Study on Hibernation-like Therapy Based on Mechanical Thrombectomy (CHILL-1)

December 18, 2024 updated by: Ji Xunming,MD,PhD, Capital Medical University

The Safety and effiCacy of HIbernation-Like Therapy Combining recanaLization in Ischemic Stroke: a Phase 1, Dose-escalation Study

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Estimated)

32

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

  • Name: Xunming Ji, Doctor
  • Phone Number: +86 13911077166
  • Email: Jixm@ccmu.edu.cn

Study Contact Backup

Study Locations

  • China
    • Shandong
      • Linyi, Shandong, China, 276000
        • Recruiting
        • Linyi People's Hospital
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: chlorpromazine and promethazine of Very low dosage
patients will receive C+P（chlorpromazine and promethazine ,10 mg each)at the beginning of endovascular thrombectomy.
Drug: chlorpromazine and promethazine
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.
Other Names:
  • C+P
  • lytic cocktail
Procedure: endovascular thrombectomy
All patients that are eligible for endovascular thrombectomy will receive this surgery in aim to remove thrombus and restore reperfusion.
Drug: rt-PA
All patients that are eligible for Intravenous thrombolysis will receive 0.9mg/kg rt-PA in aim to remove thrombus and restore reperfusion
Other Names:
  • Intravenous thrombolysis
Experimental: chlorpromazine and promethazine of low-dosage
patients will receive C+P（chlorpromazine and promethazine ,20 mg each)at the beginning of endovascular thrombectomy.
Drug: chlorpromazine and promethazine
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.
Other Names:
  • C+P
  • lytic cocktail
Procedure: endovascular thrombectomy
All patients that are eligible for endovascular thrombectomy will receive this surgery in aim to remove thrombus and restore reperfusion.
Drug: rt-PA
All patients that are eligible for Intravenous thrombolysis will receive 0.9mg/kg rt-PA in aim to remove thrombus and restore reperfusion
Other Names:
  • Intravenous thrombolysis
Experimental: chlorpromazine and promethazine of moderate dosage
patients will receive C+P（chlorpromazine and promethazine ,50 mg each)at the beginning of endovascular thrombectomy.
Drug: chlorpromazine and promethazine
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.
Other Names:
  • C+P
  • lytic cocktail
Procedure: endovascular thrombectomy
All patients that are eligible for endovascular thrombectomy will receive this surgery in aim to remove thrombus and restore reperfusion.
Drug: rt-PA
All patients that are eligible for Intravenous thrombolysis will receive 0.9mg/kg rt-PA in aim to remove thrombus and restore reperfusion
Other Names:
  • Intravenous thrombolysis
Experimental: chlorpromazine and promethazine of high dosage
patients will receive C+P（chlorpromazine and promethazine ,100 mg each)at the beginning of endovascular thrombectomy.
Drug: chlorpromazine and promethazine
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.
Other Names:
  • C+P
  • lytic cocktail
Procedure: endovascular thrombectomy
All patients that are eligible for endovascular thrombectomy will receive this surgery in aim to remove thrombus and restore reperfusion.
Drug: rt-PA
All patients that are eligible for Intravenous thrombolysis will receive 0.9mg/kg rt-PA in aim to remove thrombus and restore reperfusion
Other Names:
  • Intravenous thrombolysis
Placebo Comparator: Placebo group
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.
Procedure: endovascular thrombectomy
All patients that are eligible for endovascular thrombectomy will receive this surgery in aim to remove thrombus and restore reperfusion.
Drug: rt-PA
All patients that are eligible for Intravenous thrombolysis will receive 0.9mg/kg rt-PA in aim to remove thrombus and restore reperfusion
Other Names:
  • Intravenous thrombolysis
Drug: Placebo group
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.
Other Names:
  • Control group

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
The incidence and severity of all adverse events (AEs) and severe adverse events (SAEs)
Time Frame: 72 hours after randomization

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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
Scores of National institutes of health stroke scale (NIHSS)
Time Frame: 24 hours after randomization
Scores on the National Institutes of Health Stroke Scale (NIHSS) range from 0 to 42, with higher scores indicating worse neurologic deficit.
24 hours after randomization
Infarct volume
Time Frame: 72 hours after randomization
Infarct volume is assessed by Computed Tomography and automatically calculated by software.
72 hours after randomization
Plasma proteomics and metabolomics
Time Frame: 24 hours±6 hours
Proteomics and metabolomics will be performed using patients' plasma. The purpose is to determine what proteins or metabolites are mediated by C+P and correlated with favorable outcome.
24 hours±6 hours

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Capital Medical University

Collaborators

Linyi People's Hospital

Investigators

  • Study Chair: Xunming Ji, Doctor, Capital Medical University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 9, 2024

Primary Completion (Estimated)

January 1, 2025

Study Completion (Estimated)

February 1, 2025

Study Registration Dates

First Submitted

October 24, 2024

First Submitted That Met QC Criteria

October 27, 2024

First Posted (Actual)

October 29, 2024

Study Record Updates

Last Update Posted (Actual)

March 25, 2025

Last Update Submitted That Met QC Criteria

December 18, 2024

Last Verified

December 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CHILL-1

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

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.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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