A pilot study confirmed the feasibility and safety of neuroprotectant Y-3 intracalvariosseous(ICO) injection in patients with malignant middle cerebral artery infarction (mMCAI), showing a trend in improving 90-day functional scores compared to conventional treatment. The aim of this trial is to further investigate the efficacy and safety of ICO injection of Y-3 compared to intravenous injection in patients with acute large hemispheric infarction(LHI) who has contraindications of reperfusion therapy or have got poor reperfusion therapy outcomes.
The mortality rate of large hemispheric infarction(LHI) is up to 40%-60%, 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. Phase I and Phase II clinical trials have confirmed the safety and efficacy of intravenous infusion of Y-3 in treating cerebral infarction, with the optimal dosage being 40mg. Preclinical testing proved that ICO injection of Y-3 solution 24h post rat permanent middle cerebral artery infarction reduced rat infarction volume and improved neurological function. SOLUTION-2 is a multicentered, prospective, randomized, open-label, blinded end-point (PROBE) study The purpose of this study is to investigate the efficacy and safety of ICO injection of Y-3 compared to intravenous injection in acute LHI patients with contraindications of reperfusion therapy or poor outcomes. Patients will be randomly assigned to one of the following 2 groups at 1:1 ratio. ICO injection group: Y-3 ICO injection (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. intravenous injection group: Y-3 intravenous injection(dose was given as 40mg + 250ml normal saline), as well as standard treatment and management according to related guidelines. Face to face interviews will be made on baseline, 4±1 days after randomization, 8±1 days after randomization, 14±1 days after randomization or discharge day, and 90 days , 1year± 14 days after randomization. The primary efficacy outcomes is the modified Rankin Scale(mRS) 0-3 points at 90±7 days. A Data and Safety Monitoring Board (DSMB) will regularly monitor safety during the study. The trial has been approved by Institutional Review Board (IRB) and Ethics Committee (EC) in Being Tiantan hospital, Capital Medical University.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
134
Patients included will be given skull outer plate drilling surgery and Y-3 ICO injection under local anesthesia and sedation. The injection will be given for 3 consecutive days.
Patients included will be given Y-3 intravenous injection for 7 consecutive days.
standard treatment and management according to related guidelines during the entire treatment period
The first affiliated hospital of Wannan Medical College
Wuhu, Anhui, China
RECRUITINGBeijing Tiantan Hospital
Beijing, Beijing Municipality, China
RECRUITINGNorth China University of Science and Technology Affiliated Hospital
Tangshan, Heibei, China
RECRUITINGTangshan Municipal Worker's Hospital
Tangshan, Heibei, China
WITHDRAWNShaanxi Provincial People's Hospital
Xi'an, Shaanxi, China
RECRUITINGTianjin Huanhu hospital
Tianjin, China
RECRUITING90-day favorable clinical outcome
Favorable clinical outcome defined as a dichotomized mRS 0-3 outcome The modified Rankin Scale (mRS) is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. The scale runs from 0-6 with "0" being perfect health without symptoms to "6" being death. Score 0: No symptoms Score 1: No significant disability. Able to carry out all usual activities, despite some symptoms. Score 2: Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities. Score 3: Moderate disability. Requires some help, but able to walk unassisted. Score 4: Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted. Score 5: Severe disability. Requires constant nursing care and attention, bedridden, incontinent. Score 6: Dead
Time frame: 90±7 days after randomization
Change of infarct volume from baseline to 8-day
The infarct volume is determined on a diffusion-weighted MRI map based on an ADC threshold of less than 620 ×10\^-6mm\^2/s or on CTP image with rCBF\<30%
Time frame: baseline,8±1 days after randomization
Neurofunctional deficit defined as the National Institutes of Health Stroke Scale (NIHSS) .
NIHSS is a standardized neurological examination score that is a valid and reliable measure of disability and recovery after acute stroke. Scores range from 0 to 42, with higher scores indicating increasing severity.
Time frame: 8±1 days after randomization,14±1 days after randomization,90±7 days after randomization
Patients with symptoms improvement from baseline to 14-day
Symptoms improvement defined as the NIHSS scores improved by 4 points from baseline to 14-day
Time frame: baseline,14±1 days after randomization
Rate of decompressive hemicraniectomy
Rate of decompressive hemicraniectomy
Time frame: 90±7 days after randomization
Depression scale scores at 90-day
Depression scale scores including Stroke Aphasic Depression Questionnaire-Hospital Version(SADQ-H) and Aphasia Depression Rating Scale(ADRS)
Time frame: 90±7 days after randomization
Proportion of combined adverse events at 90-day
Combined adverse events defined as mRS 4-5, decompressive craniotomy, vascular death
Time frame: 90±7 days after randomization
90-day modified Rankin Scale
The modified Rankin Scale (mRS) is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. The scale runs from 0-6 with "0" being perfect health without symptoms to "6" being death. Score 0: No symptoms Score 1: No significant disability. Able to carry out all usual activities, despite some symptoms. Score 2: Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities. Score 3: Moderate disability. Requires some help, but able to walk unassisted. Score 4: Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted. Score 5: Severe disability. Requires constant nursing care and attention, bedridden, incontinent. Score 6: Dead
Time frame: 90±7 days after randomization
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