Safety and Efficacy of Selective Intra-Arterial Cooling Infusion Combined With EVT in Acute Ischemic Stroke

Beijing Shijitan Hospital, Capital Medical University258 enrolled

Overview

This is a multicenter, randomized, controlled, subject- and assessor-blinded clinical trial. The research objective is to evaluate the safety and efficacy of selective intra-arterial cooling infusion combined with endovascular therapy in the treatment of acute anterior circulation large vessel occlusion stroke. This trial aims to enroll 258 subjects. Patients assigned to the control group will receive best medical management (BMM) and endovascular therapy (EVT). Those in the selective intra-arterial cooling infusion group (IA-SCI group) will undergo selective intra-arterial cold saline infusion, in addition to BMM and EVT. Subjects will be interviewed face-to-face at randomization, 24±6 hours, 48±6 hours after randomization, 7±2 days/discharge. Telephone interviews/ face-to face interviews will be performed at 30±3 days and 90±7 days after randomization. The primary outcome is the distribution of Modified Rankin Score at 90±7days after randomization.

Acute ischemic stroke (AIS) is the leading cause of death and disability in China. Randomized trials involving patients with acute stroke due to large-artery occlusion in the anterior circulation have shown a benefit of endovascular therapy (EVT). Although EVT achieves successful recanalization in over 80% of patients, only 46% of patients are functionally independent (mRS 0-2) after the intervention . Therefore, new ancillary therapeutic strategies are needed to further improve the clinical outcomes. Therapeutic systemic hypothermia has been suggested to be one such potential approach offering a viable neuroprotective strategy. However, several adverse events associated with the systematic hypothermia treatment have been reported. Those offset the therapeutic benefits of systemic hypothermia. Selective intra-arterial cooling infusion (IA-SCI) targets precisely the ischemic brain tissue with the infusion of hypothermic solutions. This approach induces a state of mild hypothermia in the ischemic region without causing substantial drops in core body temperature, thereby minimizing the incidence of systemic side effects. Previous studies have shown that IA-SCI with cold saline combined with EVT in AIS is safe and feasible. Hence, the investigators design a multicenter, randomized, controlled, subject- and assessor-blinded clinical trial. The objective of this trial is to further explore the safety and efficacy of selective intra-arterial cooling infusion combined with EVT in the treatment of acute anterior circulation large vessel occlusion stroke, and 258 subjects will be enrolled. Subjects assigned to the control group will receive best medical management (BMM) and endovascular therapy (EVT). Those in the selective intra-arterial cooling infusion group (IA-SCI group) will undergo selective intra-arterial cold saline infusion, in addition to BMM and EVT. Subjects will be interviewed face-to-face at randomization, 24±6 hours, 48±6 hours after randomization, 7±2 days/discharge. Telephone interviews/ face-to face interviews will be performed at 30±3 days and 90±7 days after randomization. The primary outcome is the distribution of Modified Rankin Score at 90±7days after randomization.

Interventions

Selective Intra-arterial Cooling Infusion (IA-SCI)PROCEDURE

Pre-recanalization: During the procedure, the micro-catheter is advanced over a micro-guide wire, traveling up through the neck until it reaches beyond the clot. A 50 mL cold 0.9% saline (4 ℃) is infused intro into the ischemic territory at a rate of 10 mL/min via the micro-catheter. This enables the cold solution to infuse into the ischemic territory prior to revascularization. Post-recanalization: After recanalization, cold 0.9% saline (4 ℃) is reinfused into the vessel via the catheter at a rate of 22 mL/min for 10 min, repeated twice with a 10-minute interval between infusions.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 80 Years

