Sivelestat Sodium as an Adjunct to Endovascular Thrombectomy for Acute Anterior Circulation Large-Vessel Occlusion

Official title

Efficacy and Safety of Sivelestat Sodium as an Adjunct to Endovascular Thrombectomy in Acute Anterior Circulation Large-Vessel Occlusion: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study

Overview

Stroke remains a major global health burden, with acute ischemic stroke (AIS) accounting for more than 65% of all cases. Endovascular thrombectomy (EVT) has been established as a standard treatment for large vessel occlusion (LVO) stroke; however, "futile recanalization" remains common, with many patients failing to achieve favorable functional outcomes despite successful vessel reperfusion. Increasing evidence indicates that neutrophils and neutrophil extracellular traps (NETs) play important roles in post-reperfusion inflammation, thrombosis, and microcirculatory dysfunction, which may contribute to thrombolysis resistance and poor prognosis. Neutrophil elastase (NE), a key component associated with NETs, may further aggravate vascular injury and thrombus formation. Sivelestat Sodium is a selective NE inhibitor that has demonstrated anti-inflammatory and organ-protective effects in patients with acute respiratory distress syndrome and in experimental models of cerebral ischemia. It may help preserve blood-brain barrier integrity, reduce brain edema, and improve neurological outcomes. Based on these findings, this study is designed as a multicenter, randomized, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of sivelestat sodium as an adjunct to EVT in patients with acute anterior circulation large-vessel occlusive stroke within 24 hours of onset. The results of this study are expected to provide further clinical evidence for anti-inflammatory adjunctive treatment strategies aimed at reducing futile recanalization and improving functional outcomes in AIS.

Interventions

• Drug Sivelestat sodium
  Sivelestat sodium is a selective neutrophil elastase inhibitor administered as an adjunctive treatment to endovascular thrombectomy in this study. Treatment will be initiated within 2 hours after randomization and continued once daily until Day 7 after randomization or hospital discharge, whichever occurs first. The daily dose is 4.8 mg/kg, administered by continuous intravenous infusion using a microinfusion pump or by intravenous drip.
• Drug Placebo
  The placebo does not contain sivelestat sodium and consists of the same excipients as the investigational product without the active ingredient. It will be administered in the same manner, timing, and schedule as sivelestat sodium, beginning within 2 hours after randomization and continuing once daily until Day 7 after randomization or hospital discharge, whichever occurs first, in order to maintain blinding.
• Procedure Endovascular Thrombectomy
  Endovascular thrombectomy will be performed according to standard clinical practice using NMPA-approved thrombectomy devices. First-line techniques may include aspiration thrombectomy, stent retriever thrombectomy, or a combined approach, with rescue procedures permitted when necessary at the investigator's discretion.

Primary outcome measures

• Rate of modified Rankin Scale (mRS) score of 0-2 [Time frame: 90 days (±7 days) after randomization]

Secondary outcome measures (11)

• Rate of modified Rankin Scale (mRS) score of 0-1 [Time frame: 90 days (±7 days) after randomization]
• Rate of mRS score of 0-3 [Time frame: 90 days (±7 days) after randomization]
• Proportional distribution of modified Rankin Score [Time frame: 90 days (±7 days) after randomization]
• Improvement of the National Institutes of Health Stroke Scale (NIHSS) score [Time frame: 48 hours (±12 hours) after randomization]
• Rate of early neurological improvement [Time frame: 48 hours (±12 hours) after randomization]
• Improvement of the NIHSS score [Time frame: 7 days (±1 days) after randomization or discharge]
• EQ-5D-5L [Time frame: 90 days (±7 days) after randomization]
• Barthel Index [Time frame: 90 days (±7 days) after randomization]
• Rate of intracranial hemorrhage (ICH) [Time frame: Within 48 hours after randomization]
• Rate of symptomatic intracranial hemorrhage (sICH) [Time frame: Within 48 hours after randomization]
• All-cause mortality [Time frame: 90 days (±7 days) after randomization]

Eligibility criteria

Inclusion criteria

• 1.Symptoms and signs consistent with focal ischemia in the anterior circulation;
• 2.Large vessel occlusion of the anterior circulation (internal carotid artery, M1/M2 segment of the middle cerebral artery) confirmed by CTA/MRA/DSA;
• 3.Undergoing mechanical thrombectomy;
• 4.Age between 18-80 years, both male and female;
• 5.Pre-stroke modified Rankin Scale (mRS) score ≤1;
• 6.Time from symptom onset to thrombectomy ≤24 hours, including wake-up stroke or unwitnessed stroke; symptom onset is defined as the "last known well" (LKW);
• 7.National Institutes of Health Stroke Scale (NIHSS) score ≥6 at admission;
• 8.ASPECTS ≥3 for anterior circulation occlusion;
• 9.Written informed consent provided by the patient or their legal representative.

Exclusion criteria

• 1．Simultaneous acute occlusion of both the anterior and posterior circulation, or bilateral acute large-vessel occlusion in the anterior circulation;
• 2．Failure to obtain a baseline NIHSS score before sedation or intubation by a neurologist or emergency physician;
• 3．Seizure at stroke onset that precludes assessment of the baseline NIHSS score;
• 4．Bilateral dilated pupils;
• 5．Known allergy to sivelestat sodium or any of its excipients;
• 6．Severe allergy or absolute contraindication to iodinated contrast agents;
• 7．Systolic blood pressure >185 mmHg or diastolic blood pressure >110 mmHg that cannot be controlled with antihypertensive therapy;
• 8．Blood glucose <50 mg/dL (2.8 mmol/L) or >400 mg/dL (22.2 mmol/L);
• 9．Platelet count <50 \* 10⁹/L;
• 10．Hereditary or acquired bleeding tendency, coagulation factor deficiency, current oral anticoagulant use with INR >1.7, or oral anticoagulant treatment within the previous 48 hours;
• 11．Severe renal failure, defined as serum creatinine >3.0 mg/dL (265.2 μmol/L), glomerular filtration rate (GFR) <30 mL/min, or requirement for hemodialysis or peritoneal dialysis;
• 12．Inability to complete the 90-day follow-up (e.g., no fixed residence or overseas patients);
• 13．Suspected vasculitis or septic embolism;
• 14．Suspected aortic dissection;
• 15．Evidence of intracranial tumor (except small meningioma), acute intracranial hemorrhage, tumor, or arteriovenous malformation;
• 16．Significant mass effect with midline shift;
• 17．Evidence of internal carotid artery dissection causing flow limitation;
• 18．Neurological disease or psychiatric disorder that may interfere with evaluation of the patient's condition;
• 19．Pregnant or breastfeeding women;
• 20．Confirmed rheumatic or autoimmune disease with long-term use of immunosuppressants or corticosteroids;
• 21．Current treatment with chemotherapy or other immunomodulatory agents (e.g., recombinant human granulocyte colony-stimulating factor, Xuebijing, or ulinastatin);
• 22．Participation in another clinical trial that may interfere with the results of this study;
• 23．Any other condition that, in the opinion of the investigator, would make the patient unsuitable for participation or may pose a significant risk to the patient.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

China · 2 centers

• Gaomi People's Hospital — Weifang
• Xuanwu Hospital, Capital Medical University. — Beijing

Identifiers

NCT: NCT07552610 · IAT-TOP II

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