science and Technology Major Project, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, National Natural Science Foundation of China, and China Shijiazhuang Pharmaceutical Company Recomgen Pharmaceutical (Guangzhou).