Short-duration Selective Brain Cooling for Patients Undergoing Mechanical Thrombectomy

Short-duration Selective Brain Cooling for Ischemic Stroke Patients Undergoing Mechanical Thrombectomy: a Randomized Controlled Trial

To determine the efficacy and safety of short-duration intra-artery selective brain cooling in addition to mechanical thrombectomy in patients with acute ischemic stroke.

Study Overview

• Status: Suspended
• Conditions: Hypothermia; Stroke, Acute
• Intervention / Treatment: Device: mechanical thrombectomy; Drug: selective brain cooling by cold saline perfusion

Detailed Description

Acute ischemic stroke remains one of the leading causes of disability and death in both developed and developing countries. Using intravenous thrombolysis combined with intra-arterial therapy to recanalize occluded vessels in eligible patients is recommended by current guidelines. Five randomized clinical trials showed that modified thrombolysis in cerebral ischemia (mTICI) 2b/3 recanalization can be achieved in 59-88% of acute ischemic stroke patients with anterior circulation large artery occlusion，but only an average of 46% of patients have a favorable outcome (modified Rankin Scale score [mRS] 0-2). Therefore, new therapeutic strategies in addition to thrombectomy for acute ischemic stroke are urgently needed.

As early as 1987, Busto et al. found that lowering of the brain temperature by only a few degrees during ischemia confers a marked neuroprotective effect. Therapeutic hypothermia has been suggested to be the most potent neuroprotective strategy in recent years5，and a number of clinical studies in patients with acute cerebral infarction also showed that mild hypothermia (33-35 ℃) can increase tolerance to ischemic insults and play a significant neuroprotective role after reperfusion. However, adverse events such as pneumonia, affecting up to 35% of treated patients occurs with hypothermia. Since selective brain cooling does not require a reduction in core body temperature, it is theoretically possible to avoid many serious adverse effects caused by whole body hypothermia.

The investigators have previous shown that short-duration selective brain cooling by the intra-arterial infusion of cold saline combined with mechanical thrombectomy in acute ischemic stroke is feasible and safe. The efficacy of selective brain cooling in patients undergoing mechanical thrombectomy, however, is not established. The investigators therefore conducted this RCT study to explore the efficacy of short-duration selective brain cooling in patients with acute ischemic stroke who underwent mechanical thrombectomy.

• Study Type: Interventional
• Enrollment (Anticipated): 120
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100069
      • Xuan Wu Hospital，Capital Medical University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Acute ischemic stroke within 6 hours from symptom onset/last seen well.
• Occlusion (TIMI 0-1) of the basilar artery or distal intracranial carotid artery or middle (M1/M2) or anterior (A1/A2) cerebral artery as evidenced by CTA/MRA/DSA.
• Age ≥18 and ≤80
• No significant pre-stroke functional disability (mRS ≤ 1)
• The possibility to start treatment within 6 hours from onset.
• Informed consent given

Exclusion Criteria:

