Efficacy and safety of early butylphthalide initiation in acute ischemic stroke: A multicenter, randomized, clinical trial (BENEFIT) protocol

Background: Acute ischemic stroke (AIS) is a major cause of disability and death worldwide. While time windows for reperfusion therapies are well defined, the optimal timing for neuroprotective agents remains unknown. This study aims to investigate whether early initiation (<3 hours) of DL- 3-n-butylphthalide (NBP), a promising neuroprotective agent, leads to better outcomes compared to late initiation (3-6 hours) in AIS patients. Methods: This study is an exploratory, prospective, multicenter, randomized, open-label trial with blinded endpoint assessment. The study plans to recruit approximately 200 AIS patients presenting within 3 hours of symptom onset from around 20 stroke centers in China. Patients will be randomized in a 1:1 ratio into either the early group (<3 hours of intravenous NBP administration) or the late group (3–6 hours of intravenous NBP administration). The treatment regimen consists of 100 mL of NBP administered intravenously twice daily for 12±2 days. The primary objective of the study is to evaluate the efficacy and safety of early versus late intravenous administration of NBP in AIS patients and to explore the optimal therapeutic time window for neuroprotection. The primary outcome is the proportion of patients achieving an excellent functional outcome, defined as a modified Rankin Scale (mRS) score of 0–2, at 90±7 days post-randomization. Secondary outcomes include changes in stroke severity scores, rates of neurological deterioration, stroke recurrence, and safety outcomes. Conclusion: This trial will provide valuable evidence for the efficacy and safety of early versus late initiation of intravenous NBP for improving 90-day functional outcomes in patients with AIS. This trial will provide evidence regarding the optimal timing of neuroprotective therapy in AIS and potentially establish a new therapeutic paradigm. Registration details: ClinicalTrials.gov (NCT06472921), registered on June 19, 2024.