The Feasibility and Safety of RK-4 Injection Bypassing Blood-brain Barrier in the Treatment of Acute Large Hemispheric Infarction Using Intracalvariosseous Injection Device

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• 18≤Age≤80 years
• First stroke or complete self-care before the onset of current stroke (mRS 0-1)
• Administration of drugs can be completed within 24h of the onset of signs and symptoms of neurological deficits (in patients with wake-up strokes or unwitnessed strokes, the time of onset is defined as the time of last normal presentation)
• Clinical symptoms, signs and imaging diagnosis of cerebral infarction in the area supplied by the middle cerebral artery, together with the following features:; 16≤ NIHSS ≤32 points, and the sum of the scores of motor arm and motor leg is ≥6; Imaging suggestive of core infarct area: apparent diffusion coefficient (ADC) values <620×10-6mm2/s lesion volume on magnetic resonance imaging (MRI) diffusion-weighted imaging (DWI) sequences or cerebral blood flow (CBF) <30% of volume 70-300 ml on computed tomography perfusion imaging (CTP) or an Alberta Stroke Program Early CT Score (ASPECTS) of 0-6, with inconsistent findings, the investigator is required to make a reasoned judgement by taking into account all the information (scanning time, the imaging method that best responds to the size of infarct, etc.) and record it
• NIHSS score not improving or progressing after reperfusion therapy and total score still ≤32
• Informed consent signed

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• Complications with other cerebrovascular diseases meet one of the following conditions:; Complicated with acute cerebral hemorrhage and subarachnoid hemorrhage; Complicated with acute posterior circulation cerebral infarction or severe posterior circulation stenosis (>70%); Or imaging suggests that the area of cerebral infarction is involved bilaterally; The cause of the TOAST classification was considered as intracranial artery dissection, vasculitis, moyamoya disease and other etiological types
• Hemorrhage transformation in the infarction area, hematoma area ≥30% of the infarction area, and has obvious space-occupying effect
• Refractory hypertension (systolic > 200mmHg or diastolic > 110mmHg) or hypotension (systolic < 70mmHg or diastolic < 50mmHg) that is difficult to control with medication
• Acute ST-elevation myocardial infarction (MI) and/or decompensated heart failure (meeting the New York College of Cardiology (NYHA) Heart function grades III and IV) within the past 3 months
• Presence of contraindications to intracalvariosseous injection, e.g., skull fracture in the last 3 months, skull infection, subdural/extradural hematoma, subcutaneous hematoma, skin or subcutaneous infection of the scalp, poorly displayed skull bone marrow niches
• Patients with severe respiratory diseases (severe chronic obstructive pulmonary disease, respiratory failure, etc.) should be corrected by intubation, tracheotomy, or ventilator
• The subjects were considered to have developed clinically significant serious infections, including severe local infections or systemic infections
• Diagnosed severe degenerative diseases of the central nervous system such as Alzheimer's Disease (AD), Parkinson's Disease (PD), and severe dementia of all causes, or psychiatric disorders (e.g., schizophrenia, depression, etc.)
• Subjects with a life expectancy of less than 3 months due to conditions not considered current by the investigators, such as tumors
• Known allergy to any component of investigational process therapy drugs and contrast agents
• Abnormal blood glucose before randomization (random venous blood glucose < 2.8mmol/L or > 23mmol/L)
• Presence of significant abnormal liver function markers or renal function markers prior to randomization; Note: Severe liver function abnormalities were defined as serum alanine aminotransferase (ALT), or aspartate aminotransferase (AST) > 3 times the upper limit of normal (ULN). Significant renal insufficiency is defined as eGFR less than 60 mL/min/1.73 m2 (eGFR, calculated using the CKD-EPI formula)
• Bleeding tendencies considered by the investigators to be detrimental to the procedure include, but are not limited to, platelet counts < 100×109/L, and the presence of clotting disorders such as hemophilia
• Presence of severe or very severe anemia (hemoglobin <60 g/L) at randomization
• Presence of clinical signs of brain herniation formation, e.g., unilateral or bilateral pupil dilation and fixation; cerebral oedema-associated loss of consciousness (NIHSS 1a > 2 points), or other loss of brainstem reflexes in the judgement of the investigator, caused by cerebral oedema or cerebral herniation formation; or other signs of instability of vital signs that are difficult to control
• Craniotomy decompression was planned before randomization
• Subjects who are pregnant, breastfeeding or have the possibility of becoming pregnant or plan to become pregnant
• Subjects are unable to comply with trial protocols or follow-up requirements
• Other circumstances deemed by the investigators to be unsuitable for enrollment (registration of reasons for inability to enroll is required)
• Have participated in other interventional clinical trials