A Single-Center,Open-Label Clinical Study on the Safety and Preliminary Efficacy of Hibernation-Like Therapy (Chlorpromazine and Promethazine) in Patients With Acute Ischemic Stroke (AIS) Eligible for Reperfusion Therapy.
A Single-Center,Open-Label Clinical Study on the Safety and Preliminary Efficacy of Hibernation-Like Therapy (Chlorpromazine and Promethazine) in Patients With Acute Ischemic Stroke (AIS) Eligible for Reperfusion Therapy.
This is a single-center, dose-escalation and dose-expansion Phase I study designed to evaluate the safety of hibernation-like therapy (Chlorpromazine and Promethazine, C+P) and observe improvements in infarct volume in patients with AIS eligible for reperfusion therapy.
Part A is the dose-escalation phase, and Part B is the dose-expansion phase. Both Part A and Part B will enroll subjects with AIS who are eligible for endovascular treatment based on multimodality imaging assessment and who meet all inclusion criteria and none of the exclusion criteria as evaluated by the investigator. Successfully screened patients will first enter the dose-escalation study. The escalating doses are Chlorpromazine and Promethazine (C+P) at the following combinations: 50mg+50mg, 62.5mg+62.5mg, 75mg+75mg, and 100mg+100mg.
Dose escalation will follow the "3+3" rule, with a planned enrollment of 12-24 subjects. Based on the dose-escalation results, dose expansion will be initiated at an appropriate time. The dose-expansion phase will consist of three cohorts: two cohorts receiving C+P and one cohort receiving an intravenous infusion of 50ml normal saline at room temperature (infusion rate also 50ml/h) prior to endovascular treatment. The two C+P dose groups for expansion will be selected based on the dose-escalation results. Patients will receive the study drug followed by reperfusion therapy. The administration method is the same as in the dose-escalation phase. The dose-expansion phase plans to enroll 33 subjects (10 subjects each in the two C+P cohorts and 13 subjects in the normal saline cohort). See the figure below for details.
C+P is administered intravenously. The administration regimen involves dissolving C+P in 50ml of normal saline at room temperature and infusing it intravenously at a rate of 50ml/h (complete infusion over 1 hour). Subsequently, the patient will undergo endovascular thrombectomy for recanalization.
The DLT observation period in the dose-escalation phase is 3 days after administration. Escalation to the next dose cohort may proceed only after the DLT observation period for the current cohort is completed and safety is confirmed.
Patients will receive only a single administration during both the dose-escalation and dose-expansion phases. Within 24 hours after completing endovascular thrombectomy, patients will undergo ECG monitoring with close observation of vital signs and changes in consciousness level. Vital signs will continue to be monitored for up to 72 hours post-thrombectomy, and imaging follow-up will be performed at 48 ±12 hours.
Study Objectives:
Endpoints:
Primary Endpoint: Observation of DLT and MTD across different C+P dose cohorts to determine the RP2D.
Secondary Endpoints:
Exploratory Endpoint: Changes in metabolomics at 3 hours post-administration compared to pre-administration.
Inclusion Criteria:
The subject or their legal guardian voluntarily agrees to participate by providing written informed consent, and agrees to comply with the trial treatment plan and visit schedule.
Male or female, aged 18 to 80 years (inclusive).
Diagnosis of acute ischemic stroke eligible for endovascular therapy.
Clinical signs and symptoms consistent with acute anterior circulation ischemic stroke, with a National Institutes of Health Stroke Scale (NIHSS) score between 6 and 20 (inclusive).
Note: The NIHSS score ranges from 0 to 42, with higher scores indicating more severe neurological deficits. Classification:
Time from stroke onset to planned drug administration is within 24 hours.
Pre-stroke modified Rankin Scale (mRS) score of 0 or 1.
Expected survival greater than 90 days.
Imaging Inclusion Criteria:
Adequate organ function at screening, defined as:
Female subjects of childbearing potential must agree to use effective contraception (e.g., intrauterine device, oral contraceptives, or condoms) during the study and for 6 months after study completion. A negative pregnancy test is required within 7 days prior to enrollment. All subjects (male or female) must employ adequate contraceptive measures throughout the treatment period and for 6 months thereafter. (A negative pregnancy test result is mandatory for women of childbearing potential before enrollment).
Exclusion Criteria:
Presence of pathological fever at screening: axillary temperature ≥ 37.3°C or tympanic membrane temperature ≥ 37.9°C.
Clinical presentation suggestive of intracranial parenchymal hemorrhage or subarachnoid hemorrhage (even with normal imaging findings).
Stroke onset accompanied by seizures at screening, precluding accurate NIHSS assessment.
Coma or psychiatric disorders at screening that interfere with neurological evaluation.
Conditions contraindicating phenothiazine use at screening, such as Parkinson's disease, parkinsonism, basal ganglia disorders, bone marrow suppression, glaucoma, epilepsy, history of neuroleptic malignant syndrome, or history of hypersensitivity to phenothiazines.
History of severe infusion reactions deemed ineligible for inclusion upon evaluation.
History of allergy or anaphylactic shock to iodinated contrast agents.
Major surgery within 4 weeks prior to drug administration.
Blood glucose <50 mg/dL (2.78 mmol/L) or >400 mg/dL (22.20 mmol/L) prior to drug administration (fingerstick glucose results acceptable).
History of deep vein thrombosis within 6 months prior to drug administration.
Previous endovascular thrombectomy performed less than 3 months prior.
Clinically significant active bleeding (e.g., gastrointestinal or other) within 30 days prior to drug administration; coagulation factor abnormalities or bleeding tendency (e.g., on anticoagulants with INR ≥3 or PT ≥3×ULN). However, subjects may be enrolled without awaiting coagulation results if the investigator deems no coagulation dysfunction. Active infection requiring systemic therapy within 2 weeks prior to drug administration (e.g., active tuberculosis).
Clinically significant cardiac disease at screening, including but not limited to:
Severe arrhythmia requiring treatment or presence of QT interval prolongation at screening, deemed ineligible by the investigator.
Severe systemic disease at screening deemed ineligible by the investigator, including but not limited to: pulmonary embolism, pulmonary hypertension, severe COPD, active tuberculosis, severe pneumonia, pneumothorax, severe atelectasis, severe pulmonary fibrosis, bronchopulmonary dysplasia, unstable pleural effusion, acute respiratory distress syndrome, irregular breathing patterns or other severe pulmonary diseases; severe hepatic or renal insufficiency such as cirrhosis, hepatic encephalopathy, ascites, obstructive jaundice, renal failure, or uremia.
Pregnant or lactating women.
Participation in an interventional clinical trial involving investigational drugs or medical devices within 28 days prior to screening.
Subjects considered inappropriate for inclusion by the investigator.
Imaging Exclusion Criteria:
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