• Known hemorrhagic diathesis, coagulation factor deficiency, or oral anticoagulant therapy with INR > 3.0
• Baseline platelet count < 50.000/µL
• Baseline blood glucose of < 50mg/dL or >400mg/dl
• Severe, sustained hypertension (SBP > 220 mm Hg or DBP > 110 mm Hg) NOTE: If the blood pressure can be successfully reduced and maintained below these levels using commonly used medications in China for these purposes (including iv antihypertensive drips), the patient can be enrolled.
• Serious, advanced, or terminal illness with anticipated life expectancy of less than one year.
• History of life threatening allergy (more than rash) to contrast medium
• Subjects who has received iv t-PA treatment beyond 4.5 hours from the beginning of the symptoms.
• Patients with acute stroke within the first 48 hours after percutaneous cardiac, cerebrovascular interventions and major surgery
• Renal insufficiency with creatinine ≥ 3 mg/dl
• Woman of childbearing potential who is known to be pregnant or lactating or who has a positive pregnancy test on admission.
• Subject participating in a study involving an investigational drug or device that would impact this study.
• Cerebral vasculitis
• Patients with a pre-existing neurological or psychiatric disease that would confound the neurological or functional evaluations, mRS score at baseline must be ≤ 1, which includes patients who are severely demented, require constant assistance in a nursing home type setting or who live at home but are not fully independent in activities of daily living (toileting, dressing, eating, cooking and preparing meals, etc.)
• Unlikely to be available for 90 days follow-up (e.g. no fixed home address, visitor from overseas).
• CT or MR evidence of hemorrhage (the presence of microbleeds on MRI is allowed).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: mechanical thrombectomy group; Conventional mechanical thrombectomy	Device: mechanical thrombectomy; conventional mechanical thrombectomy using Solitaire
EXPERIMENTAL: mechanical thrombectomy plus selective brain cooling group; A microcatheter which was used to deploy the stent retriever was threaded into the femoral artery in the groin through a guiding catheter and up through the neck, until it reached beyond the clot causing the stroke under the assistance of micro-guide wire, 50 mL cold 0.9% saline (4°C) was infused into the ischemic territory at 10 mL/min through the microcatheter, thus allowing the cold solution to infuse into the ischemic territory prior to reperfusion. After that, mechanical thrombectomy with a stent retriever was performed to recanalize the occluded vessel as soon as possible. After the recanalization, cold 0.9% saline (4°C) was infused into the ischemic brain tissue through the guide catheter at 30 mL/min for 10 minutes.	Device: mechanical thrombectomy; conventional mechanical thrombectomy using Solitaire; Drug: selective brain cooling by cold saline perfusion; During the procedure, a microcatheter which was used to deploy the stent retriever was threaded into the femoral artery in the groin through a guiding catheter and up through the neck, until it reached beyond the clot causing the stroke under the assistance of micro-guide wire, 50 mL cold 0.9% saline (4°C) was infused into the ischemic territory at 10 mL/min through the microcatheter, thus allowing the cold solution to infuse into the ischemic territory prior to reperfusion. After that, mechanical thrombectomy with a stent retriever was performed to recanalize the occluded vessel as soon as possible. After the recanalization, cold 0.9% saline (4°C) was infused into the ischemic brain tissue through the guide catheter at 30 mL/min for 10 minutes.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients achieving favorable outcomes defined as mRS 0-2 at 90 days as evaluated by independent central assessors who are blinded to treatment	mRS 0-2	90 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dramatic early favorable response	an NIHSS of 0-2 or NIHSS improvement ≥ 8 points at 24 (-2/+12 hours) hours from randomization or before discharge if patient is discharged prior to the above time limit	24 hours
Final infarct volume evaluated on CT/MR at 24 hours (-2/+12 hours)	Final infarct volume evaluated on CT/MR at 24 hours (-2/+12 hours)	24 hours
The change of infarct volume compared with baseline.	The change of infarct volume compared with baseline.	24 hours
Vessel recanalization	Vessel recanalization evaluated by angiography (one of CT angiography , MR Angiography and conventional angiography) at 24 hours (-2/+12 hours) in both treatment groups	24 hours
Barthel Index at 90 days	Barthel Index at 90 days	90 days
NIHSS at 90 days	NIHSS at 90 days	90 days
Proportion of patients achieving excellent favorable outcomes defined as mRS 0-1 at 90 days	mRS 0-1 at 90 days	90 days
mRS shift analysis at 90 days	mRS shift analysis	90 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality at 90 days	Mortality	90 days
Clinically significant ICH rates at 24 (-2/+12) hours.	All intracerebral hemorrhages will be classified by a central core-lab using the Heidelberg criteria. Symptomatic ICH will be defined as per the SITS-MOST definition: deterioration in NIHSS score of ≥4 points within 24 hours from treatment and evidence of intraparenchymal hemorrhage type 2 in the 22 to 36 hours follow-up imaging scans. The incidence of any asymptomatic hemorrhage measured at 24 (-2/+12) hours will also be compared	24 hours
Procedural related complications	arterial perforation, arterial dissection, and embolization in a previously uninvolved vascular territory	From the operation to 24 hours after the operation
Rectal temperature	Rectal temperature	From 1 hour before operation to 1 hours after operation
Hematocrit	Hematocrit	From 3 hour before operation to 3 hours after operation
blood biochemistry	Routine blood test and blood biochemistry	From 3 hour before operation to 3 hours after operation
Vital signs	Vital signs	From 1 hour before operation to 24 hours after operation

Collaborators and Investigators

• Sponsor: Capital Medical University

Publications and helpful links

General Publications

• Chen J, Liu L, Zhang H, Geng X, Jiao L, Li G, Coutinho JM, Ding Y, Liebeskind DS, Ji X. Endovascular Hypothermia in Acute Ischemic Stroke: Pilot Study of Selective Intra-Arterial Cold Saline Infusion. Stroke. 2016 Jul;47(7):1933-5. doi: 10.1161/STROKEAHA.116.012727. Epub 2016 May 19.

Study record dates

Study Major Dates

• Study Start (ACTUAL): February 6, 2018
• Primary Completion (ANTICIPATED): September 30, 2020
• Study Completion (ANTICIPATED): December 16, 2020

Study Registration Dates

• First Submitted: May 6, 2017
• First Submitted That Met QC Criteria: May 20, 2017
• First Posted (ACTUAL): May 23, 2017

Study Record Updates

• Last Update Posted (ACTUAL): August 4, 2020
• Last Update Submitted That Met QC Criteria: August 1, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Keywords: mechanical thrombectomy; selective brain cooling
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Body Temperature Changes; Stroke; Hypothermia
• Other Study ID Numbers: ET-EH

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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