Alteplase-Tenecteplase Trial Evaluation for Stroke Thrombolysis (ATTEST): phase 2 randomised clinical trial

Background: Alteplase given within 4•5 hours of onset is the only approved medical treatment in acute ischaemic stroke. Newer thrombolytic agents may be advantageous, with higher fibrin specificity, easier administration schedules, and longer half-life. Different doses of tenectplase have been investigated previously in two small randomised trials in acute stroke in 3 or 6 hour time windows, in one study using advanced imaging-based patient selection. We evaluated the efficacy and safety of tenecteplase versus alteplase in a less selected population than previous studies, using imaging biomarkers, in order to inform the appropriate design of a definitive clinical trial. Methods: In a single-centre, phase 2, prospective randomised open-label blinded end-point evaluation (PROBE) trial, adult patients with supratentorial ischaemic stroke eligible for intravenous thrombolysis within 4•5 h of onset received tenecteplase 0•25 mg/kg (maximum 25 mg) or alteplase 0•9 mg/kg (maximum 90 mg). Treatment allocation used a mixed randomisation/minimisation algorithm including age and NIHSS score, generated by an independent statistician. Imaging comprised baseline computed tomography (CT), CT perfusion (CTP) and CT angiography (CTA), and CT+CTA at 24-48 hours. The primary end-point was penumbral salvage (CTP-defined penumbra volume minus follow-up CT infarct volume. Results: We recruited 104 patients (52 in each group) over 20 months. In the protocol-defined analysis of 96 confirmed stroke patients, groups were balanced for clinical characteristics. Among 71 subjects contributing to the imaging primary endpoint, no significant differences were observed for penumbral salvage [68 (SD 28) % tenecteplase vs 68 (SD 23) % alteplase], mean difference 1% (95% confidence interval -10%, 12%, p=0•81) or for any secondary end-point. Neither SICH incidence (1/52, 2% vs 2/51, 4%, by SITS-MOST definition, p=0•55; by ECASS-2 definition, 3/52, 6% tenecteplase vs 4/51, 8% alteplase, p=0.59) nor total ICH events differed significantly (8/52 tenecteplase, 15% vs 14/51 alteplase, 29%, p=0•091). The incidence of serious adverse events did not differ between groups (32 in the tenecteplase group, 3 considered probably or definitely related to drug treatment; 16 in the alteplase group, 5 considered drug-related). Interpretation: Neurological and radiological outcomes did not differ between tenecteplase and alteplase. Further evaluation of tenecteplase in acute stroke is warranted