Medical Language ↔ Plain English

Inclusion Criteria 1. Age ≥ 18 and ≤ 80. 2. Clinical signs consistent with acute ischemic stroke with large vessel occlusion in the anterior circulation (intracranial segment of the internal carotid artery, middle cerebral artery M1 segment) demonstrated with CTA/MRA/DSA. 3. NIHSS score obtained prior to randomization ≥ 6 and ≤ 25. 4. Modified Rankin Scale ≤ 1 prior to qualifying stroke. 5. Arterial puncture performed within 24 hours from symptom onset or LKW. 6. For the patients with symptom onset within 6 hours, the ASPECT score ≥ 6; for the patients with onset within 6-24 hours, the therapy should meet the imaging criteria of DAWN or DEFUSE-3 trial. 7. Patient/Legally Authorized Representative has signed the Informed Consent Form. Exclusion Criteria 1. Baseline CT/MRI confirms the presence of multiple vascular territory acute strokes. 2. Baseline CT/MRI confirms the presence of arterial dissection. 3. Evidence of intracranial hemorrhage or hemorrhagic transformation before thrombectomy. 4. Known allergies or intolerances to antiplatelet agents, anticoagulation drugs, iodinated contrast and/or anesthetics. 5. Severe infection (e.g. sepsis) or multiple organ failure. 6. Known hereditary or acquired hemorrhagic diathesis, coagulation factor deficiency; recent oral anticoagulant therapy with INR \> 3. Patients on factor Xa inhibitor for 48 hours ago must have a normal APTT. 7. Baseline platelet count \< 50 × 10\^9/L. 8. Blood glucose concentration\<50 mg/dL (2.7 mmol/L) or \>400 mg/dL (22.2 mmol/L). 9. Refractory hypertension that is difficult to control by medication (Defined as persistent systolic blood pressure\>185 mmHg or diastolic blood pressure\>110 mmHg). 10. Previous NHYA\>1. 11. Untreated moderate or severe coronary artery stenosis, or previous coronary artery bypass surgery. 12. Undergoing hemodialysis or peritoneal dialysis; known severe renal insufficiency with glomerular filtration rate \< 30 mL/min or serum creatinine \>220 mmol/L (2.5 mg/dL). 13. Known intracranial aneurysm, and cerebral arteriovenous malformation. 14. Malignant brain tumor or CNS infection. 15. Pre-existing neurological or psychiatric disease that would confound the neurological or functional evaluations (e.g., dementia or mental illness) 16. Female who is pregnant or lactating at time of admission. 17. Anticipated life expectancy \< 6 months. 18. Current participation in another investigational drug or device study. 19. For other reasons, the responsible clinicians believe that the patient is not suitable for continued treatment.

Locations (9)

The Second Hospital and Clinical Medical School, Lanzhou University

Lanzhou, Gansu, China

RECRUITING

Department of Neurosurgery, Nanshi Hospital of Nanyang

Nanyang, Henan, China

RECRUITING

The Affiliated Hospital of Xuzhou Medical University

Xuzhou, Jiangsu, China

RECRUITING

Beijing Shijitan Hospital, Capital Medical University

Beijing, China

RECRUITING

Peking University Internation Hospital

Beijing, China

RECRUITING

967 Hospital of the Joint Logistics Support Force of PLA

Dalian, China

RECRUITING

Dalian Municipal Central Hospital

Dalian, China

RECRUITING

The First Affiliated Hospital of Harbin Medical University

Ha’erbin, China

RECRUITING

Affiliated Hospital of Inner Mongolia University for the Nationalities

Tongliao, China

RECRUITING

Outcomes

Primary Outcomes

Distribution of Modified Rankin scale

the distribution of Modified Rankin scale (mRS) \[ranging from 0 (normal) to 6 (death)\]

Time frame: 90 ±7days

Secondary Outcomes

Percentage of functional independence (mRS scale 0-2)

the percentage of mRS scale 0-2 (Modified Rankin scale \[ranging from 0 (normal) to 6 (death)\])

Time frame: 90 ±7days

Percentage of favorable outcome (mRS scale 0-1)

the percentage of mRS scale 0-1(Modified Rankin scale \[ranging from 0 (normal) to 6 (death)\])

Time frame: 90 ±7days

Final infarction volume

A plain computed tomography (CT) scan will be performed. The infarct area is defined as the low-density area. The infarct area is semi-automatically delineated by the software. The infarct volume= the sum of the infarct area of each layer × layer thickness (5mm).

