Clinical trial NCT06447701: Interleukin-6 Receptor Inhibition for Symptomatic Intracranial Atherosclerosis
Official title: Effect of Interleukin-6 Receptor Inhibition for Avoiding Recurrence of Ischemic Stroke in Patients With Symptomatic Intracranial Atherosclerosis: a Double-blind, Randomized, Placebo-controlled Trial
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
Conditions: Brain Diseases
Ischemic Stroke
Ischemia
Stroke
Cerebral Infarction
Atherosclerosis of Artery
Atheroscleroses, Intracranial
Keywords: Tocilizumab
Symptomatic intracranial atherosclerotic stenosis
Recurrence
Ischemic stroke
Lead sponsor: Zhujiang Hospital
Sponsor class: OTHER
Collaborators: name: Shenzhen Second People's Hospital
name: Central People's Hospital of Zhanjiang
name: Shantou Central Hospital
name: Eighth Affiliated Hospital, Sun Yat-sen University
name: Guangzhou First People's Hospital
name: Peking University Shenzhen Hospital
name: Guangdong Provincial People's Hospital
First posted: 2024-06-07
Enrollment: 486
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The subject numbers and corresponding medication numbers are permanently identified and unique for each successfully randomized patient. If any patients who have been successfully randomized do not receive the trial medication or cannot be reassigned to others, their medication and medication numbers will be invalidated by the medication administrator. To ensure blinding during the trial execution, unblinded personnel responsible for administering and configuring the trial drug must sign a confidentiality agreement. Investigators, other blinded investigators, subjects, and sponsors will not have access to any information regarding group assignment or related documents pertaining to the trial drug.
Primary purpose: TREATMENT

Brief summary: IRIS-sICAS is a multicenter, randomized, double-blind, placebo-controlled clinical trialis a multicenter, randomized, double-blind, placebo-controlled clinical trial, to assess the safety and efficacy of tocilizumab injection in lowering the incidence of newly diagnosis ischemic stroke and improving prognosis in symptomatic intracranial atherosclerosis patients.

Detailed description: Intracranial atherosclerosis (ICAS) is one of the most common causes of stroke worldwide, and the currently recommended intensive pharmacologic and surgical treatments show only modest efficacy, with approximately 20% of strokes still recurring, for which there is no targeted treatment. Tocilizumab is a recombinant humanized anti-human interleukin-6 receptor monoclonal antibody that exerts anti-inflammatory effects by specifically binding to the IL-6 receptor and blocking IL-6 signal transduction. Previous studies have shown that tocilizumab can effectively attenuate acute ischemic injury in the early stage of myocardial infarction and has potentially anti-atherosclerotic effects. However, application in ICAS not yet reported. This study is a multicenter, randomized, double-blind, placebo-controlled clinical trial, which enrolled patients with symptomatic ICAS occurring within 72 hours of ischemic stroke or high-risk transient ischemic attack. Patients who consented to participate in the study were randomly assigned in a 1:1 ratio to receive a single infusion of 320mg tocilizumab or placebo (saline injection), and patients were followed up to assess the safety and efficacy of tocilizumab injection in lowering the incidence of newly diagnosis ischemic stroke and improving prognosis.

Eligibility criteria: Inclusion Criteria:

* Male or non-pregnant women with acute stroke symptoms aged over 18 years.
* Patients having an ischemic stroke or a TIA prior to randomization (Patients having an acute ischemic stroke within 72 hours with NIHSS score≤5 at baseline, or patients having a TIA within 72 hours with Oxfordshire Community Stroke Project on the basis of age, blood pressure, clinical features, and duration of TIA symptoms (ABCD2) score≥4 at baseline).
* The entry event is attributed to symptomatic atherosclerosis (50-99%) in an intracranial qualifying artery (intracranial carotid artery (C4-7), middle cerebral artery (M1), intracranial vertebral artery or basilar artery) confirmed by CT, MR angiography, or digital subtraction angiography.
* Informed consent obtained from patients or their legal representatives.
* Willing to be followed up as required by the clinical study protocol.

