Butylphthalide combined with tenecteplase in mild disabling acute ischaemic stroke in China (BENEFIT-2): study protocol for a multicentre, randomised, double-blind, active-controlled trial

INTRODUCTION: Intravenous thrombolysis is the standard early treatment for acute ischaemic stroke (AIS), yet a substantial proportion of patients, particularly those with mild disabling deficits, do not achieve favourable functional recovery. Tenecteplase (TNK), a fibrin-specific thrombolytic agent administered as a single bolus, and butylphthalide (NBP), a multi-mechanism neuroprotective agent, have each shown benefit in AIS. However, whether their combination confers additional benefit in mild disabling AIS remains unknown. This trial aims to determine whether adding NBP to TNK improves functional outcomes in patients with mild disabling ischaemic stroke treated within 4.5 hours of symptom onset. METHODS AND ANALYSIS: BENEFIT-2 is a prospective, multicentre, randomised, double-blind, active-controlled trial. Eligible patients will be randomised 1:1 to receive either TNK plus NBP (combination group) or TNK plus placebo (control group) via block randomisation. The intervention comprises intravenous NBP 25 mg/100 mL two times per day for 7 days, followed by oral NBP 0.2 g three times per day up to day 14, with matching placebos for the control group. Key eligibility criteria include age 18-80 years, symptom onset within 4.5 hours, baseline National Institutes of Health Stroke Scale (NIHSS) score 2-5 with persistent unilateral weakness or speech impairment, and prestroke modified Rankin Scale (mRS) score 0 or 1. The primary outcome is the proportion of patients achieving mRS 0-1 at 90 days (allowable window ±7 days). Secondary endpoints include change in NIHSS, stroke recurrence, major vascular events, quality of life measured by EQ-5D and penumbral salvage on imaging. Safety endpoints comprise symptomatic intracranial haemorrhage, vascular death, all-cause mortality and other adverse events within 90 days. The primary analysis will follow the intention-to-treat principle. ETHICS AND DISSEMINATION: Ethics approval has been obtained from the Independent Ethics Committee of Xiangya Hospital (No. 2026020399), Central South University. Results will be published in peer-reviewed journals and presented at academic conferences. TRIAL REGISTRATION NUMBER: NCT07369999.