Stroke, Acute Ischemic Clinical Trial
Official title:
The Feasibility, Safety and Efficacy of Y-3 Injection Through Skull Bone Marrow Bypassing Blood-brain Barrier in the Treatment of Acute Malignant Middle Cerebral Artery Infarction(SOLUTION)
The mortality of malignant middle cerebral artery infarction (mMCAI) is up to 80%, while current available treatment is limited. The purpose of this study is to explore the feasibility, safety and efficacy of Intracalvaria bone marrow injection of cytoprotective drug Y-3 in mMCAI patients with contradictions of reperfusion therapy or poor reperfusion outcome.
The mortality rate of malignant middle cerebral artery infarction (mMCAI) is up to 80%, while current available treatment is limited. Mainstream therapeutics include endovascular reperfusion therapy and decompressive craniectomy. But endovascular-reperfusion has limits such as short time window and hemorrhagic transformation risk, while decompressive craniectomy can reduce mortality but not infarct volume. Curative effect of intravenous injection of neuroprotective drugs is severely limited because of the blood-brain barrier. Microchannels connecting the skull bone marrow and dura may be effective drug delivery shortcuts bypassing the blood-brain barrier. Cytoprotective drug Y-3 affects dual aspects of ischemic cascade by disrupting both function of the synaptic folding post-synaptic density protein 95 (PSD-95), as well as α2-γ⁃Aminobutyric acid type A receptor （α2-GABAAR） agonist. Preclinical testing proved that intracalvaria bone marrow injection of Y-3 solution 24h post rat permanent middle cerebral artery infarction reduced rat infarction volume and improved neurological function. The purpose of this study is to explore the feasibility, safety and efficacy of Intracalvaria bone marrow injection of cytoprotective drug Y-3 in mMCAI patients with contradictions of reperfusion therapy or poor reperfusion outcome. This is a prospective, randomized, open-label, blinded endpoint (PROBE) clinical trial. The trial planned to enroll 20 patients with mMCAI, aged 18-85 years, within 24 hours of onset, with contradictions of reperfusion therapy or poor reperfusion outcome. Patients will be randomly assigned to one of the following 2 groups at 1:1 ratio. Intracalvaria bone marrow injection group: intracalvaria bone marrow injection Y-3 (dose was given as 32 ug/kg)once a day for 3 consecutive days, as well as standard treatment and management according to the related guidelines. Conventional treatment group: standard treatment and management according to related guidelines Face to face interviews will be made on baseline, 4±1 days after randomization, 7±2 days after randomization, 14±2 days after randomization or discharge day, and 90 days after randomization. The primary outcomes include feasibility outcomes and safety outcomes. Feasibility Outcomes include the internal plate of skull was drilled throughly, drug leakage during injection, the patient refused to continue, failure for other reasons during 3 days'treatment. Safety Outcomes includes Infection events (skin infection, osteomyelitis, or intracranial infection), symptomatic and non-symptomatic intracranial hemorrhage, moderate to severe bleeding(defined by the GUSTO), hepatic insufficiency, renal insufficiency during the treatment, severe or extremely severe anaemia (hemoglobin <60g / L), mortality, incidence of other adverse events / serious adverse events reported. The secondary outcomes include change of the NIHSS scores from baseline to 14±2 days or at discharge, the NIHSS scores improved by 4 points from baseline at 7±2 days, the NIHSS limb score improved by 2 points from baseline at 7±2 days, change of core infarction volume from baseline to 7±2 days, change of Glasgow Coma Scale (GCS) scores from baseline values to 14±2 days or at discharge, the modified Rankin Scale（mRS） 0-3 points at 90±7 days, Rate of decompressive hemicraniectomy according to guidelines within 90±7 days, Rate of decompressive hemicraniectomy within 90±7 days, neurological intensive care unit (NICU) hospitalization days, cost of the NICU hospitalization Safety indicators will be compared using the Fisher exact probability method. Primary effectiveness measures will be tested by the t-test or the Wilcoxon rank-sum test. Secondary effectiveness measures will use the Fisher exact probability method, where the comparison of neurofunction scale or daily living energy scale will be performed using non-parametric analysis. NICU hospitalization days and NICU hospitalization costs differences will be compared using the t-test or Wilcoxon rank-sum test. All statistics will be two-sided, P <0.05 is considered statistically significant. ;