Study purpose:

A multicenter, prospective, randomized, open-label, blinded-endpoint (PROBE) phase III trial is planned to evaluate the efficacy and safety of intra-arterial thrombolysis (IAT) in patients with acute ischemic stroke caused by medium vessel occlusion (MeVO), compared with best medical management alone.

Eligible participants (aged 18-80 years, baseline NIHSS score 6-25 or 3-5 with disabling deficits, confirmed MeVO within 24 hours of symptom onset) will be randomly assigned 1:1 to the intra-arterial thrombolysis plus best medical management group or the best medical management alone group.

Primary endpoint: proportion of patients with favorable functional outcome (modified Rankin Scale score 0-2) at 90±7 days post-randomization.

Secondary endpoints:

1. Recanalization rate (meTICI ≥ 2b) at 24±12 hours post-randomization;
2. Early neurological improvement (NIHSS score change from baseline) at 7±1 days or discharge;
3. Overall distribution of mRS scores at 90±7 days (shift analysis);
4. Excellent functional outcome (mRS score 0-1) at 90±7 days;
5. Health-related quality of life (EQ-5D-5L) at 90±7 days;
6. Functional independence (Barthel Index score 95-100) at 90±7 days;
7. Symptomatic intracranial hemorrhage (sICH) per Heidelberg criteria within 48 hours;
8. Early neurological deterioration (NIHSS increase ≥ 4 points or any single item increase ≥ 2 points) within 7 days;
9. Any intracranial hemorrhage within 48 hours;
10. Procedure-related complications;
11. All-cause mortality within 90±7 days.

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 306 eligible patients (aged 18-80 years) with confirmed MeVO (distal M2/M3, A2/A3, P1/P2/P3 segments) and baseline NIHSS score 6-25 (or 3-5 with disabling deficits) within 24 hours of symptom onset will be enrolled. For patients presenting beyond 6 hours, perfusion imaging criteria (Tmax > 6s ≥ 10cc, with core infarct volume < 50% of the hypoperfusion area) will be applied to select those with salvageable brain tissue. Participants will be randomly assigned 1:1 to receive either intra-arterial thrombolysis (using either alteplase 0.225 mg/kg, maximum 22.5 mg, or tenecteplase 0.0625 mg/kg, maximum 6.25 mg, administered via microcatheter over 15-30 minutes) plus best medical management, or best medical management alone. The primary endpoint is the proportion of patients achieving functional independence (modified Rankin Scale score 0-2) at 90±7 days post-randomization. Secondary endpoints include recanalization rate, early neurological improvement, overall functional outcome distribution, excellent functional outcome, quality of life, functional independence, and comprehensive safety outcomes including symptomatic intracranial hemorrhage, early neurological deterioration, any intracranial hemorrhage, procedure-related complications, and all-cause mortality.

The study is led by the First Affiliated Hospital of Nanjing Medical University (Jiangsu Province Hospital) as the coordinating center, with 25 participating centers across China. An independent Data Safety Monitoring Board (DSMB) will oversee the trial, with one planned interim analysis using an O'Brien-Fleming-like alpha-spending function. The total study duration is 3 years (June 2026 to May 2029), with enrollment anticipated to be completed within 20 months. 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.

Inclusion Criteria:

• Age 18 to 80 years.
• Time from symptom onset or last known well to randomization within 24 hours.
• Clinical diagnosis of acute ischemic stroke confirmed by CTA or MRA as being caused by isolated acute medium vessel occlusion, including distal M2/M3 segments of the middle cerebral artery, A2/A3 segments of the anterior cerebral artery, or P1/P2/P3 segments of the posterior cerebral artery. Isolated occlusion is defined as a single symptomatic vessel occlusion; patients with multiple vessel occlusions or uncertain culprit vessel are excluded.
• Baseline NIHSS score ≥ 6, or 3-5 with disabling deficits (e.g., motor weakness, aphasia, visual field defects), and NIHSS score ≤ 25 at the time of randomization.
• For patients presenting beyond 6 hours from symptom onset: perfusion imaging criteria require Tmax > 6s volume ≥ 10 cc, and core infarct volume (defined as rCBF < 30%) less than 50% of the Tmax > 6s volume.
• Patient or legally authorized representative is able to understand and voluntarily sign the informed consent form.

Exclusion Criteria:

• Clinical Exclusion Criteria:
• Pre-stroke modified Rankin Scale (mRS) score > 2.
• Presence of contraindications to intravenous thrombolysis.
• Known allergy to heparin, contrast media, anesthetics, or other definite contraindications to endovascular treatment.
• Comorbid severe diseases that may affect outcome assessment, including but not limited to malignancy, severe heart failure, or renal failure, with expected life expectancy < 6 months.
• Uncontrolled hypertension refractory to medical therapy (systolic blood pressure > 220 mmHg or diastolic blood pressure > 120 mmHg).
• Baseline blood glucose < 2.8 mmol/L (50 mg/dL) or > 22.2 mmol/L (400 mg/dL).
• Known bleeding diathesis, including but not limited to: platelet count < 100 × 10⁹/L; heparin treatment within 48 hours with APTT ≥ 35 seconds; oral warfarin with INR > 3. Note: Patients without a history or suspicion of coagulation disorders do not require laboratory testing for coagulation parameters prior to enrollment.
• Stroke onset with seizure or seizure occurring during the course of stroke, precluding accurate determination of baseline NIHSS score.
• Female patients who are pregnant, lactating, or have a positive pregnancy test at hospital admission.
• Currently participating in another investigational drug or device study that may interfere with the results of this study.
• Other conditions judged by the investigator to be unsuitable for participation or posing significant risk to the patient.
• Imaging Exclusion Criteria:
• Intracranial hemorrhage confirmed by baseline head CT or MRI, including parenchymal hemorrhage, intraventricular hemorrhage, subarachnoid hemorrhage, or subdural/epidural hemorrhage.
• Presence of midline shift or cerebral herniation, or other ventricular mass effect with midline shift.
• Anticipated inability to complete endovascular treatment due to vascular tortuosity, severe vessel wall calcification, or other anatomical challenges.
• Aortic dissection.
• Multiple vessel occlusions confirmed by CTA or MRA with inability to identify the symptomatic culprit vessel, such as bilateral middle cerebral artery occlusion or concurrent middle cerebral artery and basilar artery occlusion.
• Suspected or confirmed non-acute occlusion of the symptomatic culprit vessel.

The steering committee has not yet finalized the specific IPD sharing plan, including the data repository platform, timeframe, and access review procedures. This will be determined prior to the primary publication and updated on ClinicalTrials.gov at that time.