Time frame: 7±2 days/discharge

The changes of infarction volume

the changes of infarction volume between baseline and 7±2 days/discharge assessed by CT

Time frame: 7±2 days/discharge

National Institute of Health stroke scale (NIHSS) score

National Institute of Health stroke scale (NIHSS) score \[ranging from 0 to 42 points, with higher numbers indicating greater severity\]

Time frame: 7±2 days/discharge

Barthel Index score

the Barthel Index score \[the sum of the score ranging from 0 to 100, with 100 being the most independent level of function\]

Time frame: 7±2 days/discharge

Rapid neurologic improvement

Rapid neurologic improvement is defined as a reduction of ≥8 on the National Institutes of Health Stroke Scale \[ranging from 0 to 42 points, with higher numbers indicating greater severity\] or National Institutes of Health Stroke Scale zero to one 24 hours after thrombectomy.

Time frame: 24±12 hours

Changes in ipsilateral tympanic membrane temperature

Changes in ipsilateral tympanic membrane temperature before and after intra-arterial cooling infusion in the IA-SCI group.

Time frame: during surgery.

Power spectral density (PSD) assessed by continuous electroencephalogram (EEG)

PSD is estimated using Welch's periodogram from EEG.

Time frame: within 7±2 days/discharge

(delta+theta)/(alpha+beta) power ratio (DTABR) assessed by continuous electroencephalogram (EEG)

DTABR is calculated using the absolute power for each of spectral band on EEG.

Time frame: within 7±2 days/discharge

Delta/alpha power ratio (DAR) assessed by continuous electroencephalogram (EEG)

DAR is calculated using the absolute power for each of spectral band on EEG.

Time frame: within 7±2 days/discharge

Brain symmetry index (BSI) assessed by continuous electroencephalogram (EEG)

BSI is calculated using the power values from both left and right hemispheres from EEG.

Time frame: within 7±2 days/discharge

Symptomatic intracranial hemorrhage

Defined as any intracranial hemorrhage accompanied by neurological deterioration (NIHSS score increased by more than 4 points compared with the lowest NIHSS score at enrollment or during hospitalization) or death caused by any cerebral hemorrhage according to the ECASS III study.

Time frame: 24±12 hours

Any intracranial hemorrhage

any intracranial hemorrhage assessed by CT

Time frame: 24±12 hours

Intracranial arterial vasospasm after IA-SCI that requires further therapeutic intervention.

Patients with vasospasm confirmed by DSA and requiring further therapeutic intervention

Time frame: during operation

Proportion of subjects with pulmonary, urinary tract infection and gastroenteritis

the proportion of patients with pulmonary, urinary tract infection and gastroenteritis according to the Centers for Disease Control and Prevention (CDC)/ National Healthcare Safety Network (NHSN) criteria.

Time frame: 7±2 days/discharge

Proportion of subjects with coagulation abnormalities

Defined as abnormal coagulation function

Time frame: 24±12 hours

Proportion of subjects with electrolyte imbalance

Defined as any abnormal findings, including hypernatremia, hyponatremia, hyperkalemia, or hypokalemia.

Time frame: 24±12 hours

Changes in core temperature before and after intra-arterial cooling infusion in the IA-SCI group.

Changes in rectal temperature before and after intra-arterial cooling infusion in the IA-SCI group.

Time frame: During operation

any death

Time frame: 90±7 days

other AE/SAE

other adverse events/ serious adverse events

Time frame: 90±7 days

Safety and Efficacy of Selective Intra-Arterial Cooling Infusion Combined With EVT in Acute Ischemic Stroke

Overview

Conditions

Interventions

Eligibility

Locations (9)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts