Intra-arterial Thrombolysis For Acute Ischemic Stroke With Medium Vessel Occlusion

Phase 3RecruitingNCT07668323

The First Affiliated Hospital with Nanjing Medical University372 enrolled

Overview

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, distal M2 \[above the mid-insular height\], M3 or M4; A2, A3 or A4; or P2 or P3 segments, confirmed by CTA or MRA), compared with best medical management alone. Eligible participants (aged 18-80 years, baseline NIHSS score 6-25, confirmed MeVO within 24 hours of symptom onset or last known well) will be randomly assigned 1:1 to the intra-arterial thrombolysis plus best medical management group or the best medical management alone group. The primary endpoints are (i) the proportion of patients with a favorable functional outcome, defined as a modified Rankin Scale (mRS) score of 0-2 at 90±7 days post-randomization; (ii) the proportion of patients with symptomatic intracranial hemorrhage (sICH) within 48 hours post-randomization, defined and classified according to the Heidelberg Bleeding Classification; and (iii) the proportion of patients with early neurological deterioration (END) within 7 days post-randomization, defined as an increase of ≥ 4 points in the total NIHSS score from baseline or an increase of ≥ 2 points in any single NIHSS item. Secondary endpoints: 1. Procedure-related complications within 24 hours post-randomization; 2. Recanalization rate (meTICI ≥ 2b) at 24±12 hours post-randomization; 3. Any intracranial hemorrhage within 48 hours post-randomization; 4. Early neurological improvement (NIHSS score change from baseline) at 7 days or discharge; 5. Overall distribution of mRS scores at 90±7 days (shift analysis); 6. Excellent functional outcome (mRS score 0-1) at 90±7 days; 7. Functional independence (Barthel Index score 95 or 100) at 90±7 days; 8. Health-related quality of life (EQ-5D-5L) at 90±7 days; 9. 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 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.

Interventions

Recombinant Tissue Plasminogen Activator (rt-PA)DRUG

Administered intra-arterially via microcatheter. Agent options: alteplase (rt-PA) at 0.225 mg/kg (maximum 22.5 mg) or tenecteplase (TNK) at 0.0625 mg/kg (maximum 6.25 mg), infused over 15-30 minutes. The choice of agent should be consistent with any prior intravenous thrombolysis.

Intra-arterial ThrombolysisPROCEDURE

Microcatheter is navigated to the occluded medium vessel. For small thrombus burden, positioned adjacent to or within the thrombus. For larger burden, advanced through occluded segment with staged administration distal-to-proximal (one-third per segment). Procedure ends at meTICI ≥ 2b or when risks outweigh benefits.

Best Medical ManagementDRUG

Best medical management per local guidelines, including antiplatelet therapy, anticoagulation (if indicated), statins, blood pressure and glycemic control, and rehabilitation.

Rescue therapyPROCEDURE

Rescue intra-arterial thrombolysis is permitted in both treatment groups, including participants randomized to best medical management alone, if neurological deterioration occurs after randomization, defined as an increase of ≥ 4 points in the NIHSS score from baseline after exclusion of non-stroke causes such as hypoglycemia, infection, or metabolic derangement, with imaging evidence of salvageable brain tissue (Tmax \> 6 s volume ≥ 10 mL and core infarct volume \[rCBF \< 30%\] \< 50% of the Tmax \> 6 s volume), and provided that rescue therapy can be initiated within 24 hours of symptom onset or last known well. Rescue endovascular therapy is limited to intra-arterial thrombolysis and administered with same agents (alteplase or tenecteplase) at the same doses specified for the intra-arterial thrombolysis intervention; thrombectomy devices, balloon angioplasty, and stenting are not permitted.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 80 Years

Medical Language ↔ Plain English

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/M4 segments of the middle cerebral artery, A2/A3/A4 segments of the anterior cerebral artery, or 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, and NIHSS score ≤ 25 at the time of randomization. * For patients presenting beyond 6 hours from symptom onset: perfusion imaging criteria require a Tmax \> 6 s volume ≥ 10 mL and a core infarct volume (defined as rCBF \< 30%) \< 50% of the Tmax \> 6 s 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.

Outcomes

Primary Outcomes

Proportion of patients with favorable functional outcome at 90 days

Favorable functional outcome is defined as a modified Rankin Scale (mRS) score of 0 to 2, assessed at 90±7 days post-randomization. The mRS is a 7-point ordinal scale (range 0-6) measuring functional independence and disability, with 0 indicating no symptoms and 6 indicating death.

Time frame: 90 days post-randomization (90±7 days)

Proportion of patients with symptomatic intracranial hemorrhage at 48 hours

Symptomatic intracranial hemorrhage (sICH) within 48 hours post-randomization, defined according to the Heidelberg Bleeding Classification.

Time frame: 48 hours post-randomization

Proportion of patients with early neurological deterioration at 7 days

Proportion of patients with early neurological deterioration (END) within 7 days post-randomization, defined as an increase of ≥ 4 points in total NIHSS score from baseline, or an increase of ≥ 2 points in any single NIHSS item.

Time frame: 7 days post-randomization

Secondary Outcomes

Proportion of patients with procedure-related complications

Proportion of patients experiencing procedure-related complications associated with intra-arterial intervention, including but not limited to vessel perforation, dissection, distal embolization, and vasospasm.

Time frame: Within 24 hours post-randomization

Recanalization rate at 24 hours

Proportion of patients achieving successful recanalization, defined as meTICI (modified expanded Thrombolysis in Cerebral Infarction) grade ≥ 2b, assessed at 24±12 hours post-randomization by CTA or MRA.

Time frame: 24±12 hours post-randomization

Proportion of patients with any intracranial hemorrhage at 48 hours

Proportion of patients with any type of intracranial hemorrhage occurring within 48 hours post-randomization, including site and type classified according to the Heidelberg Bleeding Classification.

Time frame: 48 hours post-randomization

Early neurological improvement at 7 days

Change in National Institutes of Health Stroke Scale (NIHSS) score from baseline to 7 days post-randomization or at hospital discharge, whichever occurs first.

Time frame: 7 days post-randomization or hospital discharge, whichever occurs first

Overall distribution of functional outcomes at 90 days

Shift analysis of the full distribution of modified Rankin Scale (mRS) scores (0-6) at 90±7 days post-randomization, assessing the shift toward better functional outcomes.