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.
BENEFIT-2 is a prospective, multicentre, randomised, double-blind, active-controlled trial designed to determine whether adding butylphthalide (NBP) to tenecteplase (TNK) improves functional outcomes in patients with mild disabling ischaemic stroke treated within 4.5 hours of symptom onset.
Key Findings
Background
The trial targets a specific understudied population: patients with mild disabling acute ischaemic stroke who have persistent unilateral weakness or speech impairment despite low NIHSS scores.
Eligible patients must have a baseline NIHSS score of 2–5 with persistent unilateral weakness or speech impairment
Age range is 18–80 years with symptom onset within 4.5 hours
Prestroke modified Rankin Scale (mRS) score must be 0 or 1
The protocol identifies that 'a substantial proportion of patients, particularly those with mild disabling deficits, do not achieve favourable functional recovery' despite standard thrombolysis
Methods
The trial uses a 1:1 randomisation to compare tenecteplase plus butylphthalide (NBP) versus tenecteplase plus placebo using block randomisation.
The combination group receives TNK plus NBP; the control group receives TNK plus placebo
Intravenous NBP dose is 25 mg/100 mL administered two times per day for 7 days
This is followed by oral NBP 0.2 g three times per day up to day 14
Matching placebos are provided for the control group to maintain blinding
The design is described as prospective, multicentre, randomised, double-blind, and active-controlled
Methods
The primary outcome is the proportion of patients achieving mRS 0–1 at 90 days, with a permissible assessment window of ±7 days.
mRS 0–1 at 90 days represents full or near-full functional independence
The assessment window is 90 days ± 7 days
The primary analysis will follow the intention-to-treat principle
This endpoint captures clinically meaningful functional recovery in the mild disabling stroke population
Methods
The trial includes multiple secondary endpoints encompassing neurological, vascular, quality-of-life, and imaging outcomes.
Secondary endpoints include change in NIHSS score
Stroke recurrence and major vascular events are assessed as secondary endpoints
Quality of life is measured using the EQ-5D instrument
Penumbral salvage on imaging is included as a secondary endpoint
These endpoints collectively capture multiple dimensions of treatment benefit beyond functional independence
Methods
Safety endpoints are comprehensively defined and monitored through 90 days post-treatment.
Safety endpoints include symptomatic intracranial haemorrhage
Vascular death and all-cause mortality within 90 days are monitored
Other adverse events within 90 days are also captured
Tenecteplase is described as 'a fibrin-specific thrombolytic agent administered as a single bolus'
NBP is described as 'a multi-mechanism neuroprotective agent' that 'has shown benefit in AIS'
Methods
Ethics approval for the trial has been obtained and the study is registered, with results planned for peer-reviewed publication.
Ethics approval was obtained from the Independent Ethics Committee of Xiangya Hospital (No. 2026020399), Central South University
The trial is registered under ClinicalTrials.gov identifier NCT07369999
Results will be published in peer-reviewed journals and presented at academic conferences
The study is described as taking place in China as a multicentre trial
What This Means
This paper describes the protocol for a clinical trial called BENEFIT-2, which is testing whether combining two treatments — tenecteplase (a clot-dissolving drug) and butylphthalide (a brain-protective drug) — works better than tenecteplase alone for people who have had a mild but disabling stroke. The patients targeted are those with strokes that, while not severe by standard scoring, still cause meaningful problems like arm weakness or difficulty speaking. These patients are often undertreated or excluded from major trials, yet many do not recover fully with standard therapy. The trial is being conducted at multiple hospitals in China and will enroll adults aged 18–80 who arrive within 4.5 hours of stroke onset.
Participants are randomly assigned to receive either tenecteplase plus butylphthalide or tenecteplase plus a placebo, with both groups and their treating clinicians kept unaware of the assignment. Butylphthalide is given first intravenously for 7 days and then as an oral tablet up to day 14. The main question the trial asks is: how many patients in each group can live independently (measured by a standard disability scale called the mRS) at 90 days after their stroke? The trial also tracks brain imaging, stroke recurrence, quality of life, and safety outcomes including bleeding into the brain.
This research suggests that combining a neuroprotective agent with a thrombolytic may offer additional recovery benefits for a group of stroke patients who currently have limited treatment options beyond standard clot-busting therapy. If the combination proves effective and safe, it could change clinical practice for mild disabling stroke, a common and important stroke subtype. The results, once available, will be published in scientific journals and presented at medical conferences.
Tang Q, Wang L, Tang L, Wang D, Wang D, Li Y, et al.. (2026). 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.. BMJ open. https://doi.org/10.1136/bmjopen-2026-119290