Acute Ischemic Stroke, Large Vessel Occlusion, Thrombectomy, Neutrophil Extracellular Trap Formation
Conditions
Keywords
Endovascular Thrombectomy, Sivelestat Sodium, Neutrophil elastase
Brief summary
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
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.
DRUGPlacebo
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.
PROCEDUREEndovascular 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.
Sponsors
Xuanwu Hospital, Beijing
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
This trial will be conducted using a double-blind design, in which neither the investigators nor the participants will be aware of the assigned intervention. In addition, outcome assessors will evaluate the study endpoints objectively while remaining blinded to treatment allocation. Participants in the investigational group and the control group will be assigned in a 1:1 ratio. The sivelestat sodium injection and placebo will be identically packaged. The investigational product and placebo will be indistinguishable in physicochemical properties, appearance, packaging, and labeling, and will differ only by drug number. The drug number will be affixed directly to the outer package. The randomization code will be kept by an unblinded statistician and must not be disclosed.
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of modified Rankin Scale (mRS) score of 0-2 | 90 days (±7 days) after randomization | The mRS score range from 0 (no disability) to 6 (death) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of modified Rankin Scale (mRS) score of 0-1 | 90 days (±7 days) after randomization | The mRS score range from 0 (no disability) to 6 (death) |
| Rate of mRS score of 0-3 | 90 days (±7 days) after randomization | The mRS score range from 0 (no disability) to 6 (death) |
| Proportional distribution of modified Rankin Score | 90 days (±7 days) after randomization | The mRS score range from 0 (no disability) to 6 (death) |
| Improvement of the National Institutes of Health Stroke Scale (NIHSS) score | 48 hours (±12 hours) after randomization | The NIHSS score range from 0 (no deficit) to 42 (maximum deficit) |
| Rate of early neurological improvement | 48 hours (±12 hours) after randomization | Early neurological improvement, defined as an NIHSS score of 0-1 at 48 hours or a reduction of ≥4 points from baseline. |
| Improvement of the NIHSS score | 7 days (±1 days) after randomization or discharge | The NIHSS score range from 0 (no deficit) to 42 (maximum deficit) |
| EQ-5D-5L | 90 days (±7 days) after randomization | The EQ-5D 5-Levels (EQ-5D-5L) range from 5 (no problems) to 25 (extreme problems), which deceased patients have a utility of 0. |
| Barthel Index | 90 days (±7 days) after randomization | The Barthel Index range from 0 (severe disability) to 100 (no disability) |
| Rate of intracranial hemorrhage (ICH) | Within 48 hours after randomization | Any intracranial hemorrhage confirmed by imaging |
| Rate of symptomatic intracranial hemorrhage (sICH) | Within 48 hours after randomization | The sICH was assessed based on the Heidelberg Bleeding Classification, defined as 1) ≥4 points total NIHSS at the time of diagnosis compared to immediately before worsening; 2) ≥2 point in one NIHSS category. The rationale for this is to capture new hemorrhages that produce new neurological symptoms, making them clearly symptomatic but not causing worsening in the original stroke territory; 3) Leading to intubation/hemicraniectomy/EVD placement or other major medical/surgical intervention; 4) Absence of alternative explanation for deterioration. |
| All-cause mortality | 90 days (±7 days) after randomization | Death is defined as a mRS score of 6 |
Countries
China
Outcome results
None listed