Efficacy and safety of sublingual cilostazol and dexborneol for the treatment of acute ischaemic stroke: a randomised phase 2 trial in China

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Background: Endovascular treatment has emerged as a cornerstone intervention for acute ischaemic stroke caused by large-vessel occlusion. However, a subset of patients experience futile recanalisation, correlating with unfavourable long-term outcomes. We aimed to investigate the efficacy and safety of Y-6 sublingual tablets (cilostazol and dexborneol) in ischaemic stroke patients with endovascular treatment. Methods: This randomised, double-blind, double-dummy, placebo-controlled phase 2 trial in 33 centres in China prospectively enrolled patients aged 35-80 years, who had ischaemic stroke with large vessel occlusion in the anterior circulation within 24 h of onset, with an NIHSS score 7-25 at randomisation. Participants were randomly assigned (1:1:1:1:1) to the Y-6 high-dose group, Y-6 low-dose group, cilostazol high-dose group, cilostazol low-dose group, and placebo group for 28 days. The modified intention-to-treat analysis included the patients receiving at least one dose of the intervention. The primary efficacy outcome was the 90-day mRS 0-1 score, and the primary safety outcome was symptomatic intracranial haemorrhage at 28 days. The trial has been registered on ClinicalTrials.govNCT06138834. Findings: Between Dec 14, 2023, and Dec 25, 2024, of 300 enrolled Chinese patients, 294 patients were included in the intention-to-treat analysis with 213 (72.4%) male. A favourable functional outcome (mRS 0-1) at 90 days occurred in 25 patients (44.6%) in the Y-6 high-dose group (RR 1.25, 95% confidence interval [CI] 0.79-1.97; p = 0.34), 29 patients (46.0%) in the Y-6 low-dose group (RR 1.29, 95% CI 0.83-2.00; p = 0.25), 25 patients (41.7%) in the cilostazol high-dose group (RR 1.17, 95% CI 0.74-1.85; p = 0.51), 22 patients (37.3%) in the cilostazol low-dose group (RR 1.04, 95% CI 0.64-1.69; p = 0.86), and 20 patients (35.7%) in the placebo group. Symptomatic intracranial haemorrhage at 28 days occurred in 1 patient (1.8%) in the Y-6 high-dose group, 3 patients (4.8%) in the Y-6 low-dose group, 2 patients (3.3%) in the cilostazol high-dose group, 4 patients (6.8%) in the cilostazol low-dose group, and 2 patients (3.6%) in the placebo group. No significant differences in efficacy and safety outcomes were found compared with that in the placebo group. Serious adverse events within 90 days occurred in 14 patients (25.0%) in the Y-6 high-dose group, 18 patients (28.6%) in the Y-6 low-dose group, 18 patients (30.0%) in the cilostazol high-dose group, 24 patients (40.7%) in the cilostazol low-dose group, and 14 patients (25.0%) in the placebo group. Interpretation: Our findings indicate that, for patients with ischaemic stroke undergoing endovascular treatment for large vessel occlusion, Y-6 sublingual tablets (cilostazol and dexborneol) were safe with tolerance. Although the trial did not demonstrate statistically significant efficacy on the primary outcome, the signal toward improved functional outcomes without haemorrhage risk supports the biological plausibility of the intervention and justifies further investigation. Large-scale phase 3 clinical trials are warranted to further this research. Funding: The National Natural Science Foundation of China; Noncommunicable Chronic Diseases-National Science and Technology Major Project; Beijing Municipal Science & Technology Commission; Capital's Funds for Health Improvement and Research; National Key R&D Program of China.

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