Study on Hibernation-like Therapy Based on Mechanical Thrombectomy

NCT06663631 | Recruiting Phase 1

• 1 other identifier: CHILL-1
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Acute Ischemic Stroke

Keywords

Hibernation-like status; Reperfusion; Neuroprotection; phenothiazine; dose-escalation

Outcome Measures

Primary Outcomes (1)

• The incidence and severity of all adverse events (AEs) and severe adverse events (SAEs)

  AEs including: 1. Severe hypothermia with body temperature\<32 degree centigrade 2. Severe hypotension with systolic blood pressure\<90mmHg that needs additional support 3. Any forms of intracranial hemorrhage 4. Coma 5. Death within 72h 6. Respiratory depression defined as respiration rate\<8 bpm/min 7. Extrapyramidal symptoms including Parkinsonism, dystonia, dyskinesia. AEs are defined as severe adverse events(SAEs) if severity reaches grade 3-5 according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) ver. 5.0.

  72 hours after randomization

Secondary Outcomes (3)

• Scores of National institutes of health stroke scale (NIHSS)

  24 hours after randomization

• Infarct volume

  72 hours after randomization

• Plasma proteomics and metabolomics

  24 hours±6 hours

Study Arms (5)

chlorpromazine and promethazine of Very low dosage

EXPERIMENTAL

patients will receive C+P（chlorpromazine and promethazine ,10 mg each)at the beginning of endovascular thrombectomy.

Drug: chlorpromazine and promethazine; Procedure: endovascular thrombectomy; Drug: rt-PA

chlorpromazine and promethazine of low-dosage

EXPERIMENTAL

patients will receive C+P（chlorpromazine and promethazine ,20 mg each)at the beginning of endovascular thrombectomy.

Drug: chlorpromazine and promethazine; Procedure: endovascular thrombectomy; Drug: rt-PA

chlorpromazine and promethazine of moderate dosage

EXPERIMENTAL

patients will receive C+P（chlorpromazine and promethazine ,50 mg each)at the beginning of endovascular thrombectomy.

Drug: chlorpromazine and promethazine; Procedure: endovascular thrombectomy; Drug: rt-PA

chlorpromazine and promethazine of high dosage

EXPERIMENTAL

patients will receive C+P（chlorpromazine and promethazine ,100 mg each)at the beginning of endovascular thrombectomy.

Drug: chlorpromazine and promethazine; Procedure: endovascular thrombectomy; Drug: rt-PA

Placebo group

PLACEBO COMPARATOR

50 ml saline solution was delivered intravenously at the beginning of endovascular thrombectomyat a velocity of 4ml/h. The whole period of drug delivery lasts for approximately 12h.

Drug: Placebo group; Procedure: endovascular thrombectomy; Drug: rt-PA

Interventions

chlorpromazine and promethazine DRUG

C+P were diluted to 50 ml saline solution and delivered intravenously at the beginning of endovascular thrombectomyat a velocity of 4ml/h. The whole period of drug delivery lasts for approximately 12h.

Also known as: C+P, lytic cocktail

chlorpromazine and promethazine of Very low dosage; chlorpromazine and promethazine of high dosage; chlorpromazine and promethazine of low-dosage; chlorpromazine and promethazine of moderate dosage

Placebo group DRUG

50 ml saline solution was set as placebo and delivered intravenously at the beginning of endovascular thrombectomyat a velocity of 4ml/h. The whole period of drug delivery lasts for approximately 12h.

Also known as: Control group

Placebo group

endovascular thrombectomy PROCEDURE

All patients that are eligible for endovascular thrombectomy will receive this surgery in aim to remove thrombus and restore reperfusion.

Placebo group; chlorpromazine and promethazine of Very low dosage; chlorpromazine and promethazine of high dosage; chlorpromazine and promethazine of low-dosage; chlorpromazine and promethazine of moderate dosage

rt-PA DRUG

All patients that are eligible for Intravenous thrombolysis will receive 0.9mg/kg rt-PA in aim to remove thrombus and restore reperfusion

Also known as: Intravenous thrombolysis

Placebo group; chlorpromazine and promethazine of Very low dosage; chlorpromazine and promethazine of high dosage; chlorpromazine and promethazine of low-dosage; chlorpromazine and promethazine of moderate dosage

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age between 18-80 years(including the critical value)
• Ischemic stroke with a National Institutes of Health Stroke Scale (NIHSS) score ranging from 6-20
• Time from last known to be well to randomization within 24h
• Pre-stroke Modified Rankin Scale scoring 0-1.
• With indications of reperfusion therapy (including intravenous thrombolysis and endovascular thrombectomy).
• Informed consent signed by patients or their legal relatives.
• CT angiography (CTA) confirmed large vessel occlusion of anterior circulation
• Alberta Stroke Program Early Computed Tomography Score (ASPECT) score of 6-10.
• 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.

