A Trial of Intravascular Hypothermia Therapy in Acute Ischemic Stroke Patients

Study Overview
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Brief Summary
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Acute ischemic stroke (AIS) has been one of the major causes of global mortality and morbidity. The superiority of endovascular therapy (EVT) over standard medical therapy in treating AIS due to large vessel occlusion (LVO) in the anterior circulation has been widely accepted. However, a critical concern is that even with an extremely high rate of successful recanalization (the modified thrombolysis in cerebral infarction [mTICI] score 2b-3) around 90%, nearly half of the patients failed to benefit from EVT. So, adjunctive therapy of EVT for neuroprotection is required. From the previous domestic and foreign literatures, hypothermia can prevent and treat secondary injury caused by ischemia-reperfusion injury and cerebral edema of acute cerebral ischemia, so as to achieve the role of neuroprotection. In this study, intravascular cooling was performed as soon as possible with careful temperature control in patients receiving thrombectomy. The temperature was controlled at 33° C for 48-72 hours. This parallel controlled study is to systematically evaluate the feasibility and safety of adjunctive therapy using early intravascular hypothermia in AIS patients receiving mechanical thrombectomy. The results will clarify a potential modality for neuroprotection and hopefully provide new evidence in improving patient prognosis.

Detailed Description
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In this study, the target subjects were AIS patients with successful recanalization (mTICI 2b-3). Early intravascular hypothermia neuroprotection therapy was given to patients after thrombectomy to evaluate its safety and effectiveness. The neuroprotection effect of endovascular hypothermia therapy is explored regarding several aspects, such as hemorrhagic conversion rate, cerebral edema, and neurological function recovery, with specific evaluation criteria described in detail in the following experimental design.

Official Title
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A Prospective, Multicenter, Randomized Clinical Trial to Evaluate the Safety and Efficacy of Intravascular Hypothermia Therapy of Patients With Acute Ischemic Stroke

Conditions
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Hypothermia, Reperfusion Injury, Ischemic Stroke, Thrombectomy

Intervention / Treatment
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* Device: ZOLL Intravascular Temperature Management system, Quattro catheter
* Other: Standard Treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age between 18 and 80 years old Clinical signs consistent with acute ischemic stroke with large vessel occlusion in the anterior circulation (internal carotid artery, middle cerebral artery M1 or M2 segment) ASPECTS score 0-10 Arterial puncture could be performed within 24 hours from symptom onset or LKN Baseline NIHSS (NIHSS) score prior to randomization ≥ 10 and NIHSS 1a ≥ 1 Candidate for endovascular thrombectomy therapy in accordance with best practices per AHA standard stroke guidelines meeting all labeling requirements for EVT in the trial Successful recanalization of occluded vessel (mTICI 2b-3) after EVT No intracranial hemorrhage postoperative CT examinations immediately after recanalization. If the subject' recanalization of vessel could not achieve mTICI 2b-3, the subject could not enter the per-protocol analysis and will separate another group Informed consent form signed by subjects or their legal guardian Exclusion Criteria: Subject who suffer serious infection (e.g. sepsis) or multiple organ failure Known presence of an IVC filter End stage renal disease on hemodialysis Known hypersensitivity to antiplatelet agents, anticoagulation drugs, iodinated contrast and/or anesthetics Known hypersensitivity to the components of the medical device Any known history of the following conditions: bleeding diathesis, coagulopathy, cryoglobulinemia, sickle cell anemia, will refuse blood transfusions or contraindication to heparin; history of genetically confirmed hypercoagulable syndrome Use of warfarin with INR > 3 Hemodynamically significant cardiac dysrhythmias (eg. QTc interval >450 msec, bradycardia (heart rate less than 50), Mobitz Type II second degree AV block (or higher AV block), and severe ventricular dysrhythmias (sustained VT or VF)) which cause significant hypotension (SBP ≤ 120 mmHg requiring more than two pressor medications) Platelet count<40×10^9/L Blood glucose concentration <2.7 or > 22.2 mmol/L Hypertension uncontrollable by drug treatment (systolic blood pressure≥185 mmHg or diastolic blood pressure≥110mmhg) Expected life expectancy<6 months Temperature < 35°C on admission to Emergency Department With a pre-existing neurological or psychiatric disease that would confound the neurological or functional evaluations (e.g., dementia or mental illness) Subject participating in a study involving an investigational drug or device that would impact the current study Baseline CT/MR evidence of multiple vascular territory acute stroke Baseline CT/MR showing evidence of arterial vasculitis or dissection Evidence of intracranial hemorrhage or hemorrhagic transformation before thrombectomy Evidence of intracranial hemorrhage or hemorrhagic transformation immediately after thrombectomy Presence of pulmonary embolism, ilio-femoral or deep vein thrombosis Brain vascular lesion (e.g. aneurysm or arteriovenous malformation) Brain tumor or CNS infection Concurrent participation in a study involving an investigational drug or device that would impact the current study Female patient of childbearing potential who is known to be pregnant or lactating For other reasons, the researchers believe that the patient is not suitable for continued treatment Patients without a legally authorized representative to sign the consent form will be excluded

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study group<br>Study Group: Intravascular hypothermia therapy group ZOLL Intravascular Temperature Management system, Quattro catheter will be used in study group | Device: ZOLL Intravascular Temperature Management system, Quattro catheter<br>* ZOLL Intravascular Temperature Management system, Quattro catheter<br>|
| Placebo Comparator: Control group<br>Control group: Without intravascular hypothermia therapy group ZOLL Intravascular Temperature Management system, Quattro catheter will not be used in control group | Other: Standard Treatment<br>* Standard Treatment for Ischemic Strokre<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intracranial hemorrhage conversion rate | ICH | 7 days after thrombectomy operation or discharge | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Modified Rankin scale (mRS) | The mRS is a 7-point scale ranging from 0 (no symptoms) to 6 (death) | 90 days | 
| The rate of functional independency (mRS 0-2) | The mRS is a 7-point scale ranging from 0 (no symptoms) to 6 (death) | 90 days | 
| The rate of mortality (mRS 6) | The mRS is a 7-point scale ranging from 0 (no symptoms) to 6 (death) | 90 days | 
| NIHSS | Scores on the National Institutes of Health Stroke Scale (NIHSS) range from 0 to 42, with higher scores indicating more severe neurologic deficits. | 24 hours, 7 days or discharge | 
| Rate of symptomatic intracranial hemorrhage (sICH) | The diagnosis of sICH was based on the association of ICH with any of the following. conditions: (1) Increase in NIHSS score > 4 points compared to the score before ICH; (2) Increase in NIHSS score by >2 points in one category; (3) deterioration leading to intubation, hemicraniectomy, external ventricular drain placement, or any other major interventions. | 7 days after thrombectomy operation or discharge | 
| Rate of malignant cerebral edema | Development of signs of herniation (including decrease in consciousness and/or anisocoria), accompanied by midline shift >= 5 mm on follow-up imaging. | 7 days after thrombectomy operation or discharge | 
| Infarct volume | measured on 5-7 days CT (or MRI if available) | 5-7 days after thrombectomy operation or discharge |