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

Selective Intra-arterial Cooling Infusion With Endovascular Thrombectomy for Acute Ischemic Stroke: a Multicenter, Randomized, Controlled Trial

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.

Study Overview

• Status: Completed
• Conditions: Hypothermia; Acute Ischemic Stroke
• Intervention / Treatment: Procedure: Selective Intra-arterial Cooling Infusion (IA-SCI)

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 258
• Phase: Not Applicable

Contacts and Locations

Study Locations

• China
  • Beijing, China
    • Beijing Chaoyang Hospital, Capital Medical University
  • Beijing, China
    • Beijing Shijitan Hospital, Capital Medical University
  • Beijing, China
    • Peking University Internation Hospital
  • Dalian, China
    • Dalian Municipal Central Hospital
  • Dalian, China
    • 967 Hospital of the Joint Logistics Support Force of PLA
  • Gansu, China
    • Gansu Province Central Hospital
  • Hangzhou, China
    • Zhejiang Provincial People's Hospital
  • Ha’erbin, China
    • The First Affiliated Hospital of Harbin Medical University
  • Tongliao, China
    • Affiliated Hospital of Inner Mongolia University for the Nationalities
  • Gansu
    • Lanzhou, Gansu, China
      • The Second Hospital and Clinical Medical School, Lanzhou University
  • Henan
    • Nanyang, Henan, China
      • Department of Neurosurgery, Nanshi Hospital of Nanyang
  • Jiangsu
    • Xuzhou, Jiangsu, China
      • The Affiliated Hospital of Xuzhou Medical University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

1. Age ≥18 and ≤80.
2. Clinical signs consistent with AIS-LVO in the anterior circulation (intracranial segment of internal carotid artery, M1 segment of middle cerebral artery (MCA) demonstrated by computed tomography angiography (CTA) / magnetic resonance angiography (MRA)/ digital subtraction angiography (DSA)).
3. National Institutes of Health Stroke Scale (NIHSS) score (at screening) ≥6 and ≤25.
4. Modified Rankin Scale (mRS) score ≤1 before stroke onset.
5. Arterial puncture performed within 24 hours of symptom onset or last known well (LKW).
6. Written informed consent obtained from the patients or legally authorized representatives.

For patients admitted to the hospital within 6 hours of symptom onset, an Alberta Stroke Program Early CT Score (ASPECTS) ≥6 is required. For those admitted between 6 and 24 hours, the neuroimaging criteria of the DAWN or DEFUSE-3 trials are applied.

Exclusion Criteria

1. Baseline CT/MRI reveals the presence of acute infarction in multiple vascular territories.
2. CTA/MRA/DSA confirms the presence of arterial dissection.
3. Evidence of intracranial hemorrhage or hemorrhagic transformation before thrombectomy.
4. Known allergies or intolerances to antiplatelet agents, anticoagulants, iodinated contrast, 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 international normalized ratio (INR)>3.

   Exception: Time elapsed since the last use of a novel oral anticoagulant ≥48 hours plus a normal activated partial thromboplastin time (APTT).

7. Baseline platelet count <50 × 109/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 (persistent systolic blood pressure (BP) >185 mmHg or diastolic BP >110 mmHg).
10. Previous New York Heart Association (NYHA) functional classification >I.
11. Coronary artery stenosis >70% or history of coronary artery bypass grafting.
12. Undergoing hemodialysis or peritoneal dialysis; severe renal insufficiency with a glomerular filtration rate <30 mL/min or serum creatinine >220 mmol/L (2.5 mg/dL).
13. Known intracranial aneurysm or cerebral arteriovenous malformation.
14. Malignant brain tumor or central nervous system infection.
15. Pre-existing neurological or psychiatric diseases that could confound the neurological or functional evaluations (e.g., dementia or mental illness)
16. Pregnant or lactating at admission.
17. Anticipated life expectancy <6 months.
18. Current participation in another interventional drug or device study. For any other reasons, the responsible clinicians believe that the patient is not suitable for SI-AC.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Control group; Subjects will receive best medical management (BMM) plus endovascular therapy (EVT) according to the clinical guidelines.
Experimental: IA-SCI group; Subjects randomized to the IA-SCI group will receive selective intra-arterial cooling infusion plus BMM and EVT.	Procedure: Selective Intra-arterial Cooling Infusion (IA-SCI); 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Distribution of Modified Rankin scale	the distribution of Modified Rankin scale (mRS) [ranging from 0 (normal) to 6 (death)]	90 ±7days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)])	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)])	90 ±7days
The changes of infarction volume	the changes of infarction volume between baseline and 7±2 days/discharge assessed by CT	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]	7±2 days/discharge
Changes in ipsilateral tympanic membrane temperature	Changes in ipsilateral tympanic membrane temperature before and after intra-arterial cooling infusion in the IA-SCI group.	during surgery.
Power spectral density (PSD) assessed by continuous electroencephalogram (EEG)	PSD is estimated using Welch's periodogram from EEG.	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.	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.	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.	within 7±2 days/discharge
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.	7±2 days/discharge
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.	During operation
any death	any death	90±7 days
other AE/SAE	other adverse events/ serious adverse events	90±7 days
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.	24±12 hours
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.	24±12 hours
Any intracranial hemorrhage	any intracranial hemorrhage assessed by CT	24±12 hours
Proportion of subjects with coagulation abnormalities	Defined as abnormal coagulation function	24±12 hours
Proportion of subjects with electrolyte imbalance	Defined as any abnormal findings, including hypernatremia, hyponatremia, hyperkalemia, or hypokalemia.	24±12 hours
Final infarction volume	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).	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]	90±7 days
Procedure-related complications	Including vascular injury, device-associated adverse events, and intracranial arterial vasospasm requiring further therapeutic intervention。	during operation

Collaborators and Investigators

• Sponsor: Beijing Shijitan Hospital, Capital Medical University
• Investigators: Principal Investigator: Shen Li, Beijing Shijitan Hospital, Capital Medical University

Study record dates

Study Major Dates

• Study Start (Actual): July 3, 2024
• Primary Completion (Actual): February 8, 2026
• Study Completion (Actual): March 1, 2026

Study Registration Dates

• First Submitted: June 22, 2024
• First Submitted That Met QC Criteria: June 30, 2024
• First Posted (Actual): July 3, 2024

Study Record Updates

• Last Update Posted (Actual): July 7, 2026
• Last Update Submitted That Met QC Criteria: July 4, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Body Temperature Changes; Stroke; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Ischemic Stroke; Hypothermia
• Other Study ID Numbers: FOCUS

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: The deidentified individual participant data underlying this article will not be publicly available. However, the data may be made available to researchers upon reasonable request to the corresponding author, subject to approval by the institutional review board and execution of a data access agreement.

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