Intra-arterial Thrombolysis for Acute Ischemic Stroke With Medium Vessel Occlusion: A Multicenter Prospective Randomized Controlled Clinical Trial

With the continuous advancement of endovascular techniques and the widespread adoption of mechanical thrombectomy, endovascular treatment has become the standard of care for acute ischemic stroke caused by large vessel occlusion. However, the optimal management strategy for acute ischemic stroke caused by medium vessel occlusion (MeVO) remains an unmet clinical need. MeVO accounts for approximately 25-40% of all acute ischemic strokes and is associated with substantial morbidity, yet existing evidence from recent randomized controlled trials, including DISTAL and ESCAPE-MeVO, has failed to demonstrate a clear benefit of mechanical thrombectomy over best medical management alone in this population. Potential reasons include the limited suitability of current thrombectomy devices-which were primarily designed for large vessel occlusions-for more distal and tortuous medium vessels, leading to lower recanalization rates and increased risks of vessel perforation, dissection, and vasospasm. Moreover, the significant heterogeneity in patient selection across previous trials, particularly the lack of unified imaging inclusion criteria, may have diluted the potential treatment effect in specific subgroups.

Intra-arterial thrombolysis (IAT), as an alternative endovascular approach, offers theoretical advantages for MeVO. By delivering thrombolytic agents directly into or adjacent to the thrombus via a microcatheter, IAT achieves high local drug concentrations while minimizing systemic exposure. Evidence from the PROACT II study demonstrated that intra-arterial prourokinase significantly improved 90-day functional outcomes in patients with middle cerebral artery occlusion compared with heparin alone. More recently, the CHOICE trial showed that adjunctive intra-arterial alteplase following successful thrombectomy improved functional outcomes in large vessel occlusion stroke. These findings suggest that IAT may effectively dissolve residual thrombi in distal vascular beds and improve microcirculatory reperfusion-mechanisms particularly relevant to MeVO, where thrombus burden is generally smaller and the target vessels are more amenable to pharmacological dissolution.

Despite these promising signals, no dedicated randomized controlled trial has specifically evaluated IAT as a primary treatment strategy for MeVO. Current guidelines provide no clear recommendation for or against endovascular treatment in this population, reflecting the urgent need for high-quality evidence. Furthermore, the optimal patient selection criteria-including imaging parameters (perfusion mismatch), clinical severity thresholds (NIHSS range), and the distinction of isolated medium vessel occlusion from other stroke subtypes-remain to be defined to maximize the therapeutic benefit.

This study intends to conduct a multicenter, prospective, randomized, open-label, blinded-endpoint (PROBE) phase III trial to compare the clinical outcomes of intra-arterial thrombolysis plus best medical management versus best medical management alone in patients with acute ischemic stroke due to medium vessel occlusion. A total of 372 eligible patients (aged 18-80 years) with confirmed isolated MeVO (distal M2 [above the mid-insular height], M3 or M4; A2, A3 or A4; or P2 or P3 segments, confirmed by CTA or MRA), a baseline NIHSS score of ≥ 6 and ≤ 25, and randomization within 24 hours of symptom onset or last known well will be enrolled. The trial is powered to detect an absolute difference of 15 percentage points in the primary endpoint (67.0% vs 52.0%), with 80% power at a two-sided alpha of 0.05; assuming a 10% dropout rate, 372 patients (186 per group) will be enrolled, of whom approximately 334 are expected to complete follow-up. For patients presenting beyond 6 hours, perfusion imaging criteria (Tmax > 6 s volume ≥ 10 mL and core infarct volume [rCBF < 30%] < 50% of the Tmax > 6 s volume) will be applied to select those with salvageable brain tissue. Participants will be randomly assigned 1:1 by central web-based randomization, stratified by occlusion site, to receive either intra-arterial thrombolysis (alteplase 0.225 mg/kg, maximum 22.5 mg, or tenecteplase 0.0625 mg/kg, maximum 6.25 mg, consistent with the intravenous thrombolytic agent administered, delivered via microcatheter as contact thrombolysis or as a distal-to-proximal segmented infusion over 15-30 minutes) plus best medical management, or best medical management alone.

The study is led by the First Affiliated Hospital with Nanjing Medical University (Jiangsu Province Hospital, the sponsor and coordinating center), with 27 participating centers across China to be activated in a staged manner (the first phase comprises 10 experienced centers, including the coordinating center). An independent Data Safety Monitoring Board (DSMB) will oversee the trial, meeting every 6 months with one planned interim analysis using an O'Brien-Fleming-like alpha-spending function (two-sided alpha of approximately 0.003 at the interim analysis, to be performed when approximately 147 patients-44% of the planned final analysis population of 334-have completed 90-day follow-up, anticipated in September-October 2027). The total study duration is 3 years (June 2026 to May 2029), with enrollment anticipated to be completed within 24 months (September 2026 to August 2028). The results of this trial are expected to provide high-level evidence on whether intra-arterial thrombolysis offers a safe and effective treatment option for patients with acute ischemic stroke due to medium vessel occlusion, potentially establishing a new standard of care in this underserved population.