The goal of this clinical trial is to learn whether chlorpromazine and promethazine（C+P）is safe in Acute Ischemic Stroke（AIS) patients and determine the maximum dosage. It will also evaluate the preliminary efficacy of C+P in AIS. The main questions it aims to answer are:

What is the optimal dosage of C+P that is safe without causing adverse effects in AIS patients? What is the optimal dosage of C+P that potentially works to treat AIS? Researchers will compare C+P with placebo (saline solution without C+P) to see if C+P is safe and effective in treating Acute Ischemic Stroke.

Participants will:

Receive C+P or placebo at the same time as endovascular thrombectomy begins. Patients will be observed for 72 hours to see if there were any adverse effects related to C+P. Infarct volumes will be evaluated using Computed Tomography. Functional outcomes will be assessed at 90 days.

Chlorpromazine and promethazine (C+P), due to their effort to induce a hibernation-like status, has been proved to be neuroprotective for ischemic stroke in pre-clinical experiments. However, whether it is safe and potentially effective in acute ischemic stroke (AIS) patients is currently unknown. The reason might be that the optimal dosage is not defined in AIS treatment. High dosage of C+P might result in hypotension and extrapyramidal symptoms that diminishes its neuroprotective effect. So it is essential to determine a safe and potentially dosage. Another reason might be that patients from previous clinical trials assessing the effectiveness of C+P did not receive reperfusion therapy. In this study，we plan to conduct a 6+2 dose-escalation clinical trial to determine the safety of C+P in AIS patients receiving endovascular thrombectomy. Four dosage groups of C+P will be set(10mg/20mg/50mg/100mg).A minimum of 32 patients will be involved if no drug related severe adverse event(SAE) was observed. A maximum of 64 patients will be required if one SAE is observed in each group. The current study aim to provide a basis for phase Ⅱ clinical trial to further explore the efficacy of C+P in AIS treatmment.

Inclusion Criteria:

• Clinical Inclusion Criteria:

  1. Age between 18-80 years(including the critical value)
  2. Ischemic stroke with a National Institutes of Health Stroke Scale (NIHSS) score ranging from 6-20
  3. Time from last known to be well to randomization within 24h
  4. Pre-stroke Modified Rankin Scale scoring 0-1.
  5. With indications of reperfusion therapy (including intravenous thrombolysis and endovascular thrombectomy).
  6. Informed consent signed by patients or their legal relatives.
  7. CT angiography (CTA) confirmed large vessel occlusion of anterior circulation
  8. Alberta Stroke Program Early Computed Tomography Score (ASPECT) score of 6-10.
  9. initial infarct volume on CT perfusion (CTP) lesser than 70ml; a ratio of hypoperfused volume to infarcted volume greater than 1.8; absolute mismatch volume greater than 15 ml according to DEFUSE-3 trial.

Exclusion Criteria:

• Clinical Exclusion Criteria:

  1. Clinical findings suggest intracranial parenchymal hemorrhage or subarachnoid hemorrhage.

  2. Accompanied by epilepsy.

  3. Accompanied by coma or mental disorders, may interfere with neurological function assessment.

  4. History of premorbid phenothiazine allergy or contraindication.

  5. History of allergy to iodine contrast medium or anaphylactic shock

  6. Baseline blood glucose <50mg/dL (2.78mmol) or >400mg/dL (22.20mmol)

     * Acceptable fingertip blood glucose results

  7. Baseline platelet <50×109 /L

  8. Recent (i.e. within 30 days prior to randomization) history of gastrointestinal or other clinically significant bleeding; Active bleeding, abnormal clotting factors, or bleeding tendency (INR≥3 or PT≥3×ULN on anticoagulants; If the investigator believes that the subject does not have coagulation dysfunction, it is not necessary to wait for the results of the coagulation test before deciding whether to enroll.)

  9. The stroke is accompanied by fever, or there is an active infection requiring systemic treatment (such as active tuberculosis, etc.)

  10. Expected survival less than 90 days (According to the Chinese Guidelines for Early Endovascular Interventional Diagnosis and Treatment of Acute Ischemic Stroke 2022, expected survival less than 90 days is a contraindication for endovascular therapy)

  11. A history of severe cardiovascular disease, including but not limited to: uncontrolled hypertension (systolic blood pressure >180 mmHg or diastolic blood pressure >105 mmHg after standard treatment), hypotension (systolic blood pressure ≤100 mmHg after standard treatment), or pulmonary hypertension; Had unstable angina pectoris, myocardial infarction, or bypass or stent surgery within 6 months before randomization; New York Heart Association (NYHA) grade 3-4 history of chronic heart failure; Clinically significant valvular disease; Severe arrhythmias requiring treatment (except atrial fibrillation and paroxysmal supraventricular tachycardia), including QT interval ≥450ms for men and ≥470ms for women

  12. accompanied by chronic obstructive pulmonary disease（COPD）, tuberculosis, pneumonia, pneumothorax, atelectasis, pulmonary fibrosis, bronchopulmonary dysplasia, pleural effusion, acute respiratory distress syndrome, respiratory irregularity and other lung diseases

  13. Severe hepatic and renal insufficiency, including but not limited to: cirrhosis, hepatic encephalopathy, ascites, renal failure or uremia (Ccr<25ml/min), hepatorenal syndrome, etc

  14. Pregnancy or lactating women

  15. Participation in other clinical trials and have used an investigational drug or medical device

  16. Patients that may not be able to complete the study for other reasons or who the investigator believes should not be included

• Image exclusion criteria:

  1. computed tomographic angiography（CTA）/magnetic resonance angiography（MRA）/digital substraction angiography（DSA） shows excessive vascular curvature, which may hinder delivery of interventional devices
  2. Cerebrovascular inflammation is suspected based on medical history and CTA/MRA/DSA
  3. Aortic dissection is suspected based on medical history and CTA/MRA/DSA
  4. CTA/MRA/DSA confirmed multi-vascular regional occlusion (such as bilateral anterior circulation or anterior/posterior circulation, extracranial carotid artery with intracranial tandem lesions), or clinical evidence of bilateral or multi-regional infarction
  5. CTA/MRA/DSA confirms moyamoya disease or moyamoya syndrome
  6. CT/MRI confirmed a significant midline shift effect
  7. CT/MRI confirms the presence of intracranial tumors (except cerebellar meningioma) CT/MRI confirmed intracranial hemorrhage

Because this study is an exploratory trial of dose-escalation, we want to decide whether to share the drug based on some of the problems and situations found during the study and the subject's personal decision. The purpose is to protect the privacy of the subjects and the implementation of the study.