Exclusion Criteria:

* Thrombolytic therapy or thrombectomy within 24 hours prior to enrollment.
* Pre-stroke mRS score ≥ 2.
* Combined or previous intracranial hemorrhage: hemorrhagic stroke, epidural hematoma, subdural hematoma, intraventricular hemorrhage, subarachnoid hemorrhage, etc.
* Any of the following unequivocal cardiac source of embolism: chronic or paroxysmal atrial fibrillation, sinus node dysfunction, mitral stenosis, prosthetic heart valves, endocarditis, left ventricular mural thrombus or valvular vegetation, myocardial infarction within three months, dilated cardiomyopathy, spontaneous echogenic defects in the left atrium or an ejection fraction of less than 30%.
* Intracranial arterial stenosis due to arterial dissection, Moya Moya disease; herpes zoster, varicella zoster or other viral vasculopathy; neurosyphilis; radiation induced vasculopathy; fibromuscular dysplasia; sickle cell disease; neurofibromatosis; post-partum angiopathy; suspected vasospastic process, suspected recanalized embolus; any known vasculitic disease.
* Extracranial stenosis ≥50%, subclavian arterial stenosis≥50% or subclavian steal syndrome.
* Previous interventions for intracranial arterial stenosis.
* Concurrent intracranial tumors, intracranial aneurysms or arteriovenous malformations
* Neutrophil \< 2×10 9/L.
* Platelet \< 100×10 9/L.
* Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels greater than 1.5 times the upper limit of normal.
* Active infections including localized.
* Evidence of HIV or hepatitis B positivity.
* Positive tuberculosis-related tests.
* Concurrent peptic ulcer, diverticulitis or inflammatory bowel disease.
* Concurrent malignant tumors, recent bone marrow transplant or recent organ transplant.
* Systolic blood pressure ≥ 180 mmHg or diastolic blood pressure ≥ 110 mmHg despite blood pressure control.
* Known allergy to tocilizumab or excipients.
* Use of immunosuppressive drugs or systemic use of antibiotics.
* Received any live or live attenuated vaccine within 4 weeks prior to enrollment or plan to receive a live or live attenuated vaccine during the study.
* History of demyelination or presence of neurological symptoms suggestive of demyelination.
* Previously existing neurological or psychiatric disorders that could potentially confuse neurological function assessment.
* An expected survival less than 90 days.
* Participation in another interventional clinical study.
* Patients unsuitable for enrollment in the clinical trial according to investigators decision making.

Primary outcomes:
measure: The proportion of patients with newly diagnosed ischemic stroke within 90(±7) days
timeFrame: 90(±7) days
Secondary outcomes:
measure: The functional neurological status at 6(±1) days or discharge if earlier from baseline
timeFrame: 6(±1) days
measure: The incidence of composite events including any type of stroke (ischemic stroke(IS), subarachnoid hemorrhage(SAH), or intracerebral hemorrhage(ICH)), myocardial infarction(MI), and transient ischemic attack(TIA) and each of foresaid events at 30(±3) days
timeFrame: 30(±3) days
measure: The incidence of composite events including any type of stroke (ischemic stroke(IS), subarachnoid hemorrhage(SAH), or intracerebral hemorrhage(ICH)), myocardial infarction(MI), and transient ischemic attack(TIA) and each of foresaid events at 90(±7) days
timeFrame: 90(±7) days
measure: Proportion of patients with functional independence at 90(±7) days
timeFrame: 90(±7) days
measure: Health-related quality of life at 90(±7) days
timeFrame: 90(±7) days
measure: Mortality at 90(±7) days
timeFrame: 90(±7) days
measure: Incidence of serious adverse events
timeFrame: 90(±7) days
measure: Change of inflammatory blood biomarkers from admission to 72 hours
timeFrame: 72 hours
measure: Change of inflammatory blood biomarkers from admission to 72 hours
timeFrame: 72 hours
Other outcomes:
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