Neuroprotection in the early window: a randomized controlled trial of butylphthalide initiation within 3 hours in acute ischemic stroke

Abstract

Neuroprotective agents have shown promise in preclinical studies but failed to demonstrate efficacy in clinical trials, potentially due to delayed treatment initiation. The optimal therapeutic window for neuroprotection in acute ischemic stroke (AIS) remains undefined. We aimed to evaluate the efficacy and safety of DL-3-n-butylphthalide (NBP) initiated within 3 h versus 3–6 h after symptom onset in AIS patients. This multicenter, randomized, open-label trial with blinded endpoint assessment was conducted across 19 stroke centers in China from July 29, 2024, to November 1, 2025. AIS patients presenting within 3 h of symptom onset and with an NIHSS score of 4–25 were randomized 1:1 to early NBP (< 3 h) or late NBP (3–6 h) groups. Both groups received intravenous NBP (100 mL twice daily) for 14 days. The primary efficacy outcome was the proportion of patients achieving favorable functional outcomes (90-day modified Rankin Scale [mRS] score 0–2, a standard disability scale from 0 [no symptoms] to 6 [death]) at 90 days, assessed by certified raters blinded to group allocation. The results are presented as the risk ratio (RR) with 95% confidence intervals (95% CI). P < 0.05 indicated statistical significance. A total of 204 patients were enrolled (early group: 104; late group: 100), with a median (IQR) age of 67 (59–74) years and 68.1% male. Favorable functional outcomes were achieved in 67.3% of the early group and 58.0% of the late group (unadjusted RR, 1.16; 95% CI, 0.94–1.44; P = 0.17). Each additional hour of delay reduced the risk of a favorable outcome by 11% (RR, 0.89; 95% CI, 0.81–0.98; P = 0.02). Serious adverse events occurred in 12.9% of the early group and 9.1% of the late group (hazard ratio, 1.43; 95% CI, 0.61–3.34; P = 0.41). In patients with AIS, initiating neuroprotective treatment with NBP less than 3 h after symptom onset, compared with initiation between 3 and 6 h, did not significantly improve the proportion of patients achieving favorable functional outcome. However, a significant dose-response relationship was observed between treatment initiation time and favorable outcome. This finding warrants further verification through larger-scale clinical trials. NCT06472921. Registered on June 19, 2024.