You may not qualify if:

• Clinical findings suggest intracranial parenchymal hemorrhage or subarachnoid hemorrhage.
• Accompanied by epilepsy.
• Accompanied by coma or mental disorders, may interfere with neurological function assessment.
• History of premorbid phenothiazine allergy or contraindication.
• History of allergy to iodine contrast medium or anaphylactic shock
• Baseline blood glucose \<50mg/dL (2.78mmol) or \>400mg/dL (22.20mmol)
• \* Acceptable fingertip blood glucose results
• Baseline platelet \<50×109 /L
• 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.)
• The stroke is accompanied by fever, or there is an active infection requiring systemic treatment (such as active tuberculosis, etc.)
• 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)
• 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
• 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
• Severe hepatic and renal insufficiency, including but not limited to: cirrhosis, hepatic encephalopathy, ascites, renal failure or uremia (Ccr\<25ml/min), hepatorenal syndrome, etc
• Pregnancy or lactating women

Sponsors & Collaborators

• Capital Medical University: lead
• Linyi People's Hospital: collaborator

Study Sites (1)

Linyi People's Hospital

Linyi, Shandong, 276000, China

RECRUITING

Related Publications (9)

• Tarahovsky YS, Fadeeva IS, Komelina NP, Khrenov MO, Zakharova NM. Antipsychotic inductors of brain hypothermia and torpor-like states: perspectives of application. Psychopharmacology (Berl). 2017 Jan;234(2):173-184. doi: 10.1007/s00213-016-4496-2. Epub 2016 Dec 8.

  PMID: 27933367 BACKGROUND

• Guan L, Guo S, Yip J, Elkin KB, Li F, Peng C, Geng X, Ding Y. Artificial Hibernation by Phenothiazines: A Potential Neuroprotective Therapy Against Cerebral Inflammation in Stroke. Curr Neurovasc Res. 2019;16(3):232-240. doi: 10.2174/1567202616666190624122727.

  PMID: 31232236 BACKGROUND

• Guo S, Cosky E, Li F, Guan L, Ji Y, Wei W, Peng C, Geng X, Ding Y. An inhibitory and beneficial effect of chlorpromazine and promethazine (C + P) on hyperglycolysis through HIF-1alpha regulation in ischemic stroke. Brain Res. 2021 Jul 15;1763:147463. doi: 10.1016/j.brainres.2021.147463. Epub 2021 Apr 1.

  PMID: 33811844 BACKGROUND

• Guo S, Li F, Wills M, Yip J, Wehbe A, Peng C, Geng X, Ding Y. Chlorpromazine and Promethazine (C+P) Reduce Brain Injury after Ischemic Stroke through the PKC-delta/NOX/MnSOD Pathway. Mediators Inflamm. 2022 Jul 15;2022:6886752. doi: 10.1155/2022/6886752. eCollection 2022.

  PMID: 35873710 BACKGROUND

• Tong Y, Elkin KB, Peng C, Shen J, Li F, Guan L, Ji Y, Wei W, Geng X, Ding Y. Reduced Apoptotic Injury by Phenothiazine in Ischemic Stroke through the NOX-Akt/PKC Pathway. Brain Sci. 2019 Dec 15;9(12):378. doi: 10.3390/brainsci9120378.

  PMID: 31847503 BACKGROUND

• Jiang Q, Wills M, Geng X, Ding Y. Chlorpromazine and promethazine reduces Brain injury through RIP1-RIP3 regulated activation of NLRP3 inflammasome following ischemic stroke. Neurol Res. 2021 Aug;43(8):668-676. doi: 10.1080/01616412.2021.1910904. Epub 2021 Apr 8.

  PMID: 33829970 BACKGROUND

• Han Y, Geng XK, Lee H, Li F, Ding Y. Neuroprotective Effects of Early Hypothermia Induced by Phenothiazines and DHC in Ischemic Stroke. Evid Based Complement Alternat Med. 2021 Jan 18;2021:1207092. doi: 10.1155/2021/1207092. eCollection 2021.

  PMID: 33531913 BACKGROUND

• Lv S, Zhao W, Rajah GB, Dandu C, Cai L, Cheng Z, Duan H, Dai Q, Geng X, Ding Y. Rapid Intervention of Chlorpromazine and Promethazine for Hibernation-Like Effect in Stroke: Rationale, Design, and Protocol for a Prospective Randomized Controlled Trial. Front Neurol. 2021 Mar 17;12:621476. doi: 10.3389/fneur.2021.621476. eCollection 2021.

  PMID: 33815250 BACKGROUND

• Seners P, Yuen N, Mlynash M, Snyder SJ, Heit JJ, Lansberg MG, Christensen S, Albucher JF, Cognard C, Sibon I, Obadia M, Savatovsky J, Baron JC, Olivot JM, Albers GW; Mismatch Prevalence Investigators. Quantification of Penumbral Volume in Association With Time From Stroke Onset in Acute Ischemic Stroke With Large Vessel Occlusion. JAMA Neurol. 2023 May 1;80(5):523-528. doi: 10.1001/jamaneurol.2023.0265.

  PMID: 36939736 BACKGROUND

MeSH Terms

Conditions

Ischemic Stroke

Interventions

Chlorpromazine; Promethazine; Control Groups

Condition Hierarchy (Ancestors)

Stroke; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Phenothiazines; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Propylamines; Amines; Epidemiologic Research Design; Epidemiologic Methods; Investigative Techniques; Research Design; Methods

Study Officials

• Xunming Ji, Doctor

  Capital Medical University

  STUDY CHAIR

Central Study Contacts

Xunming Ji, Doctor

CONTACT

+86 13911077166; Jixm@ccmu.edu.cn

Hao Wang, Doctor

CONTACT

+86 13518690201; neurology_hao@163.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: chief physician

Study Record Dates

• First Submitted: October 24, 2024
• First Posted: October 29, 2024
• Study Start: November 9, 2024
• Primary Completion: January 1, 2025
• Study Completion: February 1, 2025
• Last Updated: December 20, 2024

Record last verified: 2024-12

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)